Principles and Practice of Surgical Oncology 9781684692620, 1684692628

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Principles and Practice of

Surgical Oncology Claire Berry

Principles and Practice of Surgical Oncology

Principles and Practice of Surgical Oncology

Claire Berry

White Press Academic

Minds, Motivated!

Principles and Practice of Surgical Oncology by Claire Berry www.whitepressacademics.com

© 2019 White Press Academic

All rights reserved. No portion of this book may be reproduced in any form without permission from the publisher, except as permitted by U.S. copyright law. For permissions contact: [email protected] Price: $295 Ebook ISBN: 978-1-68469-262-0

Published by: 600 S MAESTRI PL., #30460 NEW ORLEANS, LA, US, 70130 Website: www.whitepressacademics.com

Contents

1.

Preface

xi

Skin

1

Melanoma ......................................................................................................................................................................... 1 History ................................................................................................................................................................................ 2 Signs and Symptoms .................................................................................................................................................... 2 Cause .................................................................................................................................................................................. 3 Pathophysiology ............................................................................................................................................................. 4 Diagnosis ........................................................................................................................................................................... 5 Prevention ........................................................................................................................................................................ 9 Treatment ........................................................................................................................................................................ 10 Prognosis ......................................................................................................................................................................... 13 Epidemiology ................................................................................................................................................................ 13 Research .......................................................................................................................................................................... 14 Non-melanoma Skin Cancers ................................................................................................................................. 16 What is Non-melanoma Skin Cancer? ................................................................................................................. 16 What Causes Non-melanoma Skin Cancer and am I at Risk? ..................................................................... 16 What Screening Tests are Available? .................................................................................................................... 16 What are the Signs of Non-melanoma Skin Cancer? ..................................................................................... 17 How is Non-melanoma Cancer Diagnosed? ..................................................................................................... 17 Staging of Non-melanoma Skin Cancers ............................................................................................................ 18 How is Non-melanoma Skin Cancer Treated? ................................................................................................... 19 Follow-up Care and Survivorship ........................................................................................................................... 21

2.

Breast Signs and Symptoms .................................................................................................................................................. 23 Risk Factors ..................................................................................................................................................................... 24 Lifestyle ........................................................................................................................................................................... 24 Genetics ........................................................................................................................................................................... 25 Medical Conditions ..................................................................................................................................................... 25 Pathophysiology ........................................................................................................................................................... 25 Diagnosis ......................................................................................................................................................................... 26 Classification .................................................................................................................................................................. 27 Prevention ...................................................................................................................................................................... 29 Life-style .......................................................................................................................................................................... 29 Pre-emptive Surgery .................................................................................................................................................. 29 Medications .................................................................................................................................................................... 30 Screening ........................................................................................................................................................................ 30 Management ................................................................................................................................................................. 30 Surgery ............................................................................................................................................................................. 31 Medication ...................................................................................................................................................................... 31 Radiation ......................................................................................................................................................................... 32 Prognosis ......................................................................................................................................................................... 33 Prognostic Factors ........................................................................................................................................................ 34 Psychological Aspects ................................................................................................................................................ 35 Epidemiology ................................................................................................................................................................ 35

23

vi Hormones ....................................................................................................................................................................... 36 Birth Control ................................................................................................................................................................... 36 Menopausal Hormone Replacement ................................................................................................................... 36 Research .......................................................................................................................................................................... 36 Cryoablation ................................................................................................................................................................... 36 Breast Cancer Cell Lines ........................................................................................................................................... 36 Molecular Markers ....................................................................................................................................................... 37 Non-invasive or Invasive Breast Cancer .............................................................................................................. 37 Locally Advanced Breast Cancer (LABC) ............................................................................................................ 38 Classification .................................................................................................................................................................. 39 Clinical Features and Diagnosis ............................................................................................................................. 39 Staging ............................................................................................................................................................................. 40 Natural History .............................................................................................................................................................. 40 Multidisciplinary Therapy .......................................................................................................................................... 41 Primary Chemotherapy Results ............................................................................................................................. 41 Local/Regional Treatment and Local Control .................................................................................................... 44 Tolerance and Toxicity ................................................................................................................................................ 44 Dose Intensification .................................................................................................................................................... 45 Breast Conservation .................................................................................................................................................... 45 Inflammatory Breast Carcinoma ............................................................................................................................ 46 BRCA 1 and BRCA 2 in Breast Cancer and Ovarian Cancer ......................................................................... 47 Genes and Mutations .................................................................................................................................................. 47 Getting Tested ............................................................................................................................................................... 49 Breast and Ovarian Cancer Risk .............................................................................................................................. 50 Cancer Detection and Prevention Strategies ................................................................................................... 51 Other Cancers ............................................................................................................................................................... 55 Childbearing and Fertility Effects .......................................................................................................................... 56 Evolutionary Advantage ............................................................................................................................................ 57 Patent Enforcement and Litigation ....................................................................................................................... 57 Treatment ........................................................................................................................................................................ 58 Surgery and Radiation Therapy ............................................................................................................................... 58 Chemotherapy .............................................................................................................................................................. 58 Hormone Therapy and Targeted Therapy ............................................................................................................ 58

3.

Gastrointestinal Esophageal Cancer ...................................................................................................................................................... 59 Signs and Symptoms .................................................................................................................................................. 59 Causes .............................................................................................................................................................................. 60 Diagnosis ......................................................................................................................................................................... 63 Prevention ...................................................................................................................................................................... 64 Management ................................................................................................................................................................. 64 Prognosis ......................................................................................................................................................................... 65 Stomach Cancer/ Gastric Cancer ........................................................................................................................... 66 Signs and Symptoms .................................................................................................................................................. 66 Causes .............................................................................................................................................................................. 67 Diagnosis ......................................................................................................................................................................... 68 Prevention ...................................................................................................................................................................... 70 Management ................................................................................................................................................................. 70 Prognosis ......................................................................................................................................................................... 71 Small Intestine Cancer/ Small Bowel Cancer .................................................................................................... 71 Risk Factors ..................................................................................................................................................................... 71 Research .......................................................................................................................................................................... 72 Gallbladder Cancer ...................................................................................................................................................... 72 Signs and Symptoms .................................................................................................................................................. 72 Risk Factors ..................................................................................................................................................................... 73 Diagnosis ......................................................................................................................................................................... 73 Treatment ........................................................................................................................................................................ 73 Cholangiocarcinoma .................................................................................................................................................. 74 Signs and Symptom .................................................................................................................................................... 74 Risk Factors ..................................................................................................................................................................... 74 Pathophysiology ........................................................................................................................................................... 75

59

vii Diagnosis ......................................................................................................................................................................... 76 Staging ............................................................................................................................................................................. 77 Treatment ........................................................................................................................................................................ 77 Prognosis ......................................................................................................................................................................... 78 Pancreatic Cancer ........................................................................................................................................................ 79 Types ................................................................................................................................................................................. 79 Signs and Symptoms .................................................................................................................................................. 81 Risk Factors ..................................................................................................................................................................... 82 Pathophysiology ........................................................................................................................................................... 83 Diagnosis ......................................................................................................................................................................... 84 Staging ............................................................................................................................................................................. 85 Prevention and Screening ........................................................................................................................................ 87 Management ................................................................................................................................................................. 87 Outcomes ....................................................................................................................................................................... 90 Hepatocellular Carcinoma ........................................................................................................................................ 91 Signs and Symptoms .................................................................................................................................................. 91 Risk Factors ..................................................................................................................................................................... 91 'Pathogenesis ................................................................................................................................................................ 92 Diagnosis ......................................................................................................................................................................... 93 Prevention ...................................................................................................................................................................... 95 Treatment ........................................................................................................................................................................ 95 Prognosis ......................................................................................................................................................................... 98 Colorectal Cancer ........................................................................................................................................................ 98 Signs and Symptoms .................................................................................................................................................. 98 Cause ................................................................................................................................................................................ 99 Pathogenesis ................................................................................................................................................................. 99 Diagnosis ...................................................................................................................................................................... 101 Prevention ................................................................................................................................................................... 102 Treatment ..................................................................................................................................................................... 104 Prognosis ...................................................................................................................................................................... 106 Rectal Cancer ............................................................................................................................................................. 106 Symptoms .................................................................................................................................................................... 107 Causes ........................................................................................................................................................................... 107 Risk Factors .................................................................................................................................................................. 107 Prevention ................................................................................................................................................................... 108 Surgical Management of Liver Metastases from Colorectal Cancer ..................................................... 108 Treatment Options ................................................................................................................................................... 109 Surgical Treatment .................................................................................................................................................... 109 Hereditary Colorectal Cancer and Polyposis Syndromes .......................................................................... 114 Hereditary Colorectal Syndromes ...................................................................................................................... 114 Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy ....................................... 116 Interdisciplinary Concept ....................................................................................................................................... 116 Hyperthermic Intraperitoneal Chemotherapy .............................................................................................. 116 Neo-adjuvant Chemotherapy .............................................................................................................................. 117 Organ Preserving Cytoreductive Surgery ........................................................................................................ 117 Second Look Surgery ............................................................................................................................................... 117 Squamous Cell Carcinoma of the Anal Margin ............................................................................................. 118 Diagnosis and Staging ............................................................................................................................................. 118 Natural History and Spread Patterns .................................................................................................................. 119 Surgical Management ............................................................................................................................................. 119 Radiation Therapy ..................................................................................................................................................... 120 Adjuvant Chemotherapy ....................................................................................................................................... 120

4.

Endocrine

121

Thyroid Cancer ........................................................................................................................................................... 121 Signs and Symptoms ............................................................................................................................................... 121 Causes ........................................................................................................................................................................... 121 Diagnosis ...................................................................................................................................................................... 122 Treatment ..................................................................................................................................................................... 126 Prognosis ...................................................................................................................................................................... 126 Pancreatic Neuroendocrine Tumors (PNETs) ................................................................................................. 128

viii Types .............................................................................................................................................................................. 128 Signs and Symptoms ............................................................................................................................................... 128 Diagnosis ...................................................................................................................................................................... 129 Staging .......................................................................................................................................................................... 129 Treatment ..................................................................................................................................................................... 132 Genetics ........................................................................................................................................................................ 133 Multiple Endocrine Neo-plasia (MEN) Syndromes ....................................................................................... 133 Terminology ................................................................................................................................................................ 133 Related Conditions ................................................................................................................................................... 133 History ........................................................................................................................................................................... 133 Comparison ................................................................................................................................................................. 134 Multiple Endocrine Neo-plasia Type 1 (MEN1) .............................................................................................. 135 Carcinoid Tumors ....................................................................................................................................................... 136 Signs and Symptoms ............................................................................................................................................... 136 Cause ............................................................................................................................................................................. 137 Treatment ..................................................................................................................................................................... 137 Goblet Cell Carcinoid .............................................................................................................................................. 138

5.

Sarcoma

139

Introduction ................................................................................................................................................................ 139 Diagnosis ...................................................................................................................................................................... 139 Grade ............................................................................................................................................................................. 139 Awareness ................................................................................................................................................................... 139 Chondrosarcoma ....................................................................................................................................................... 140 Classification and grading ..................................................................................................................................... 140 Symptoms .................................................................................................................................................................... 140 Causes ........................................................................................................................................................................... 140 Diagnosis ...................................................................................................................................................................... 141 Treatment ..................................................................................................................................................................... 141 Prognosis ...................................................................................................................................................................... 141 Ewing's sarcoma ........................................................................................................................................................ 141 Presentation ................................................................................................................................................................ 142 Causes ........................................................................................................................................................................... 142 Diagnosis ...................................................................................................................................................................... 142 Treatment ..................................................................................................................................................................... 143 Prognosis ...................................................................................................................................................................... 144 Epidemiology ............................................................................................................................................................. 144 Research, information and support ................................................................................................................... 144 Hemangioendothelioma ....................................................................................................................................... 144 Classification ............................................................................................................................................................... 145 Signs and symptoms ................................................................................................................................................ 146 Treatment ..................................................................................................................................................................... 146 Osteosarcoma ............................................................................................................................................................ 146 Signs and symptoms ................................................................................................................................................ 146 Causes ........................................................................................................................................................................... 147 Mechanism .................................................................................................................................................................. 147 Diagnosis ...................................................................................................................................................................... 148 Treatment ..................................................................................................................................................................... 148 Epidemiology ............................................................................................................................................................. 149 Prognosis ...................................................................................................................................................................... 149 Sarcoma botryoides ................................................................................................................................................. 150 Clinical characteristics ............................................................................................................................................. 150 Histology ...................................................................................................................................................................... 150 Treatment and prognosis ....................................................................................................................................... 150 Epidemiology ............................................................................................................................................................. 150 Soft-tissue sarcoma .................................................................................................................................................. 150 Signs and symptoms ................................................................................................................................................ 150 Risk factors ................................................................................................................................................................... 150 Diagnosis ...................................................................................................................................................................... 151 Treatment ..................................................................................................................................................................... 151 Epidemiology ............................................................................................................................................................. 152

ix Tables ............................................................................................................................................................................. 152 Alveolar soft part sarcoma ..................................................................................................................................... 153 Angiosarcoma ............................................................................................................................................................ 154 Phyllodes tumor ........................................................................................................................................................ 154 Dermatofibrosarcoma protuberans ................................................................................................................... 155 Aggressive fibromatosis ......................................................................................................................................... 156 Desmoplastic small-round-cell tumor .............................................................................................................. 157 Epithelioid sarcoma .................................................................................................................................................. 159 Fibrosarcoma .............................................................................................................................................................. 166 Hemangiopericytoma ............................................................................................................................................. 167 Hemangiosarcoma ................................................................................................................................................... 167 Kaposi's sarcoma ....................................................................................................................................................... 169 Leiomyosarcoma ....................................................................................................................................................... 172 Liposarcoma ................................................................................................................................................................ 173 Lymphangiosarcoma ............................................................................................................................................... 174 Lymphoma .................................................................................................................................................................. 174 Undifferentiated pleomorphic sarcoma .......................................................................................................... 179 Malignant peripheral nerve sheath tumor ...................................................................................................... 180 Rhabdomyosarcoma ................................................................................................................................................ 181 Synovial sarcoma ....................................................................................................................................................... 186 Gastrointestinal stromal tumor ............................................................................................................................ 188 Classification ............................................................................................................................................................... 188 Signs and symptoms ................................................................................................................................................ 188 Pathophysiology ........................................................................................................................................................ 188 Diagnosis ...................................................................................................................................................................... 189 Management .............................................................................................................................................................. 191 Epidemiology ............................................................................................................................................................. 192

6.

Gynecology

193

Ovarian cancer ........................................................................................................................................................... 193 Signs and symptoms ................................................................................................................................................ 193 Risk factors ................................................................................................................................................................... 194 Pathophysiology ........................................................................................................................................................ 197 Diagnosis ...................................................................................................................................................................... 198 Screening ..................................................................................................................................................................... 216 Prevention ................................................................................................................................................................... 217 Management .............................................................................................................................................................. 217 Prognosis ...................................................................................................................................................................... 222 Epidemiology ............................................................................................................................................................. 224 In pregnancy ............................................................................................................................................................... 225 Research ....................................................................................................................................................................... 225 Adnexal mass ............................................................................................................................................................. 227 Causes ........................................................................................................................................................................... 227 Treatment ..................................................................................................................................................................... 227 Ovarian tumor ............................................................................................................................................................ 228 Benign tumors ........................................................................................................................................................... 228 Cancer ........................................................................................................................................................................... 228 Clear-cell ovarian carcinoma ................................................................................................................................ 228 Description .................................................................................................................................................................. 228 Prognosis ...................................................................................................................................................................... 228 High-grade serous carcinoma .............................................................................................................................. 228 Risk factors ................................................................................................................................................................... 229 Pathophysiology ........................................................................................................................................................ 229 Diagnosis ...................................................................................................................................................................... 231 Prevention ................................................................................................................................................................... 232 Treatment ..................................................................................................................................................................... 232 Krukenberg tumor .................................................................................................................................................... 233 Signs and symptoms ................................................................................................................................................ 233 Cause and incidence ............................................................................................................................................... 233 Pathogenesis .............................................................................................................................................................. 233 Treatment and prognosis ....................................................................................................................................... 233

x Leydig cell tumour ................................................................................................................................................... 234 Presentation ................................................................................................................................................................ 234 Diagnosis ...................................................................................................................................................................... 234 Treatment ..................................................................................................................................................................... 234 Luteoma ....................................................................................................................................................................... 235 Presentation ................................................................................................................................................................ 235 Detection ..................................................................................................................................................................... 235 Treatment ..................................................................................................................................................................... 236 Causes ........................................................................................................................................................................... 236

Bibliography

237

Index

241

Preface

Cancer is a disease which is increasing day by day and so are the challenges to its treatment. Cancer which was synonymous with death a few years ago is not so deadly now with better understanding of cancer biology and availability of better technology for treatment of cancer patients. With use of multimodality treatment the results have started improving. Surgery is commonly used for the prevention and treatment of cancer. Various types of surgeries are performed based on the type of cancer, its intensity and its location. Surgery helps in removing the tumor and surrounding tissue and has been considered as an effective way to treat various types of cancer. Surgery is done after locating the cancerous tumour, finding its spread, and diagnosing cancer. It may also be used to restore body's appearance and relieve the body of the side effects that may have been caused by the disease or its treatment. The cancer surgery is also dependent on the growth and spread of the tumour. Staging Surgery is used to find out the size of the tumour and its spread. This, along with the results of other laboratory tests helps the doctor to decide on the kind of treatment the patient should receive. Surgical oncology is the branch of surgery applied to oncology; it focuses on the surgical management of tumors, especially cancerous tumors. As one of several modalities in the management of cancer, the specialty of surgical oncology, before modern medicine the only cancer treatment with a chance of success, has evolved in steps similar to medical oncology, which grew out of hematology, and radiation oncology, which grew out of radiology.

Chapter 1

Skin MEL ANOMA MELANOMA Melanoma, also known as malignant melanoma, is a type of cancer that develops from the pigment-containing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye. In women, they most commonly occur on the legs, while in men they are most common on the back. Sometimes they develop from a mole with concerning changes including an increase in size, irregular edges, change in colour, itchiness, or skin breakdown. The primary cause of melanoma is ultraviolet light (UV) exposure in those with low levels of skin pigment. The UV light may be from either the sun or from other sources, such as tanning devices. About 25% develop from moles. Those with many moles, a history of affected family members, and who have poor immune function are at greater risk. A number of rare genetic defects such as xeroderma pigmentosum also increase risk. Diagnosis is by biopsy of any concerning skin lesion. Using sunscreen and avoiding UV light may prevent melanoma. Treatment is typically removal by surgery. In those with slightly larger cancers, nearby lymph nodes may be tested for spread.

2

Surgical Oncology: Theory and Multidisciplinary Practice

Most people are cured if spread has not occurred. For those in whom melanoma has spread, immunotherapy, biologic therapy, radiation therapy, or chemotherapy may improve survival. With treatment the five-year survival rates in the United States is 98% among those with localized disease and 17% among those in whom spread has occurred. The likelihood that it will come back or spread depends how thick the melanoma is, how fast the cells are dividing, and whether or not the overlying skin has broken down. Melanoma is the most dangerous type of skin cancer. Globally, in 2012, it newly occurred in 232,000 people. In 2015 there were 3.1 million with active disease which resulted in 59,800 deaths. Australia and New Zealand have the highest rates of melanoma in the world. There are also high rates in Northern Europe and North America, while it is less common in Asia, Africa, and Latin America. Melanoma is more common in men than women. Melanoma has become more common since the 1960s in areas which are mostly populated with white people.

HISTORY Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather scarce. However, one example lies in a 1960s examination of nine Peruvian mummies, radiocarbon dated to be approximately 2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases to the bones. John Hunter is reported to be the first to operate on metastatic melanoma in 1787. Although not knowing precisely what it was, he described it as a “cancerous fungous excrescence”. The excised tumor was preserved in the Hunterian Museum of the Royal College of Surgeons of England. It was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma. The French physician Rene Laennec was the first to describe melanoma as a disease entity. His report was initially presented during a lecture for the Faculte de Medecine de Paris in 1804 and then published as a bulletin in 1806. The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820. In his later work in 1857 he remarked that there is a familial predisposition for development of melanoma (Eight Cases of Melanosis with Pathological and Therapeutical Remarks on That Disease). Norris was also a pioneer in suggesting a link between nevi and melanoma and the possibility of a relationship between melanoma and environmental exposures, by observing that most of his patients had pale complexions. He also described that melanomas could be amelanotic and later showed the metastatic nature of melanoma by observing that they can disseminate to other visceral organs. The first formal acknowledgment of advanced melanoma as untreatable came from Samuel Cooper in 1840. He stated that the only chance for a cure depends upon the early removal of the disease (i.e., early excision of the malignant mole)...’ More than one and a half centuries later this situation remains largely unchanged. The word melanoma is from the Greek µελας melas meaning “dark”.

SIGNS AND SYMPTOMS Early signs of melanoma are changes to the shape or colour of existing moles or, in the case of nodular melanoma, the appearance of a new lump anywhere on the skin. At later stages, the mole may itch, ulcerate or bleed. Early signs of melanoma are summarized by the mnemonic “ABCDE”: • Asymmetry • Borders (irregular with edges and corners) • Colour (variegated) • Diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser) • Evolving over time.

Skin

3

These classifications do not, however, apply to the most dangerous form of melanoma, nodular melanoma, which has its own classifications: • Elevated above the skin surface • Firm to the touch • Growing. Metastatic melanoma may cause non-specific paraneoplastic symptoms, including loss of appetite, nausea, vomiting and fatigue. Metastasis of early melanoma is possible, but relatively rare: less than a fifth of melanomas diagnosed early become metastatic. Brain metastases are particularly common in patients with metastatic melanoma. It can also spread to the liver, bones, abdomen or distant lymph nodes.

CAUSE Melanomas are usually caused by DNA damage resulting from exposure to ultraviolet light from the sun. Genetics also plays a role. Having more than fifty moles indicates an increased risk melanoma might arise. A weakened immune system makes it easier for cancer to arise due to the body’s weakened ability to fight cancer cells.

UV Radiation The ultraviolet radiation from tanning beds increases the risk of melanoma. The International Agency for Research on Cancer finds that tanning beds are “carcinogenic to humans” and that people who begin using tanning devices before the age of thirty years are 75% more likely to develop melanoma. Those who work in airplanes also appear to have an increased risk, believed to be due to greater exposure to UV. Ultraviolet UVB light (wavelengths between 315 – 280 nm) from the sun is absorbed by skin cell DNA and results in a type of direct DNA damage called cyclobutane pyrimidine dimers (CPDs). Thymine-thymine, cytosine-cytosine or cytosine-thymine dimers are formed by the joining of two adjacent pyrimidine bases within a DNA strand. Somewhat similarly to UVB, UVA light (longer wavelengths between 400 – 315 nm) from the sun or from tanning beds can also be directly absorbed by skin DNA (at about 100 to 1000 fold lower efficiency than UVB is absorbed). Studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. Occasional extreme sun exposure (resulting in “sunburn”) is causally related to melanoma. Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers. Other factors are mutations in or total loss of tumor suppressor genes. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma. Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Melanoma rates tend to be highest in countries settled by migrants from northern Europe that have a large amount of direct, intense sunlight that the skin of the settlers is not adapted to, most notably Australia. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia. Having multiple severe sunburns increases the likelihood that future sunburns develop into melanoma due to cumulative damage. The sun and tanning beds are the main sources of UV radiation that increase the risk for melanoma and living close to the equator increases exposure to UV radiation.

Genetics A number of rare mutations, which often run in families, greatly increase melanoma susceptibility. Several genes increase risks. Some rare genes have a relatively high risk of causing melanoma; some more common

4

Surgical Oncology: Theory and Multidisciplinary Practice

genes, such as a gene called MC1R that causes red hair, have a relatively lower elevated risk. Genetic testing can be used to search for the mutations. One class of mutations affects the gene CDKN2A. An alternative reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis and in fifty percent of human cancers. Another mutation in the same gene results in a non-functional inhibitor of CDK4, a cyclin-dependent kinase that promotes cell division. Mutations that cause the skin condition xeroderma pigmentosum (XP) also increase melanoma susceptibility. Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant (the chances of a carrier to express the phenotype is high). Familial melanoma is genetically heterogeneous, and loci for familial melanoma appear on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to melanoma’s pathogenesis (disease development). The multiple tumor suppressor 1 (CDKN2A/MTS1) gene encodes p16INK4a – a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs) – which has been localised to the p21 region of human chromosome 9. Other mutations confer lower risk, but are more common in the population. People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type (typical unaffected type) copies. MC1R mutations are very common; in fact, all red-haired people have a mutated copy. Mutation of the MDM2 SNP309 gene is associated with increased risks for younger women. Fair- and red-haired people, persons with multiple atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk. A family history of melanoma greatly increases a person’s risk because mutations in several genes have been found in melanoma-prone families. People with a history of one melanoma are at increased risk of developing a second primary tumor. Fair skin is the result of having less melanin in the skin, which means there is less protection from UV radiation. A family history could indicate a genetic predisposition to melanoma.

PATHOPHYSIOLOGY The earliest stage of melanoma starts when melanocytes begin out-of-control growth. Melanocytes are found between the outer layer of the skin (the epidermis) and the next layer (the dermis). This early stage of the disease is called the radial growth phase, when the tumor is less than 1 mm thick. Because the cancer cells have not yet reached the blood vessels deeper in the skin, it is very unlikely that this early-stage melanoma will spread to other parts of the body. If the melanoma is detected at this stage, then it can usually be completely removed with surgery. When the tumor cells start to move in a different direction — vertically up into the epidermis and into the papillary dermis — cell behaviour changes dramatically. The next step in the evolution is the invasive radial growth phase, which is a confusing term; however, it explains the process of the radial growth, in which individual cells start to acquire invasive potential. From this point on the melanoma is capable of spreading. The Breslow’s depth of the lesion is usually less than 1 mm (0.04 in), while the Clark level is usually 2. The vertical growth phase (VGP) following is the invasive melanoma. The tumor becomes able to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than 1 mm (0.04 in), and the tumor involves the deeper parts of the dermis. The host elicits an immunological reaction against the tumor during the VGP, which is judged by the presence and activity of the tumor infiltrating lymphocytes (TILs). These cells sometimes completely destroy the primary tumor; this is called regression, which is the latest stage of development. In certain cases, the primary tumor is completely destroyed and only the metastatic tumor is discovered. About 40% of human melanomas contain activating mutations affecting the structure of the B-Raf protein, resulting in constitutive signaling through the Raf to MAP kinase pathway. In general, cancers are caused by damage to DNA. UVA light mainly causes thymine-thymine dimers. UVA also produces reactive oxygen species and these inflict other DNA damage, primarily single-strand breaks, oxidized pyrimidines and the oxidized purine 8-oxoguanine (a mutagenic DNA

Skin

5

change) at 1/10th, 1/10th and 1/3rd the frequencies of UVA-induced thymine-thymine dimers, respectively. If unrepaired, CPD photoproducts can lead to mutations by inaccurate translesion synthesis during DNA replication or repair. The most frequent mutations due to inaccurate synthesis past CPDs are cytosine to thymine (C>T) or CC>TT transition mutations. These are commonly referred to as UV fingerprint mutations, as they are the most specific mutation caused by UV, being frequently found in sun-exposed skin but rarely found in internal organs. Errors in DNA repair of UV photoproducts, or inaccurate synthesis past these photoproducts, can also lead to deletions, insertions and chromosomal translocations. The entire genomes of 25 melanomas were sequenced. On average, about 80,000 mutated bases (mostly C>T transitions) and about 100 structural rearragements were found per melanoma genome. This is much higher than the approximately 70 mutations across generations (parent to child). Among the 25 melanomas, about 6,000 protein-coding genes had missense, non-sense or splice site mutations. The transcriptomes of over 100 melanomas has also been sequenced and analyzed. Almost 70% of all human protein coding genes are expressed in melanoma. Most of these genes are also expressed in other normal and cancer tissues, with some 200 genes showing a more specific expression pattern in melanoma compared to other forms of cancer. Examples of melanoma specific genes are tyrosinase, MLANA and PMEL. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell’s genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of activating transcription factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells; studies from mice on skin cancer tend to confirm a role for activating transcription factor-2 in cancer progression. Cancer stem cells may also be involved.

DIAGNOSIS Visual inspection is the most common diagnostic technique. Moles that are irregular in colour or shape are typically treated as candidates. To detect melanomas (and increase survival rates), it is recommended to learn to recognize them, to regularly examine moles for changes (shape, size, colour, itching or bleeding) and to consult a qualified physician when a candidate appears.

ABCDE A popular method for remembering the signs and symptoms of melanoma is the mnemonic “ABCDE”: • Asymmetrical skin lesion. • Border of the lesion is irregular. • Colour: melanomas usually have multiple colors. • Diameter: moles greater than 6 mm are more likely to be melanomas than smaller moles. • Enlarging: Enlarging or evolving However, many melanomas present as lesions smaller than 6 mm in diameter; and all melanomas are malignant when they first appear as a small dot. Physicians typically examine all moles, including those less than 6 mm in diameter. Seborrheic keratosis may meet some or all of the ABCD criteria, and can lead to false alarms. Doctors can generally distinguish seborrheic keratosis from melanoma upon examination, or with dermatoscopy. Some advocate replacing enlarging with evolution. Certainly moles that change and evolve will be a concern. Alternatively, some practitioners prefer elevation. Elevation can help identify a melanoma, but lack of elevation does not mean that the lesion is not a melanoma. Most melanomas in the US are detected before they become elevated. By the time elevation is visible, they may have progressed to the more dangerous invasive stage.

6

Surgical Oncology: Theory and Multidisciplinary Practice

Nodular melanomas do not fulfill these criteria, having their own mnemonic, “EFG”: • Elevated: the lesion is raised above the surrounding skin. • Firm: the nodule is solid to the touch. • Growing: the nodule is increasing in size.

Fig. ABCD rule illustration: On the left side from top to bottom: melanomas showing (A) Asymmetry, (B) a border that is uneven, ragged, or notched, (C) coloring of different shades of brown, black, or tan and (D) diameter that had changed in size. The normal moles on the right side do not have abnormal characteristics (no asymmetry, even border, even colour, no change in diameter).

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Ugly Duckling A recent and novel method is the “ugly duckling sign”. It is simple, easy to teach, and highly effective. Correlation of common lesion characteristics is made. Lesions that greatly deviate from the common characteristics are labeled an “Ugly Duckling”, and a further professional exam is required. The “Little Red Riding Hood” sign suggests that individuals with fair skin and light-colored hair might have difficult-to-diagnose amelanotic melanomas. Extra care is required when examining such individuals, as they might have multiple melanomas and severely dysplastic nevi. A dermatoscope must be used to detect “ugly ducklings”, as many melanomas in these individuals resemble non-melanomas or are considered to be “wolves in sheep’s clothing”. These fair-skinned individuals often have lightly pigmented or amelanotic melanomas that do not present easy-to-observe colour changes and variations. Their borders are often indistinct, complicating visual identification without a dermatoscope. Amelanotic melanomas and melanomas arising in fair-skinned individuals are very difficult to detect, as they fail to show many of the characteristics in the ABCD rule, break the “Ugly Duckling” sign and are hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines.

Biopsy Following a visual examination and a dermatoscopic exam, or in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. A skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining severity. Elliptical excisional biopsies may remove the tumor, followed by histological analysis and Breslow scoring. Incisional biopsies such as punch biopsies are usually contraindicated in suspected melanomas, because of the possibility of sampling error or local implantation causing misestimation of tumour thickness. However, fears that such biopsies may increase the risk of metastatic disease seem unfounded. Total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up for high-risk patients. The technique has been reported to enable early detection and provides a cost-effective approach (with any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes. The diagnosis method should be used in conjunction with (and not as a replacement for) dermoscopic imaging, with a combination of both methods appearing to give extremely high rates of detection.

Classification Melanoma is divided into the following types: • Lentigo maligna • Lentigo maligna melanoma • Superficial spreading melanoma • Acral lentiginous melanoma • Mucosal melanoma • Nodular melanoma • Polypoid melanoma • Desmoplastic melanoma • Melanoma with small nevus-like cells • Melanoma with features of a Spitz nevus • Uveal melanoma • Vaginal melanoma.

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Surgical Oncology: Theory and Multidisciplinary Practice

Laboratory Lactate dehydrogenase (LDH) tests are often used to screen for metastases, although many patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates metastatic spread of the disease to the liver. It is common for patients diagnosed with melanoma to have chest X-rays and an LDH test, and in some cases CT, MRI, PET and/or PET/CT scans. Although controversial, sentinel lymph node biopsies and examination of the lymph nodes are also performed in patients to assess spread to the lymph nodes. A diagnosis of melanoma is supported by the presence of the S-100 protein marker. HMB-45 is a monoclonal antibody that reacts against an antigen present in melanocytic tumors such as melanomas. It is used in anatomic pathology as a marker for such tumors. The antibody was generated to an extract of melanoma. It reacts positively against melanocytic tumors but not other tumors, thus demonstrating specificity and sensitivity. The antibody also reacts positively against junctional nevus cells but not intradermal nevi, and against fetal melanocytes but not normal adult melanocytes. HMB-45 is non-reactive with almost all non-melanoma human malignancies, with the exception of rare tumors showing evidence of melanogenesis (e.g., pigmented schwannoma, clear cell sarcoma) or tumors associated with tuberous sclerosis complex (angiomyolipoma and lymphangiomyoma).

Staging Also of importance are the “Clark level” and “Breslow’s depth”, which refer to the microscopic depth of tumor invasion. Melanoma stages: 5 year survival rates:

Fig. T stages of melanoma

Stage 0: Melanoma in situ (Clark Level I), 99.9% survival Stage I/ II: Invasive melanoma, 89–95% survival • T1a: Less than 1.0 mm primary tumor thickness, without ulceration, and mitosis < 1/mm2 • T1b: Less than 1.0 mm primary tumor thickness, with ulceration or mitoses ≥ 1/mm2 • T2a: 1.01–2.0 mm primary tumor thickness, without ulceration. Stage II: High risk melanoma, 45–79% survival • T2b: 1.01–2.0 mm primary tumor thickness, with ulceration • T3a: 2.01–4.0 mm primary tumor thickness, without ulceration • T3b: 2.01–4.0 mm primary tumor thickness, with ulceration • T4a: Greater than 4.0 mm primary tumor thickness, without ulceration • T4b: Greater than 4.0 mm primary tumor thickness, with ulceration.

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Skin

Fig. F18-FDG PET/CT in a melanoma patient showing multiple lesions, most likely metastases

Stage III: Regional metastasis, 24–70% survival • N1: Single positive lymph node • N2: Two to three positive lymph nodes or regional skin/in-transit metastasis • N3: Four positive lymph nodes or one lymph node and regional skin/in-transit metastases. Stage IV: Distant metastasis, 7–19% survival • M1a: Distant skin metastasis, normal LDH • M1b: Lung metastasis, normal LDH • M1c: Other distant metastasis or any distant metastasis with elevated LDH. Based upon AJCC five-year survival from initial melanoma diagnosis with proper treatment.

PREVENTION

Avoiding Ultraviolet Radiation Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds), following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. Using artificial light for tanning was once believed to help prevent skin cancers, but it can actually lead to an increased incidence of melanomas. The body uses UV light to generate vitamin D so there is a need to balance getting enough sunlight to maintain healthy vitamin D levels and reducing the risk of melanoma; it takes around a half hour of sunlight for the body to generate its vitamin D for the day and this is about the same amount of time it takes for fair-skinned people to get a sunburn. Exposure to sunlight can be intermittent instead of all at one time.

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Surgical Oncology: Theory and Multidisciplinary Practice

Sunscreen Sunscreen appears to be effective in preventing melanoma. In the past, use of sunscreens with a sun protection factor (SPF) rating of 50 or higher on exposed areas were recommended; as older sunscreens more effectively blocked UVA with higher SPF. Currently, newer sunscreen ingredients (avobenzone, zinc oxide, and titanium dioxide) effectively block both UVA and UVB even at lower SPFs. Sunscreen also protects against squamous cell carcinoma, another skin cancer. Concerns have been raised that sunscreen might create a false sense of security against sun damage.

TREATMENT Confirmation of the clinical diagnosis is done with a skin biopsy. This is usually followed up with a wider excision of the scar or tumor. Depending on the stage, a sentinel lymph node biopsy is done, as well, although controversy exists around trial evidence for this procedure. Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.

Fig. Extensive malignant melanoma on a person’s chest

Surgery Excisional biopsies may remove the tumor, but further surgery is often necessary to reduce the risk of recurrence. Complete surgical excision with adequate surgical margins and assessment for the presence of

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detectable metastatic disease along with short- and long-term followup is standard. Often this is done by a wide local excision (WLE) with 1 to 2 cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2 to 0.5 cm. Many surgeons consider 0.5 cm the standard of care for standard excision of melanoma-in-situ, but 0.2 cm margin might be acceptable for margin controlled surgery (Mohs surgery, or the double-bladed technique with margin control). The wide excision aims to reduce the rate of tumor recurrence at the site of the original lesion. This is a common pattern of treatment failure in melanoma. Considerable research has aimed to elucidate appropriate margins for excision with a general trend towards less aggressive treatment during the last decades. Mohs surgery has been reported with cure rate as low as 77% and as high as 98.0% for melanoma-in-situ. CCPDMA and the “double scalpel” peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this “intra-epithelial” type of melanoma. Melanomas that spread usually do so to the lymph nodes in the area of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications, but no overall survival benefit. Recently, the technique of sentinel lymph node biopsy has been developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of nodes with tumor. Biopsy of sentinel lymph nodes is a widely used procedure when treating cutaneous melanoma. Neither sentinel lymph node biopsy nor other diagnostic tests should be performed to evaluate early, thin melanoma, including melanoma in situ, T1a melanoma or T1b melanoma ≤ 0.5mm. People with these conditions are unlikely to have the cancer spread to their lymph nodes or anywhere else and already have a 97% 5-year survival rate. Because of these things, sentinel lymph node biopsy is unnecessary health care for them. Furthermore, baseline blood tests and radiographic studies should not be performed only based on identifying this kind of melanoma, as there are more accurate tests for detecting cancer and these tests have high falsepositive rates. To potentially correct false positives, gene expression profiling may be used as auxiliary testing for ambiguous and small lesions. Sentinel lymph node biopsy is often performed, especially for T1b/T2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs. A process called lymphoscintigraphy is performed in which a radioactive tracer is injected at the tumor site to localize the sentinel node(s). Further precision is provided using a blue tracer dye, and surgery is performed to biopsy the node(s). Routine hematoxylin and eosin (H&E) and immunoperoxidase staining will be adequate to rule out node involvement. Polymerase chain reaction (PCR) tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with a negative sentinel lymph node actually had a small number of positive cells in their nodes. Alternatively, a fine-needle aspiration biopsy may be performed and is often used to test masses. If a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection will often be performed. If the disease is completely resected, the patient will be considered for adjuvant therapy. Excisional skin biopsy is the management of choice. Here, the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2 mm) ellipse of surrounding skin and tissue. To avoid disruption of the local lymphatic drainage, the preferred surgical margin for the initial biopsy should be narrow (1 mm). The biopsy should include the epidermal, dermal, and subcutaneous layers of the skin. This enables the histopathologist to determine the thickness of the melanoma by microscopic examination. This is described by Breslow’s thickness (measured in millimeters). However, for large lesions, such as suspected lentigo maligna, or for lesions in surgically difficult areas (face, toes, fingers, eyelids), a small punch biopsy in representative areas will give adequate information and will not disrupt the final staging or depth determination. In no circumstances should the initial biopsy include the final surgical margin (0.5 cm, 1.0 cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. A large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram-directed lymphnode dissection. A small punch biopsy can be used at any time where for logistical and personal reasons a patient refuses more invasive excisional biopsy. Small punch biopsies are minimally invasive and heal quickly, usually without noticeable scarring.

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Surgical Oncology: Theory and Multidisciplinary Practice

Add on Treatment High-risk melanomas may require adjuvant treatment, although attitudes to this vary in different countries. In the United States, most patients in otherwise good health will begin up to a year of high-dose interferon treatment, which has severe side effects, but may improve the patient’s prognosis slightly. However, the British Association of Dermatologists guidelines on melanoma state that interferon is not recommended as a standard adjuvant treatment for melanoma. A 2011 meta-analysis showed that interferon could lengthen the time before a melanoma comes back but increased survival by only 3% at 5 years. The unpleasant side effects also greatly decrease quality of life. In Europe, interferon is usually not used outside the scope of clinical trials. Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.

Chemotherapy and Immunotherapy Various chemotherapy agents, including temozolomide, dacarbazine (also termed DTIC), immunotherapy (with interleukin-2 (IL-2) or interferon (IFN)), as well as local perfusion, are used by different centers. The overall success in metastatic melanoma is quite limited. IL-2 (Proleukin) was the first new therapy approved (1990 Europe, 1992 USA) for the treatment of metastatic melanoma in 20 years. Studies have demonstrated that IL-2 offers the possibility of a complete and long-lasting remission in this disease, although only in a small percentage of patients. Intralesional IL-2 for in-transit metastases has a high complete response rate ranging from 40 to 100%. By 2005 a number of new agents and novel approaches were under evaluation and showed promise. In 2009 Clinical trial participation was considered the standard of care for metastatic melanoma. Therapies for metastatic melanoma include biologic immunotherapy agents ipilimumab, pembrolizumab, and nivolumab; BRAF inhibitors, such as vemurafenib and dabrafenib; and a MEK inhibitor trametinib. Ongoing research is looking at treatment by adoptive cell transfer. For this purpose, application of prestimulated or modified T cells or dendritic cells is possible.

Lentigo Maligna Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceedingly high (up to 50%). This is due to the ill-defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The narrow surgical margin used, combined with the limitation of the standard “bread-loafing” technique of fixed tissue histology — result in a high “false negative” error rate, and frequent recurrences. Margin control (peripheral margins) is necessary to eliminate the false negative errors. If bread loafing is used, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control. Mohs surgery has been done with cure rate reported to be as low as 77%, and as high as 95% by another author. The “double scalpel” peripheral margin controlled excision method approximates the Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods. Some melanocytic nevi, and melanomain-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months.

Radiation Therapy Radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. Kilovoltage x-ray beams are often used for these

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treatments and have the property of the maximum radiation dose occurring close to the skin surface. It may reduce the rate of local recurrence but does not prolong survival. Radioimmunotherapy of metastatic melanoma is currently under investigation. Radiotherapy has a role in the palliation of metastatic melanoma.

PROGNOSIS Features that affect prognosis are tumor thickness in millimeters (Breslow’s depth), depth related to skin structures (Clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion, presence of tumor-infiltrating lymphocytes (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant metastasis. Certain types of melanoma have worse prognoses but this is explained by their thickness. Interestingly, less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging. Local recurrences tend to behave similarly to a primary unless they are at the site of a wide local excision (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion. When melanomas have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy. Extent of malignancy within a node is also important; micrometastases in which malignancy is only microscopic have a more favourable prognosis than macrometastases. In some cases micrometastases may only be detected by special staining, and if malignancy is only detectable by a rarely employed test known as the polymerase chain reaction (PCR), the prognosis is better. Macrometastases in which malignancy is clinically apparent (in some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is extracapsular extension, the prognosis is worse still. In addition to these variables, expression levels and copy number variations of a number of relevant genes may be used to support assessment of malignant melanoma prognosis. When there is distant metastasis, the cancer is generally considered incurable. The five-year survival rate is less than 10%. The median survival is 6–12 months. Treatment is palliative, focusing on life extension and quality of life. In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment). Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis. Survival is better with metastasis in which the location of the primary tumor is unknown. There is not enough definitive evidence to adequately stage, and thus give a prognosis for, ocular melanoma and melanoma of soft parts, or mucosal melanoma (e.g. rectal melanoma), although these tend to metastasize more easily. Even though regression may increase survival, when a melanoma has regressed, it is impossible to know its original size and thus the original tumor is often worse than a pathology report might indicate. About 200 genes are prognostic in melanoma, with both unfavourable genes where high expression is correlated to poor survival and favourable genes where high expression is associated with longer survival times. Examples of unfavourable genes are MCM6 and TIMELESS and an example of a favourable gene is WIPI1.

EPIDEMIOLOGY Globally, in 2012, melanoma occurred in 232,000 people and resulted in 55,000 deaths. Australia and New Zealand have the highest rates of melanoma in the world. It has become more common in the last 20 years in areas that are mostly Caucasian. The rate of melanoma has increased in the recent years, but it is not clear to what extent changes in behaviour, in the environment, or in early detection are involved.

Australia Australia has a very high — and increasing — rate of melanoma. In 2012, deaths from melanoma occurred in 7.3-9.8 per 100,000 population. In Australia, melanoma is the third most common cancer in either sex;

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Surgical Oncology: Theory and Multidisciplinary Practice

indeed, its incidence is higher than for lung cancer, although the latter accounts for more deaths. It is estimated that in 2012, more than 12,000 Australians were diagnosed with melanoma: given Australia’s modest population, this is better expressed as 59.6 new cases per 100,000 population per year; >1 in 10 of all new cancer cases were melanomas. Melanoma incidence in Australia is matter of significance, for the following reasons: • Australian melanoma incidence has increased by more than 30 per cent between 1991 and 2009. • Australian melanoma age-standardised incidence rates were, as of 2008, at least 12 times higher than the world average. • Australian melanoma incidence is, by some margin, the highest in the world. • Overall age-standardised cancer incidence in Australia is the highest in the world, and this is attributable to melanoma alone. Age-standardised overall cancer incidence is similar to New Zealand, but there is a statistically-significant difference between Australia and all other parts of the developed world including North America, Western Europe, and the Mediterranean.

United States In the United States about 9,000 people die from melanoma a year. In 2011 it affected 19.7 per 100,000, and resulted in death in 2.7 per 100,000. In 2013: • 71,943 people in the United States were diagnosed with melanomas of the skin, including 42,430 men and 29,513 women. • 9,394 people in the United States died from melanomas of the skin, including 6,239 men and 3,155 women. The American Cancer Society’s estimates for melanoma incidence in the United States for 2017 are: • About 87,110 new melanomas will be diagnosed (about 52,170 in men and 34,940 in women). • About 9,730 people are expected to die of melanoma (about 6,380 men and 3,350 women). Melanoma is more than 20 times more common in whites than in African Americans. Overall, the lifetime risk of getting melanoma is about 2.5% (1 in 40) for whites, 0.1% (1 in 1,000) for African Americans, and 0.5% (1 in 200) for Hispanics. The risk of melanoma increases as people age. The average age of people when the disease is diagnosed is 63.

RESEARCH Pharmacotherapy research for unresectable or metastatic malignant melanoma is ongoing.

Targeted Therapies In clinical research setting other therapies, such as adoptive cell therapy or gene therapy, are being tested. Two kinds of experimental treatments developed at the National Cancer Institute (NCI), have been used in metastatic melanoma with tentative success. The first treatment involves adoptive cell therapy (ACT) using TILs immune cells (tumor infiltrating lymphocytes) isolated from a person’s own melanoma tumor. These cells are grown in large numbers in a laboratory and returned to the patient after a treatment that temporarily reduces normal T cells in the patient’s body. TIL therapy following lymphodepletion can result in durable complete response in a variety of setups. The second treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient’s lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them. A vaccine to train the immune system to fight cancer showed modest benefit in late-stage testing in 2009 against melanoma.

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BRAF Inhibitors About 60% of melanomas contain a mutation in the B-Raf gene. Early clinical trials suggested that B-Raf inhibitors including Plexxicon’s vemurafenib could lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation. In June 2011, a large clinical trial confirmed the positive findings from those earlier trials. In August 2011 Vemurafenib received FDA approval for the treatment of late-stage melanoma. In May 2013 the US FDA approved dabrafenib as a single agent treatment for patients with BRAF V600E mutationpositive advanced melanoma. Some researchers believe that combination therapies that simultaneously block multiple pathways may improve efficacy by making it more difficult for the tumor cells to mutate before being destroyed. In October 2012 a study reported that combining Dabrafenib with a MEK inhibitor trametinib led to even better outcomes. Compared to Dabrafenib alone, progression-free survival was increased to 41% from 9%, and the median progression-free survival increased to 9.4 months versus 5.8 months. Some side effects were, however, increased in the combined study. In January 2014, the FDA approved the combination of dabrafenib and trametinib for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma. Eventual resistance to BRAF and MEK inhibitors may be due to a cell surface protein known as EphA2 which is now being investigated.

Ipilimumab At the American Society of Clinical Oncology Conference in June 2010, the Bristol-Myers Squibb pharmaceutical company reported the clinical findings of their drug ipilimumab. The study found an increase in median survival from 6.4 to 10 months in patients with advanced melanomas treated with the monoclonal ipilimumab, versus an experimental vaccine. It also found a one-year survival rate of 25% in the control group using the vaccine, 44% in the vaccine and ipilimumab group, and 46% in the group treated with ipilimumab alone. However, some have raised concerns about this study for its use of the unconventional control arm, rather than comparing the drug against a placebo or standard treatment. The criticism was that although Ipilimumab performed better than the vaccine, the vaccine has not been tested before and may be causing toxicity, making the drug appear better by comparison. Ipilimumab was approved by the FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery. In June 2011, a clinical trial of ipilimumab plus dacarbazine combined this immune system booster with the standard chemotherapy drug that targets cell division. It showed an increase in median survival for these late stage patients to 11 months instead of the 9 months normally seen. Researchers were also hopeful that perhaps 10– 20% of patients could live a long time. Some serious side-effects of revving up the immune system were seen in some patients. A course of treatment costs $120,000. The drug’s brandname is Yervoy.

Surveillance Methods Advances in high resolution ultrasound scanning have enabled surveillance of metastatic burden to the sentinel lymph nodes. The Screening and Surveillance of Ultrasound in Melanoma trial (SUNMEL) is evaluating ultrasound as an alternative to invasive surgical methods.

Oncolytic Virotherapy In some countries oncolytic virotherapy methods are studied and used to treat melanoma. Oncolytic virotherapy is a promising branch of virotherapy, where oncolytic viruses are used to treat diseases; viruses can increase metabolism, reduce anti-tumor immunity and disorganize vasculature. Talimogene laherparepvec (T-VEC) (which is a herpes simplex virus type 1–derived oncolytic immunotherapy), was shown to be useful against metastatic melanoma in 2015 with an increased survival of 4.4 months.

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Surgical Oncology: Theory and Multidisciplinary Practice

NON-MEL ANOMA SKIN CANCERS NON-MELANOMA Skin, which is a thin layer of tissue and the largest organ in the body, serves numerous functions. The most obvious function of skin is serving as a barrier between the outside world and internal organs. It is made up of three layers, the epidermis, the dermis and the hypodermis. The epidermis is the outermost layer. The dermis, which is the layer underneath the epidermis, contains connective tissue, hair follicles and sweat glands. The hypodermis is made up of fat and connective tissue. Over the course of years of exposure, skin is exposed to numerous potential carcinogens, or cancer causing agents, most importantly the sun and its damaging ultraviolet rays.

WHAT IS NON-MELANOMA SKIN CANCER? Non-melanoma skin cancer is any type of cancer affecting the skin that is not melanoma. Cancer cells are abnormal cells that grow and can affect other organs in the body. There are numerous types of non-melanoma skin cancers including: basal cell, squamous cell, angiosarcoma, cutaneous B and T cell lymphomas, dermatofibrosarcoma protuberans, Merkel cell carcinoma, and sebaceous gland carcinoma. There are two primary types of non-melanoma skin cancers - basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) and these are the two discussed in this article. These cancers derive their name from the cells in which they originate. Both types of cells, basal and squamous, are located within the epidermis, or the outer layer of our skin. Pre-malignant lesions generally precede the development of non-melanoma skin cancers.

WHAT CAUSES NON-MELANOMA SKIN CANCER AND AM I AT RISK? Skin cancer is the most common type of cancer diagnosed each year. The incidence of skin cancers exceeds that of all other cancers, and it is estimated that nearly half of cancers diagnosed every year will be skin cancers. Over the past decade, the incidence of skin cancers has increased dramatically. About 5.4 million basal and squamous cell skin cancers are diagnosed each year, with 8 out of 10 being basal cell and 2 out of 10 being squamous cell. About 2,000 people in the US die each year from non-melanoma skin cancer but frequently these are people with a compromised immune system. Although these cancers can be locally progressive, they rarely metastasize or spread to other parts of the body. Because of early detection and the decreased metastatic potential, non-melanoma skin cancer is often effectively treated and cured with only local treatment. Risk factors for developing non-melanoma skin cancers are numerous, including fair complexion, occupational exposures to radium and arsenic, personal history of atypical moles, history of skin cancers, family history of skin cancers, smoking tobacco, immuno suppression from medications and HIV, chronic non-healing wounds and previous burns, genetic syndromes such as basal cell nevus syndrome and xeroderma pigmentosum, and HPV; however, the most common risk factor for development of skin cancer is exposure to ultraviolet radiation from the sun. The vast majority (90%) of skin cancers will occur in individuals with no risk factors other than excess sun exposure. Ultraviolet radiation from both sun exposure and tanning salons damage the epidermis and the DNA in the cells found throughout the skin. This damage continues to occur with repeated exposure, eventually leading to mutations that accumulate to cause cancerous cells. It has been shown that severe sunburns are particularly damaging when they occur in children. Childhood sun exposure is the strongest correlate with the development of basal cell carcinomas, while sun damage in the decade preceding diagnosis is closely correlated with the development of squamous cell carcinomas.

WHAT SCREENING TESTS ARE AVAILABLE? As we age, our years of sun exposure increase, and therefore the risk of skin cancer increases. Because of this increasing risk of cancer with age, it is crucial to examine our own skin regularly and to notice changes

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early. Be aware of the shapes and coloring of any freckles and moles you have. Skin cancer often develops from an existing lesion, causing its appearance to change. Examine your skin routinely in a mirror, including your back, face, lips, hands, forearms, and scalp. Furthermore, it is recommended that you follow up with your physician regularly. Early diagnosis is crucial in achieving the most appropriate treatment. Because skin cancers are related to exposures, people who have previously developed skin cancers are at much higher risk for future skin cancers, either in the primary (original) site or somewhere else on the body. Because of this, a complete skin exam should be performed by a health care provider at regularly scheduled visits.

WHAT ARE THE SIGNS OF NON-MELANOMA SKIN CANCER? BCC typically presents as a small pearly or crusty patch that fails to heal. Because they are painless and typically develop slowly, they are often present for months to years before they are brought to the attention of the health care provider. Often, BCC can be identified by blood vessels that are prominent within the bump. As the lesions grow, crusting and bleeding ulcers that will not heal are frequently the reason individuals present to their provider. The lesions are most often identified on the face, with more than 70% of BCC diagnosed on the lips, cheeks, ears, nose, and scalp. Other regions of the body commonly diagnosed with BCC include the back of the neck, the shoulders, the forearms and hands, the back, and lower legs. Although the lesions are slow-growing and rarely develop the ability to spread to lymphatics or other parts of the body, the lesions can progress locally, leading to destruction of nearby structures which can be disfiguring. Lesions are frequently neglected because of their slow growth. As the BCC grows, it may invade adjacent areas, including blood vessels, cartilage, and bone. Risk factors for recurrence after treatment of basal cell carcinomas include depth of invasion, pathologic sub-type, and perineural invasion. The appearance of squamous cell carcinoma is typically a small, painless, elevated and crusty lump. As the lesions grow, they can become an ulceration and may bleed. SCCs tend to develop more rapidly than BCCs, and unlike BCC, SCC can spread to the local lymphatic system. Risk factors for lymph node involvement include tumors > 3 cm, poorly differentiated pathology, recurrent tumors, and tumors with > 4 mm depth of invasion. They can also be rather aggressive locally, causing significant damage and disfiguration to local structures. Risk factors for recurrence after treatment of squamous cell carcinomas include perineural invasion, tumor thickness, and poorly differentiated histology. The most common location of squamous cell carcinomas is the face. Other areas at high risk include the back, shoulders, forearms and hands, and lower legs. Actinic keratosis, which is a precancerous dry, scaly lesion, and carcinoma in situ (Bowen’s disease) are typically located in areas of significant sun damage and often possess the potential to become malignant basal cell or squamous cell carcinomas. These lesions initially develop into dysplasia, or atypical cells. Approximately 10% of actinic keratoses will develop into invasive cancer.

HOW IS NON-MELANOMA CANCER DIAGNOSED? When non-melanoma skin cancer is suspected, a biopsy is frequently performed to establish the diagnosis. This biopsy removes either the entire lesion or part of it and the layers beneath it, allowing the depth of the lesion to be accurately determined. There are a number of different types of biopsies: • Shave Biopsy: A blade is used to shave off the top layers of skin. • Punch Biopsy: A tool that looks similar to a small, round cookie cutter is used to remove a deep sample of skin.

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Surgical Oncology: Theory and Multidisciplinary Practice

• Incisional Biopsy: A scalpel is used to remove part of the lesion. • Excisional Biopsy: A scalpel is used to remove the entire lesion. The sample of lesion is sent to a lab to be looked at by a pathologist who determines if the lesion is cancerous and if cancerous what type of skin cancer it is. Along with the biopsy your provider will do a full physical exam and health history. Your provider may order further testing to see if the cancer has spread. Imaging tests like MRI, CT and chest x-rays may be used.

STAGING OF NON-MELANOMA SKIN CANCERS Ark’s level, which describes depth of invasion by the tissue it invades (levels I-V). Clark’s level is an indication of the depth of penetration only, not the stage of disease. • Clark’s Level I involves the epidermis only (outermost level). • Clark’s Level II involves the epidermis and the layer of skin immediately below, the papillary dermis. • Clark’s Level III goes one layer deeper into the reticular dermis. • Clark’s Level IV involves the deep dermis. • Clark’s Level V invades beyond the skin layers into the subcutaneous fat. Non-melanoma skin cancer is most commonly staged using the TNM staging system, which is determined by the American Joint Committee on Cancer 7th edition (2010) The “T stage” represents the extent of the primary tumor itself. The “N stage” represents the degree of involvement of the lymph nodes. The “M stage” represents whether or not there is spread of the cancer to distant parts of the body. These are scored as follows: >2 cm or has greater than 2 high-risk features.

Primary Tumor (T) TX T0 Tis T1 T2 T3 T4

The primary tumor cannot be assessed. No evidence of primary tumor. Carcinoma in situ (tumor remained in epidermis). The tumor is 2cm across or smaller and has only 1 high risk feature. The tumor is larger than 2cm across, or is any size with 2 or more high-risk features. The tumor has grown into the facial bones. The tumor has grown into other bones in the body or into the base of the skull.

High risk features: These features help distinguish between some T1 and T2 tumors. • The tumor is thicker than 2mm. • The tumor has invaded down into the lower dermis or subcutis. • The tumor has grown into tiny nerves in the skin. • The tumor is on the ear or on part of the lip. • The tumor cells look very abnormal under a microscope.

Regional Lymph Nodes (N) NX N0 N1 N2a N2b N2c N3

Nearby lymph nodes cannot be assessed. The cancer has not spread to nearby lymph nodes. The cancer has spread to 1 nearby lymph node, which is on the same side of the body as the main tumor and is 3cm or less across. The cancer has spread to 1 nearby lymph node, which is on the same side of the body as the main tumor and is larger than 3cm but not larger than 6cm across. The cancer has spread to more than 1 nearby lymph node on the same side of the body as the main tumor, none of which are larger than 6cm across. The cancer has spread to nearby lymph node(s) on the other side of the body from the main tumor, none of which are larger than 6cm across. The cancer has spread to any nearby lymph node that is larger than 6cm across.

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Skin

Metastasis (M) M0 M1

The cancer has not spread. The cancer had spread to other parts of the body.

Stages 0 I II III

Tis, N0, M0 T1, N0, M0 T2, N0, M0 T3, N0, M0

IV

T1 to T3, N1, M0 T1 to T3, N2, M0 Any T, N3, M0 T4, any N, M0 Any T, any N, M1

Although this system of cancer staging is quite complicated, it is designed to help physicians describe the extent of the cancer, and therefore, helps to direct what type of treatment is given.

HOW IS NON-MELANOMA SKIN CANCER TREATED? The treatment of SCC and BCC is dependent on location of the tumor, the age of the individual at diagnosis, the extent of disease, and whether the area has been treated before. Non-melanoma skin cancers are generally addressed with local treatments, including surgery, cryotherapy, and radiation. When lesions are discovered and thought to be suspicious, they are frequently biopsied to ensure they are not a more aggressive type of skin cancer. For lesions that are small and not locally progressive, the treatment options are numerous and include Moh’s surgery, excisional surgery, cryotherapy, curettage and electrodessication, photodynamic therapy, topical chemotherapy, and radiation therapy. In some instances, more than one treatment modality will be used to treat the cancer.

Cryotherapy This type of treatment involves freezing off the lesions with liquid nitrogen. Cryotherapy is best for very small, well-defined superficial BCC and well-demarcated SCC. It is frequently used in patients that are not ideal surgical candidates.

Excisional Surgery This traditional simple surgical resection involves numbing the area with local anesthesia and removing the entire area of concern with a border or margin of healthy tissue, generally 3-10 mm. The skin is then closed with sutures (stitches) and the tissue is sent to a laboratory for a pathologist to ensure all the cancer has been removed.

Curettage and Electrodessication The type of therapy is the most common method for treating BCC. The treatment involves local anesthesia followed by removal of the tumor by curettage (scraping). The abnormality is scooped out with a curette until

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Surgical Oncology: Theory and Multidisciplinary Practice

normal skin is appreciated. The entire area is then treated with an electrical current to stop any bleeding. The difficulty with curettage is found in evaluating the margins (edges) and depth of the tumor. Similar to cryotherapy, this technique is best for very small, well-defined superficial BCC and well-demarcated SCC.

Moh’s Surgery Moh’s surgery is a procedure often performed by a dermatologist or a trained specialist in the office under local anesthesia. With Moh’s surgery, very precise surgery is performed with attempts to remove the least amount of tissue while the margins, or edges, of the resection are examined under a microscope immediately to ensure all of the cancer is removed. While other types of resection can have recurrence rates as high as 50%, Moh’s cure rates have been documented higher than 90%. This type of surgery is also very useful in traditionally difficult areas, including the face. Indications for Moh’s surgery include large lesions where cosmesis can be difficult and maximum skin preservation is crucial.

Radiation Therapy Radiation therapy, which involves the use of non-invasive, painless, highly focused beams of ionizing energy, is often used when lesions are in locations that are not easily addressed with surgery, such as eyelids, lips, the nose, or ears. Radiation therapy involves daily treatments for several weeks. Radiation is used in the primary treatment of non-melanoma skin cancers, achieving local control nearing 90%. Radiation is more frequently used for skin cancers in the head and neck region as it offers improved cosmetic outcomes. The effectiveness of radiation as a primary treatment is related to tumor size, with smaller tumors generally responding better. As late skin effects from radiation are a concern, radiation is generally reserved for older patients. Radiation therapy can also be used in conjunction with surgery when tumors are considered high risk or have positive margins as well as with recurrent tumors.

Topical Medications and Chemotherapies Topical medications are occasionally used to treat BCC. Fluorouracil (5-FU) is a type of chemotherapy often used intravenously for other types of cancer; however, it is also approved for topical use for basal cell carcinomas. The 5-FU cream is applied to the area twice daily for several weeks. Imiquimod is also an approved topical medication for BCC. This cream, which is thought to work by stimulating the immune system, is applied to the tumor five times a week for 6 weeks. This type of therapy is reserved for pre-malignant and very superficial lesions.

Photodynamic Therapy Photodynamic therapy is a treatment in which a topical photosensitizing agent is put on the lesion and then the lesion is exposed to a to a wavelength of light. When the light is activated the photosensitizer reacts with the oxygen causing destruction of the cancer cells.

Advanced Lesions Locally advanced lesions that involve invasion into adjacent areas, the treatments are typically more aggressive. Frequently, the surgery will involve reconstruction if a large amount of tissue will be removed. When reconstruction must occur, a skin graft or muscle is often used to aid healing and reach an acceptable cosmetic outcome. Radiation therapy will be used in addition to surgery to improve local control for lesions that are large and/ or total resections are not possible. When tumors recur at the primary (original) site, treatment becomes

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more complex and is often referred to specialists. The majority of recurrences occur within the first few years following diagnosis. When possible, surgery to achieve negative margins is the best option. However, as lesions often occur on the face near important structures such as the nose, lips, ears, and eyes, radiation is often used when surgery would result in disfigurement.

Clinical Trials Clinical trials are extremely important in furthering our knowledge of this disease. It is through clinical trials that we know what we do today, and many exciting new therapies are currently being tested. Talk to your health care provider about participating in clinical trials in your area. You can also explore currently open clinical trials using the OncoLink Clinical Trials Matching Service.

FOLLOW-UP CARE AND SURVIVORSHIP Patients with a history of non-melanoma skin cancer have been documented to be at greater risk of developing a secondary skin cancer. Therefore, all patients require close follow-up. Patients with BCC should be evaluated with a complete skin exam every 6 to 12 months for life. Patients with localized SCC should be evaluated with a complete skin exam every 3 to 6 months for the first 2 years after diagnosis, then every 6 to 12 months for 3 years, and then annually. It is important for patients to continue to examine his or her own skin for any changes or new lesions. As soon as you notice any changes you should contact your provider. It is also very important to practice sun safety. Fear of recurrence, financial impact of cancer treatment, employment issues and coping strategies are common emotional and practical issues experienced by non-melanoma skin cancer survivors. Your health care team can identify resources for support and management of these practical and emotional challenges faced during and after cancer. Cancer survivorship is a relatively new focus of oncology care. With some 15 million cancer survivors in the US alone, there is a need to help patients transition from active treatment to survivorship. What happens next, how do you get back to normal, what should you know and do to live healthy going forward? A survivorship care plan can be a first step in educating yourself about navigating life after cancer and helping you communicate knowledgeably with your health care providers. Create a survivorship care plan today on OncoLink.

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Surgical Oncology: Theory and Multidisciplinary Practice

Breast

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Chapter 2

Breast Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, or a red scaly patch of skin. In those with distant spread of the disease, there may be bone pain, swollen lymph nodes, shortness of breath, or yellow skin. Risk factors for developing breast cancer include being female, obesity, lack of physical exercise, drinking alcohol, hormone replacement therapy during menopause, ionizing radiation, early age at first menstruation, having children late or not at all, older age, and family history. About 5–10% of cases are due to genes inherited from a person’s parents, including BRCA1 and BRCA2 among others. Breast cancer most commonly develops in cells from the lining of milk ducts and the lobules that supply the ducts with milk. Cancers developing from the ducts are known as ductal carcinomas, while those developing from lobules are known as lobular carcinomas. In addition, there are more than 18 other sub-types of breast cancer. Some cancers, such as ductal carcinoma in situ, develop from pre-invasive lesions. The diagnosis of breast cancer is confirmed by taking a biopsy of the concerning lump. Once the diagnosis is made, further tests are done to determine if the cancer has spread beyond the breast and which treatments it may respond to. The balance of benefits versus harms of breast cancer screening is controversial. A 2013 Cochrane review stated that it is unclear if mammographic screening does more good or harm. A 2009 review for the US Preventive Services Task Force found evidence of benefit in those 40 to 70 years of age, and the organization recommends screening every two years in women 50 to 74 years old. The medications tamoxifen or raloxifene may be used in an effort to prevent breast cancer in those who are at high risk of developing it. Surgical removal of both breasts is another preventative measure in some high risk women. In those who have been diagnosed with cancer, a number of treatments may be used, including surgery, radiation therapy, chemotherapy, hormonal therapy and targeted therapy. Types of surgery vary from breast-conserving surgery to mastectomy. Breast reconstruction may take place at the time of surgery or at a later date. In those in whom the cancer has spread to other parts of the body, treatments are mostly aimed at improving quality of life and comfort. Outcomes for breast cancer vary depending on the cancer type, extent of disease, and person’s age. Survival rates in the developed world are high, with between 80% and 90% of those in England and the United States alive for at least 5 years. In developing countries survival rates are poorer. Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases. In 2012 it resulted in 1.68 million new cases and 522,000 deaths. It is more common in developed countries and is more than 100 times more common in women than in men.

SIGNS AND SYMPT OMS SYMPTOMS The first noticeable symptom of breast cancer is typically a lump that feels different from the rest of the breast tissue. More than 80% of breast cancer cases are discovered when the woman feels a lump. The earliest breast cancers are detected by a mammogram. Lumps found in lymph nodes located in the armpits can also indicate breast cancer. Indications of breast cancer other than a lump may include thickening different from the

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Surgical Oncology: Theory and Multidisciplinary Practice

other breast tissue, one breast becoming larger or lower, a nipple changing position or shape or becoming inverted, skin puckering or dimpling, a rash on or around a nipple, discharge from nipple/s, constant pain in part of the breast or armpit, and swelling beneath the armpit or around the collarbone. Pain (“mastodynia”) is an unreliable tool in determining the presence or absence of breast cancer, but may be indicative of other breast health issues. Inflammatory breast cancer is a particular type of breast cancer which can pose a substantial diagnostic challenge. Symptoms may resemble a breast inflammation and may include itching, pain, swelling, nipple inversion, warmth and redness throughout the breast, as well as an orange-peel texture to the skin referred to as peau d’orange. As inflammatory breast cancer does not present as a lump there can sometimes be a delay in diagnosis. Another reported symptom complex of breast cancer is Paget’s disease of the breast. This syndrome presents as skin changes resembling eczema, such as redness, discoloration, or mild flaking of the nipple skin. As Paget’s disease of the breast advances, symptoms may include tingling, itching, increased sensitivity, burning, and pain. There may also be discharge from the nipple. Approximately half of women diagnosed with Paget’s disease of the breast also have a lump in the breast. In rare cases, what initially appears as a fibroadenoma (hard, movable non-cancerous lump) could in fact be a phyllodes tumor. Phyllodes tumors are formed within the stroma (connective tissue) of the breast and contain glandular as well as stromal tissue. Phyllodes tumors are not staged in the usual sense; they are classified on the basis of their appearance under the microscope as benign, borderline, or malignant. Occasionally, breast cancer presents as metastatic disease—that is, cancer that has spread beyond the original organ. The symptoms caused by metastatic breast cancer will depend on the location of metastasis. Common sites of metastasis include bone, liver, lung and brain. Unexplained weight loss can occasionally signal breast cancer, as can symptoms of fevers or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological symptoms. These symptoms are called non-specific, meaning they could be manifestations of many other illnesses. Most symptoms of breast disorders, including most lumps, do not turn out to represent underlying breast cancer. Fewer than 20% of lumps, for example, are cancerous, and benign breast diseases such as mastitis and fibroadenoma of the breast are more common causes of breast disorder symptoms. Nevertheless, the appearance of a new symptom should be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancer at almost any age.

RISK FFA ACT ORS CTORS Risk factors can be divided into two categories: • Modifiable risk factors (things that people can change themselves, such as consumption of alcoholic beverages), and • Fixed risk factors (things that cannot be changed, such as age and biological sex). The primary risk factors for breast cancer are being female and older age. Other potential risk factors include genetics, lack of childbearing or lack of breastfeeding, higher levels of certain hormones, certain dietary patterns, and obesity. One study indicates that exposure to light pollution is a risk factor for the development of breast cancer.

LIFESTYLE Smoking tobacco appears to increase the risk of breast cancer, with the greater the amount smoked and the earlier in life that smoking began, the higher the risk. In those who are long-term smokers, the risk is increased 35% to 50%. A lack of physical activity has been linked to about 10% of cases. Sitting regularly for prolonged periods is associated with higher mortality from breast cancer. The risk is not negated by regular exercise, though it is lowered. There is an association between use of hormonal birth control and the development of premenopausal breast cancer, but whether oral contraceptives use may actually cause premenopausal breast

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cancer is a matter of debate. If there is indeed a link, the absolute effect is small. Additionally, it is not clear if the association exists with newer hormonal birth controls. In those with mutations in the breast cancer susceptibility genes BRCA1 or BRCA2, or who have a family history of breast cancer, use of modern oral contraceptives does not appear to affect the risk of breast cancer. The association between breast feeding and breast cancer has not been clearly determined; some studies have found support for an association while others have not. In the 1980s, the abortion–breast cancer hypothesis posited that induced abortion increased the risk of developing breast cancer. This hypothesis was the subject of extensive scientific enquiry, which concluded that neither miscarriages nor abortions are associated with a heightened risk for breast cancer. A number of dietary factors have been linked to the risk for breast cancer. Dietary factors which may increase risk include a high fat diet, high alcohol intake, and obesity-related high cholesterol levels. Dietary iodine deficiency may also play a role. Evidence for fibre is unclear. A 2015 review found that studies trying to link fibre intake with breast cancer produced mixed results. In 2016 a tentative association between low fibre intake during adolescence and breast cancer was observed. Other risk factors include radiation and shift-work. A number of chemicals have also been linked, including polychlorinated biphenyls, polycyclic aromatic hydrocarbons, and organic solvents Although the radiation from mammography is a low dose, it is estimated that yearly screening from 40 to 80 years of age will cause approximately 225 cases of fatal breast cancer per million women screened.

GENETICS Some genetic susceptibility may play a minor role in most cases. Overall, however, genetics is believed to be the primary cause of 5–10% of all cases. Women whose mother was diagnosed before 50 have an increased risk of 1.7 and those whose mother was diagnosed at age 50 or after has an increased risk of 1.4. In those with zero, one or two affected relatives, the risk of breast cancer before the age of 80 is 7.8%, 13.3%, and 21.1% with a subsequent mortality from the disease of 2.3%, 4.2%, and 7.6% respectively. In those with a first degree relative with the disease the risk of breast cancer between the age of 40 and 50 is double that of the general population. In less than 5% of cases, genetics plays a more significant role by causing a hereditary breast–ovarian cancer syndrome. This includes those who carry the BRCA1 and BRCA2 gene mutation. These mutations account for up to 90% of the total genetic influence with a risk of breast cancer of 60–80% in those affected. Other significant mutations include p53 (Li–Fraumeni syndrome), PTEN (Cowden syndrome), and STK11 (Peutz–Jeghers syndrome), CHEK2, ATM, BRIP1, and PALB2. In 2012, researchers said that there are four genetically distinct types of the breast cancer and that in each type, hallmark genetic changes lead to many cancers.

MEDICAL CONDITIONS Breast changes like atypical ductal hyperplasia and lobular carcinoma in situ, found in benign breast conditions such as fibrocystic breast changes, are correlated with an increased breast cancer risk. Diabetes mellitus might also increase the risk of breast cancer. Autoimmune diseases such as lupus erythematosus seem also to increase the risk for the acquisition of breast cancer.

PA THOPHY SIOL OGY PATHOPHY THOPHYSIOL SIOLOGY Breast cancer, like other cancers, occurs because of an interaction between an environmental (external) factor and a genetically susceptible host. Normal cells divide as many times as needed and stop. They attach to other cells and stay in place in tissues. Cells become cancerous when they lose their ability to stop dividing, to attach to other cells, to stay where they belong, and to die at the proper time. Normal cells will commit cell suicide (programmed cell death) when they are no longer needed. Until then, they are protected from cell suicide by several protein clusters and pathways. One of the protective pathways is the PI3K/AKT pathway;

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Surgical Oncology: Theory and Multidisciplinary Practice

another is the RAS/MEK/ERK pathway. Sometimes the genes along these protective pathways are mutated in a way that turns them permanently “on”, rendering the cell incapable of committing suicide when it is no longer needed. This is one of the steps that causes cancer in combination with other mutations. Normally, the PTEN protein turns off the PI3K/AKT pathway when the cell is ready for programmed cell death. In some breast cancers, the gene for the PTEN protein is mutated, so the PI3K/AKT pathway is stuck in the “on” position, and the cancer cell does not commit suicide. Mutations that can lead to breast cancer have been experimentally linked to estrogen exposure. Abnormal growth factor signaling in the interaction between stromal cells and epithelial cells can facilitate malignant cell growth. In breast adipose tissue, overexpression of leptin leads to increased cell proliferation and cancer. In the United States, 10 to 20 percent of people with breast cancer and people with ovarian cancer have a first- or second-degree relative with one of these diseases. The familial tendency to develop these cancers is called hereditary breast–ovarian cancer syndrome. The best known of these, the BRCA mutations, confer a lifetime risk of breast cancer of between 60 and 85 percent and a lifetime risk of ovarian cancer of between 15 and 40 percent. Some mutations associated with cancer, such as p53, BRCA1 and BRCA2, occur in mechanisms to correct errors in DNA. These mutations are either inherited or acquired after birth. Presumably, they allow further mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant organs. However, there is strong evidence of residual risk variation that goes well beyond hereditary BRCA gene mutations between carrier families. This is caused by unobserved risk factors. This implicates environmental and other causes as triggers for breast cancers. The inherited mutation in BRCA1 or BRCA2 genes can interfere with repair of DNA cross links and DNA double strand breaks (known functions of the encoded protein). These carcinogens cause DNA damage such as DNA cross links and double strand breaks that often require repairs by pathways containing BRCA1 and BRCA2. However, mutations in BRCA genes account for only 2 to 3 percent of all breast cancers. Levin et al. say that cancer may not be inevitable for all carriers of BRCA1 and BRCA2 mutations. About half of hereditary breast–ovarian cancer syndromes involve unknown genes. GATA-3 directly controls the expression of estrogen receptor (ER) and other genes associated with epithelial differentiation, and the loss of GATA-3 leads to loss of differentiation and poor prognosis due to cancer cell invasion and metastasis.

DIA GNOSIS DIAGNOSIS Most types of breast cancer are easy to diagnose by microscopic analysis of a sample—or biopsy—of the affected area of the breast. Also, there are types of breast cancer that require specialized lab exams. The two most commonly used screening methods, physical examination of the breasts by a health care provider and mammography, can offer an approximate likelihood that a lump is cancer, and may also detect some other lesions, such as a simple cyst. When these examinations are inconclusive, a health care provider can remove a sample of the fluid in the lump for microscopic analysis (a procedure known as fine needle aspiration, or fine needle aspiration and cytology—FNAC) to help establish the diagnosis. The needle aspiration may be performed in a health care provider’s office or clinic using local anaesthetic if required. A finding of clear fluid makes the lump highly unlikely to be cancerous, but bloody fluid may be sent off for inspection under a microscope for cancerous cells. Together, physical examination of the breasts, mammography, and FNAC can be used to diagnose breast cancer with a good degree of accuracy. Other options for biopsy include a core biopsy or vacuumassisted breast biopsy, which are procedures in which a section of the breast lump is removed; or an excisional biopsy, in which the entire lump is removed. Very often the results of physical examination by a health care provider, mammography, and additional tests that may be performed in special circumstances (such as imaging by ultrasound or MRI) are sufficient to warrant excisional biopsy as the definitive diagnostic and primary treatment method.

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Breast

CLASSIFICATION Breast cancers are classified by several grading systems. Each of these influences the prognosis and can affect treatment response. Description of a breast cancer optimally includes all of these factors. • Histopathology. Breast cancer is usually classified primarily by its histological appearance. Most breast cancers are derived from the epithelium lining the ducts or lobules, and these cancers are classified as ductal or lobular carcinoma. Carcinoma in situ is growth of low-grade cancerous or precancerous cells within a particular tissue compartment such as the mammary duct without invasion of the surrounding tissue. In contrast, invasive carcinoma does not confine itself to the initial tissue compartment. • Grade. Grading compares the appearance of the breast cancer cells to the appearance of normal breast tissue. Normal cells in an organ like the breast become differentiated, meaning that they take on specific shapes and forms that reflect their function as part of that organ. Cancerous cells lose that differentiation. In cancer, the cells that would normally line up in an orderly way to make up the milk ducts become disorganized. Cell division becomes uncontrolled. Cell nuclei become less uniform. Pathologists describe cells as well differentiated (low grade), moderately differentiated (intermediate grade), and poorly differentiated (high grade) as the cells progressively lose the features seen in normal breast cells. Poorly differentiated cancers (the ones whose tissue is least like normal breast tissue) have a worse prognosis. • Stage. Breast cancer staging using the TNM system is based on the size of the tumor (T), whether or not the tumor has spread to the lymph nodes (N) in the armpits, and whether the tumor has metastasized (M) (i.e. spread to a more distant part of the body). Larger size, nodal spread, and metastasis have a larger stage number and a worse prognosis. The main stages are: • Stage 0 is a pre-cancerous or marker condition, either ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS). • Stages 1–3 are within the breast or regional lymph nodes. • Stage 4 is ‘metastatic’ cancer that has a less favourable prognosis since it has spread beyond the breast and regional lymph nodes.

Fig. Stage T1 breast cancer

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Surgical Oncology: Theory and Multidisciplinary Practice

Fig. Stage T2 breast cancer

Fig. Stage T3 breast cancer

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Where available, imaging studies may be employed as part of the staging process in select cases to look for signs of metastatic cancer. However, in cases of breast cancer with low risk for metastasis, the risks associated with PET scans, CT scans, or bone scans outweigh the possible benefits, as these procedures expose the patient to a substantial amount of potentially dangerous ionizing radiation. • Receptor status. Breast cancer cells have receptors on their surface and in their cytoplasm and nucleus. Chemical messengers such as hormones bind to receptors, and this causes changes in the cell. Breast cancer cells may or may not have three important receptors: estrogen receptor (ER), progesterone receptor (PR), and HER2. ER+ cancer cells (that is, cancer cells that have estrogen receptors) depend on estrogen for their growth, so they can be treated with drugs to block estrogen effects (e.g. tamoxifen), and generally have a better prognosis. Untreated, HER2+ breast cancers are generally more aggressive than HER2- breast cancers, but HER2+ cancer cells respond to drugs such as the monoclonal antibody trastuzumab (in combination with conventional chemotherapy), and this has improved the prognosis significantly. Cells that do not have any of these three receptor types (estrogen receptors, progesterone receptors, or HER2) are called triple-negative, although they frequently do express receptors for other hormones, such as androgen receptor and prolactin receptor. • DNA assays. DNA testing of various types including DNA microarrays have compared normal cells to breast cancer cells. The specific changes in a particular breast cancer can be used to classify the cancer in several ways, and may assist in choosing the most effective treatment for that DNA type.

PRE VENTION PREVENTION LIFE-STYLE Women may reduce their risk of breast cancer by maintaining a healthy weight, drinking less alcohol, being physically active and breastfeeding their children. These modifications might prevent 38% of breast cancers in the US, 42% in the UK, 28% in Brazil and 20% in China. The benefits with moderate exercise such as brisk walking are seen at all age groups including postmenopausal women. High levels of physical activity reduce the risk of breast cancer by about 14%. Strategies that encourage regular physical activity and reduce obesity could also have other benefits, such as reduced risks of cardiovascular disease and diabetes. High intake of citrus fruit has been associated with a 10% reduction in the risk of breast cancer. Marine omega-3 polyunsaturated fatty acids appear to reduce the risk. High consumption of soy-based foods may reduce risk.

PRE-EMPTIVE SURGERY Removal of both breasts before any cancer has been diagnosed or any suspicious lump or other lesion has appeared (a procedure known as prophylactic bilateral mastectomy) may be considered in people with BRCA1 and BRCA2 mutations, which are associated with a substantially heightened risk for an eventual diagnosis of breast cancer. Evidence is not strong enough to support this procedure in anyone but those at the highest risk. BRCA testing is recommended in those with a high family risk after genetic counseling. It is not recommended routinely. This is because there are many forms of changes in BRCA genes, ranging from harmless polymorphisms to obviously dangerous frameshift mutations. The effect of most of the identifiable changes in the genes is uncertain. Testing in an average-risk person is particularly likely to return one of these indeterminate, useless results. It is unclear if removing the second breast in those who have breast cancer in one is beneficial.

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Surgical Oncology: Theory and Multidisciplinary Practice

MEDICATIONS The selective estrogen receptor modulators (such as tamoxifen) reduce the risk of breast cancer but increase the risk of thromboembolism and endometrial cancer. There is no overall change in the risk of death. They are thus not recommended for the prevention of breast cancer in women at average risk but may be offered for those at high risk. The benefit of breast cancer reduction continues for at least five years after stopping a course of treatment with these medications.

SCREENING Breast cancer screening refers to testing otherwise-healthy women for breast cancer in an attempt to achieve an earlier diagnosis under the assumption that early detection will improve outcomes. A number of screening tests have been employed including clinical and self breast exams, mammography, genetic screening, ultrasound, and magnetic resonance imaging. A clinical or self breast exam involves feeling the breast for lumps or other abnormalities. Clinical breast exams are performed by health care providers, while self-breast exams are performed by the person themselves. Evidence does not support the effectiveness of either type of breast exam, as by the time a lump is large enough to be found it is likely to have been growing for several years and thus soon be large enough to be found without an exam. Mammographic screening for breast cancer uses X-rays to examine the breast for any uncharacteristic masses or lumps. During a screening, the breast is compressed and a technician takes photos from multiple angles. A general mammogram takes photos of the entire breast, while a diagnostic mammogram focuses on a specific lump or area of concern. A number of national bodies recommend breast cancer screening. For the average woman, the U.S. Preventive Services Task Force recommends mammography every two years in women between the ages of 50 and 74, the Council of Europe recommends mammography between 50 and 69 with most programmes using a 2-year frequency, and in Canada screening is recommended between the ages of 50 and 74 at a frequency of 2 to 3 years. These task force reports point out that in addition to unnecessary surgery and anxiety, the risks of more frequent mammograms include a small but significant increase in breast cancer induced by radiation. The Cochrane collaboration (2013) states that the best quality evidence neither demonstrates a reduction in cancer specific, nor a reduction in all cause mortality from screening mammography. When less rigorous trials are added to the analysis there is a reduction in mortality due to breast cancer of 0.05% (a decrease of 1 in 2000 deaths from breast cancer over 10 years or a relative decrease of 15% from breast cancer). Screening over 10 years results in a 30% increase in rates of overdiagnosis and over-treatment (3 to 14 per 1000) and more than half will have at least one falsely positive test. This has resulted in the view that it is not clear whether mammography screening does more good or harm. Cochrane states that, due to recent improvements in breast cancer treatment, and the risks of false positives from breast cancer screening leading to unnecessary treatment, “it therefore no longer seems beneficial to attend for breast cancer screening” at any age. Whether MRI as a screening method has greater harms or benefits when compared to standard mammography is not known.

MANA GEMENT MANAGEMENT The management of breast cancer depends on various factors, including the stage of the cancer and the age of the patient. Increasingly aggressive treatments are employed in accordance with the poorer the patient’s prognosis and the higher the risk of recurrence of the cancer following treatment. Breast cancer is usually treated with surgery, which may be followed by chemotherapy or radiation therapy, or both. A multidisciplinary approach is preferable. Hormone receptor-positive cancers are often treated with hormone-blocking therapy over courses of several years. Monoclonal antibodies, or other immune-modulating treatments, may be administered in certain cases of metastatic and other advanced stages of breast cancer.

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Breast

SURGERY Surgery involves the physical removal of the tumor, typically along with some of the surrounding tissue. One or more lymph nodes may be biopsied during the surgery; increasingly the lymph node sampling is performed by a sentinel lymph node biopsy. Standard surgeries include: • Mastectomy: Removal of the whole breast. • Quadrantectomy: Removal of one-quarter of the breast. • Lumpectomy: Removal of a small part of the breast. Once the tumor has been removed, if the patient desires, breast reconstruction surgery, a type of plastic surgery, may then be performed to improve the aesthetic appearance of the treated site. Alternatively, women use breast prostheses to simulate a breast under clothing, or choose a flat chest. Nipple prosthesis can be used at any time following the mastectomy.

Fig. Chest after right breast mastectomy

MEDICATION Drugs used after and in addition to surgery are called adjuvant therapy. Chemotherapy or other types of therapy prior to surgery are called neo-adjuvant therapy. Aspirin may reduce mortality from breast cancer. There are currently three main groups of medications used for adjuvant breast cancer treatment: hormoneblocking agents, chemotherapy, and monoclonal antibodies.

Hormone Blocking Therapy Some breast cancers require estrogen to continue growing. They can be identified by the presence of estrogen receptors (ER+) and progesterone receptors (PR+) on their surface (sometimes referred to together as hormone

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Surgical Oncology: Theory and Multidisciplinary Practice

receptors). These ER+ cancers can be treated with drugs that either block the receptors, e.g. tamoxifen, or alternatively block the production of estrogen with an aromatase inhibitor, e.g. anastrozole or letrozole. The use of tamoxifen is recommended for 10 years. Letrozole is recommended for 5 years. Aromatase inhibitors are only suitable for women after menopause; however, in this group, they appear better than tamoxifen. This is because the active aromatase in postmenopausal women is different from the prevalent form in premenopausal women, and therefore these agents are ineffective in inhibiting the predominant aromatase of premenopausal women. Aromatase inhibitors should not be given to premenopausal women with intact ovarian function (unless they are also on treatment to stop their ovaries from working).

Chemotherapy Chemotherapy is predominantly used for cases of breast cancer in stages 2–4, and is particularly beneficial in estrogen receptor-negative (ER-) disease. The chemotherapy medications are administered in combinations, usually for periods of 3–6 months. One of the most common regimens, known as “AC”, combines cyclophosphamide with doxorubicin. Sometimes a taxane drug, such as docetaxel, is added, and the regime is then known as “CAT”. Another common treatment is cyclophosphamide, methotrexate, and fluorouracil (or “CMF”). Most chemotherapy medications work by destroying fast-growing and/or fast-replicating cancer cells, either by causing DNA damage upon replication or by other mechanisms. However, the medications also damage fast-growing normal cells, which may cause serious side effects. Damage to the heart muscle is the most dangerous complication of doxorubicin, for example.

Monoclonal Antibodies Trastuzumab, a monoclonal antibody to HER2 (a cell receptor that is especially active in some breast cancer cells), has improved the 5-year disease free survival of stage 1–3 HER2-positive breast cancers to about 87% (overall survival 95%). When stimulated by certain growth factors, HER2 causes cellular growth and division; in the absence of stimulation by the growth factor, the cell will normally stop growing. Between 25% and 30% of breast cancers overexpress the HER2 gene or its protein product, and overexpression of HER2 in breast cancer is associated with increased disease recurrence and worse prognosis. When trastuzumab binds to the HER2 in breast cancer cells that overexpress the receptor, trastuzumab prevents growth factors from being able to bind to and stimulate the receptors, effectively blocking the growth of the cancer cells. Trastuzumab, however, is very expensive, and its use may cause serious side effects (approximately 2% of patients who receive it suffer significant heart damage). Further, trastuzumab is only effective in patients with HER2 amplification/ overexpression.

RADIATION Radiotherapy is given after surgery to the region of the tumor bed and regional lymph nodes, to destroy microscopic tumor cells that may have escaped surgery. It may also have a beneficial effect on tumor microenvironment. Radiation therapy can be delivered as external beam radiotherapy or as brachytherapy (internal radiotherapy). Conventionally radiotherapy is given after the operation for breast cancer. Radiation can also be given at the time of operation on the breast cancer. Radiation can reduce the risk of recurrence by 50–66% (1/2 – 2/3 reduction of risk) when delivered in the correct dose and is considered essential when breast cancer is treated by removing only the lump (Lumpectomy or Wide local excision).

33

Breast

Fig. Internal radiotherapy for breast cancer

PR OGNOSIS PROGNOSIS Prognosis

Fig. Breasts after double mastectomy followed by nipple-sparing reconstruction with implants

Fig. An example of an advanced recurrent breast cancer with an ulcerating axillary mass

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Surgical Oncology: Theory and Multidisciplinary Practice

Prognosis is usually given for the probability of progression-free survival (PFS) or disease-free survival (DFS). These predictions are based on experience with breast cancer patients with similar classification. A prognosis is an estimate, as patients with the same classification will survive a different amount of time, and classifications are not always precise. Survival is usually calculated as an average number of months (or years) that 50% of patients survive, or the percentage of patients that are alive after 1, 5, 15, and 20 years. Prognosis is important for treatment decisions because patients with a good prognosis are usually offered less invasive treatments, such as lumpectomy and radiation or hormone therapy, while patients with poor prognosis are usually offered more aggressive treatment, such as more extensive mastectomy and one or more chemotherapy drugs.

PROGNOSTIC FACTORS Prognostic factors are reflected in the classification scheme for breast cancer including stage, (i.e., tumor size, location, whether disease has spread to lymph nodes and other parts of the body), grade, recurrence of the disease, and the age and health of the patient. The Nottingham Prognostic Index is a commonly used prognostic tool. The stage of the breast cancer is the most important component of traditional classification methods of breast cancer, because it has a greater effect on the prognosis than the other considerations. Staging takes into consideration size, local involvement, lymph node status and whether metastatic disease is present. The higher the stage at diagnosis, the poorer the prognosis. The stage is raised by the invasiveness of disease to lymph nodes, chest wall, skin or beyond, and the aggressiveness of the cancer cells. The stage is lowered by the presence of cancer-free zones and close-to-normal cell behaviour (grading). Size is not a factor in staging unless the cancer is invasive. For example, Ductal Carcinoma In Situ (DCIS) involving the entire breast will still be stage zero and consequently an excellent prognosis with a 10-year disease free survival of about 98%. • Stage 1 cancers (and DCIS, LCIS) have an excellent prognosis and are generally treated with lumpectomy and sometimes radiation. HER2+ cancers should be treated with the trastuzumab (Herceptin) regime. Chemotherapy is uncommon for other types of stage 1 cancers. • Stage 2 and 3 cancers with a progressively poorer prognosis and greater risk of recurrence are generally treated with surgery (lumpectomy or mastectomy with or without lymph node removal), chemotherapy (plus trastuzumab for HER2+ cancers) and sometimes radiation (particularly following large cancers, multiple positive nodes or lumpectomy). • Stage 4, metastatic cancer, (i.e. spread to distant sites) has poor prognosis and is managed by various combination of all treatments from surgery, radiation, chemotherapy and targeted therapies. Tenyear survival rate is 5% without treatment and 10% with optimal treatment. The breast cancer grade is assessed by comparison of the breast cancer cells to normal breast cells. The closer to normal the cancer cells are, the slower their growth and the better the prognosis. If cells are not well differentiated, they will appear immature, will divide more rapidly, and will tend to spread. Well differentiated is given a grade of 1, moderate is grade 2, while poor or undifferentiated is given a higher grade of 3 or 4 (depending upon the scale used). The most widely used grading system is the Nottingham scheme; details are provided in the discussion of breast cancer grade. The presence of estrogen and progesterone receptors in the cancer cell is important in guiding treatment. Those who do not test positive for these specific receptors will not be able to respond to hormone therapy, and this can affect their chance of survival depending upon what treatment options remain, the exact type of cancer, and how advanced the disease is. In addition to hormone receptors, there are other cell surface proteins that may affect prognosis and treatment. HER2 status directs the course of treatment. Patients whose cancer cells are positive for HER2 have a more aggressive disease and may be treated with the ‘targeted therapy’, trastuzumab (Herceptin), a monoclonal antibody that targets this protein and improves the prognosis significantly. Younger women with an age of less than 40 years or women over 80 years tend to

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35

have a poorer prognosis than post-menopausal women due to several factors. Their breasts may change with their menstrual cycles, they may be nursing infants, and they may be unaware of changes in their breasts. Therefore, younger women are usually at a more advanced stage when diagnosed. There may also be biologic factors contributing to a higher risk of disease recurrence for younger women with breast cancer. High mammographic breast density, which is a marker of increased risk of developing breast cancer, may not mean an increased risk of death among breast cancer patients, according to a 2012 report of a study involving 9232 women by the National Cancer Institute (NCI). On the other hand, more recent research has shown that women with extremely low mammographic densities (50% have more than four nodes involved. Most of the LABCs are operable; only 25%-30% are diagnosed at an inoperable stage. Therefore, we can extrapolate that only 5% of all newly diagnosed breast cancers in the USA are found in stage IIIB/IV (inoperable). A physical examination, bilateral mammogram and ultrasound of the breast and its draining lymphatics determine the extent of involvement within the breast and the nodal chains, the presence of additional tumor foci within the same breast or the contralateral breast, and the extension of the tumor to deeper structures. A core needle biopsy is quite effective in establishing the diagnosis and also allowing tumor samples to be obtained for hormone receptors, DNA studies and other biomarkers. The sensitivity and specificity of fine-needle aspiration are quite high in LABC. The only disadvantages of cytological diagnosis are the inability to differentiate between in situ and invasive carcinoma, and scant material on which to perform additional studies. Excisional biopsies are not indicated in patients with LABC.

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Surgical Oncology: Theory and Multidisciplinary Practice

STAGING Appropriate staging procedures should be performed in patients with LABC since the probability of distant metastases is high. Approximately 20% of these patients, appropriately staged, have detectable distant metastases at the time of diagnosis. We recommend that after a complete history, a physical examination be performed with great attention to the evaluation of both breasts and all surrounding lymph node-bearing areas. All tumors should be described by the longest perpendicular diameters in cm, and the presence of palpable axillary, supraclavicular and subclavicular nodes, with exact measurements of their longest perpendicular diameters, should be included. A close-up photograph is useful in the staging of patients with T4 tumors. Ideally, the initial evaluation should be done simultaneously by the medical oncologist, surgical oncologist and radiotherapist. After the physical examination and bilateral mammogram, the following additional tests are recommended: a biochemical profile, including tests of liver and renal function, and calcium level; chest x-ray; bone scans; radiographs of areas that appear to be abnormal on the bone scan; computed tomography of the liver and an ultrasonography of the breast and regional lymph nodes to precisely assess the tumor extent. The importance of an accurate initial assessment of the extent of primary tumor burden cannot be overemphasized since the efficacy of subsequent local treatment will depend mostly on this initial assessment.

NATURAL HISTORY There is no recorded information about the natural history of untreated LABC. Many of the published series of patients treated with radical surgery, RT or combinations of both were published 20 or 30 years ago. From the surgical point of view, we can subdivide LABC into operable, stage IIB (T3, N0; previously classified as stage IIIA) and IIIA, and inoperable, stage IIIB and regional IV (previously classified as stage IIIB) breast cancer. Patient selection influenced outcome substantially more than treatment did. Some authors have tried to compare the results of surgery alone to RT alone, or combinations of both. However, the groups were hardly comparable because many of the tumors treated with RT alone were not suitable for surgical resection in the first place. For instance, although most surgical series that included stage IIIB breast cancer included patients with pectoral muscle fixation or skin involvement, most excluded cases with supraclavicular node involvement, arm edema or chest wall fixation. Since these patients are known to have the worst prognosis after local therapy alone, this exclusion probably substantially improved the outcome of the surgical series. On the other hand, the older RT series had fewer selective inclusion criteria, accepting all patients. Therefore, the outcomes in RT series were usually inferior to those reported in surgical series. For all types of LABC, whether or not operable, distant metastases were the most frequent type of treatment failure, and appeared in the majority of patients within 24 months after diagnosis. In addition, a very high percentage of patients developed locoregional failure, whether the initial treatment consisted of surgery alone or RT alone. The radical mastectomy was developed especially for LABC, but the local failure rate after surgery alone may be as high as 60%. The five- and 10-year survival rates for patients with LABC after radical mastectomy vary between 10%40% and 0%-30%, respectively. The outcomes in RT series were usually inferior to those reported in surgical series. The five-year survival figures varied from 10% to 30%, and very few reports provided 10-year survival figures, in part because few patients survived 10 years. Local recurrence rates ranged from 25% to 72%, suggesting that even local control was often inadequate. Several investigators have shown a clear dose-response correlation for RT. Therefore, the local control rate may vary, depending on the administered dose. Mastectomy combined with preoperative or postoperative RT seemed to produce improved local and regional control rates but did not modify survival rates since distant metastases were the ultimate determinants of outcome. When only local therapies were used, the median DFS and OS durations for patients with LABC ranged from 8-12 months and

41

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24 months, respectively. The 10-year survival in 3,575 patients with LABC after locoregional therapy was 22% (Table ⇓). In conclusion, the outcome for patients with LABC treated with local therapies only was, in general, consistently very poor. Table. Survival of patients with LABC after local/regional therapy Survival (10-year) Treatment Surgery Radiotherapy Combined surgery and radiotherapy Total

Patients # 853 978 1,744 3,575

Alive (%) 19 23 22 22

MULTIDISCIPLINARY THERAPY Theoretical and Clinical Considerations In the early 1970s, recognizing the high propensity of early breast cancer to generate distant micrometastases, several groups pioneered the use of adjuvant systemic therapy as a curative strategy against breast cancer. Based on these theoretical considerations and the poor prognosis of patients with LABC, systemic combination CT was introduced as the primary treatment in these patients. In this strategy, systemic therapy is known as neo-adjuvant or primary CT. This treatment was preferred because the major problem in LABC is distant metastases, rather than the local disease. After CT is administered for three to four cycles and its efficacy is assessed, regional therapy is administered in the form of surgery, RT, or both, and is followed, in turn, by additional postoperative CT, followed by RT and hormonotherapy (>50 years, estrogen receptor positive [ER]). The advantages and disadvantages of this strategy are detailed in Table ⇓. The advantages include the earlier initiation of systemic therapy, before the vasculature of the tumor is altered by surgery or RT, and before many resistant clones have the chance to arise. Furthermore, the medical oncologist has the opportunity to assess the efficacy of systemic therapy in vivo. If systemic treatment is not effective, the oncologist can discontinue the ineffective therapy, avoid unnecessary toxicity and institute an alternative form of systemic therapy. Moreover, downstaging of a tumor may allow for breast-conserving surgery and render inoperable tumors resectable. On the other hand, the disadvantages of this strategy include the lack of accurate initial pathological staging and the potential for emerging drug resistance due to the large tumor burden. In addition, if CT is ineffective, local treatment is delayed for several weeks. Table. Primary chemotherapy Advantages ∆ Early systemic treatment ∆ No postsurgical growth spurt ∆ Intact tumor vasculature ∆ In vivo assessment of response ∆ Decrease radical local therapy ∆ Downstaging ∆ Increase breast conservation ∆ Improving resectability Disadvantages ∆ Delayed local treatment ∆ May induce drug resistance ∆ Large tumor burden ∆ Only clinical staging ∆ May increase risk of( surgical/RT complications

PRIMARY CHEMOTHERAPY RESULTS Our group pioneered multidisciplinary therapy, including primary CT with anthracycline-containing regimens. We enrolled 598 patients in three studies. In the first two studies, after three cycles of CT, local treatment in the

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Surgical Oncology: Theory and Multidisciplinary Practice

form of a total mastectomy with level one and two axillary dissection, RT, or both were completed. After local therapy, additional CT was administered. In the second study, the role of a non-cross-resistant postoperative CT regimen (vinblastine, methotrexate, fluorouracil and folinic acid) was randomly investigated. In the third study, all patients received four cycles of primary CT with an anthracycline-containing regimen. Doxorubicin was given as a 72-h continuous infusion. In all, 367 patients with non-inflammatory LABC were evaluated in the first two studies (174/193); 148 of them had stage IIB/IIIA, and 219 had stage IIIB/regional IV disease. After primary CT, 63 (17%) and 250 (68%) patients achieved clinical complete remissions (CR) and partial remissions (PR), respectively. All but nine patients were rendered disease-free after primary CT and initial local therapy. In the first study, at a median follow up of 11 years, the median DFS for patients with stage IIB/IIIA disease had not been reached; for the patients with stage IIIB/regional IV disease it was 30 months. The median OS for stage IIB/IIIA disease had not been reached and for stage IIIB it was 48 months. The five- and 10-year DFS rates for patients with stage IIB/IIIA disease were 71% and 40%, respectively. The five- and 10-year DFS rates for patients with stage IIIB/regional IV disease were 33% and 30%, respectively. The five-year OS rates for stage IIB/IIIA and stage IIIB/regional IV were 84% and 44%; the 10-year OS figures were 56% and 26%, respectively. The five-year DFS and OS rates in the second study were similar to those of the first study. Treatment with a noncross-resistant postoperative CT regimen did not significantly affect DFS and OS. The high objective response rate was also confirmed in our third study. The objective response rate to primary CT was 73% in 160 evaluable patients with LABC. Compared to our historical institutional experience, the local control rate, and five- and 10-year DFS and OS rates for LABC were substantially improved by this multidisciplinary programme. A number of other centers have developed similar strategies (Table ⇓). The common theme is the use of primary or induction CT, followed by local treatment, which is “sandwiched” between primary and adjuvant systemic treatments. There are major variations in CT programmes, type and aggressiveness of local therapy, duration of treatment and eligibility criteria. Several CT combinations have been used for the treatment of LABC, although in most published trials an anthracycline-based regimen was preferred. The overall response and CR rates following primary CT are depicted in Table 3!. As the table shows, 50%-95% of patients with LABC achieved an objective response, including 5%-50% clinical CR rates. This latter range is somewhat deceiving since only two of the many trials have shown CR rates in excess of 25%. The trial conducted by Lippman et al. reported a 52% clinical CR rate, but it is likely that this CR rate was artificially high due to the methods used to evaluate and define a CR. The trial conducted by Powles and associates, included mostly patients with stage I and stage II breast cancer, and the higher CR rate reported might be due to patient selection rather than increased efficacy of primary chemotherapy. As a consequence of this high frequency of objective responses, approximately 70% of patients with LABC undergo downstaging (the primary tumor or regional lymph nodes decrease by at least one stage category). Table. LABC response to primary chemotherapy Author

Treatment Programme

# Patients Treated

# Patients with >50 Response (%)

Complete Response (%)

A = Adriamycin; V = Vincristine; F = 5-Fluorouracil; C = Cyclophosphamide; DES = Diethylstilbestrol; T = Tamoxifen; P = Premarin; L = Leucovorin; M = Mitomycin; Pr = Prednisone; Vb = Vinblastine; Mi = Mitoxantrone; Me = Methotrexate, Vi = Vindesin Hortobagyi Hortobagyi Booser DeLena DeLena Rubens Hobar Conte

FAC × 3 VACP × 3 FAC × 4 AV × 4 AV × 3 AV × 4 FAC × 3 DES-FAC × 3

174 193 160 74 132 12 36 39

152 (87) 161 (83) 116 (73) 64 (86) 70 (53) 6 (50) 26 (72) 28 (72)

17 18 8 4 15 17 8 15

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Breast Lippman Cocconi Perloff Jacquillat Powles Rosso Poddubnaya Calais Touboul

CATPMFL × (3-11) CMF(T) × 4 CAFVPr × 3 VbTMAFPr × (2-4) MMiMe × 4 FAC × 3 AMC/CMF MiViCF FACV × 4

51 49 113 98 34 113 503 80 82

45 (88) 23 (47) 78 (69) 89 (91) 32 (94) 73 (65) 317 (63) 41 (51) 45 (55)

52 8 18 23 44 10 2 18 10

In most of these trials, a fixed number of primary CT cycles was employed. However, in a few trials primary CT was continued until reaching maximal response. These trials have shown that there is immense variability in the time required to achieve maximum response. Some patients reached maximal response after one month, whereas others needed up to eight months to reach such a response. A clinical CR does not necessarily represent a pathologically proven CR. In fact, the pathological CR rate varied from 3%-33% in different trials and approximately only two-thirds of the patients with a clinical CR had a pathologically proven CR (Table ⇓). Conversely, only two-thirds of the patients with a pathologically proven CR were found to have a CR prior to surgical resection. Of course, patients treated with RT alone have no pathologically demonstrable remission. Table. Locally advanced breast cancer Local Control Author Hortobagyi Touboul Cardenas Hobar Conte Jacquillat Perloff DeLena DeLena Aisner Calais Boyages DeLena

CT CT CT CT CT CT CT CT CT CT CT CT CT

Treatment ± S ± RT + CT + RT ± S + CT + S/RT + CT + S ± RT + CT + S + CT ± RT + RT + CT + S/RT + CT + RT + CT + S + CT + S + CT + S + RT + CT + RT + CT + RT ± CT

# Patients 367 82 23 36 39 98 113 67 65 27 80 35 110

Median F/U 80 m 70 m 52 m 34 m 24 m 40 m 37 m 36 m 36 m 24 m 38 m 24 m 18 m

Local Control Rate (%) 84 82 78 81 72 87 63 69 70 59 94 71 54

IIB-IIIA/IIIB-IV 148/219 42/40 ? 13/21 11/28 30/68 36/77 5/62 7/58 “/27 ? 8/27 5/105

Randomized Studies Several randomized trials that included a substantial minority of patients with stage III breast cancer, or that specifically targeted stage III breast cancer, demonstrated that adjuvant CT, or adjuvant CT and RT, increased DFS and OS rates. What is not known at this time is whether the timing of systemic treatments (postoperative versus preoperative) alters the probability of benefit. One randomized clinical trial suggested that adjuvant CT after primary CT and RT resulted in longer time to progression and survival than the use of only primary CT and RT Several small randomized trials failed to show an additional survival benefit of primary CT over postoperative CT. However, these trials included small numbers of patients, and sizable differences in outcome could have easily been overlooked because of low statistical significance. More recently (Table ⇓)], several randomized trials were instituted comparing primary (neo-adjuvant) and postoperative (adjuvant) CT. These trials included a mixture of stage II and stage III patients. One of these trials was recently updated and suggested a survival benefit in favour of primary CT. However, there was no benefit in DFS, making interpretation of these data more complex. Four trials showed increased survival in patients who received primary CT; however, only one of these trials did reach statistical significance. Longer follow-up in additional, larger studies will be needed to determine the relative benefits of primary versus adjuvant therapies.

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Surgical Oncology: Theory and Multidisciplinary Practice

Table. Randomized trials of primary versus postoperative chemotherapy for primary breast cancer Author

Treatment

# Patients

Response Rate

Median Follow up

Disease-Free (%)

Alive (%)

32 patients did not receive CT calculated from survival curve Pierga Ragaz Scholl DeOliveira Rubens Semiglazov Mauriac Olsen

Primary Post-op Primary Post-op Primary Post-op Primary Post-op Primary Post-RT Primary Post-RT Primary Post-op Primary Post-RT

200 190 69 30 196 194 81 90 12 12 137 134 133 134 119

64% NA — NA 82% NA — NA 50% — 69% 61% 63% NA 77% 76%

36 m

68 66 57 47 59 55 68 66 50 42 86 72 80 79 NS —

48 m 54 m 60 m 40 m 53 m 34 m 96 m

93 86 69 60 86 78 82 71 50 50 86 79 95 88 19 19

LOCAL/REGIONAL TREATMENT AND LOCAL CONTROL After primary CT, some programmes have used surgical therapy alone, RT alone, or a combination of both treatments. Two prospective randomized trials have been reported in which surgery was compared with RT after primary CT. In both trials, surgery appeared to be equivalent to RT for local control and long-term survival. However, the local control rate in the studies was relatively low, in the 60%-70% range. In contrast, those phase II studies in which primary CT was followed by both surgery and RT have reported higher local control rates, in some cases reaching 85% (Table ⇓). In our first two studies (367 patients), the locoregional failure rate for stage IIB/IIIA and IIIB/regional IV were 7% and 26%, respectively. Table. Locally advanced breast cancer—complete remissions after primary chemotherapy Author

Treatment Programme

Hortobagyi Booser Hobar Conte Lippman Schwartz Cocconi

CT CT CT CT CT CT CT

± + + + ± + +

S S S S S S S

+ + ± + + + +

RT CT RT CT RT CT CT

– CT + RT + CT + CT ± RT + RT

# Patients 174 160 36 39 51 90 49

Clinical (%) 17 8 8 15 52 NA 8

Pathological (%) 8 11 11 8 33 3 14

TOLERANCE AND TOXICITY The same side effects and toxicity usually associated with adjuvant CT have been routinely reported with combined modality programmes that included primary CT. In our initial trial, the acute and chronic major side effects included 19 febrile episodes, but no deaths related to infection. Nine patients developed clinical congestive heart failure and two died as a result. Two patients developed acute non-lymphocytic leukemia. In general, surgical complications and short- and long-term complications of radiotherapy also appear to be similar to what had been previously reported in the literature. The use of primary CT does not appear to enhance surgical complications compared to complications that occur after primary surgical procedures. It is not clear at this time whether the sequential use of CT and RT results in additive or synergistic toxicity. In our own experience, in the early days of combined modality therapy, RT with photons to the internal mammary chain in combination with anthracycline-containing CT was associated with an increased risk of cardiac damage if the lesion originated in the left breast. However, over the past decade, the use of electron beam therapy to cover the internal mammary

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chain, and the administration of anthracyclines by a 72- to 96-h continuous infusion has eliminated this overlapping toxicity. In patients whose tumors are not amenable to breast conservation, delayed chest wall reconstruction is an alternative option.

Prognostic Factors Initial tumor size, the presence of skin edema, tumor S-phase fraction, thymidine labeling index, number of axillary nodes involved, ER, PR, histological and nuclear grade, extent of residual disease, and objective response after primary CT are all important prognostic factors for this group of patients. In our first study, patients with ER or unknown tumors had better DFS and OS rates than did those with ER. Response to primary CT correlated closely with prognosis. Patients who achieved CR had DFS and OS rates considerably superior to those with a PR or no change after the primary CT regimen. Compliance with the treatment regimen was also an important prognostic factor for survival. It is of interest that pathologic lymph node involvement after primary CT retains prognostic importance, and, in fact, in our evaluation by multivariate analysis, is the most important prognostic indicator. Predictors of tumor response to primary CT have also been reported. Initial tumor size and nuclear grade are independent predictors of response. Other predictors of tumor response to primary CT include Sphase fraction, ER, and ploidy. A recent report suggested that patients with tumors with high S-phase fractions responded more often than those with low S-phase fractions. The results of new prognostic factors such as p53 and c-erbB-2 oncogene expression were recently reviewed. Whether these prognostic indicators can select individual patients who might benefit more than others from multidisciplinary strategies remains to be established. Therefore, their clinical usefulness outside of a clinical trial remains in question.

DOSE INTENSIFICATION One of the research directions to improve the survival of patients with LABC is dose intensification of primary or postoperative CT. A recent study in patients with early breast cancer treated with anthracyclinecontaining regimens demonstrated that doses lower than the standard dose produce an inferior DFS and OS. On the other hand, a recent report from a randomized study with higher doses of cyclophosphamide plus granulocyte colony-stimulating factor failed to show any additional benefit from higher doses. It is unclear if doses higher than the standard dose would impact the outcome of these patients. Several reports of open phase II trials in patients with LABC have suggested a higher response rate [55,56]. No definite survival benefits have been reported; however, comparative trials are necessary to assess the relative value of dose intensification in this group of patients. A randomized phase III study is under way at The University of Texas MD Anderson Cancer Center. The preliminary results of this trial showed a higher objective response rate in the higher dose arm (98% versus 76%), but the pathological CR rates were similar. The role of very high-dose CT with peripheral hematopoietic stem cell rescue is being studied in patients with a higher risk of relapse after primary CT, such as patients with four or more positive axillary nodes after primary CT. The role of this strategy is also being investigated after primary CT as a consolidation CT.

BREAST CONSERVATION Historically, patients with LABC were not considered candidates for breast-conserving surgery. The inclusion of primary CT in the multidisciplinary treatment of patients with LABC resulted in 10%-40% of patients achieving such a remarkable reduction in tumor size that treatment with a segmental mastectomy followed by RT resulted in a realistic option for patients with LABC. The goal of this strategy is to obtain optimal localregional control with minimal disfigurement. Breast-conserving surgery for LABC was developed by several institutions following the same criteria used for breast conservation in stage I or small stage II breast cancer.

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Surgical Oncology: Theory and Multidisciplinary Practice

However, there is great variability in the methods and patients’ selection criteria utilized for breast conservation. Whether the same criteria used for patients with early breast cancer are appropriate for breast conservation in LABC is unknown. Other centers employed different multidisciplinary breast-sparing strategy, primary CT, followed by RT, followed by postoperative CT. After primary CT, the primary tumor may disappear completely or may partially decrease in size. The tumor may lose all its infiltrating components so that only residual noninvasive carcinoma is left. It is unknown at this point which is the most frequent manner in which primary tumors decrease in size after primary CT. However, documentation of downstaging is absolutely necessary in order to define the optimal terms of surgical removal and to maximize local control. Only prospective collection of data will determine what is the optimal limit of surgical excision, whether positive margins have the same implications after primary CT as they do in untreated patients, and whether a persistent tumor with marked CTrelated changes compromises local control. Our current practice includes primary CT with a doxorubicincontaining regimen for four cycles. Multidisciplinary evaluation is performed at baseline and after primary CT. If patients fulfill the rigorous criteria (including absence of extensive intramammary lymphatic invasion, negative resection margin, resolution of skin edema, small residual tumor size, no evidence of multicentric lesions or diffuse calcifications, and appropriate tumor: breast size ratios) for breast conserving surgery, then this option is offered to our patients with LABC, followed by postoperative CT. RT is given at the completion of all CT. In summary, to augment the probability of breast conservation for LABC, several strategies can be pursued. Primary CT could be followed by wide excision and RT for patients with excellent tumor reduction. Primary CT can be followed by RT in patients with less marked tumor reduction to maximize downstaging and permit a limited surgical resection. Chemotherapy can also be combined simultaneously with RT, expecting additive effects on the primary tumor volume. Finally, primary CT can be followed by RT alone in those patients who had significant tumor downstaging, after maximal response to CT. At this time it is unknown which of these strategies is optimal in terms of tumor reduction, cosmetic outcome, and local control. Therefore, well-designed, multicentric randomized clinical trials are needed to determine the optimal strategy.

INFLAMMATORY BREAST CARCINOMA IBC is a very rare oncological entity. It constitutes only 1%-4% of breast cancer cases in the USA. IBC is a clinical-pathological entity that has been defined in many different ways. We define IBC as a clinical entity characterized by rapid onset and an evolution shorter than three months, with diffuse involvement of the breast, usually without an underlying palpable mass. The physical exam is characterized by erythema, skin edema, and the presence of ridging. Histopathological demonstration of dermal lymphatic invasion is considered confirmatory evidence but is neither necessary nor pathognomic for the diagnosis. Like LABC, distant metastases were and are the most frequent type of treatment failure, and a very high percentage of patients develop locoregional failure. Few if any patients survive beyond two years. The results after treatment consisting of surgery alone were totally inadequate. RT used as the only therapeutic strategy produced local control in a substantial fraction of patients but was unable to modify the natural history of this entity. Anthracycline-containing primary CT produces objective responses in 60%-80% of patients, and the majority of them are rendered disease-free with the multidisciplinary therapy (primary CT and RT, or CT, surgery and RT). In contrast with historical experience, five-year survival rates in the 30%-50% range have been reported consistently, and at 10 years, 30% of patients remain alive, most of them free of metastatic breast cancer. In general, the DFS and OS data after multidisciplinary therapy are similar to those achieved with stage IIIB/IV, non-inflammatory LABC. The results from our institute were recently reviewed by Buzdar et al.; we treated 178 patients in four trials. Of these patients, 72% achieved a major objective response, including 12% who achieved CR. Only one patient developed progressive disease during primary CT. After primary CT and RT, 92% of patients were rendered disease-free. The median DFS and OS for this group were 21 months and 40 months, respectively. The overall locoregional control rate was 82%.

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At 10 years after diagnosis, 30% of patients remained disease-free and alive. Objective response (CR + PR) to primary induction CT was the main prognostic factor. Fifty percent of patients with CR remained disease-free after 10 years. In summary, the introduction of primary CT to the multidisciplinary management of IBC has changed the uniformly lethal natural history of this unique entity. It is in this group of patients that the most dramatic demonstration of the efficacy of multidisciplinary therapy that includes primary CT was observed.

BR CA 1 AND BR CA 2 IN BREAST CANCER AND OV ARIAN CANCER BRC BRC OVARIAN A BRCA mutation is a mutation in either of the BRCA1 and BRCA2 genes, which are tumour suppressor genes. Hundreds of different types of mutations in these genes have been identified, some of which have been determined to be harmful, while others have no proven impact. Harmful mutations in these genes may produce a hereditary breast-ovarian cancer syndrome in affected persons. Only 5-10% of breast cancer cases in women are attributed to BRCA1 and BRCA2 mutations (with BRCA1 mutations being slightly more common than BRCA2 mutations), but the impact on women with the gene mutation is more profound. Women with harmful mutations in either BRCA1 or BRCA2 have a risk of breast cancer that is about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times normal. The risk of breast and ovarian cancer is higher for women with a high-risk BRCA1 mutation than with a BRCA2 mutation. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or imply that any cancer that appears was actually caused by the mutation, rather than some other factor. High-risk mutations, which disable an important error-free DNA repair process (homology directed repair), significantly increase the person’s risk of developing breast cancer, ovarian cancer and certain other cancers. Why BRCA1 and BRCA2 mutations lead preferentially to cancers of the breast and ovary is not known, but lack of BRCA1 function seems to lead to nonfunctional X-chromosome inactivation. Not all mutations are high-risk; some appear to be harmless variations. The cancer risk associated with any given mutation varies significantly and depends on the exact type and location of the mutation and possibly other individual factors. Mutations can be inherited from either parent and may be passed on to both sons and daughters. Each child of a genetic carrier, regardless of sex, has a 50% chance of inheriting the mutated gene from the parent who carries the mutation. As a result, half of the people with BRCA gene mutations are male, who would then pass the mutation on to 50% of their offspring, male or female. The risk of BRCA-related breast cancers for men with the mutation is higher than for other men, but still low. However, BRCA mutations can increase the risk of other cancers, such as colon cancer, pancreatic cancer, and prostate cancer. Methods to diagnose the likelihood of a patient with mutations in BRCA1 and BRCA2 getting cancer were covered by patents owned or controlled by Myriad Genetics. Myriad’s business model of exclusively offering the diagnostic test led to Myriad growing from being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012; it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit.

GENES AND MUTATIONS Both BRCA genes are tumor suppressor genes that produce proteins that are used by the cell in an enzymatic pathway that makes very precise, perfectly matched repairs to DNA molecules that have doublestranded breaks. The pathway requires proteins produced by several other genes, including CHK2, FANCD2 and ATM. Harmful mutations in any of these genes disable the gene or the protein that it produces. The cancer risk caused by BRCA1 and BRCA2 mutations are inherited in a dominant fashion even though usually only one mutated allele is directly inherited. This is because people with the mutation are likely to acquire a second mutation, leading to dominant expression of the cancer. A mutated BRCA gene can be inherited from either parent. Because they are inherited from the parents, they are classified as hereditary or germline mutations

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rather than acquired or somatic mutations. Cancer caused by a mutated gene inherited from an individual’s parents is a hereditary cancer rather than a sporadic cancer. Because humans have a diploid genome, each cell has two copies of the gene (one from each biological parent). Typically only one copy contains a disabling, inherited mutation, so the affected person is heterozygous for the mutation. If the functional copy is harmed, however, then the cell is forced to use alternate DNA repair mechanisms, which are more error-prone. The loss of the functional copy is called loss of heterozygosity (LOH). Any resulting errors in DNA repair may result in cell death or a cancerous transformation of the cell. There are many variations in BRCA genes, and not all changes confer the same risks. Some variants are harmless; others are known to be very harmful. Some single nucleotide polymorphisms may confer only a small risk, or may only confer risk in the presence of other mutations or under certain circumstances. In other cases, whether the variant is harmful is unknown. Variants are classified as follows: • Deleterious mutation: The change is proven to cause significant risks. Often, these are frameshift mutations that prevent the cell from producing more than the first part of the necessary protein. • Suspected deleterious: While nothing is proven, the variation is currently believed to be harmful. • Variant of uncertain significance (VUS): Whether the change has any effect is uncertain. This is a common test result, and most variations began in this category. As more evidence is acquired, these are re-classified. • Variant, favour polymorphism: While nothing is proven, the variation is currently believed to be harmless. • Benign polymorphism: The change is classified as harmless. These may be reported as “no mutation”. Deleterious mutations have high, but not complete, genetic penetrance, which means that people with the mutation have a high risk of developing disease as a result, but that some people will not develop cancer despite carrying a harmful mutation.

Fig. BRCA mutations are inherited in a genetically dominant fashion, from either parent.

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GETTING TESTED

Indications Genetic counseling is commonly recommended to people whose personal or family health history suggests a greater than average likelihood of a mutation. Genetic counselors are allied health professionals who are trained to explain genetics to people; some of them are also licensed as registered nurses or social workers. A medical geneticist is a physician who specializes in genetics. The purpose of genetic counseling is to educate the person about the likelihood of a positive result, the risks and benefits of being tested, the limitations of the tests, the practical meaning of the results, and the risk-reducing actions that could be taken if the results are positive. They are also trained to support people through any emotional reactions and to be a neutral person who helps the client make his or her own decision in an informed consent model, without pushing the client to do what the counselor might do. Because the knowledge of a mutation can produce substantial anxiety, some people choose not to be tested or to postpone testing until a later date. Relative indications for testing for a mutation in BRCA1 or BRCA2 for newly diagnosed or family members include a family history among 1st (FDR), 2nd (SDR), or 3rd(TDR) degree relatives usually on the same side of the family but not limited: • A known mutation (BRCA1 or BRCA2) in a cancer susceptibility gene within the family • Women affected with any Breast cancer diagnosed under the age of 30 • Women affected with triple negative breast cancer (TNBC) (estrogen receptor negative, progesterone receptor negative, and HER2/neu negative) under the age of 50 • Two relatives (FDR/SDR) diagnosed under the age of 45 • Three relatives (FDR/SDR) diagnosed with average age of 50 or less • Four relatives at any ages • Ovarian cancer with either an additional diagnosed relative or a relative with male breast cancer • A single family member with both breast and ovarian cancer • Male breast cancer • Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the family • Ashkenazi Jewish or Polish ancestry with one FDR family member affected by breast or ovarian cancer at any age Testing young children is considered medically unethical because the test results would not change the way the child’s health is cared for.

Test Procedure If the person chooses to be tested, then two types of tests are available. Both commonly use a blood sample, although testing can be done on saliva. The quickest, simplest, and lowest cost test uses positive test results from a blood relative and checks only for the single mutation that is known to be present in the family. If no relative has previously disclosed positive test results, then a full test that checks the entire sequence of both BRCA1 and BRCA2 can be performed. In some cases, because of the founder effect, Jewish ethnicity can be used to narrow the testing to quickly check for the three most common mutations seen among Ashkenazi Jews. Testing is commonly covered by health insurance and public health care programmes for people at high risk for having a mutation, and not covered for people at low risk. The purpose of limiting the testing to high-risk people is to increase the likelihood that the person will receive a meaningful, actionable result from the test, rather than identifying a variant of unknown significance (VUS). In Canada, people who demonstrate their

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high-risk status by meeting specified guidelines are referred initially to a specialized programme for hereditary cancers, and, if they choose to be tested, the cost of the test is fully covered. In the USA in 2010, single-site testing had a retail cost of US$400 to $500, and full-length analysis cost about $3,000 per gene, and the costs were commonly covered by private health insurance for people deemed to be at high risk. The test is ordered by a physician, usually an oncologist, and the results are always returned to the physician, rather than directly to the patient. How quickly results are returned depends on the test—single-site analysis requires less lab time— and on the infrastructure in place. In the USA, test results are commonly returned within one to several weeks; in Canada, patients commonly wait for eight to ten months for test results.

Test Interpretation A positive test result for a known deleterious mutation is proof of a predisposition, although it does not guarantee that the person will develop any type of cancer. A negative test result, if a specific mutation is known to be present in the family, shows that the person does not have a BRCA-related predisposition for cancer, although it does not guarantee that the person will not develop a non-hereditary case of cancer. By itself, a negative test result does not mean that the patient has no hereditary predisposition for breast or ovarian cancer. The family may have some other genetic predisposition for cancer, involving some other gene.

BREAST AND OVARIAN CANCER RISK Women with deleterious mutations in either the BRCA1 or BRCA2 genes have a high risk of developing breast and/or ovarian cancer. Because different studies look at different populations, and because different types of mutations have somewhat different risks, the risk is best expressed as a range, rather than a single number. Approximately 50% to 65% of women born with a deleterious mutation in BRCA1 will develop breast cancer by age 70, and 35% to 46% will develop ovarian cancer by age 70. Approximately 40% to 57% of women with a deleterious mutation in BRCA2 will develop breast cancer by age 70, and 13% to 23% will develop ovarian cancer by age 70. Women with a breast cancer associated with a BRCA mutation have up to a 40% probability of developing a new primary breast cancer within 10 years following initial diagnosis if they did not receive tamoxifen treatment or have an oophorectomy. The woman’s ten-year risk for ovarian cancer is also increased by 6-12% under these conditions. Statistics for BRCA-related ovarian cancer typically encompass not only cancer of the ovaries themselves, but also peritoneal cancer and the very rare, but somewhat easier to detect, cancer of the Fallopian tubes. Women with a BRCA mutation have more than 100 times the normal rate of Fallopian tube cancer. These three types of these cancers can be difficult to distinguish in their advanced stages.

When Cancer Appears BRCA-related breast cancer appears at an earlier age than sporadic breast cancer. It has been asserted that BRCA-related breast cancer is more aggressive than normal breast cancer, however most studies in specific populations suggest little or no difference in survival rates despite seemingly worse prognostic factors. • BRCA1 is associated with triple-negative breast cancer, which does not respond to hormonal treatments and cannot be usefully treated with some drugs, such as trastuzumab. Breast cancer often appears about two decades earlier than normal. • BRCA2 is associated primarily with post-menopausal breast cancer, although the risk of premenopausal breast cancer is significant. It is typically highly responsive to hormonal treatments. BRCA-related ovarian and Fallopian tube cancer is more treatable than average because it is unusually susceptible to platinum-based chemotherapy like cisplatin. BRCA1-related ovarian cancer appears at younger ages, but the risk for women with BRCA2 climbs markedly at or shortly after menopause.

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Survival Impact Likelihood of a 25-year-old woman surviving to age 70 (without screening or medical interventions to prevent cancer) Group BRCA1 mutation BRCA2 mutation Typical woman

Percentage surviving to age 70 53 71 84

A 25-year-old woman with no mutation in her BRCA genes has an 84% probability to reach at least the age of 70. Of those not surviving, 11% die from either breast or ovarian cancer, and 89% from other causes. Compared to that, a woman with a high-risk BRCA1 mutation, if she had breast cancer screening but no prophylactic medical or surgical intervention, would have only 59% chance to reach age 70, twenty-five percentage points lower than normal. Of those women not surviving, 26% would die of breast cancer, 46% ovarian cancer, and 28% other causes. Women with high-risk BRCA2 mutations, with screening but with no prophylactic medical or surgical intervention, would have only 71% chance to reach age 70, thirteen percentage points lower than normal. Of those not surviving, 21% would die of breast cancer, 25% ovarian cancer and 54% other causes. The likelihood of surviving to at least age 70 can be improved by several medical interventions, notably prophylactic mastectomy and oophorectomy.

Male Breast Cancer Men with a BRCA mutation have a dramatically elevated relative risk of developing breast cancer, but because the overall incidence of breast cancer in men is so low, the absolute risk is equal to or lower than the risk for women without a BRCA mutation. Approximately 1% to 2% of men with a BRCA1 mutation will develop breast cancer by age 70. Approximately 6% of men with a BRCA2 mutation will develop breast cancer by age 70, which is approximately equal to the risk for women without a BRCA mutation. Very few men, with or without a predisposing mutation, develop breast cancer before age 50. Approximately half of men who develop breast cancer have a mutation in a BRCA gene or in one of the other genes associated with hereditary breast–ovarian cancer syndromes. Breast cancer in men can be treated as successfully as breast cancer in women, but men often ignore the signs and symptoms of cancer, such as a painful area or an unusual swelling, which may be no bigger than a grain of rice, until it has reached a late stage. Unlike other men, men with a BRCA mutation, especially a BRCA2 mutation, may benefit from professional and self breast exams. Medical imaging is not usually recommended, but because male BRCA2 carriers have a risk of breast cancer that is very similar to the general female population, the standard annual mammogram programme can be adapted to these high-risk men.

CANCER DETECTION AND PREVENTION STRATEGIES A variety of screening options and interventions are available to manage BRCA-related cancer risks. Screenings are adjusted to individual and familial risk factors. As these screening methods do not prevent cancer, but merely attempt to catch it early, numerous methods of prevention are sometimes practiced, with varying results.

Screening An intensive cancer screening regimen is usually advised for women with deleterious or suspected deleterious BRCA mutations in order to detect new cancers as early as possible. A typical recommendation includes frequent breast cancer screening as well as tests to detect ovarian cancer. Breast imaging studies usually include a breast MRI (magnetic resonance imaging) once a year, beginning between ages 20 and 30, depending on the age at which any relatives were diagnosed with breast cancer. Mammograms are typically used only at advanced age

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as there is reason to believe that BRCA carriers are more susceptible to breast cancer induction by X-ray damage than general population. Alternatives include breast ultrasonography, CT scans, PET scans, scintimammography, elastography, thermography, ductal lavage, and experimental screening protocols, some of which hope to identify biomarkers for breast cancer (molecules that appear in the blood when breast cancer begins). Ovarian cancer screening usually involves ultrasonography of the pelvic region, typically twice a year. Women may also use a blood test for CA-125 and clinical pelvic exams. The blood test has relatively poor sensitivity and specificity for ovarian cancer. In both breast and ovarian screening, areas of tissue that look suspicious are investigated with either more imaging, possibly using a different type of imaging or after a delay, or with biopsies of the suspicious areas.

Prophylactic Medication Oral contraceptives is associated with substantially lower risk of ovarian cancer in women with BRCA mutations. A 2013 meta-analysis found that oral contraceptive use was associated with a 42% reduction of the relative risk of ovarian cancer, the association was similar for BRCA1 and BRCA2 mutations. Use of oral contraceptives was not significantly associated with breast cancer risk although a small increase of risk that did not reach statistical significance was observed. A 2011 meta-analysis found that OC use was associated with a 43% relative reduction in risk of ovarian cancer in women with BRCA mutations, while data on the risk of breast cancer in BRCA mutation carriers with oral contraceptive use were heterogeneous and results were inconsistent. Selective estrogen receptor modulators, specifically tamoxifen, have been found to reduce breast cancer risk in women with BRCA mutations who do not have their breast removed. It is effective as for primary prevention (preventing the first case of breast cancer) in women with BRCA2 mutations, but not BRCA1 mutations, and for secondary prevention (preventing a second, independent breast cancer) in both groups of women. Taking tamoxifen for five years has been found to halve the breast cancer risk in women who have a high risk of breast cancer for any reason, but potentially serious adverse effects like cataracts, blood clots, and endometrial cancer, along with quality of life issues like hot flashes, result in some women discontinuing its use and some physicians limiting its use to women with atypical growths in the breasts. Tamoxifen is contraindicated for women who are most likely to be harmed by the common complications. Raloxifene (Evista), which has a reduced risk of side effects, is used as an alternative, but it has not been studied in BRCA mutation carriers specifically. Tamoxifen use can be combined with oophorectomy for even greater reduction of breast cancer risk, particularly in women with BRCA2 mutations. Aromatase inhibitors are medications that prevent estrogen production in the adrenal glands and adipose tissue. They have fewer side effects than selective estrogen receptor modulators like tamoxifen, but do not work in premenopausal women, because they do not prevent the ovaries from producing estrogen.

Prophylactic Surgery Several type of preventive surgeries are known to substantially reduce cancer risk for women with high-risk BRCA mutations. The surgeries may be used alone, in combination with each other, or in combination with nonsurgical interventions to reduce the risk of breast and ovarian cancer. Note that surgeries such as mastectomy and oophorectomy do not completely eliminate the chance of breast cancer; cases have reportedly emerged despite these procedures. • Tubal ligation is the least invasive of these surgeries and appears to reduce ovarian cancer risk for BRCA1 carriers by over 60%. Salpingectomy is another option which is more invasive than tubal ligation and may result in additional risk reduction. Both of these can be performed anytime after childbearing is complete. Unlike other prophylactic surgeries, these two surgeries do not reduce the risk of breast cancer.

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•

Prophylactic (preventive) mastectomy is associated with small risks and a large drop in breast cancer risk. • Prophylactic salpingo-oophorectomy (removal of the ovaries and Fallopian tubes) results in a very large reduction in ovarian cancer risk, and a large reduction in breast cancer risk if performed before natural menopause. However, it also comes with the risk of substantial adverse effects if performed at a young age. • Hysterectomy has no direct effect on BRCA-related cancers, but it enables the women to use some medications that reduce breast cancer risk (such as tamoxifen) with the risk of uterine cancer and to use fewer hormones to manage the adverse effects of a prophylactic oophorectomy. Whether and when to perform which preventive surgeries is a complex personal decision. Current medical knowledge offers some guidance about the risks and benefits. Even carriers of the same mutation or from the same family may have substantially different risks for the kind and severity of cancer they are likely to get, as well as the age at which they may get them. Different people also have different values. They may choose to focus on total cancer prevention, psychological benefits, current quality of life, or overall survival. The possible impact of future medical developments in treatment or prognosis may also be of some importance for very young women and family planning. The decision is individualized and is usually based on many factors, such as earliest occurrence of BRCA-related cancer in close relatives. The protective effect of prophylactic surgery is greater when done at young age; however, oophorectomy also has adverse effects that are greatest when done long before natural menopause. For this reason, oophorectomy is mostly recommended after age 35 or 40, assuming childbearing is complete. The risk of ovarian cancer is low before this age, and the negative effects of oophorectomy are less serious as the woman nears natural menopause. • For carriers of high-risk BRCA1 mutations, prophylactic oophorectomy around age 40 reduces the risk of ovarian and breast cancer and provides a substantial long-term survival advantage. Having this surgery at a very young age provides little or no additional survival advantage, but it does increase the adverse effects from the surgery. Compared to no intervention, having this surgery around age 40 increases the woman’s chance of reaching age 70 by fifteen percentage points, from 59% to 74%. Adding prophylactic mastectomy increases the expected survival by several more percentage points. • For carriers of high-risk BRCA2 mutations, oophorectomy around age 40 has a smaller effect. The surgery increases the woman’s chance of reaching age 70 by only five percentage points, from 75% to 80%. When only preventive mastectomy is done at age 40 instead, the improvement is similar, with the expected chance rising from 75% to 79%. Doing both surgeries together around age 40 is expected to improve the woman’s chance of reaching age 70 from 75% to 82% For comparison, women in the general population have an 84% chance of living to age 70.

Prophylactic Mastectomy In a woman who has not developed breast cancer, removing the breasts may reduce her risk of ever being diagnosed with breast cancer by 90%, to a level that is approximately half the average woman’s risk. Bilateral mastectomy is the removal of both breasts by a breast surgeon. The modified radical mastectomy is only used in women diagnosed with invasive breast cancer. Techniques for prophylactic mastectomies include: • Simple mastectomy, which is recommended for women not having breast reconstruction, leaves the least amount of breast tissue in the body and therefore achieves the greatest risk reduction. In addition to prophylactic use, it is also used by women who have been diagnosed with earlier stages of cancer.

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•

Skin-sparing mastectomy removes the tissue of the breast, nipple, and areola, but leave the “excess” skin in place for reconstruction. It has less visible scar tissue than a simple mastectomy. • Nipple-sparing mastectomy removes the breast tissue, but leaves the nipple and the areola intact for a more natural appearance. • Subcutaneous mastectomy removes the breast tissue, but leaves the nipple and areola intact. The scars are hidden in the inframammary fold under the breast. • Areola-sparing mastectomy removes the breast tissue and the nipple, but not the areola. • Nerve-sparing mastectomy is an effort to maintain the nerves that provide sensation to the skin over the breasts. Breasts that have undergone any of these surgeries have much less tactile sensation than natural breasts. Nerve-sparing techniques are an effort to retain some feeling in the breasts, with limited and often only partial success. Which technique is used is determined by the existence of any cancer and overall health, as well as by the woman’s desire, if any, for breast reconstruction surgery for aesthetic purposes. Women who choose a flatchested appearance or use external breast prostheses typically choose simple mastectomy, with its greater risk reduction. Breast reconstruction is usually done by a plastic surgeon, and may be started as part of the same multi-hour surgery that removes the breasts. Multiple techniques for reconstruction have been used, with different locations and amounts of scarring. Some techniques use tissue from another part of the body, such as fat tissue from the lower abdomen or occasionally muscles from other parts of the torso. Others use breast implants, possibly preceded by tissue expanders, to provide volume. Some reconstruction techniques require multiple surgeries. Afterwards, some women have tattoos added to simulate breast areolas or have the skin reshaped to form a nipple.

Prophylactic Salpingo-oophorectomy Oophorectomy (surgical removal of the ovaries) and salpingectomy (surgical removal of the Fallopian tubes) are strongly recommended to women with BRCA mutations. Salpingo-oophorectomy is the single most effective method of preventing ovarian and Fallopian tube cancer in women with a BRCA mutation. However, a small risk of primary peritoneal cancer remains, at least among women with BRCA1 mutations, since the peritoneal lining is the same type of cells as parts of the ovary. This risk is estimated to produce about five cases of peritoneal cancer per 100 women with harmful BRCA1 mutations in the 20 years after the surgery. BRCA2 related ovarian cancer tends to present in perimenopausal or menopausal women, so salpingo-oophorectomy is recommended between ages 45 and 50. If it is done before menopause, then the women also benefit from a reduced risk of breast cancer. The surgery is often done in conjunction with a hysterectomy (surgical removal of the uterus) and sometimes a cervicectomy (surgical removal of the cervix), especially in women who want to take tamoxifen, which is known to cause uterine cancer, or who have uterine fibroids. Multiple styles of surgery are available, including laparoscopic (keyhole) surgery. Because about 5% of women with a BRCA mutation have undetected ovarian cancer at the time of their planned surgery, the surgery should be treated as if it were a removal of a known cancer. Salpingo-oophorectomy makes the woman sterile (unable to bear children). Infertility services can be used to preserve her eggs, if wanted. However, as the benefits to the surgery are greatest close to menopause, most women simply postpone the surgery until they have already borne as many children as they choose to. The surgery also artificially induces menopause, which causes hot flashes, sleep disturbances, mood swings, vaginal dryness, sexual difficulties, difficulty with word recall, and other medical signs and symptoms. The side effects range from mild to severe; most can be treated at least partially. Many women with a BRCA take hormone replacement therapy to reduce these effects: estrogen-progesterone combinations for women who have a uterus, and unopposed estrogen for women whose uterus was removed. Estrogen can cause breast cancer, but as the amount of estrogen taken is less than the amount produced by the

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now-removed ovaries, the net risk is usually judged to be acceptable. Some sources assume that oophorectomy before age 50 doubles the risk of cardiovascular disease and increases risk of hip fractures caused by osteoporosis in the relevant population.

Non-medical Choices Given the high risks and the low benefit of lifestyle choices in BRCA mutation carriers, no lifestyle choices provide sufficient protection. Having her first child at a younger age, having more children than average, and breastfeeding for more than one year decreases the risk of breast cancer for an average-risk woman. Studies about this effect among BRCA mutation carriers have produced conflicting results, but generally speaking, having children is believed to provide little or no protection against breast cancer for women with BRCA1 mutations, and to paradoxically increase the risk of breast cancer for women with BRCA2 mutations. Being physically active and maintaining a healthy body weight prevents breast and other cancers in the general population, as well as preventing heart disease and other medical conditions. Among women with a BRCA mutation, being physically active and having had a healthy body weight as an adolescent has no effect on ovarian cancer and delays, but does not entirely prevent, breast cancer after menopause. In some studies, only significant, strenuous exercise produced any benefit. Obesity and weight gain as an adult are associated with breast cancer diagnoses. Studies on specific foods, diets, or dietary supplements have generally produced conflicting information or, in the case of dietary fat, soy consumption, and drinking green tea, have only been conducted in average-risk women. The only dietary intervention that is generally accepted as preventing breast cancer in BRCA mutation carriers is minimizing consumption of alcoholic beverages. Consuming more than one alcoholic drink per day is strongly associated with a higher risk of developing breast cancer, and carriers are usually encouraged to consume no more than one alcoholic drink per day, and no more than four total in a week. In a study conducted with Ashkenazi Jewish women, it was observed that mutation carriers born before 1940 have a much lower risk of being diagnosed with breast cancer by age 50 than those born after 1940; this was also observed in the non-carrier population. The reasons for the difference is unknown. Unlike the general population, age at menarche and age at menopause has no effect on breast cancer risk for BRCA mutation carriers.

OTHER CANCERS Mutations have been associated with increased risk of developing any kind of invasive cancer, including stomach cancer, pancreatic cancer, prostate cancer, and colon cancer. Carriers have the normal risks of developing cancer (and other diseases) associated with increased age, smoking, alcohol consumption, poor diet, lack of exercise, and other known risk factors, plus the additional risk from the genetic mutations and an increased susceptibility to damage from ionizing radiation, including natural background radiation. Men with BRCA mutations cannot get ovarian cancer, but they may be twice as likely as non-carriers to develop prostate cancer at a younger age. The risk is smaller and disputed for BRCA1 carriers; up to one-third of BRCA2 mutation carriers are expected to develop prostate cancer before age 65. Prostate cancer in BRCA mutation carriers tends to appear a decade earlier than normal, and it tends to be more aggressive than normal. As a result, annual prostate screening, including a digital rectal examination, is appropriate at age 40 among known carriers, rather than age 50. Cancer of the pancreas tends to run in families, even among BRCA families. A BRCA1 mutation approximately doubles or triples the lifetime risk of developing pancreatic cancer; a BRCA2 mutation triples to quintuples it. Between 4% and 7% of people with pancreatic cancer have a BRCA mutation. However, since pancreatic cancer is relatively rare, people with a BRCA2 mutation probably face an absolute risk of about 5%. Like ovarian cancer, it tends not to produce symptoms in the early, treatable stages.

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Like prostate cancer, pancreatic cancer associated with a BRCA mutation tends to appear about a decade earlier than non-hereditary cases. Asymptomatic screening is invasive and may be recommended only to BRCA2 carriers who also have a family history of pancreatic cancer. Melanoma is the most deadly skin cancer, although it is easily cured in the early stages. The normal likelihood of developing melanoma depends on race, the number of moles the person has, family history, age, sex, and how much the person has been exposed to UV radiation. BRCA2 mutation carriers have approximately double or triple the risk that they would normally have, including a higher than average risk of melanoma of the eye. Cancer of the colon is approximately as common in both men and women in the developed world as breast cancer is among average-risk women, with about 6% of people being diagnosed with it, usually over the age of 50. Like sporadic prostate cancer, it is a multifactorial disease, and is affected by age, diet, and similar factors. BRCA mutation carriers have a higher than average risk of this common cancer, but the risk is not as high as in some other hereditary cancers. The risk might be as high as four times normal in some BRCA1 families, and double the normal risk among BRCA2 carriers. Like pancreatic cancer, it may be that only some BRCA mutations or some BRCA families have the extra risk; unlike other BRCA-caused cancers, it does not appear at an earlier age than usual. Normal colon cancer screening is usually recommended to BRCA mutation carriers. Mutations in BRCA1 and BRCA2 are strongly implicated in some hematological malignancies. BRCA1 mutations are associated acute myelogenous leukemia and chronic myelogenous leukemia. Mutations of BRCA2 are also found in many T-cell lymphomas and chronic lymphocytic leukemias.

CHILDBEARING AND FERTILITY EFFECTS The dilemma of whether or not to have children is a significant source of stress for women who learn of their BRCA mutations during their childbearing years. There is likely little or no effect of a BRCA gene mutation on overall fertility, although women with a BRCA mutation may be more likely to have primary ovarian insufficiency. BRCA mutation carriers may be more likely to give birth to girls than boys, however this observation has been attributed to ascertainment bias. If both parents are carriers of a BRCA mutation, then pre-implantation genetic diagnosis is sometimes used to prevent the birth of a child with BRCA mutations. Inheriting two BRCA1 mutations (one from each parent) has never been reported and is believed to be a lethal birth defect. Inheriting one BRCA1 mutation and one BRCA2 mutation has been reported occasionally; the child’s risk for any given type of cancer is the higher risk of the two genes (e.g., the ovarian cancer risk from BRCA1 and the pancreatic cancer risk from BRCA2). Inheriting two BRCA2 mutations produces Fanconi anemia. Each pregnancy in genetically typical women is associated with a significant reduction in the mother’s risk of developing breast cancer after age 40. The younger the woman is at the time of her first birth, the more protection against breast cancer she receives. Breastfeeding for more than one year protects against breast cancer. Pregnancy also protects against ovarian cancer in genetically typical women. Although some studies have produced different results, women with BRCA mutations are generally not expected to receive these significant protective benefits. Current research is too limited and imprecise to permit calculation of specific risks. However, the following general trends have been identified: • For women with a BRCA1 mutation, the woman’s age when she first gives birth has no association with her risk of breast cancer. Childbearing provides no protection against breast cancer, unless the woman has five or more full-term pregnancies, at which point she receives only modest protection. Similar to genetically typical women, pregnancy protects against ovarian cancer in BRCA1 women. Breastfeeding for more than one year significantly protects against breast cancer. This effect may be as high as 19% per year of breastfeeding, which is much higher than that seen among genetically typical women. The effect, if any, of long-term breastfeeding on ovarian cancer is unclear.

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For women with a BRCA2 mutation, each pregnancy is paradoxically associated with a statistically significant increase in the risk for breast cancer. Unlike genetically typical women or women with BRCA1 mutations, breastfeeding has no effect on either cancer in women with BRCA2 mutations. Limited and conflicting data suggest that, also unlike other women, pregnancy does not reduce ovarian cancer risk significantly in women with a BRCA2 mutation and might increase it.

EVOLUTIONARY ADVANTAGE Several hypotheses propose that BRCA mutations might have evolutionary advantages, such as higher intelligence. The Ashkenazi intelligence hypothesis was proposed by Gregory Cochran and asserts that a defect in the BRCA1 gene might unleash neural growth. Studies have shown that BRCA1 mutations are not random, but under adaptive selection, indicating that although BRCA1 mutations are linked to breast cancer, the mutations likely have a beneficial effect as well.

PATENT ENFORCEMENT AND LITIGATION A patent application for the isolated BRCA1 gene and cancer-cancer promoting mutations discussed above, as well as methods to diagnose the likelihood of getting breast cancer, was filed by the University of Utah, National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics in 1994; over the next year, Myriad, in collaboration with investigators from Endo Recherche, Inc., HSC Research and Development Limited Partnership, and University of Pennsylvania, isolated and sequenced the BRCA2 gene and identified key mutations, and the first BRCA2 patent was filed in the U.S. by Myriad and other institutions in 1995. Myriad is the exclusive licensee of these patents and has enforced them in the US against clinical diagnostic labs. This business model led to Myriad growing being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012; it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit. The patents begin to expire in 2014. According to an article published in the journal, Genetic Medicine, in 2010, “The patent story outside the United States is more complicated.... For example, patents have been obtained but the patents are being ignored by provincial health systems in Canada. In Australia and the UK, Myriad’s licensee permitted use by health systems, but announced a change of plans in August 2008.... Only a single mutation has been patented in Myriad’s lone European-wide patent, although some patents remain under review of an opposition proceeding. In effect, the United States is the only jurisdiction where Myriad’s strong patent position has conferred sole-provider status.” Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has “other competitive advantages that may make such [patent] enforcement unnecessary” in Europe. Legal decisions surrounding the BRCA1 and BRCA2 patents will affect the field of genetic testing in general. In June 2013, in Association for Molecular Pathology v. Myriad Genetics (No. 12-398), the US Supreme Court unanimously ruled that, “A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated,” invalidating Myriad’s patents on the BRCA1 and BRCA2 genes. However, the Court also held that manipulation of a gene to create something not found in nature could still be eligible for patent protection.

Breast Cancer During Pregnancy Most breast cancers in pregnant women are found during a clinical breast exam. Pregnant women may get a clinical breast exam as part of their prenatal care. Screening mammography isn’t used in pregnant women because the radiation may harm the fetus. And, younger women (under age 40) usually don’t get screening mammography. If a lump is found during the first trimester, tests such as breast ultrasound (rather than

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mammography) are used to check for breast cancer. After the first trimester, a pregnant woman may have a diagnostic mammogram with a shield covering her abdomen to protect the fetus. Breast cancer can be hard to detect in pregnant women. The increased size and change in the texture of the breasts during pregnancy can make smaller cancers hard to feel. So, breast cancers in pregnant women may be diagnosed at a more advanced stage than in non-pregnant women.

TREATMENT • • •

There are special treatment concerns for pregnant women who have breast cancer. Although cancer itself does not seem to affect the fetus, some breast cancer treatments can be harmful. Your treatment plan and the timing of your treatments are chosen to treat your cancer as well as protect the fetus.

SURGERY AND RADIATION THERAPY Breast cancer surgery is safe during pregnancy. Although the anesthesia used during surgery can cross the placenta to the fetus, it doesn’t appear to cause birth defects or serious pregnancy problems. Breast reconstruction, however, should be delayed until after the baby is born to avoid further anesthesia and the chance of blood loss. Mastectomy (instead of lumpectomy) is usually recommended for pregnant women who are in their first trimester and want to continue their pregnancy. Radiation therapy is needed after a lumpectomy and radiation can harm the fetus. However, some women in their second or third trimester may consider lumpectomy. In these cases, radiation therapy is delayed until after the baby is born. This delay does not affect prognosis. Some women in their second or third trimester may have chemotherapy before surgery (neo-adjuvant chemotherapy).

CHEMOTHERAPY Chemotherapy is not given during the first trimester, since this is the time when the chances for drug-related birth defects and miscarriage are greatest. During the second and third trimesters, some chemotherapy drugs can be used safely. However, chemotherapy should not be given after week 35 of pregnancy or within 3 weeks of the due date (or planned delivery date). This gives a woman time to recover from chemotherapy before delivery. Many women diagnosed in their third trimester often wait and have chemotherapy after giving birth.

HORMONE THERAPY AND TARGETED THERAPY Hormone therapies (such as tamoxifen and aromatase inhibitors) and targeted therapies (such as trastuzumab (Herceptin)) are not used at any point during pregnancy because of risks to the fetus.

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Chapter 3

Gastrointestinal ESOPHA GEAL C ANCER ESOPHAGEAL CANCER Esophageal cancer is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include difficulty in swallowing and weight loss. Other symptoms may include pain when swallowing, a hoarse voice, enlarged lymph nodes (“glands”) around the collarbone, a dry cough, and possibly coughing up or vomiting blood. The two main sub-types of the disease are esophageal squamous-cell carcinoma (often abbreviated to ESCC), which is more common in the developing world, and esophageal adenocarcinoma (EAC), which is more common in the developed world. A number of less common types also occur. Squamous-cell carcinoma arises from the epithelial cells that line the esophagus. Adenocarcinoma arises from glandular cells present in the lower third of the esophagus, often where they have already transformed to intestinal cell type (a condition known as Barrett’s esophagus). Causes of the squamous-cell type include tobacco, alcohol, very hot drinks, poor diet, and chewing betel nut. The most common causes of the adenocarcinoma type are smoking tobacco, obesity, and acid reflux. The disease is diagnosed by biopsy done by an endoscope (a fibreoptic camera). Prevention includes stopping smoking and eating a healthy diet. Treatment is based on the cancer’s stage and location, together with the person’s general condition and individual preferences. Small localized squamouscell cancers may be treated with surgery alone with the hope of a cure. In most other cases, chemotherapy with or without radiation therapy is used along with surgery. Larger tumors may have their growth slowed with chemotherapy and radiation therapy. In the presence of extensive disease or if the affected person is not fit enough to undergo surgery, palliative care is often recommended. As of 2012, esophageal cancer was the eighthmost common cancer globally with 456,000 new cases during the year. It caused about 400,000 deaths that year, up from 345,000 in 1990. Rates vary widely among countries, with about half of all cases occurring in China. It is around three times more common in men than in women. Outcomes are related to the extent of the disease and other medical conditions, but generally tend to be fairly poor, as diagnosis is often late. Five-year survival rates are around 13% to 18%.

SIGNS AND SYMPTOMS Prominent symptoms usually do not appear until the cancer has infiltrated over 60% of the circumference of the esophageal tube, by which time the tumor is already in an advanced stage. Onset of symptoms is usually caused by narrowing of the tube due to the physical presence of the tumor. The first and the most common symptom is usually difficulty in swallowing, which is often experienced first with solid foods and later with softer foods and liquids. Pain when swallowing is less usual at first. Weight loss is often an initial symptom in cases of squamous-cell carcinoma, though not usually in cases of adenocarcinoma. Eventual weight loss due to

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reduced appetite and undernutrition is common. Pain behind the breastbone or in the region around the stomach often feels like heartburn. The pain can frequently be severe, worsening when food of any sort is swallowed. Another sign may be an unusually husky, raspy, or hoarse-sounding cough, a result of the tumor affecting the recurrent laryngeal nerve. The presence of the tumor may disrupt the normal contractions of the esophagus when swallowing. This can lead to nausea and vomiting, regurgitation of food and coughing. There is also an increased risk of aspiration pneumonia due to food entering the airways through the abnormal connections (fistulas) that may develop between the esophagus and the trachea (windpipe). Early signs of this serious complication may be coughing on drinking or eating. The tumor surface may be fragile and bleed, causing vomiting of blood. Compression of local structures occurs in advanced disease, leading to such problems as upper airway obstruction and superior vena cava syndrome. Hypercalcemia (excess calcium in the blood) may occur. If the cancer has spread elsewhere, symptoms related to metastatic disease may appear. Common sites of spread include nearby lymph nodes, the liver, lungs and bone. Liver metastasis can cause jaundice and abdominal swelling (ascites). Lung metastasis can cause, among other symptoms, impaired breathing due to excess fluid around the lungs (pleural effusion), and dyspnea (the feelings often associated with impaired breathing).

Fig. Endoscopic image of an esophageal adenocarcinoma

CAUSES The two main types (i.e. squamous-cell carcinoma and adenocarcinoma) have distinct sets of risk factors. Squamous-cell carcinoma is linked to lifestyle factors such as smoking and alcohol. Adenocarcinoma has been linked to effects of long-term acid reflux. Tobacco is a risk factor for both types. Both types are more common in people over 60 years of age.

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Squamous-cell Carcinoma The two major risk factors for esophageal squamous-cell carcinoma are tobacco (smoking or chewing) and alcohol. The combination of tobacco and alcohol has a strong synergistic effect. Some data suggest that about half of all cases are due to tobacco and about one-third to alcohol, while over three-quarters of the cases in men are due to the combination of smoking and heavy drinking. Risks associated with alcohol appear to be linked to its aldehyde metabolite and to mutations in certain related enzymes. Such metabolic variants are relatively common in Asia. Other relevant risk factors include regular consumption of very hot drinks (over 65 °C or 149 °F) and ingestion of caustic substances. High levels of dietary exposure to nitrosamines (chemical compounds found both in tobacco smoke and certain foodstuffs) also appear to be a relevant risk factor. Unfavourable dietary patterns seem to involve exposure to nitrosamines through processed and barbecued meats, pickled vegetables, etc., and a low intake of fresh foods. Other associated factors include nutritional deficiencies, low socioeconomic status, and poor oral hygiene. Chewing betel nut (areca) is an important risk factor in Asia. Physical trauma may increase the risk. This may include the drinking of very hot drinks.

Adenocarcinoma Male predominance is particularly strong in this type of esophageal cancer, which occurs about 7 to 10 times more frequently in men. This imbalance may be related to the characteristics and interactions of other known risk factors, including acid reflux and obesity. The long-term erosive effects of acid reflux (an extremely common condition, also known as gastroesophageal reflux disease or GERD) have been strongly linked to this type of cancer. Longstanding GERD can induce a change of cell type in the lower portion of the esophagus in response to erosion of its squamous lining. This phenomenon, known as Barrett’s esophagus, seems to appear about 20 years later in women than in men, maybe due to hormonal factors. Having symptomatic GERD or bile reflux makes Barrett’s esophagus more likely, which in turn raises the risk of further changes that can ultimately lead to adenocarcinoma. The risk of developing adenocarcinoma in the presence of Barrett’s esophagus is unclear, and may in the past have been overestimated. Being obese or overweight both appear to be associated with increased risk. The association with obesity seems to be the strongest of any type of obesity-related cancer, though the reasons for this remain unclear. Abdominal obesity seems to be of particular relevance, given the closeness of its association with this type of cancer, as well as with both GERD and Barrett’s esophagus. This type of obesity is characteristic of men. Physiologically, it stimulates GERD and also has other chronic inflammatory effects. Helicobacter pylori infection (a common occurrence thought to have affected over half of the world’s population) is not a risk factor for esophageal adenocarcinoma and actually appears to be protective. Despite being a cause of GERD and a risk factor for gastric cancer, the infection seems to be associated with a reduced risk of esophageal adenocarcinoma of as much as 50%. The biological explanation for a protective effect is somewhat unclear. One explanation is that some strains of H. pylori reduce stomach acid, thereby reducing damage by GERD. Decreasing rates of H. pylori infection in Western populations over recent decades, which have been linked to better hygiene and increased refrigeration of food, could be a factor in the concurrent increase in esophageal adenocarcinoma. Female hormones may also have a protective effect, as EAC is not only much less common in women but develops later in life, by an average of 20 years. Although studies of many reproductive factors have not produced a clear picture, risk seems to decline for the mother in line with prolonged periods of breastfeeding. Tobacco smoking increases risk, but the effect in esophageal adenocarcinoma is slight compared to that in squamous cell carcinoma, and alcohol has not been demonstrated to be a cause.

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Fig. Esophageal cancer (lower part) as a result of Barrettˆs esophagus

Related Conditions •

• • •

•

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Head and neck cancer is associated with second primary tumors in the region, including esophageal squamous-cell carcinomas, due to field cancerization (i.e. a regional reaction to long-term carcinogenic exposure). History of radiation therapy for other conditions in the chest is a risk factor for esophageal adenocarcinoma. Corrosive injury to the esophagus by accidentally or intentionally swallowing caustic substances is a risk factor for squamous cell carcinoma. Tylosis with esophageal cancer is a rare familial disease with autosomal dominant inheritance that has been linked to a mutation in the RHBDF2 gene, present on chromosome 17: it involves thickening of the skin of the palms and soles and a high lifetime risk of squamous cell carcinoma. Achalasia (i.e. lack of the involuntary reflex in the esophagus after swallowing) appears to be a risk factor for both main types of esophageal cancer, at least in men, due to stagnation of trapped food and drink. Plummer–Vinson syndrome (a rare disease that involves esophageal webs) is also a risk factor. There is some evidence suggesting a possible causal association between human papillomavirus (HPV) and esophageal squamous-cell carcinoma. The relationship is unclear. Possible relevance of HPV could be greater in places that have a particularly high incidence of this form of the disease, as in some Asian countries, including China.

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There is an association between celiac disease and esophageal cancer. People with untreated celiac disease have a higher risk, but this risk decreases with time after diagnosis, probably due to the adoption of a gluten-free diet, which seems to have a protective role against development of malignancy in people with celiac disease. However, the delay in diagnosis and initiation of a glutenfree diet seems to increase the risk of malignancy. Moreover, in some cases the detection of celiac disease is due to the development of cancer, whose early symptoms are similar to some that may appear in celiac disease.

DIAGNOSIS

Clinical Evaluation Although an occlusive tumor may be suspected on a barium swallow or barium meal, the diagnosis is best made with an examination using an endoscope. This involves the passing of a flexible tube with a light and camera down the esophagus and examining the wall, and is called an esophagogastroduodenoscopy. Biopsies taken of suspicious lesions are then examined histologically for signs of malignancy. Additional testing is needed to assess how much the cancer has spread. Computed tomography (CT) of the chest, abdomen and pelvis can evaluate whether the cancer has spread to adjacent tissues or distant organs (especially liver and lymph nodes). The sensitivity of a CT scan is limited by its ability to detect masses (e.g. enlarged lymph nodes or involved organs) generally larger than 1 cm. Positron emission tomography is also used to estimate the extent of the disease and is regarded as more precise than CT alone. Esophageal endoscopic ultrasound can provide staging information regarding the level of tumor invasion, and possible spread to regional lymph nodes. The location of the tumor is generally measured by the distance from the teeth. The esophagus (25 cm or 10 in long) is commonly divided into three parts for purposes of determining the location. Adenocarcinomas tend to occur nearer the stomach and squamous cell carcinomas nearer the throat, but either may arise anywhere in the esophagus.

Types Esophageal cancers are typically carcinomas that arise from the epithelium, or surface lining, of the esophagus. Most esophageal cancers fall into one of two classes: esophageal squamous-cell carcinomas (ESCC), which are similar to head and neck cancer in their appearance and association with tobacco and alcohol consumption— and esophageal adenocarcinomas (EAC), which are often associated with a history of GERD and Barrett’s esophagus. A rule of thumb is that a cancer in the upper two-thirds is likely to be ESCC and one in the lower one-third EAC. Rare histologic types of esophageal cancer include different variants of squamous-cell carcinoma, and non-epithelial tumors, such as leiomyosarcoma, malignant melanoma, rhabdomyosarcoma and lymphoma, among others.

Staging Staging is based on the TNM staging system, which classifies the amount of tumor invasion (T), involvement of lymph nodes (N), and distant metastasis (M). The currently preferred classification is the 2010 AJCC staging system for cancer of the esophagus and the esophagogastric junction. To help guide clinical decision making, this system also incorporates information on cell type (ESCC, EAC, etc.), grade (degree of differentiation – an indication of the biological aggressiveness of the cancer cells), and tumor location (upper, middle, lower, or junctional).

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PREVENTION Prevention includes stopping smoking or chewing tobacco. Overcoming addiction to areca chewing in Asia is another promising strategy for the prevention of esophageal squamous-cell carcinoma. The risk can also be reduced by maintaining a normal body weight. According to the National Cancer Institute, “diets high in cruciferous (cabbage, broccoli/broccolini, cauliflower, Brussels sprouts) and green and yellow vegetables and fruits are associated with a decreased risk of esophageal cancer.” Dietary fibre is thought to be protective, especially against esophageal adenocarcinoma. There is no evidence that vitamin supplements change the risk.

Screening People with Barrett’s esophagus (a change in the cells lining the lower esophagus) are at much higher risk, and may receive regular endoscopic screening for the early signs of cancer. Because the benefit of screening for adenocarcinoma in people without symptoms is unclear, it is not recommended in the United States. Some areas of the world with high rates of squamous-carcinoma have screening programmes.

MANAGEMENT Treatment is best managed by a multidisciplinary team covering the various specialties involved. Adequate nutrition must be assured, and appropriate dental care is essential. Factors that influence treatment decisions include the stage and cellular type of cancer (EAC, ESCC, and other types), along with the person’s general condition and any other diseases that are present. In general, treatment with a curative intention is restricted to localized disease, without distant metastasis: in such cases a combined approach that includes surgery may be considered. Disease that is widespread, metastatic or recurrent is managed palliatively: in this case, chemotherapy may be used to lengthen survival, while treatments such as radiotherapy or stenting may be used to relieve symptoms and make it easier to swallow.

Surgery If the cancer has been diagnosed while still in an early stage, surgical treatment with a curative intention may be possible. Some small tumors that only involve the mucosa or lining of the esophagus may be removed by endoscopic mucosal resection (EMR). Otherwise, curative surgery of early-stage lesions may entail removal of all or part of the esophagus (esophagectomy), although this is a difficult operation with a relatively high risk of mortality or post-operative difficulties. The benefits of surgery are less clear in early-stage ESCC than EAC. There are a number of surgical options, and the best choices for particular situations remain the subject of research and discussion. As well as characteristics and location of the tumor, other factors include the patient’s condition, and the type of operation the surgical team is most experienced with. The likely quality of life after treatment is a relevant factor when considering surgery. Surgical outcomes are likely better in large centers where the procedures are frequently performed. If the cancer has spread to other parts of the body, esophagectomy is nowadays not normally performed. Esophagectomy is the removal of a segment of the esophagus; as this shortens the length of the remaining esophagus, some other segment of the digestive tract is pulled up through the chest cavity and interposed. This is usually the stomach or part of the large intestine (colon) or jejunum. Reconnection of the stomach to a shortened esophagus is called an esophagogastric anastomosis. Esophagectomy can be performed using several methods. The choice of the surgical approach depends on the characteristics and location of the tumor, and the preference of the surgeon. Clear evidence from clinical trials for which approaches give the best outcomes in different circumstances is lacking. A first decision, regarding the point of entry, is between a transhiatial and a transthoracic procedure. The more recent transhiatial approach avoids the

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need to open the chest; instead the surgeon enters the body through an incision in the lower abdomen and another in the neck. The lower part of the esophagus is freed from the surrounding tissues and cut away as necessary. The stomach is then pushed through the esophageal hiatus (the hole where the esophagus passes through the diaphragm) and is joined to the remaining upper part of the esophagus at the neck. The traditional transthoracic approach enters the body through the chest, and has a number of variations. The thoracoabdominal approach opens the abdominal and thoracic cavities together, the two-stage Ivor Lewis (also called Lewis– Tanner) approach involves an initial laparotomy and construction of a gastric tube, followed by a right thoracotomy to excise the tumor and create an esophagogastric anastomosis. The three-stage McKeown approach adds a third incision in the neck to complete the cervical anastomosis. Recent approaches by some surgeons use what is called extended esophagectomy, where more surrounding tissue, including lymph nodes, is removed en bloc. If the person cannot swallow at all, an esophageal stent may be inserted to keep the esophagus open; stents may also assist in occluding fistulas. A nasogastric tube may be necessary to continue feeding while treatment for the tumor is given, and some patients require a gastrostomy (feeding hole in the skin that gives direct access to the stomach). The latter two are especially important if the patient tends to aspirate food or saliva into the airways, predisposing for aspiration pneumonia.

Chemotherapy and Radiotherapy Chemotherapy depends on the tumor type, but tends to be cisplatin-based (or carboplatin or oxaliplatin) every three weeks with fluorouracil (5-FU) either continuously or every three weeks. In more recent studies, addition of epirubicin was better than other comparable regimens in advanced non-resectable cancer. Chemotherapy may be given after surgery (adjuvant, i.e. to reduce risk of recurrence), before surgery (neoadjuvant) or if surgery is not possible; in this case, cisplatin and 5-FU are used. Ongoing trials compare various combinations of chemotherapy; the phase II/III REAL-2 trial – for example – compares four regimens containing epirubicin and either cisplatin or oxaliplatin, and either continuously infused fluorouracil or capecitabine. Radiotherapy is given before, during, or after chemotherapy or surgery, and sometimes on its own to control symptoms. In patients with localised disease but contraindications to surgery, “radical radiotherapy” may be used with curative intent.

Other Approaches Forms of endoscopic therapy have been used for stage 0 and I disease: endoscopic mucosal resection (EMR) and mucosal ablation using radiofrequency ablation, photodynamic therapy, Nd-YAG laser, or argon plasma coagulation. Laser therapy is the use of high-intensity light to destroy tumor cells while affecting only the treated area. This is typically done if the cancer cannot be removed by surgery. The relief of a blockage can help with pain and difficulty swallowing. Photodynamic therapy, a type of laser therapy, involves the use of drugs that are absorbed by cancer cells; when exposed to a special light, the drugs become active and destroy the cancer cells.

Follow-up Patients are followed closely after a treatment regimen has been completed. Frequently, other treatments are used to improve symptoms and maximize nutrition.

PROGNOSIS In general, the prognosis of esophageal cancer is quite poor, because most patients present with advanced disease. By the time the first symptoms (such as difficulty swallowing) appear, the disease has already progressed.

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The overall five-year survival rate (5YSR) in the United States is around 15%, with most people dying within the first year of diagnosis. The latest survival data for England and Wales (patients diagnosed during 2007) show that only one in ten people survive esophageal cancer for at least ten years. Individualized prognosis depends largely on stage. Those with cancer restricted entirely to the esophageal mucosa have about an 80% 5YSR, but submucosal involvement brings this down to less than 50%. Extension into the muscularis propria (muscle layer of the esophagus) suggests a 20% 5YSR, and extension to the structures adjacent to the esophagus predict a 7% 5YSR. Patients with distant metastases (who are not candidates for curative surgery) have a less than 3% 5YSR.

ST OMA CH C ANCER/ GASTRIC CANCER STOMA OMACH CANCER/ Stomach cancer, also known as gastric cancer, is cancer developing from the lining of the stomach. Early symptoms may include heartburn, upper abdominal pain, nausea and loss of appetite. Later signs and symptoms may include weight loss, yellowing of the skin and whites of the eyes, vomiting, difficulty swallowing and blood in the stool among others. The cancer may spread from the stomach to other parts of the body, particularly the liver, lungs, bones, lining of the abdomen and lymph nodes. The most common cause is infection by the bacterium Helicobacter pylori, which accounts for more than 60% of cases. Certain types of H. pylori have greater risks than others. Smoking, dietary factors such as pickled vegetables and obesity are other risk factors. About 10% of cases run in families, and between 1% and 3% of cases are due to genetic syndromes inherited from a person’s parents such as hereditary diffuse gastric cancer. Most cases of stomach cancers are gastric carcinomas. This type can be divided into a number of subtypes. Lymphomas and mesenchymal tumors may also develop in the stomach. Most of the time, stomach cancer develops in stages over years. Diagnosis is usually by biopsy done during endoscopy. This is followed by medical imaging to determine if the disease has spread to other parts of the body. Japan and South Korea, two countries that have high rates of the disease, screen for stomach cancer. A Mediterranean diet lowers the risk of cancer as does the stopping of smoking. There is tentative evidence that treating H. pylori decreases the future risk. If cancer is treated early, many cases can be cured. Treatments may include some combination of surgery, chemotherapy, radiation therapy and targeted therapy. If treated late, palliative care may be advised. Outcomes are often poor with a less than 10% five-year survival rate globally. This is largely because most people with the condition present with advanced disease. In the United States, five-year survival is 28%, while in South Korea it is over 65%, partly due to screening efforts. Globally, stomach cancer is the fifth leading cause of cancer and the third leading cause of death from cancer, making up 7% of cases and 9% of deaths. In 2012, it newly occurred in 950,000 people and caused 723,000 deaths. Before the 1930s, in much of the world, including most Western developed countries, it was the most common cause of death from cancer. Rates of death have been decreasing in many areas of the world since then. This is believed to be due to the eating of less salted and pickled foods as a result of the development of refrigeration as a method of keeping food fresh. Stomach cancer occurs most commonly in East Asia and Eastern Europe. It occurs twice as often in males as in females.

SIGNS AND SYMPTOMS Stomach cancer is often either asymptomatic (producing no noticeable symptoms) or it may cause only nonspecific symptoms (symptoms that may also be present in other related or unrelated disorders) in its early stages. By the time symptoms occur, the cancer has often reached an advanced stage and may have metastasized (spread to other, perhaps distant, parts of the body), which is one of the main reasons for its relatively poor prognosis. Stomach cancer can cause the following signs and symptoms: Early cancers may be associated with indigestion or a burning sensation (heartburn). However, less than 1 in every 50 people referred for endoscopy due to indigestion has cancer. Abdominal discomfort and loss of appetite, especially for meat, can occur. Gastric

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cancers that have enlarged and invaded normal tissue can cause weakness, fatigue, bloating of the stomach after meals, abdominal pain in the upper abdomen, nausea and occasional vomiting, diarrhea or constipation. Further enlargement may cause weight loss or bleeding with vomiting blood or having blood in the stool, the latter apparent as black discolouration (melena) and sometimes leading to anemia. Dysphagia suggests a tumour in the cardia or extension of the gastric tumour into the esophagus. These can be symptoms of other problems such as a stomach virus, gastric ulcer, or tropical sprue.

CAUSES Gastric cancer occurs as a result of many factors. It occurs twice as commonly in males as females. Estrogen may protect women against the development of this form of cancer.

Infections Helicobacter pylori infection is an essential risk factor in 65–80% of gastric cancers, but only 2% of people with Helicobacter infections develop stomach cancer. The mechanism by which H. pylori induces stomach cancer potentially involves chronic inflammation, or the action of H. pylori virulence factors such as CagA. It was estimated that Epstein–Barr virus is responsible for 84,000 cases per year. AIDS is also associated with elevated risk.

Smoking Smoking increases the risk of developing gastric cancer significantly, from 40% increased risk for current smokers to 82% increase for heavy smokers. Gastric cancers due to smoking mostly occur in the upper part of the stomach near the esophagus. Some studies show increased risk with alcohol consumption as well.

Diet Dietary factors are not proven causes and the association between stomach cancer and various foods and beverages is weak. Some foods including smoked foods, salt and salt-rich foods, red meat, processed meat, pickled vegetables, and bracken are associated with a higher risk of stomach cancer. Nitrates and nitrites in cured meats can be converted by certain bacteria, including H. pylori, into compounds that have been found to cause stomach cancer in animals. Fresh fruit and vegetable intake, citrus fruit intake, and antioxidant intake are associated with a lower risk of stomach cancer. A Mediterranean diet is associated with lower rates of stomach cancer, as is regular aspirin use. Obesity is a physical risk factor that has been found to increase the risk of gastric adenocarcinoma by contributing to the development of gastroesophageal reflux disease (GERD). The exact mechanism by which obesity causes GERD is not completely known. Studies hypothesize that increased dietary fat leading to increased pressure on the stomach and the lower esophageal sphincter, due to excess adipose tissue, could play a role, yet no statistically significant data has been collected. However, the risk of gastric cardia adenocarcinoma, with GERD present, has been found to increase more than 2 times for an obese person. There is a correlation between iodine deficiency and gastric cancer.

Genetics About 10% of cases run in families and between 1% and 3% of cases are due to genetic syndromes inherited from a person’s parents such as hereditary diffuse gastric cancer. A genetic risk factor for gastric cancer is a genetic defect of the CDH1 gene known as hereditary diffuse gastric cancer (HDGC). The CDH1 gene, which codes for E-cadherin, lies on the 16th chromosome. When the gene experiences a particular mutation, gastric

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cancer develops through a mechanism that is not fully understood. This mutation is considered autosomal dominant meaning that half of a carrier’s children will likely experience the same mutation. Diagnosis of hereditary diffuse gastric cancer usually takes place when at least two cases involving a family member, such as a parent or grandparent, are diagnosed, with at least one diagnosed before the age of 50. The diagnosis can also be made if there are at least three cases in the family, in which case age is not considered. The International Cancer Genome Consortium is leading efforts to identify genomic changes involved in stomach cancer. A very small percentage of diffuse-type gastric cancers arise from an inherited abnormal CDH1 gene. Genetic testing and treatment options are available for families at risk.

Other Other risks include diabetes, pernicious anemia, chronic atrophic gastritis, Menetrier’s disease (hyperplastic, hypersecretory gastropathy), and intestinal metaplasia.

DIAGNOSIS To find the cause of symptoms, the doctor asks about the patient’s medical history, does a physical exam, and may order laboratory studies. The patient may also have one or all of the following exams: • Gastroscopic exam is the diagnostic method of choice. This involves insertion of a fibre optic camera into the stomach to visualise it. • Upper GI series (may be called barium roentgenogram). • Computed tomography or CT scanning of the abdomen may reveal gastric cancer. It is more useful to determine invasion into adjacent tissues or the presence of spread to local lymph nodes. Wall thickening of more than 1 cm that is focal, eccentric and enhancing favours malignancy. In 2013, Chinese and Israeli scientists reported a successful pilot study of a breathalyzer-style breath test intended to diagnose stomach cancer by analyzing exhaled chemicals without the need for an intrusive endoscopy. A larger-scale clinical trial of this technology was completed in 2014. Abnormal tissue seen in a gastroscope examination will be biopsied by the surgeon or gastroenterologist. This tissue is then sent to a pathologist for histological examination under a microscope to check for the presence of cancerous cells. A biopsy, with subsequent histological analysis, is the only sure way to confirm the presence of cancer cells. Various gastroscopic modalities have been developed to increase yield of detected mucosa with a dye that accentuates the cell structure and can identify areas of dysplasia. Endocytoscopy involves ultra-high magnification to visualise cellular structure to better determine areas of dysplasia. Other gastroscopic modalities such as optical coherence tomography are being tested investigationally for similar applications. A number of cutaneous conditions are associated with gastric cancer. A condition of darkened hyperplasia of the skin, frequently of the axilla and groin, known as acanthosis nigricans, is associated with intra-abdominal cancers such as gastric cancer. Other cutaneous manifestations of gastric cancer include tripe palms (a similar darkening hyperplasia of the skin of the palms) and the LeserTrelat sign, which is the rapid development of skin lesions known as seborrheic keratoses. Various blood tests may be done including a complete blood count (CBC) to check for anaemia, and a fecal occult blood test to check for blood in the stool.

Histopathology •

Gastric adenocarcinoma is a malignant epithelial tumour, originating from glandular epithelium of the gastric mucosa. Stomach cancers are overwhelmingly adenocarcinomas (90%). Histologically,

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there are two major types of gastric adenocarcinoma (Lauren classification): intestinal type or diffuse type. Adenocarcinomas tend to aggressively invade the gastric wall, infiltrating the muscularis mucosae, the submucosa and then the muscularis propria. Intestinal type adenocarcinoma tumour cells describe irregular tubular structures, harbouring pluristratification, multiple lumens, reduced stroma (“back to back” aspect). Often, it associates intestinal metaplasia in neighbouring mucosa. Depending on glandular architecture, cellular pleomorphism and mucosecretion, adenocarcinoma may present 3 degrees of differentiation: well, moderate and poorly differentiated. Diffuse type adenocarcinoma (mucinous, colloid, linitis plastica or leather-bottle stomach) tumour cells are discohesive and secrete mucus, which is delivered in the interstitium, producing large pools of mucus/ colloid (optically “empty” spaces). It is poorly differentiated. If the mucus remains inside the tumour cell, it pushes the nucleus to the periphery: “signet-ring cell”. Around 5% of gastric malignancies are lymphomas (MALTomas, or MALT lymphoma). Carcinoid and stromal tumors may occur.

Staging If cancer cells are found in the tissue sample, the next step is to stage, or find out the extent of the disease. Various tests determine whether the cancer has spread and, if so, what parts of the body are affected. Because stomach cancer can spread to the liver, the pancreas, and other organs near the stomach as well as to the lungs, the doctor may order a CT scan, a PET scan, an endoscopic ultrasound exam, or other tests to check these areas. Blood tests for tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) may be ordered, as their levels correlate to extent of metastasis, especially to the liver, and the cure rate. Staging may not be complete until after surgery. The surgeon removes nearby lymph nodes and possibly samples of tissue from other areas in the abdomen for examination by a pathologist. The clinical stages of stomach cancer are: • Stage 0. Limited to the inner lining of the stomach. Treatable by endoscopic mucosal resection when found very early (in routine screenings); otherwise by gastrectomy and lymphadenectomy without need for chemotherapy or radiation. • Stage I. Penetration to the second or third layers of the stomach (Stage 1A) or to the second layer and nearby lymph nodes (Stage 1B). Stage 1A is treated by surgery, including removal of the omentum. Stage 1B may be treated with chemotherapy (5-fluorouracil) and radiation therapy. • Stage II. Penetration to the second layer and more distant lymph nodes, or the third layer and only nearby lymph nodes, or all four layers but not the lymph nodes. Treated as for Stage I, sometimes with additional neo-adjuvant chemotherapy. • Stage III. Penetration to the third layer and more distant lymph nodes, or penetration to the fourth layer and either nearby tissues or nearby or more distant lymph nodes. Treated as for Stage II; a cure is still possible in some cases. • Stage IV. Cancer has spread to nearby tissues and more distant lymph nodes, or has metastasized to other organs. A cure is very rarely possible at this stage. Some other techniques to prolong life or improve symptoms are used, including laser treatment, surgery, and/or stents to keep the digestive tract open, and chemotherapy by drugs such as 5-fluorouracil, cisplatin, epirubicin, etoposide, docetaxel, oxaliplatin, capecitabine or irinotecan. The TNM staging system is also used. In a study of open-access endoscopy in Scotland, patients were diagnosed 7% in Stage I 17% in Stage II, and 28% in Stage III. A Minnesota population was diagnosed 10% in Stage I, 13% in Stage II, and 18% in Stage III. However, in a high-risk population in the Valdivia Province of southern Chile, only 5% of patients were diagnosed in the first two stages and 10% in stage III.

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PREVENTION Getting rid of H. pylori in those who are infected decreases the risk of stomach cancer, at least in those who are Asian. A 2014 meta-analysis of observational studies found that a diet high in fruits, mushrooms, garlic, soybeans, and green onions was associated with a lower risk of stomach cancer in the Korean population. Low doses of vitamins, especially from a healthy diet, decrease the risk of stomach cancer. A previous review of antioxidant supplementation did not find supporting evidence and possibly worse outcomes.

MANAGEMENT Cancer of the stomach is difficult to cure unless it is found at an early stage (before it has begun to spread). Unfortunately, because early stomach cancer causes few symptoms, the disease is usually advanced when the diagnosis is made. Treatment for stomach cancer may include surgery, chemotherapy, and/or radiation therapy. New treatment approaches such as immunotherapy or gene therapy and improved ways of using current methods are being studied in clinical trials.

Surgery Surgery remains the only curative therapy for stomach cancer. Of the different surgical techniques, endoscopic mucosal resection (EMR) is a treatment for early gastric cancer (tumor only involves the mucosa) that was pioneered in Japan and is available in the United States at some centers. In this procedure, the tumor, together with the inner lining of stomach (mucosa), is removed from the wall of the stomach using an electrical wire loop through the endoscope. The advantage is that it is a much smaller operation than removing the stomach. Endoscopic submucosal dissection (ESD) is a similar technique pioneered in Japan, used to resect a large area of mucosa in one piece. If the pathologic examination of the resected specimen shows incomplete resection or deep invasion by tumor, the patient would need a formal stomach resection. A 2016 Cochrane review found low quality evidence of no difference in short-term mortality between laparoscopic and open gastrectomy (removal of stomach), and that benefits or harms of laparoscopic gastrectomy cannot be ruled out. Those with metastatic disease at the time of presentation may receive palliative surgery and while it remains controversial, due to the possibility of complications from the surgery itself and the fact that it may delay chemotherapy the data so far is mostly positive, with improved survival rates being seen in those treated with this approach.

Chemotherapy The use of chemotherapy to treat stomach cancer has no firmly established standard of care. Unfortunately, stomach cancer has not been particularly sensitive to these drugs, and chemotherapy, if used, has usually served to palliatively reduce the size of the tumor, relieve symptoms of the disease and increase survival time. Some drugs used in stomach cancer treatment have included: 5-FU (fluorouracil) or its analog capecitabine, BCNU (carmustine), methyl-CCNU (semustine) and doxorubicin (Adriamycin), as well as mitomycin C, and more recently cisplatin and taxotere, often using drugs in various combinations. The relative benefits of these different drugs, alone and in combination, are unclear. Clinical researchers are exploring the benefits of giving chemotherapy before surgery to shrink the tumor, or as adjuvant therapy after surgery to destroy remaining cancer cells.

Targeted Therapy Recently, treatment with human epidermal growth factor receptor 2 (HER2) inhibitor, trastuzumab, has been demonstrated to increase overall survival in inoperable locally advanced or metastatic gastric carcinoma over-

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expressing the HER2/neu gene. In particular, HER2 is overexpressed in 13–22% of patients with gastric cancer. Of note, HER2 overexpression in gastric neo-plasia is heterogeneous and comprises a minority of tumor cells (less than 10% of gastric cancers overexpress HER2 in more than 5% of tumor cells). Hence, this heterogeneous expression should be taken into account for HER2 testing, particularly in small samples such as biopsies, requiring the evaluation of more than one bioptic sample.

Radiation Radiation therapy (also called radiotherapy) may be used to treat stomach cancer, often as an adjuvant to chemotherapy and/or surgery.

PROGNOSIS The prognosis of stomach cancer is generally poor, due to the fact the tumour has often metastasised by the time of discovery and the fact that most people with the condition are elderly (median age is between 70 and 75 years) at presentation. The five-year survival rate for stomach cancer is reported to be less than 10 percent. Almost 300 genes are related to outcomes in stomach cancer with both unfavourable genes where high expression related to poor survival and favourable genes where high expression associated with longer survival times. Examples of poor prognosis genes include ITGAV and DUSP1.

SMALL INTESTINE C ANCER/ SMALL BO WEL CANCER CANCER/ BOWEL In oncology, small intestine cancer, also small bowel cancer and cancer of the small bowel, is a cancer of the small intestine. It is relatively rare compared to other gastrointestinal malignancies such as gastric cancer (stomach cancer) and colorectal cancer. Small intestine cancer can be subdivided into duodenal cancer (the first part of the small intestine) and cancer of the jejunum and ileum (the later two parts of the small intestine). Duodenal cancer has more in common with stomach cancer, while cancer of the jejunum and ileum have more in common with colorectal cancer. Five year survival rates are 65%. Several different subtypes of small intestine cancer exist. These include: • Adenocarcinoma • Gastrointestinal stromal tumor • Lymphoma • Ileal carcinoid tumor.

RISK FACTORS Risk factors for small intestine cancer include: • Crohn’s disease • Celiac disease • Radiation exposure • Hereditary gastrointestinal cancer syndromes: familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome • Males are 25% more likely to develop the disease. Benign tumours and conditions that may be mistaken for cancer of the small bowel: • Hamartoma • Tuberculosis.

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RESEARCH Little research is conducted on these cancers due to their relative rarity when compared to the more common colorectal cancers. APC-min mice which carry a gene deficiency corresponding to that of humans with FAP also go on to develop small intestinal tumors, though humans do not.

GALLBL ADDER CANCER GALLBLADDER Gallbladder cancer is a relatively uncommon cancer. It has peculiar geographical distribution being common in central and South America, central and eastern Europe, Japan and northern India; it is also common in certain ethnic groups e.g. Native American Indians and Hispanics. If it is diagnosed early enough, it can be cured by removing the gallbladder, part of the liver and associated lymph nodes. Most often it is found after symptoms such as abdominal pain, jaundice and vomiting occur, and it has spread to other organs such as the liver. It is a rare cancer that is thought to be related to gallstones building up, which also can lead to calcification of the gallbladder, a condition known as porcelain gallbladder. Porcelain gallbladder is also rare. Some studies indicate that people with porcelain gallbladder have a high risk of developing gallbladder cancer, but other studies question this. The outlook is poor for recovery if the cancer is found after symptoms have started to occur, with a 5-year survival rate close to 3%.

SIGNS AND SYMPTOMS • • • • •

Steady pain in the upper right abdomen Indigestion Dyspepsia (gas) Bile (dark green colour) in vomit. Weakness Loss of appetite

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• Weight loss • Jaundice and vomiting due to obstruction. Early symptoms mimic gallbladder inflammation due to gallstones. Later, the symptoms may be that of biliary and stomach obstruction. Of note, Courvoisier’s law states that in the presence of a palpably enlarged gallbladder which is non-tender and accompanied with mild painless jaundice, the cause is unlikely to be gallstones. This implicates possible malignancy of the gallbladder or pancreas, and the swelling is unlikely due to gallstones due to the chronic inflammation association with gallstones leading to a shunken, non-distensible gallbladder. However, Ludwig Georg Courvoisier’s original observations, published in Germany in 1890, were not originally cited as a ‘law’, and no mention of malignancy or pain (tenderness) was made. These points are commonly missquoted or confused in the medical literature.

RISK FACTORS • • • • •

•

Gender—approx. twice more common in women than men, usually in seventh and eighth decades. Obesity increases the risk for gallbladder cancer. Chronic cholecystitis and cholelithiasis. Primary sclerosing cholangitis Chronic typhoid infection of gallbladder. Chronic Salmonella typhi carriers have 3 to 200 times higher risk of gallbladder cancer than non-carriers and 1–6% lifetime risk of development of cancer. Various single nucleotide polymorphisms (SNPs) have been shown to be associated with gallbladder cancer. However, existing genetic studies in GBC susceptibility have so far been insufficient to confirm any association.

DIAGNOSIS Early diagnosis is not generally possible. People at high risk, such as women or Native Americans with gallstones, are evaluated closely. Transabdominal ultrasound, CT scan, endoscopic ultrasound, MRI, and MR cholangio-pancreatography (MRCP) can be used for diagnosis. A biopsy is the only certain way to tell whether the tumorous growth is malignant or not.

Differential Diagnosis Xanthogranulomatous cholecystitis (XGC) is a rare form of gallbladder disease which mimics gallbladder cancer although it is not cancerous. It was first discovered and reported in the medical literature in 1976 by J.J. McCoy, Jr., and colleagues.

TREATMENT The most common and most effective treatment is surgical removal of the gallbladder (cholecystectomy) with part of liver and lymph node dissection. However, with gallbladder cancer’s extremely poor prognosis, most patients will die within a year of surgery. If surgery is not possible, endoscopic stenting of the biliary tree can reduce jaundice and a stent in stomach may relieve vomiting. Chemotherapy and radiation may also be used with surgery. If gall bladder cancer is diagnosed after cholecystectomy for stone disease (incidental cancer), reoperation to remove part of liver and lymph nodes is required in most cases. When it is done as early as possible, patients have the best chance of long-term survival and even cure.

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CHOL ANGIOC AR CINOMA CHOLANGIOC ANGIOCAR ARCINOMA Cholangiocarcinoma, also known as bile duct cancer, is a form of cancer that is composed of mutated epithelial cells (or cells showing characteristics of epithelial differentiation) that originate in the bile ducts which drain bile from the liver into the small intestine. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater. Cholangiocarcinoma is a relatively rare neo-plasm that is classified as an adenocarcinoma (a cancer that forms glands or secretes significant amounts of mucins). It has an annual incidence rate of 1–2 cases per 100,000 in the Western world, but rates of cholangiocarcinoma have been rising worldwide over the past few decades. Prominent signs and symptoms of cholangiocarcinoma include abnormal liver function tests, abdominal pain, jaundice, and weight loss. Other symptoms such as generalized itching, fever, and changes in colour of stool or urine may also occur. The disease is diagnosed through a combination of blood tests, imaging, endoscopy, and sometimes surgical exploration, with confirmation obtained after a pathologist examines cells from the tumor under a microscope. Known risk factors for cholangiocarcinoma include primary sclerosing cholangitis (an inflammatory disease of the bile ducts), infection with the parasitic liver flukes Opisthorchis viverrini or Clonorchis sinensis, some congenital liver malformations, and exposure to Thorotrast (thorium dioxide), a chemical formerly used in medical imaging. However, most people with cholangiocarcinoma have no identifiable risk factors. Cholangiocarcinoma is considered to be an incurable and rapidly lethal cancer unless both the primary tumor and any metastases can be fully removed by surgery. No potentially curative treatment exists except surgery, but most people have advanced stage disease at presentation and are inoperable at the time of diagnosis. People with cholangiocarcinoma are generally managed - though not cured - with chemotherapy, radiation therapy, and other palliative care measures. These are also used as additional therapies after surgery in cases where resection has apparently been successful (or nearly so).

SIGNS AND SYMPTOM The most common physical indications of cholangiocarcinoma are abnormal liver function tests, jaundice (yellowing of the eyes and skin occurring when bile ducts are blocked by tumor), abdominal pain (30%–50%), generalized itching (66%), weight loss (30%–50%), fever (up to 20%), and changes in the colour of stool or urine. To some extent, the symptoms depend upon the location of the tumor: patients with cholangiocarcinoma in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, while those with tumors of the bile ducts within the liver more often have pain without jaundice. Blood tests of liver function in patients with cholangiocarcinoma often reveal a so-called “obstructive picture,” with elevated bilirubin, alkaline phosphatase, and gamma glutamyl transferase levels, and relatively normal transaminase levels. Such laboratory findings suggest obstruction of the bile ducts, rather than inflammation or infection of the liver parenchyma, as the primary cause of the jaundice.

RISK FACTORS Although most patients present without any known risk factors evident, a number of risk factors for the development of cholangiocarcinoma have been described. In the Western world, the most common of these is primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts which is closely associated with ulcerative colitis (UC). Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is on the order of 10%–15%, although autopsy series have found rates as high as 30% in this population. Certain parasitic liver diseases may be risk factors as well. Colonization with the liver flukes Opisthorchis viverrini (found in Thailand, Laos PDR, and Vietnam) or Clonorchis sinensis

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(found in China, Taiwan, eastern Russia, Korea, and Vietnam) has been associated with the development of cholangiocarcinoma. Control programmes aimed at discouraging the consumption of raw and undercooked food have been successful at reducing the incidence of cholangiocarcinoma in some countries. Patients with chronic liver disease, whether in the form of viral hepatitis (e.g. hepatitis B or hepatitis C), alcoholic liver disease, or cirrhosis of the liver due to other causes, are at significantly increased risk of cholangiocarcinoma. HIV infection was also identified in one study as a potential risk factor for cholangiocarcinoma, although it was unclear whether HIV itself or other correlated and confounding factors (e.g. hepatitis C infection) were responsible for the association. Infection with the bacteria Helicobacter bilis and Helicobacter hepaticus species can cause biliary cancer. Congenital liver abnormalities, such as Caroli’s syndrome (a specific type of five recognized choledochal cysts), have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma. The rare inherited disorders Lynch syndrome II and biliary papillomatosis have also been found to be associated with cholangiocarcinoma. The presence of gallstones (cholelithiasis) is not clearly associated with cholangiocarcinoma. However, intrahepatic stones (called hepatolithiasis), which are rare in the West but common in parts of Asia, have been strongly associated with cholangiocarcinoma. Exposure to Thorotrast, a form of thorium dioxide which was used as a radiologic contrast medium, has been linked to the development of cholangiocarcinoma as late as 30–40 years after exposure; Thorotrast was banned in the United States in the 1950s due to its carcinogenicity.

PATHOPHYSIOLOGY Cholangiocarcinoma can affect any area of the bile ducts, either within or outside the liver. Tumors occurring in the bile ducts within the liver are referred to as intrahepatic, those occurring in the ducts outside the liver are extrahepatic, and tumors occurring at the site where the bile ducts exit the liver may be referred to as perihilar. A cholangiocarcinoma occurring at the junction where the left and right hepatic ducts meet to form the common hepatic duct may be referred to eponymously as a Klatskin tumor. Although cholangiocarcinoma is known to have the histological and molecular features of an adenocarcinoma of epithelial cells lining the biliary tract, the actual cell of origin is unknown.

Fig. Digestive system diagram showing bile duct location.

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Recent evidence has suggested that the initial transformed cell that generates the primary tumor may arise from a pluripotent hepatic stem cell. Cholangiocarcinoma is thought to develop through a series of stages - from early hyperplasia and metaplasia, through dysplasia, to the development of frank carcinoma - in a process similar to that seen in the development of colon cancer. Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression. Histologically, cholangiocarcinomas may vary from undifferentiated to well-differentiated. They are often surrounded by a brisk fibrotic or desmoplastic tissue response; in the presence of extensive fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive epithelium. There is no entirely specific immunohistochemical stain that can distinguish malignant from benign biliary ductal tissue, although staining for cytokeratins, carcinoembryonic antigen, and mucins may aid in diagnosis. Most tumors (>90%) are adenocarcinomas.

DIAGNOSIS

Blood tests There are no specific blood tests that can diagnose cholangiocarcinoma by themselves. Serum levels of carcinoembryonic antigen (CEA) and CA19-9 are often elevated, but are not sensitive or specific enough to be used as a general screening tool. However, they may be useful in conjunction with imaging methods in supporting a suspected diagnosis of cholangiocarcinoma.

Abdominal Imaging Ultrasound of the liver and biliary tree is often used as the initial imaging modality in patients with suspected obstructive jaundice. Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be sufficient to diagnose cholangiocarcinoma. Computed tomography (CT) scanning may also play an important role in the diagnosis of cholangiocarcinoma.

Imaging of the Biliary Tree While abdominal imaging can be useful in the diagnosis of cholangiocarcinoma, direct imaging of the bile ducts is often necessary. Endoscopic retrograde cholangiopancreatography (ERCP), an endoscopic procedure performed by a gastroenterologist or specially trained surgeon, has been widely used for this purpose. Although ERCP is an invasive procedure with attendant risks, its advantages include the ability to obtain biopsies and to place stents or perform other interventions to relieve biliary obstruction. Endoscopic ultrasound can also be performed at the time of ERCP and may increase the accuracy of the biopsy and yield information on lymph node invasion and operability. As an alternative to ERCP, percutaneous transhepatic cholangiography (PTC) may be utilized. Magnetic resonance cholangiopancreatography (MRCP) is a non-invasive alternative to ERCP. Some authors have suggested that MRCP should supplant ERCP in the diagnosis of biliary cancers, as it may more accurately define the tumor and avoids the risks of ERCP.

Surgery Surgical exploration may be necessary to obtain a suitable biopsy and to accurately stage a patient with cholangiocarcinoma. Laparoscopy can be used for staging purposes and may avoid the need for a more invasive surgical procedure, such as laparotomy, in some patients.

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Fig. Photograph of cholangiocarcinoma in human liver.

Pathology Histologically, cholangiocarcinomas are classically well to moderately differentiated adenocarcinomas. Immunohistochemistry is useful in the diagnosis and may be used to help differentiate a cholangiocarcinoma from hepatocellular carcinoma and metastasis of other gastrointestinal tumors. Cytological scrapings are often non-diagnostic, as these tumors typically have a desmoplastic stroma and, therefore, do not release diagnostic tumor cells with scrapings.

STAGING Although there are at least three staging systems for cholangiocarcinoma (e.g. those of Bismuth, Blumgart, and the American Joint Committee on Cancer), none have been shown to be useful in predicting survival. The most important staging issue is whether the tumor can be surgically removed, or whether it is too advanced for surgical treatment to be successful. Often, this determination can only be made at the time of surgery. General guidelines for operability include: • Absence of lymph node or liver metastases • Absence of involvement of the portal vein • Absence of direct invasion of adjacent organs • Absence of widespread metastatic disease.

TREATMENT Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all the tumors can be fully resected (cut out surgically). Since the operability of the tumor can only be assessed during surgery in

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most cases, a majority of patients undergo exploratory surgery unless there is already a clear indication that the tumor is inoperable. However, the Mayo Clinic has reported significant success treating early bile duct cancer with liver transplantation using a protocolized approach and strict selection criteria. Adjuvant therapy followed by liver transplantation may have a role in treatment of certain unresectable cases.

Adjuvant Chemotherapy and Radiation Therapy If the tumor can be removed surgically, patients may receive adjuvant chemotherapy or radiation therapy after the operation to improve the chances of cure. If the tissue margins are negative (i.e. the tumor has been totally excised), adjuvant therapy is of uncertain benefit. Both positive and negative results have been reported with adjuvant radiation therapy in this setting, and no prospective randomized controlled trials have been conducted as of March 2007. Adjuvant chemotherapy appears to be ineffective in patients with completely resected tumors. The role of combined chemoradiotherapy in this setting is unclear. However, if the tumor tissue margins are positive, indicating that the tumor was not completely removed via surgery, then adjuvant therapy with radiation and possibly chemotherapy is generally recommended based on the available data.

Treatment of Advanced Disease The majority of cases of cholangiocarcinoma present as inoperable (unresectable) disease in which case patients are generally treated with palliative chemotherapy, with or without radiotherapy. Chemotherapy has been shown in a randomized controlled trial to improve quality of life and extend survival in patients with inoperable cholangiocarcinoma. There is no single chemotherapy regimen which is universally used, and enrollment in clinical trials is often recommended when possible. Chemotherapy agents used to treat cholangiocarcinoma include 5-fluorouracil with leucovorin, gemcitabine as a single agent, or gemcitabine plus cisplatin, irinotecan, or capecitabine. A small pilot study suggested possible benefit from the tyrosine kinase inhibitor erlotinib in patients with advanced cholangiocarcinoma.

PROGNOSIS Surgical resection offers the only potential chance of cure in cholangiocarcinoma. For non-resectable cases, the 5-year survival rate is 0% where the disease is inoperable because distal lymph nodes show metastases, and less than 5% in general. Overall mean duration of survival is less than 6 months in patients with metastatic disease. For surgical cases, the odds of cure vary depending on the tumor location and whether the tumor can be completely, or only partially, removed. Distal cholangiocarcinomas (those arising from the common bile duct) are generally treated surgically with a Whipple procedure; long-term survival rates range from 15%–25%, although one series reported a five-year survival of 54% for patients with no involvement of the lymph nodes. Intrahepatic cholangiocarcinomas (those arising from the bile ducts within the liver) are usually treated with partial hepatectomy. Various series have reported survival estimates after surgery ranging from 22%–66%; the outcome may depend on involvement of lymph nodes and completeness of the surgery. Perihilar cholangiocarcinomas (those occurring near where the bile ducts exit the liver) are least likely to be operable. When surgery is possible, they are generally treated with an aggressive approach often including removal of the gallbladder and potentially part of the liver. In patients with operable perihilar tumors, reported 5-year survival rates range from 20%–50%. The prognosis may be worse for patients with primary sclerosing cholangitis who develop cholangiocarcinoma, likely because the cancer is not detected until it is advanced. Some evidence suggests that outcomes may be improving with more aggressive surgical approaches and adjuvant therapy.

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PANCREA TIC C ANCER PANCREATIC CANCER Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. There are a number of types of pancreatic cancer. The most common, pancreatic adenocarcinoma, accounts for about 85% of cases, and the term “pancreatic cancer” is sometimes used to refer only to that type. These adenocarcinomas start within the part of the pancreas which makes digestive enzymes. Several other types of cancer, which collectively represent the majority of the non-adenocarcinomas, can also arise from these cells. One to two percent of cases of pancreatic cancer are neuroendocrine tumors, which arise from the hormoneproducing cells of the pancreas. These are generally less aggressive than pancreatic adenocarcinoma. Signs and symptoms of the most common form of pancreatic cancer may include yellow skin, abdominal or back pain, unexplained weight loss, light-colored stools, dark urine and loss of appetite. There are usually no symptoms in the disease’s early stages, and symptoms that are specific enough to suggest pancreatic cancer typically do not develop until the disease has reached an advanced stage. By the time of diagnosis, pancreatic cancer has often spread to other parts of the body. Pancreatic cancer rarely occurs before the age of 40, and more than half of cases of pancreatic adenocarcinoma occur in those over 70. Risk factors for pancreatic cancer include tobacco smoking, obesity, diabetes, and certain rare genetic conditions. About 25% of cases are linked to smoking, and 5–10% are linked to inherited genes. Pancreatic cancer is usually diagnosed by a combination of medical imaging techniques such as ultrasound or computed tomography, blood tests, and examination of tissue samples (biopsy). The disease is divided into stages, from early (stage I) to late (stage IV). Screening the general population has not been found to be effective. The risk of developing pancreatic cancer is lower among nonsmokers, and people who maintain a healthy weight and limit their consumption of red or processed meat. A smoker’s chance of developing the disease decreases if they stop smoking, and almost returns to that of the rest of the population after 20 years. Pancreatic cancer can be treated with surgery, radiotherapy, chemotherapy, palliative care, or a combination of these. Treatment options are partly based on the cancer stage. Surgery is the only treatment that can cure pancreatic adenocarcinoma, and may also be done to improve quality of life without the potential for cure. Pain management and medications to improve digestion are sometimes needed. Early palliative care is recommended even for those receiving treatment that aims for a cure. In 2015, pancreatic cancers of all types resulted in 411,600 deaths globally. Pancreatic cancer is the fifth most common cause of death from cancer in the United Kingdom, and the fourth most common in the United States. The disease occurs most often in the developed world, where about 70% of the new cases in 2012 originated. Pancreatic adenocarcinoma typically has a very poor prognosis: after diagnosis, 25% of people survive one year and 5% live for five years. For cancers diagnosed early, the five-year survival rate rises to about 20%. Neuroendocrine cancers have better outcomes; at five years from diagnosis, 65% of those diagnosed are living, though survival varies considerably depending on the type of tumor.

TYPES The many types of pancreatic cancer can be divided into two general groups. The vast majority of cases (about 99%) occur in the part of the pancreas which produces digestive enzymes, known as the exocrine component. There are several sub-types of exocrine pancreatic cancers, but their diagnosis and treatment have much in common. The small minority of cancers that arise in the hormone-producing (endocrine) tissue of the pancreas have different clinical characteristics. Both groups occur mainly (but not exclusively) in people over 40, and are slightly more common in men, but some rare sub-types mainly occur in women or children.

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Fig. The pancreas has multiple functions, served by the endocrine cells in the islets of Langerhans and the exocrine acinar cells. Pancreatic cancer may arise from any of these and disrupt any of their functions.

Exocrine Cancers The exocrine group is dominated by pancreatic adenocarcinoma (variations of this name may add “invasive” and “ductal”), which is by far the most common type, representing about 85% of all pancreatic cancers. Nearly all these start in the ducts of the pancreas, as pancreatic ductal adenocarcinoma (PDAC). This is despite the fact that the tissue from which it arises – the pancreatic ductal epithelium – represents less than 10% of the pancreas by cell volume, because it constitutes only the ducts (an extensive but capillary-like duct-system fanning out) within the pancreas. This cancer originates in the ducts that carry secretions (such as enzymes and bicarbonate) away from the pancreas. About 60–70% of adenocarcinomas occur in the head of the pancreas. The next most common type, acinar cell carcinoma of the pancreas, arises in the clusters of cells that produce these enzymes, and represents 5% of exocrine pancreas cancers. Like the ‘functioning’ endocrine cancers described below, acinar cell carcinomas may cause over-production of certain molecules, in this case digestive enzymes, which may cause symptoms such as skin rashes and joint pain. Cystadenocarcinomas account for 1% of pancreatic cancers, and they have a better prognosis than the other exocrine types. Pancreatoblastoma is a rare form, mostly occurring in childhood, and with a relatively good prognosis. Other exocrine cancers include adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas,

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undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells. Solid pseudopapillary tumor is a rare low-grade neo-plasm that mainly affects younger women, and generally has a very good prognosis. Pancreatic mucinous cystic neo-plasms are a broad group of pancreas tumors that have varying malignant potential. They are being detected at a greatly increased rate as CT scans become more powerful and common, and discussion continues as how best to assess and treat them, given that many are benign.

Neuroendocrine The small minority of tumors that arise elsewhere in the pancreas are mainly pancreatic neuroendocrine tumors (PanNETs). Neuroendocrine tumors (NETs) are a diverse group of benign or malignant tumors that arise from the body’s neuroendocrine cells, which are responsible for integrating the nervous and endocrine systems. NETs can start in most organs of the body, including the pancreas, where the various malignant types are all considered to be rare. PanNETs are grouped into ‘functioning’ and ‘non-functioning’ types, depending on the degree to which they produce hormones. The functioning types secrete hormones such as insulin, gastrin, and glucagon into the bloodstream, often in large quantities, giving rise to serious symptoms such as low blood sugar, but also favouring relatively early detection. The most common functioning PanNETs are insulinomas and gastrinomas, named after the hormones they secrete. The non-functioning types do not secrete hormones in a sufficient quantity to give rise to overt clinical symptoms. For this reason, non-functioning PanNETs are often diagnosed only after the cancer has spread to other parts of the body. As with other neuroendocrine tumors, the history of the terminology and classification of PanNETs is complex. PanNETs are sometimes called “islet cell cancers”, even though it is now known that they do not actually arise from islet cells as previously thought.

SIGNS AND SYMPTOMS Since pancreatic cancer usually does not cause recognizable symptoms in its early stages, the disease is typically not diagnosed until it has spread beyond the pancreas itself. This is one of the main reasons for the generally poor survival rates. Exceptions to this are the functioning PanNETs, where over-production of various active hormones can give rise to symptoms (which depend on the type of hormone). Bearing in mind that the disease is rarely diagnosed before the age of 40, common symptoms of pancreatic adenocarcinoma occurring before diagnosis include: • Pain in the upper abdomen or back, often spreading from around the stomach to the back. The location of the pain can indicate the part of the pancreas where a tumor is located. The pain may be worse at night and may increase over time to become severe and unremitting. It may be slightly relieved by bending forward. In the UK, about half of new cases of pancreatic cancer are diagnosed following a visit to a hospital emergency department for pain or jaundice. In up to two-thirds of people abdominal pain is the main symptom, for 46% of the total accompanied by jaundice, with 13% having jaundice without pain. • Jaundice, a yellow tint to the whites of the eyes or skin, with or without pain, and possibly in combination with darkened urine. This results when a cancer in the head of the pancreas obstructs the common bile duct as it runs through the pancreas. • Unexplained weight loss, either from loss of appetite, or loss of exocrine function resulting in poor digestion. • The tumor may compress neighbouring organs, disrupting digestive processes and making it difficult for the stomach to empty, which may cause nausea and a feeling of fullness. The undigested fat leads to foul-smelling, fatty feces that are difficult to flush away. Constipation is common.

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•

At least 50% of people with pancreatic adenocarcinoma have diabetes at the time of diagnosis. While long-standing diabetes is a known risk factor for pancreatic cancer, the cancer can itself cause diabetes, in which case recent onset of diabetes could be considered an early sign of the disease. People over 50 who develop diabetes have eight times the usual risk of developing pancreatic adenocarcinoma within three years, after which the relative risk declines.

Other Findings •

Trousseau’s syndrome, in which blood clots form spontaneously in the portal blood vessels, the deep veins of the extremities, or the superficial veins anywhere on the body, may be associated with pancreatic cancer, and is found in about 10% of cases. • Clinical depression has been reported in association with pancreatic cancer in some 10–20% of cases, and can be a hindrance to optimal management. The depression sometimes appears before the diagnosis of cancer, suggesting that it may be brought on by the biology of the disease. Other common manifestations of the disease include: weakness and tiring easily; dry mouth; sleep problems; and a palpable abdominal mass.”

Symptoms of Spread The spread of pancreatic cancer to other organs (metastasis) may also cause symptoms. Typically, pancreatic adenocarcinoma first spreads to nearby lymph nodes, and later to the liver or to the peritoneal cavity, large intestine or lungs. It is uncommon for it to spread to the bones or brain. Cancers in the pancreas may also be secondary cancers that have spread from other parts of the body. This is uncommon, found in only about 2% of cases of pancreatic cancer. Kidney cancer is by far the most common cancer to spread to the pancreas, followed by colorectal cancer, and then cancers of the skin, breast, and lung. Surgery may be performed on the pancreas in such cases, whether in hope of a cure or to alleviate symptoms.

RISK FACTORS Risk factors for pancreatic adenocarcinoma include: • Age, gender, and ethnicity; the risk of developing pancreatic cancer increases with age. Most cases occur after age 65, while cases before age 40 are uncommon. The disease is slightly more common in men than women, and in the United States is over 1.5 times more common in African Americans, though incidence in Africa is low. • Cigarette smoking is the best-established avoidable risk factor for pancreatic cancer, approximately doubling risk among long-term smokers, the risk increasing with the number of cigarettes smoked and the years of smoking. The risk declines slowly after smoking cessation, taking some 20 years to return to almost that of non-smokers. • Obesity; a BMI greater than 35 increases relative risk by about half. • Family history; 5–10% of pancreatic cancer cases have an inherited component, where people have a family history of pancreatic cancer. The risk escalates greatly if more than one first-degree relative had the disease, and more modestly if they developed it before the age of 50. Most of the genes involved have not been identified. Hereditary pancreatitis gives a greatly increased lifetime risk of pancreatic cancer of 30–40% to the age of 70. Screening for early pancreatic cancer may be offered to individuals with hereditary pancreatitis on a research basis. Some people may choose to have their pancreas surgically removed to prevent cancer developing in the future.

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Pancreatic cancer has been associated with the following other rare hereditary syndromes: Peutz–Jeghers syndrome due to mutations in the STK11 tumor suppressor gene (very rare, but a very strong risk factor); dysplastic nevus syndrome (or familial atypical multiple mole and melanoma syndrome, FAMMM-PC) due to mutations in the CDKN2A tumor suppressor gene; autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene; hereditary non-polyposis colon cancer (Lynch syndrome); and familial adenomatous polyposis. PanNETs have been associated with multiple endocrine neo-plasia type 1 (MEN1) and von Hippel Lindau syndromes. • Chronic pancreatitis appears to almost triple risk, and as with diabetes, new-onset pancreatitis may be a symptom of a tumor. The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high. • Diabetes mellitus is a risk factor for pancreatic cancer and (as noted in the Signs and symptoms section) new-onset diabetes may also be an early sign of the disease. People who have been diagnosed with Type 2 diabetes for longer than ten years may have a 50% increased risk, as compared with non-diabetics. • Specific types of food (as distinct from obesity) have not been clearly shown to increase the risk of pancreatic cancer. Dietary factors for which there is some evidence of slightly increased risk include processed meat, red meat, and meat cooked at very high temperatures (e.g. by frying, broiling or barbecuing).

Alcohol Drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer. However, considerable research has failed to firmly establish alcohol consumption as a direct risk factor for pancreatic cancer. Overall, the association is consistently weak and the majority of studies have found no association, with smoking a strong confounding factor. The evidence is stronger for a link with heavy drinking, of at least six drinks per day.

PATHOPHYSIOLOGY

Precancer Exocrine cancers are thought to arise from several types of precancerous lesions within the pancreas. But these lesions do not always progress to cancer, and the increased numbers detected as a by-product of the increasing use of CT scans for other reasons are not all treated. Apart from pancreatic serous cystadenomas (SCNs), which are almost always benign, four types of precancerous lesion are recognized. The first is pancreatic intraepithelial neo-plasia. These lesions are microscopic abnormalities in the pancreas and are often found in autopsies of people with no diagnosed cancer. These lesions may progress from low to high grade and then to a tumor. More than 90% of cases at all grades carry a faulty KRAS gene, while in grades 2 and 3 damage to three further genes – CDKN2A (p16), p53 and SMAD4 – are increasingly often found. A second type are the intraductal papillary mucinous neo-plasms (IPMNs). These are macroscopic lesions, which are found in about 2% of all adults. This rate rises to ~10% by age 70. These lesions have about a 25% risk of developing into invasive cancer. They may have KRAS gene mutations (~40–65% of cases) and in the GNAS Gs alpha subunit and RNF43, affecting the Wnt signaling pathway. Even if removed surgically, there remains a considerably increased risk of pancreatic cancer developing subsequently. The third type, pancreatic mucinous cystic neo-plasms (MCNs) mainly occur in women, and may remain benign or progress to cancer. If these lesions become large, cause symptoms, or have suspicious features, they can usually be successfully removed by surgery.

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A fourth type of cancer that arises in the pancreas is the intraductal tubulopapillary neo-plasm. This type was recognised by the WHO in 2010 and constitutes about 1-3% of all pancreatic neo-plasms. Mean age at diagnosis is 61 years (range 35–78 years). About 50% of these lesions become invasive. Diagnosis depends on histology as these lesions are very difficult to differentiate from other lesions on either clinical or radiological grounds.

Invasive Cancer The genetic events found in ductal adenocarcinoma have been well characterized, and complete exome sequencing has been done for the common types of tumor. Four genes have each been found to be mutated in the majority of adenocarcinomas: KRAS (in 95% of cases), CDKN2A (also in 95%), TP53 (75%), and SMAD4 (55%). The last of these are especially associated with a poor prognosis. SWI/SNF mutations/deletions occur in about 10–15% of the adenocarcinomas. The genetic alterations in several other types of pancreatic cancer and precancerous lesions have also been researched. Transcriptomics analyses and mRNA sequencing for the common forms of pancreatic cancer have found that 75% of human genes are expressed in the tumors, with some 200 genes more specifically expressed in pancreatic cancer as compared to other tumor types.

PanNETs The genes often found mutated in PanNETs are different from those in exocrine pancreatic cancer. For example, KRAS mutation is normally absent. Instead, hereditary MEN1 gene mutations give rise to MEN1 syndrome, in which primary tumors occur in two or more endocrine glands. About 40–70% of people born with a MEN1 mutation eventually develop a PanNet. Other genes that are frequently mutated include DAXX, mTOR and ATRX.

DIAGNOSIS The symptoms of pancreatic adenocarcinoma do not usually appear in the disease’s early stages, and are individually not distinctive to the disease. The symptoms at diagnosis vary according to the location of the cancer in the pancreas, which anatomists divide (from left to right on most diagrams) into the thick head, the neck, and the tapering body, ending in the tail. Regardless of a tumor’s location, the most common symptom is unexplained weight loss, which may be considerable. A large minority (between 35% and 47%) of people diagnosed with the disease will have had nausea, vomiting or a feeling of weakness. Tumors in the head of the pancreas typically also cause jaundice, pain, loss of appetite, dark urine, and light-colored stools. Tumors in the body and tail typically also cause pain. People sometimes have recent onset of atypical type 2 diabetes that is difficult to control, a history of recent but unexplained blood vessel inflammation caused by blood clots (thrombophlebitis) known as Trousseau sign, or a previous attack of pancreatitis. A doctor may suspect pancreatic cancer when the onset of diabetes in someone over 50 years old is accompanied by typical symptoms such as unexplained weight loss, persistent abdominal or back pain, indigestion, vomiting, or fatty feces. Jaundice accompanied by a painlessly swollen gallbladder (known as Courvoisier’s sign) may also raise suspicion, and can help differentiate pancreatic cancer from gallstones. Medical imaging techniques, such as computed tomography (CT scan) and endoscopic ultrasound (EUS) are used both to confirm the diagnosis and to help decide whether the tumor can be surgically removed (its “resectability”). On contrast CT scan, pancreatic cancer typically shows a gradually increasing radiocontrast uptake, rather than a fast washout as seen in a normal pancreas or a delayed washout as seen in chronic pancreatitis. Magnetic resonance imaging and positron emission tomography may also be used, and magnetic resonance cholangiopancreatography may be useful in some cases. Abdominal ultrasound is less sensitive and will miss small tumors, but can identify cancers that have spread to the liver and build-up of fluid in the peritoneal cavity (ascites). It may be used for a quick and cheap first examination before other techniques. A biopsy by fine needle aspiration, often guided by endoscopic ultrasound, may be used where there is uncertainty

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over the diagnosis, but a histologic diagnosis is not usually required for removal of the tumor by surgery to go ahead. Liver function tests can show a combination of results indicative of bile duct obstruction (raised conjugated bilirubin, ã-glutamyl transpeptidase and alkaline phosphatase levels). CA19-9 (carbohydrate antigen 19.9) is a tumor marker that is frequently elevated in pancreatic cancer. However, it lacks sensitivity and specificity, not least because 5% of people lack the Lewis (a) antigen and cannot produce CA19-9. It has a sensitivity of 80% and specificity of 73% in detecting pancreatic adenocarcinoma, and is used for following known cases rather than diagnosis. The most common form of pancreatic cancer (adenocarcinoma) is typically characterized by moderately to poorly differentiated glandular structures on microscopic examination. There is typically considerable desmoplasia or formation of a dense fibrous stroma or structural tissue consisting of a range of cell types (including myofibroblasts, macrophages, lymphocytes and mast cells) and deposited material (such as type I collagen and hyaluronic acid). This creates a tumor microenvironment that is short of blood vessels (hypovascular) and so of oxygen (tumor hypoxia). It is thought that this prevents many chemotherapy drugs from reaching the tumor, as one factor making the cancer especially hard to treat.

STAGING

Exocrine Cancers Pancreatic cancer is usually staged following a CT scan. The most widely used cancer staging system for pancreatic cancer is the one formulated by the American Joint Committee on Cancer (AJCC) together with the Union for International Cancer Control (UICC). The AJCC-UICC staging system designates four main overall stages, ranging from early to advanced disease, based on TNM classification of Tumor size, spread to lymph Nodes, and Metastasis. To help decide treatment, the tumors are also divided into three broader categories based on whether surgical removal seems possible: in this way, tumors are judged to be “resectable”, “borderline resectable”, or “unresectable”. When the disease is still in an early stage (AJCC-UICC stages I and II), without spread to large blood vessels or distant organs such as the liver or lungs, surgical resection of the tumor can normally be performed, if the patient is willing to undergo this major operation and is thought to be sufficiently fit. The AJCC-UICC staging system allows distinction between stage III tumors that are judged to be “borderline resectable” (where surgery is technically feasible because the celiac axis and superior mesenteric artery are still free) and those that are “unresectable” (due to more locally advanced disease); in terms of the more detailed TNM classification, these two groups correspond to T3 and T4 respectively. • Pancreatic cancer staging (TNM classification).

Fig. Stage T1 pancreatic cancer

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Fig. Stage T2 pancreatic cancer

Fig. Stage T3 pancreatic cancer

Fig. Stage T4 pancreatic cancer

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Fig. Pancreatic cancer in nearby lymph nodes – Stage N1

Locally advanced adenocarcinomas have spread into neighbouring organs, which may be any of the following (in roughly decreasing order of frequency): the duodenum, stomach, transverse colon, spleen, adrenal gland, or kidney. Very often they also spread to the important blood or lymphatic vessels and nerves that run close to the pancreas, making surgery far more difficult. Typical sites for metastatic spread (stage IV disease) are the liver, peritoneal cavity and lungs, all of which occur in 50% or more of fully advanced cases.

PanNETs The 2010 WHO classification of tumors of the digestive system grades all the pancreatic neuroendocrine tumors (PanNETs) into three categories, based on their degree of cellular differentiation (from “NET G1” through to the poorly differentiated “NET G3”). The U.S. National Comprehensive Cancer Network recommends use of the same AJCC-UICC staging system as pancreatic adenocarcinoma. Using this scheme, the stage-bystage outcomes for PanNETs are dissimilar to those of the exocrine cancers. A different TNM system for PanNETs has been proposed by the European Neuroendocrine Tumor Society.

PREVENTION AND SCREENING Apart from not smoking, the American Cancer Society recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains, while decreasing consumption of red and processed meat, although there is no consistent evidence this will prevent or reduce pancreatic cancer specifically. A 2014 review of research concluded that there was evidence that consumption of citrus fruits and curcumin reduced risk of pancreatic cancer, while there was possibly a beneficial effect from whole grains, folate, selenium, and non-fried fish. In the general population, screening of large groups is not currently considered effective, although newer techniques, and the screening of tightly targeted groups, are being evaluated. Nevertheless, regular screening with endoscopic ultrasound and MRI/CT imaging is recommended for those at high risk from inherited genetics.

MANAGEMENT

Exocrine Cancer A key assessment that is made after diagnosis is whether surgical removal of the tumor is possible, as this is the only cure for this cancer. Whether or not surgical resection can be offered depends on how much the cancer

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has spread. The exact location of the tumor is also a significant factor, and CT can show how it relates to the major blood vessels passing close to the pancreas. The general health of the person must also be assessed, though age in itself is not an obstacle to surgery. Chemotherapy and, to a lesser extent, radiotherapy are likely to be offered to most people, whether or not surgery is possible. Specialists advise that the management of pancreatic cancer should be in the hands of a multidisciplinary team including specialists in several aspects of oncology, and is, therefore, best conducted in larger centers.

Surgery Surgery with the intention of a cure is only possible in around one-fifth (20%) of new cases. Although CT scans help, in practice it can be difficult to determine whether the tumor can be fully removed (its “resectability”), and it may only become apparent during surgery that it is not possible to successfully remove the tumor without damaging other vital tissues. Whether or not surgical resection can be offered depends on various factors, including the precise extent of local anatomical adjacency to, or involvement of, the venous or arterial blood vessels, as well as surgical expertise and a careful consideration of projected post-operative recovery. The age of the person is not in itself a reason not to operate, but their general performance status needs to be adequate for a major operation. One particular feature that is evaluated is the encouraging presence, or discouraging absence, of a clear layer or plane of fat creating a barrier between the tumor and the vessels. Traditionally, an assessment is made of the tumor’s proximity to major venous or arterial vessels, in terms of “abutment” (defined as the tumor touching no more than half a blood vessel’s circumference without any fat to separate it), “encasement” (when the tumor encloses most of the vessel’s circumference), or full vessel involvement. A resection that includes encased sections of blood vessels may be possible in some cases, particularly if preliminary neo-adjuvant therapy is feasible, using chemotherapy and/or radiotherapy. Even when the operation appears to have been successful, cancerous cells are often found around the edges (“margins”) of the removed tissue, when a pathologist examines them microscopically (this will always be done), indicating the cancer has not been entirely removed. Furthermore, cancer stem cells are usually not evident microscopically, and if they are present they may continue to develop and spread. An exploratory laparoscopy (a small, camera-guided surgical procedure) may therefore be performed to gain a clearer idea of the outcome of a full operation. For cancers involving the head of the pancreas, the Whipple procedure is the most commonly attempted curative surgical treatment. This is a major operation which involves removing the pancreatic head and the curve of the duodenum together (“pancreato-duodenectomy”), making a bypass for food from the stomach to the jejunum (“gastrojejunostomy”) and attaching a loop of jejunum to the cystic duct to drain bile (“cholecysto-jejunostomy”). It can be performed only if the person is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can, therefore, be performed only in a minority of cases. Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy, which often also entails removal of the spleen. Nowadays, this can often be done using minimally invasive surgery. Although curative surgery no longer entails the very high death rates that occurred until the 1980s, a high proportion of people (about 30–45%) still have to be treated for a post-operative sickness that is not caused by the cancer itself. The most common complication of surgery is difficulty in emptying the stomach. Certain more limited surgical procedures may also be used to ease symptoms: for instance, if the cancer is invading or compressing the duodenum or colon. In such cases, bypass surgery might overcome the obstruction and improve quality of life but is not intended as a cure.

Chemotherapy After surgery, adjuvant chemotherapy with gemcitabine or 5-FU can be offered if the person is sufficiently fit, after a recovery period of one to two months. In people not suitable for curative surgery, chemotherapy may

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be used to extend life or improve its quality. Before surgery, neo-adjuvant chemotherapy or chemoradiotherapy may be used in cases that are considered to be “borderline resectable” in order to reduce the cancer to a level where surgery could be beneficial. In other cases neo-adjuvant therapy remains controversial, because it delays surgery. Gemcitabine was approved by the United States Food and Drug Administration (FDA) in 1997, after a clinical trial reported improvements in quality of life and a 5-week improvement in median survival duration in people with advanced pancreatic cancer. This was the first chemotherapy drug approved by the FDA primarily for a non-survival clinical trial endpoint. Chemotherapy using gemcitabine alone was the standard for about a decade, as a number of trials testing it in combination with other drugs failed to demonstrate significantly better outcomes. However, the combination of gemcitabine with erlotinib was found to increase survival modestly, and erlotinib was licensed by the FDA for use in pancreatic cancer in 2005. The FOLFIRINOX chemotherapy regimen using four drugs was found more effective than gemcitabine, but with substantial side effects, and is thus only suitable for people with good performance status. This is also true of protein-bound paclitaxel (nabpaclitaxel), which was licensed by the FDA in 2013 for use with gemcitabine in pancreas cancer. By the end of 2013, both FOLFIRINOX and nab-paclitaxel with gemcitabine were regarded as good choices for those able to tolerate the side-effects, and gemcitabine remained an effective option for those who were not. A head-to-head trial between the two new options is awaited, and trials investigating other variations continue. However, the changes of the last few years have only increased survival times by a few months. Clinical trials are often conducted for novel adjuvant therapies.

Radiotherapy The role of radiotherapy as an auxiliary (adjuvant) treatment after potentially curative surgery has been controversial since the 1980s. The European Society for Medical Oncology recommends that adjuvant radiotherapy should only be used for people enrolled in clinical trials. However, there is a continuing tendency for clinicians in the US to be more ready to use adjuvant radiotherapy than those in Europe. Many clinical trials have tested a variety of treatment combinations since the 1980s, but have failed to settle the matter conclusively. Radiotherapy may form part of treatment to attempt to shrink a tumor to a resectable state, but its use on unresectable tumors remains controversial as there are conflicting results from clinical trials. The preliminary results of one trial, presented in 2013, “markedly reduced enthusiasm” for its use on locally advanced tumors.

PanNETs Treatment of PanNETs, including the less common malignant types, may include a number of approaches. Some small tumors of less than 1 cm. that are identified incidentally, for example on a CT scan performed for other purposes, may be followed by watchful waiting. This depends on the assessed risk of surgery which is influenced by the site of the tumor and the presence of other medical problems. Tumors within the pancreas only (localized tumors), or with limited metastases, for example to the liver, may be removed by surgery. The type of surgery depends on the tumor location, and the degree of spread to lymph nodes. For localized tumors, the surgical procedure may be much less extensive than the types of surgery used to treat pancreatic adenocarcinoma described above, but otherwise surgical procedures are similar to those for exocrine tumors. The range of possible outcomes varies greatly; some types have a very high survival rate after surgery while others have a poor outlook. As all this group are rare, guidelines emphasize that treatment should be undertaken in a specialized center. Use of liver transplantation may be considered in certain cases of liver metastasis. For functioning tumors, the somatostatin analog class of medications, such as octreotide, can reduce the excessive production of hormones. Lanreotide can slow tumor growth. If the tumor is not amenable to surgical

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removal and is causing symptoms, targeted therapy with everolimus or sunitinib can reduce symptoms and slow progression of the disease. Standard cytotoxic chemotherapy is generally not very effective for PanNETs, but may be used when other drug treatments fail to prevent the disease from progressing, or in poorly differentiated PanNET cancers. Radiation therapy is occasionally used if there is pain due to anatomic extension, such as metastasis to bone. Some PanNETs absorb specific peptides or hormones, and these PanNETs may respond to nuclear medicine therapy with radiolabeled peptides or hormones such as iobenguane (iodine-131-MIBG). Radiofrequency ablation (RFA), cryoablation, and hepatic artery embolization may also be used.

Palliative Care Palliative care is medical care which focuses on treatment of symptoms from serious illness, such as cancer, and improving quality of life. Because pancreatic adenocarcinoma is usually diagnosed after it has progressed to an advanced stage, palliative care as a treatment of symptoms is often the only treatment possible. Palliative care focuses not on treating the underlying cancer, but on treating symptoms such as pain or nausea, and can assist in decision-making, including when or if hospice care will be beneficial. Pain can be managed with medications such as opioids or through procedural intervention, by a nerve block on the celiac plexus (CPB). This alters or, depending on the technique used, destroys the nerves that transmit pain from the abdomen. CPB is a safe and effective way to reduce the pain, which generally reduces the need to use opioid painkillers, which have significant negative side effects. Other symptoms or complications that can be treated with palliative surgery are obstruction by the tumor of the intestines or bile ducts. For the latter, which occurs in well over half of cases, a small metal tube called a stent may be inserted by endoscope to keep the ducts draining. Palliative care can also help treat depression that often comes with the diagnosis of pancreatic cancer. Both surgery and advanced inoperable tumors often lead to digestive system disorders from a lack of the exocrine products of the pancreas (exocrine insufficiency). These can be treated by taking pancreatin which contains manufactured pancreatic enzymes, and is best taken with food. Difficulty in emptying the stomach (delayed gastric emptying) is common and can be a serious problem, involving hospitalization. Treatment may involve a variety of approaches, including draining the stomach by nasogastric aspiration and drugs called proton-pump inhibitors or H2 antagonists, which both reduce production of gastric acid. Medications like metoclopramide can also be used to clear stomach contents.

OUTCOMES Pancreatic adenocarcinoma and the other less common exocrine cancers have a very poor prognosis, as they are normally diagnosed at a late stage when the cancer is already locally advanced or has spread to other parts of the body. Outcomes are much better for PanNETs: many are benign and completely without clinical symptoms, and even those cases not treatable with surgery have an average five-year survival rate of 16%, although the outlook varies considerably according to the type. For locally advanced and metastatic pancreatic adenocarcinomas, which together represent over 80% of cases, numerous recent trials comparing chemotherapy regimes have shown increased survival times, but not to more than one year. Overall five-year survival for pancreatic cancer in the US has improved from 2% in cases diagnosed in 1975–77, and 4% in 1987–89 diagnoses, to 6% in 2003–09. In the less than 20% of cases of pancreatic adenocarcinoma with a diagnosis of a localized and small cancerous growth (less than 2 cm in Stage T1), about 20% of Americans survive to five years. About 1500 genes are linked to outcomes in pancreatic adenocarcinoma. These include both unfavourable genes, where high expression is related to poor outcome, for example C-Met and MUC-1, and favourable genes where high expression is associated with better survival, for example the transcription factor PELP1.

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HEP ATOCELL UL AR CAR CINOMA HEPA OCELLUL ULAR CARCINOMA Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults, and is the most common cause of death in people with cirrhosis. It occurs in the setting of chronic liver inflammation, and is most closely linked to chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol or aflatoxin. Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency, markedly increase the risk of developing HCC. Metabolic syndrome and NASH are also increasingly recognized as risk factors for HCC. As with any cancer, the treatment and prognosis of HCC vary depending on the specifics of tumor histology, size, how far the cancer has spread, and overall health. The vast majority of HCC occurs in Asia and sub-Saharan Africa, in countries where hepatitis B infection is endemic and many are infected from birth. The incidence of HCC in the United States and other developing countries is increasing due to an increase in hepatitis C virus infections. It is more common in males than females for unknown reasons.

SIGNS AND SYMPTOMS Most cases of HCC occur in people who already have signs and symptoms of chronic liver disease. They may present either with worsening of symptoms or may be without symptoms at the time of cancer detection. HCC may directly present with yellow skin, abdominal swelling due to fluid in the abdominal cavity, easy bruising from blood clotting abnormalities, loss of appetite, unintentional weight loss, abdominal pain, nausea, vomiting, or feeling tired.

RISK FACTORS HCC mostly occurs in people with cirrhosis of the liver, and so risk factors generally include factors which cause chronic liver disease that may lead to cirrhosis. Still, certain risk factors are much more highly associated with HCC than others. For example, while heavy alcohol consumption is estimated to cause 6070% of cirrhosis, the vast majority of HCC occurs in cirrhosis attributed to viral hepatitis (although there may be overlap). Recognized risk factors include: • Chronic viral hepatitis (estimated cause of 80% cases globally) a. Chronic hepatitis B (approximately 50% cases) b. Chronic hepatitis C (approximately 25% cases) • Toxins: a. Alcohol abuse: the most common cause of cirrhosis b. Aflatoxin c. Iron overload state (Hemochromatosis) • Metabolic: a. Non-alcoholic steatohepatitis: up to 20% progress to cirrhosis b. Type 2 diabetes (probably aided by obesity) • Congenital disorders: a. Alpha 1-antitrypsin deficiency b. Wilson’s disease (controversial; while some theorise the risk increases, case studies are rare and suggest the opposite where Wilson’s disease actually may confer protection) c. Hemophilia, although statistically associated with higher risk of HCC, this is due to coincident chronic viral hepatitis infection related to repeated blood transfusions over lifetime. The significance of these risk factors varies globally. In regions where hepatitis B infection is endemic, such as southeast China, this is the predominant cause. In populations largely protected by hepatitis B vaccination,

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such as the United States, HCC is most often linked to causes of cirrhosis such as chronic hepatitis C, obesity, and alcohol abuse. Certain benign liver tumors, such as hepatocellular adenoma, may sometimes be associated with coexisting malignant HCC. There is limited evidence for the true incidence of malignancy associated with benign adenomas; however, the size of hepatic adenoma is considered to correspond to risk of malignancy and so larger tumors may be surgically removed. Certain subtypes of adenoma, particularly those with β-catenin activation mutation, are particularly associated with increased risk of HCC. Children and adolescents are unlikely to have chronic liver disease, however, if they suffer from congenital liver disorders, this fact increases the chance of developing hepatocellular carcinoma. Specifically, children with biliary atresia, infantile cholestasis, glycogen-storage diseases, and other cirrhotic diseases of the liver are predisposed to developing HCC in childhood. Young adults afflicted by the rare fibrolamellar variant of hepatocellular carcinoma may have none of the typical risk factors, i.e. cirrhosis and hepatitis.

Diabetes Mellitus The risk of hepatocellular carcinoma in type 2 diabetics is greater (from 2.5 to 7.1 times the non diabetic risk) depending on the duration of diabetes and treatment protocol. A suspected contributor to this increased risk is circulating insulin concentration such that diabetics with poor insulin control or on treatments that elevate their insulin output (both states that contribute to a higher circulating insulin concentration) show far greater risk of hepatocellular carcinoma than diabetics on treatments that reduce circulating insulin concentration. On this note, some diabetics who engage in tight insulin control (by keeping it from being elevated) show risk levels low enough to be indistinguishable from the general population. This phenomenon is thus not isolated to diabetes mellitus type 2 since poor insulin regulation is also found in other conditions such as metabolic syndrome (specifically, when evidence of non alcoholic fatty liver disease or NAFLD is present) and again there is evidence of greater risk here too. While there are claims that anabolic steroid abusers are at greater risk (theorized to be due to insulin and IGF exacerbation), the only evidence that has been confirmed is that anabolic steroid users are more likely to have hepatocellular adenomas (a benign form of HCC) transform into the more dangerous hepatocellular carcinoma.

‘PATHOGENESIS Hepatocellular carcinoma, like any other cancer, develops when there are epigenetic alterations and mutations affecting the cellular machinery that cause the cell to replicate at a higher rate and/or result in the cell avoiding apoptosis. In particular, chronic infections of hepatitis B and/or C can aid the development of hepatocellular carcinoma by repeatedly causing the body’s own immune system to attack the liver cells, some of which are infected by the virus, others merely bystanders. Activated immune system inflammatory cells release free radicals, such as reactive oxygen species and nitric oxide reactive species, which in turn can cause DNA damage and lead to carcinogenic gene mutations. Reactive oxygen species also cause epigenetic alterations at the sites of DNA repair. While this constant cycle of damage followed by repair can lead to mistakes during repair which in turn lead to carcinogenesis, this hypothesis is more applicable, at present, to hepatitis C. Chronic hepatitis C causes HCC through the stage of cirrhosis. In chronic hepatitis B, however, the integration of the viral genome into infected cells can directly induce a non-cirrhotic liver to develop HCC. Alternatively, repeated consumption of large amounts of ethanol can have a similar effect. The toxin aflatoxin from certain Aspergillus species of fungus is a carcinogen and aids carcinogenesis of hepatocellular cancer by building up in the liver. The combined high prevalence of rates of aflatoxin and hepatitis B in settings like China and West Africa has led to relatively high rates of hepatocellular carcinoma in these regions. Other viral hepatitides such as hepatitis A have no potential to become a chronic infection and thus are not related to hepatocellular carcinoma.

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DIAGNOSIS Methods of diagnosis in HCC have evolved with the improvement in medical imaging. The evaluation of both asymptomatic patients and those with symptoms of liver disease involves blood testing and imaging evaluation. Although historically a biopsy of the tumor was required to prove the diagnosis, imaging (especially MRI) findings may be conclusive enough to obviate histopathologic confirmation.

Screening HCC remains associated with a high mortality rate, in part related to initial diagnosis commonly at an advanced stage of disease. As with other cancers, outcomes are significanty improved if treatment is initiated earlier in the disease process. Because the vast majority of HCC occurs in people with certain chronic liver diseases, especially those with cirrhosis, liver screening is commonly advocated in this population. Specific screening guidelines continue to evolve over time as evidence of its clinical impact becomes available. In the United States, the most commonly observed guidelines are those published by the American Association for the Study of Liver Diseases (AASLD). The AASLD recommends screening people with cirrhosis with ultrasound every 6 months, with or without measurement of blood levels of tumor marker AFP. Elevated levels of AFP are associated with active HCC disease, although inconsistently reliable. At levels >20 sensitivity is 41-65% and specificity is 80-94%. However, at levels >200 sensitivity is 31, specificity is 99%. On US, HCC often appears as a small hypoechoic lesion with poorly defined margins and coarse irregular internal echoes. When the tumor grows, it can sometimes appear heterogeneous with fibrosis, fatty change, and calcifications. This heterogeneity can look similar to cirrhosis and the surrounding liver parenchyma. A systematic review found that the sensitivity was 60 percent (95% CI 44-76%) and specificity was 97 percent (95% CI 95-98%) compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity increases to 79% with AFP correlation. There remains controversy as to the most effective screening protocols. For example, while there is data to support decreased mortality related to screening in people with hepatitis B infection, the AASLD notes that “there are no randomized trials [for screening] in Western populations with cirrhosis secondary to chronic hepatitis C or fatty liver disease, and thus there is some controversy surrounding whether surveillance truly leads to a reduction in mortality in this population of patients with cirrhosis.”

Higher Risk People In a person where there is higher suspicion of HCC, such as a person with symptoms or abnormal blood tests (i.e. alpha-fetoprotein and des-gamma carboxyprothrombin levels), evaluation requires imaging of the liver by CT or MRI scans. Optimally, these scans are performed with intravenous contrast in multiple phases of hepatic perfusion in order to improve detection and accurate classification of any liver lesions by the interpreting radiologist. Due to the characteristic blood flow pattern of HCC tumors, a specific perfusion pattern of any detected liver lesion may conclusively detect an HCC tumor. Alternatively, the scan may detect an indeterminate lesion and further evaluation may be performed by obtaining a physical sample of the lesion.

Imaging Ultrasound, CT scan, and MRI may be used to evaluate the liver for HCC. On CT and MRI, HCC can have three distinct patterns of growth: • A single large tumor • Multiple tumors • Poorly defined tumor with an infiltrative growth pattern.

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A systematic review of CT diagnosis found that the sensitivity was 68 percent (95% CI 55-80%) and specificity was 93 percent (95% CI 89-96%) compared with pathologic examination of an explanted or resected liver as the reference standard. With triple-phase helical CT, the sensitivity 90% or higher, but this data has not been confirmed with autopsy studies. However, MRI has the advantage of delivering high-resolution images of the liver without ionizing radiation. HCC appears as a high-intensity pattern on T2 weighted images and a lowintensity pattern on T1 weighted images. The advantage of MRI is that is has improved sensitivity and specificity when compared to US and CT in cirrhotic patients with whom it can be difficult to differentiate HCC from regenerative nodules. A systematic review found that the sensitivity was 81 percent (95% CI 70-91%) and specificity was 85 percent (95% CI 77-93%) compared with pathologic examination of an explanted or resected liver as the reference standard. The sensitivity is further increased if gadolinium contrast-enhanced and diffusionweighted imaging are combined. MRI is more sensitive and specific than CT. Liver Image Reporting and Data System (LI-RADS) is a classification system for the reporting of liver lesions detected on CT and MRI. Radiologists use this standardized system to report on suspicious lesions and to provide an estimated likelihood of malignancy. Categories range from LI-RADS (LR) 1 to 5, in order of concern for cancer. A biopsy is not needed to confirm the diagnosis of HCC if certain imaging criteria are met.

Pathology Macroscopically, liver cancer appears as a nodular or infiltrative tumor. The nodular type may be solitary (large mass) or multiple (when developed as a complication of cirrhosis). Tumor nodules are round to oval, gray or green (if the tumor produces bile), well circumscribed but not encapsulated. The diffuse type is poorly circumscribed and infiltrates the portal veins, or the hepatic veins (rarely). Microscopically, there are four architectural and cytological types (patterns) of hepatocellular carcinoma: fibrolamellar, pseudoglandular (adenoid), pleomorphic (giant cell) and clear cell. In well-differentiated forms, tumor cells resemble hepatocytes, form trabeculae, cords, and nests, and may contain bile pigment in the cytoplasm. In poorly differentiated forms, malignant epithelial cells are discohesive, pleomorphic, anaplastic, giant. The tumor has a scant stroma and central necrosis because of the poor vascularization.

Staging The prognosis of HCC is affected by the staging of the tumor as well as the liver’s function due to the effects of liver cirrhosis. There are a number of staging classifications for HCC available; however, due to the unique nature of the carcinoma in order to fully encompass all the features that affect the categorization of the HCC, a classification system should incorporate; tumor size and number, presence of vascular invasion and extrahepatic spread, liver function (levels of serum bilirubin and albumin, presence of ascites and portal hypertension) and general health status of the patient (defined by the ECOG classification and the presence of symptoms). Out of all the staging classification systems available the Barcelona Clinic Liver Cancer (BCLC) staging classification encompasses all of the above characteristics. This staging classification can be used in order to select people for treatment. Important features that guide treatment include the following: • Size • Spread (stage) • Involvement of liver vessels • Presence of a tumor capsule • Presence of extrahepatic metastases • Presence of daughter nodules • Vascularity of the tumor.

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MRI is the best imaging method to detect the presence of a tumor capsule. The most common sites of metastasis are the lung, abdominal lymph nodes, and bone.

PREVENTION Since hepatitis B or C is one of the main causes of hepatocellular carcinoma, prevention of this infection is key to then prevent hepatocellular carcinoma. Thus, childhood vaccination against hepatitis B may reduce the risk of liver cancer in the future. In the case of patients with cirrhosis, alcohol consumption is to be avoided. Also, screening for hemochromatosis may be beneficial for some patients. It is unclear if screening those with chronic liver disease for hepatocellular carcinoma improves outcomes.

TREATMENT Treatment of hepatocellular carcinoma varies by the stage of disease, a person’s likelihood to tolerate surgery, and availability of liver transplant: • Curative intention: for limited disease, when the cancer is limited to one or more areas of within the liver, surgically removing the malignant cells may be curative. This may be accomplished by resection the affected portion of the liver (partial hepatectomy) or in some cases by orthotopic liver transplantation of the entire organ. • “Bridging” intention: for limited disease which qualifies for potential liver transplantation, the person may undergo targeted treatment of some or all of the known tumor while waiting for a donor organ to become available. • “Downstaging” intention: for moderately advanced disease which has not spread beyond the liver, but is too advanced to qualify for curative treatment. The person may be treated by targeted therapies in order to reduce the size or number of active tumors, with the goal of once again qualifying for liver transplant after this treatment. • Palliative intention: for more advanced disease, including spread of cancer beyond the liver or in persons who may not tolerate surgery, treatment intended to decrease symptoms of disease and maximize duration of survival. Loco-regional therapy (also referred to as liver-directed therapy) refers to any one of several minimallyinvasive treatment techniques to focally target HCC within the liver. These procedures are alternatives to surgery, and may be considered in combination with other strategies, such as a later liver transplantation. Generally, these treatment procedures are performed by interventional radiologists or surgeons, in coordination with a medical oncologist. Loco-regional therapy may refer to either percutaneous therapies (e.g. cryoablation), or arterial catheter-based therapies (chemoembolization or radioembolization).

Surgical Resection Surgical removal of the tumor is associated with better cancer prognosis, but only 10-15% of patients are suitable for surgical resection due to the extent of disease or poor liver function. Surgery is only considered if the entire tumor can be safely removed while preserving sufficient functional liver to maintain normal physiology. Thus, pre-operative imaging assessment is critical in order to determine both the extent of HCC and to estimate the amount of residual liver remaining after surgery. In order to maintain liver function, residual liver volume should exceed 25% of total liver volume in a non-cirrhotic liver, greater than 40% in a cirrhotic liver. Surgery on diseased or cirrhotic livers is generally associated with higher morbidity and mortality. The overall recurrence rate after resection is 50-60%. The Singapore Liver Cancer Recurrence (SLICER) score can be used to estimate risk of recurrence after surgery.

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Liver Transplantation Liver transplantation, replacing the diseased liver with a cadaveric or a living donor liver, plays an increasing role in treatment of HCC. Although outcomes following liver transplant were initially poor (20%-36% survival rate), outcomes have significantly improved with improvement in surgical techniques and adoption of the Milan criteria at US transplantation centers. Expanded Shanghai criteria in China have resulted in overall survival and disease-free survival rates similar to those achieved using the Milan criteria. Studies from the late 2000s obtained higher survival rates ranging from 67% to 91%. The risks of liver transplantation extend beyond risk of the procedure itself. The immunosuppressive medication which are required after surgery to prevent rejection of the donor liver also impair the body’s natural ability to combat dysfunctional cells. If tumor has spread undetected outside the liver before the transplant, the medication effectively increases the rate of disease progression and decreases survival. With this in mind, liver transplant “can be a curative approach for patients with advanced HCC without extrahepatic metastasis”. Patient selection is considered a major key for success.

Ablation •

•

•

Radiofrequency ablation (RFA) uses high-frequency radio waves to destroy tumor by local heating. The electrodes are inserted into the liver tumor under ultrasound image guidance using percutaneous, laparoscopic or open surgical approach. It is suitable for small tumors (5 cm, 2.1 to 5 cm, and ≤2 cm were 59, 74, and 91 percent, respectively. A large randomized trial comparing surgical resection and RFA for small HCC showed similar 4 year survival and less morbidities for patients treated with RFA. Cryoablation: Cryoablation is a technique used to destroy tissue using cold temperature. The tumor is not removed and the destroyed cancer is left to be reabsorbed by the body. Initial results in properly selected patients with unresectable liver tumors are equivalent to those of resection. Cryosurgery involves the placement of a stainless steel probe into the center of the tumor. Liquid nitrogen is circulated through the end of this device. The tumor and a half inch margin of normal liver are frozen to -190 °C for 15 minutes, which is lethal to all tissues. The area is thawed for 10 minutes and then re-frozen to 190 °C for another 15 minutes. After the tumor has thawed, the probe is removed, bleeding is controlled, and the procedure is complete. The patient will spend the first post-operative night in the intensive care unit and typically is discharged in 3 – 5 days. Proper selection of patients and attention to detail in performing the cryosurgical procedure are mandatory in order to achieve good results and outcomes. Frequently, cryosurgery is used in conjunction with liver resection as some of the tumors are removed while others are treated with cryosurgery. Percutaneous ethanol injection (PEI) well tolerated, high RR in small (8 cm), the presence of portal vein thrombus, tumors with a portal-systemic shunt, and patients with poor liver function. Selective internal radiation therapy (SIRT) can be used to destroy the tumor from within (thus minimizing exposure to healthy tissue). Similar to TACE, this is a procedure in which an interventional radiologist selectively injects the artery or arteries supplying the tumor with a chemotherapeutic agent. The agent is typically Yttrium-90 (Y-90) incorporated into embolic microspheres that lodge in the tumor vasculature causing ischemia and delivering their radiation dose directly to the lesion. This technique allows for a higher, local dose of radiation to be delivered directly to the tumor while sparing normal healthy tissue. While not curative, patients have increased survival. No studies have been done to compare whether SIRT is superior to TACE in terms of survival outcomes, although retrospective studies suggest similar efficacy. There are currently two products available, SIR-Spheres and TheraSphere. The latter is an FDA approved treatment for primary liver cancer (HCC) which has been shown in clinical trials to increase the survival rate of low-risk patients. SIR-Spheres are FDA approved for the treatment of metastatic colorectal cancer but outside the US SIR-Spheres are approved for the treatment of any non-resectable liver cancer including primary liver cancer.

Systemic In disease which has spread beyond the liver, systemic therapy may be a consideration. In 2007, sorafenib, an oral multikinase inhibitor, was the first systemic agent approved for first-line treatment of advanced HCC. Trials have found modest improvement in overall survival: 10.7 months vs 7.9 months and 6.5 months vs 4.2 months. The most common side effects of sorafenib include a hand-foot skin reaction and diarrhea. Sorafenib is thought to work by blocking growth of both tumor cells and new blood vessels. Numerous other molecular targeted drugs are being tested as alternative first and second-line treatments for advanced HCC.

Other •

• •

Portal Vein Embolization (PVE): This technique is sometimes used to increase the volume of healthy liver, in order to improve chances of survival following surgical removal of diseased liver. For example, embolization of the right main portal vein would result in compensatory hypertrophy of the left lobe, which may qualify the patient for a partial hepatectomy. Embolization is performed by an interventional radiologist using a percutaneous transhepatic approach. This procedure can also serve as a bridge to transplant. High intensity focused ultrasound (HIFU) (as opposed to diagnostic ultrasound) is an experimental technique which uses high-powered ultrasound waves to destroy tumor tissue. A systematic review assessed 12 articles involving a total of 318 patients with hepatocellular carcinoma treated with Yttrium-90 radioembolization. Excluding a study of only one patient, post-treatment CT evaluation of the tumor showed a response ranging from 29 to 100% of patients evaluated, with all but two studies showing a response of 71% or greater.

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PROGNOSIS The usual outcome is poor, because only 10–20% of hepatocellular carcinomas can be removed completely using surgery. If the cancer cannot be completely removed, the disease is usually deadly within 3 to 6 months. This is partially due to late presentation with tumors, but also the lack of medical expertise and facilities in the regions with high HCC prevalence. However, survival can vary, and occasionally people will survive much longer than 6 months. The prognosis for metastatic or unresectable hepatocellular carcinoma has recently improved due to the approval of sorafenib (Nexavar®) for advanced hepatocellular carcinoma.

COL ORECT AL C ANCER COLORECT ORECTAL CANCER Colorectal cancer (CRC), also known as bowel cancer and colon cancer, is the development of cancer from the colon or rectum (parts of the large intestine). A cancer is the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Signs and symptoms may include blood in the stool, a change in bowel movements, weight loss, and feeling tired all the time. Most colorectal cancers are due to old age and lifestyle factors with only a small number of cases due to underlying genetic disorders. Some risk factors include diet, obesity, smoking, and lack of physical activity. Dietary factors that increase the risk include red and processed meat as well as alcohol. Another risk factor is inflammatory bowel disease, which includes Crohn’s disease and ulcerative colitis. Some of the inherited genetic disorders that can cause colorectal cancer include familial adenomatous polyposis and hereditary non-polyposis colon cancer; however, these represent less than 5% of cases. It typically starts as a benign tumor, often in the form of a polyp, which over time becomes cancerous. Bowel cancer may be diagnosed by obtaining a sample of the colon during a sigmoidoscopy or colonoscopy. This is then followed by medical imaging to determine if the disease has spread. Screening is effective for preventing and decreasing deaths from colorectal cancer. Screening, by one of a number of methods, is recommended starting from the age of 50 to 75. During colonoscopy, small polyps may be removed if found. If a large polyp or tumor is found, a biopsy may be performed to check if it is cancerous. Aspirin and other non-steroidal anti-inflammatory drugs decrease the risk. Their general use is not recommended for this purpose, however, due to side effects. Treatments used for colorectal cancer may include some combination of surgery, radiation therapy, chemotherapy and targeted therapy. Cancers that are confined within the wall of the colon may be curable with surgery while cancer that has spread widely are usually not curable, with management being directed towards improving quality of life and symptoms. The five-year survival rate in the United States is around 65%. The individual likelihood of survival depends on how advanced the cancer is, whether or not all the cancer can be removed with surgery, and the person’s overall health. Globally, colorectal cancer is the third most common type of cancer, making up about 10% of all cases. In 2012, there were 1.4 million new cases and 694,000 deaths from the disease. It is more common in developed countries, where more than 65% of cases are found. It is less common in women than men.

SIGNS AND SYMPTOMS The signs and symptoms of colorectal cancer depend on the location of the tumor in the bowel, and whether it has spread elsewhere in the body (metastasis). The classic warning signs include: worsening constipation, blood in the stool, decrease in stool calibre (thickness), loss of appetite, loss of weight, and nausea or vomiting in someone over 50 years old. While rectal bleeding or anemia are high-risk features in those over the age of 50, other commonly described symptoms including weight loss and change in bowel habit are typically only concerning if associated with bleeding.

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CAUSE Greater than 75–95% of colorectal cancer occurs in people with little or no genetic risk. Risk factors include older age, male gender, high intake of fat, alcohol, red meat, processed meats, obesity, smoking, and a lack of physical exercise. Approximately 10% of cases are linked to insufficient activity. The risk from alcohol appears to increase at greater than one drink per day. Drinking 5 glasses of water a day is linked to a decrease in the risk of colorectal cancer and adenomatous polyps. Streptococcus gallolyticus is associated with colorectal cancer. Some strains of Streptococcus bovis/Streptococcus equinus complex are consumed by millions of people daily and thus may be safe. 25 to 80% of people with Streptococcus bovis/gallolyticus bacteremia have concomitant colorectal tumors. Seroprevalence of Streptococcus bovis/gallolyticus is considered as a candidate practical marker for the early prediction of an underlying bowel lesion at high risk population. It has been suggested that the presence of antibodies to Streptococcus bovis/gallolyticus antigens or the antigens themselves in the bloodstream may act as markers for the carcinogenesis in the colon.

Inflammatory Bowel Disease People with inflammatory bowel disease (ulcerative colitis and Crohn’s disease) are at increased risk of colon cancer. The risk increases the longer a person has the disease, and the worse the severity of inflammation. In these high risk groups, both prevention with aspirin and regular colonoscopies are recommended. People with inflammatory bowel disease account for less than 2% of colon cancer cases yearly. In those with Crohn’s disease 2% get colorectal cancer after 10 years, 8% after 20 years, and 18% after 30 years. In those with ulcerative colitis approximately 16% develop either a cancer precursor or cancer of the colon over 30 years.

Genetics Those with a family history in two or more first-degree relatives (such as a parent or sibling) have a two to threefold greater risk of disease and this group accounts for about 20% of all cases. A number of genetic syndromes are also associated with higher rates of colorectal cancer. The most common of these is hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of people with colorectal cancer. Other syndromes that are strongly associated with colorectal cancer include Gardner syndrome, and familial adenomatous polyposis (FAP). For people with these syndromes, cancer almost always occurs and makes up 1% of the cancer cases. A total proctocolectomy may be recommended for people with FAP as a preventative measure due to the high risk of malignancy. Colectomy, removal of the colon, may not suffice as a preventative measure because of the high risk of rectal cancer if the rectum remains. Most deaths due to colon cancer are associated with metastatic disease. A gene that appears to contribute to the potential for metastatic disease, metastasis associated in colon cancer 1 (MACC1), has been isolated. It is a transcriptional factor that influences the expression of hepatocyte growth factor. This gene is associated with the proliferation, invasion and scattering of colon cancer cells in cell culture, and tumor growth and metastasis in mice. MACC1 may be a potential target for cancer intervention, but this possibility needs to be confirmed with clinical studies. Epigenetic factors, such as abnormal DNA methylation of tumor suppressor promoters play a role in the development of colorectal cancer.

PATHOGENESIS Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract, most frequently as a result of mutations in the Wnt signaling pathway that increase signaling activity. The mutations can be inherited or acquired, and most probably occur in the intestinal crypt stem cell.

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The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein. The APC protein prevents the accumulation of β-catenin protein. Without APC, β-catenin accumulates to high levels and translocates (moves) into the nucleus, binds to DNA, and activates the transcription of proto-oncogenes. These genes are normally important for stem cell renewal and differentiation, but when inappropriately expressed at high levels, they can cause cancer. While APC is mutated in most colon cancers, some cancers have increased β-catenin because of mutations in β-catenin (CTNNB1) that block its own breakdown, or have mutations in other genes with function similar to APC such as AXIN1, AXIN2, TCF7L2, or NKD1. Beyond the defects in the Wnt signaling pathway, other mutations must occur for the cell to become cancerous. The p53 protein, produced by the TP53 gene, normally monitors cell division and kills cells if they have Wnt pathway defects. Eventually, a cell line acquires a mutation in the TP53 gene and transforms the tissue from a benign epithelial tumor into an invasive epithelial cell cancer. Sometimes the gene encoding p53 is not mutated, but another protective protein named BAX is mutated instead. Other proteins responsible for programmed cell death that are commonly deactivated in colorectal cancers are TGF-β and DCC (Deleted in Colorectal Cancer). TGF-β has a deactivating mutation in at least half of colorectal cancers. Sometimes TGF-β is not deactivated, but a downstream protein named SMAD is deactivated. DCC commonly has a deleted segment of a chromosome in colorectal cancer. Approximately 70% of all human genes are expressed in colorectal cancer, with just over 1% of having increased expression in colorectal cancer compared to other forms of cancer. Some genes are oncogenes: they are overexpressed in colorectal cancer. For example, genes encoding the proteins KRAS, RAF, and PI3K, which normally stimulate the cell to divide in response to growth factors, can acquire mutations that result in over-activation of cell proliferation. The chronological order of mutations is sometimes important. If a previous APC mutation occurred, a primary KRAS mutation often progresses to cancer rather than a self-limiting hyperplastic or borderline lesion. PTEN, a tumor suppressor, normally inhibits PI3K, but can sometimes become mutated and deactivated. Comprehensive, genome-scale analysis has revealed that colorectal carcinomas can be categorized into hypermutated and non-hypermutated tumor types. In addition to the oncogenic and inactivating mutations described for the genes above, non-hypermutated samples also contain mutated CTNNB1, FAM123B, SOX9, ATM, and ARID1A. Progressing through a distinct set of genetic events, hypermutated tumors display mutated forms of ACVR2A, TGFBR2, MSH3, MSH6, SLC9A9, TCF7L2, and BRAF. The common theme among these genes, across both tumor types, is their involvement in WNT and TGF-β signaling pathways, which results in increased activity of MYC, a central player in colorectal cancer.

Field Defects The term “field cancerization” was first used in 1953 to describe an area or “field” of epithelium that has been preconditioned (by what were largely unknown processes at the time) to predispose it towards development of cancer. Since then, the terms “field cancerization”, “field carcinogenesis”, “field defect”, and “field effect” have been used to describe pre-malignant or pre-neoplastic tissue in which new cancers are likely to arise. Field defects are important in progression to colon cancer. However, in most cancer research, as pointed out by Rubin “The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neo-plastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion.” Similarly, Vogelstein et al. pointed out that more than half of somatic mutations identified in tumors occurred in a pre-neo-plastic phase (in a field defect), during growth of apparently normal cells. Likewise, epigenetic alterations present in tumors may have occurred in pre-neo-plastic field defects. An expanded view of field effect has been termed “etiologic field effect”, which encompasses not only molecular and pathologic changes in pre-neo-plastic cells but also influences of exogenous environmental factors and molecular changes in the local microenvironment on neo-plastic evolution from tumor initiation to death.

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Epigenetics Epigenetic alterations are much more frequent in colon cancer than genetic (mutational) alterations. As described by Vogelstein et al., an average cancer of the colon has only 1 or 2 oncogene mutations and 1 to 5 tumor suppressor mutations (together designated “driver mutations”), with about 60 further “passenger” mutations. The oncogenes and tumor suppressor genes are well studied and are described above under Pathogenesis. However, by comparison, epigenetic alterations in colon cancers are frequent and affect hundreds of genes. For instance, there are types of small RNAs called microRNAs that are about 22 nucleotides long. These microRNAs (or miRNAs) do not code for proteins, but they can target protein coding genes and reduce their expression. Expression of these miRNAs can be epigenetically altered. As one example, the epigenetic alteration consisting of CpG island methylation of the DNA sequence encoding miR-137 reduces its expression. This is a frequent early epigenetic event in colorectal carcinogenesis, occurring in 81% of colon cancers and in 14% of the normal appearing colonic mucosa adjacent to the cancers. The altered adjacent tissues associated with these cancers are called field defects. Silencing of miR-137 can affect expression of about 500 genes, the targets of this miRNA. Changes in the level of miR-137 expression result in changed mRNA expression of the target genes by 2 to 20-fold and corresponding, though often smaller, changes in expression of the protein products of the genes. Other microRNAs, with likely comparable numbers of target genes, are even more frequently epigenetically altered in colonic field defects and in the colon cancers that arise from them. These include miR-124a, miR-34b/c and miR-342 which are silenced by CpG island methylation of their encoding DNA sequences in primary tumors at rates of 99%, 93% and 86%, respectively, and in the adjacent normal appearing mucosa at rates of 59%, 26% and 56%, respectively. In addition to epigenetic alteration of expression of miRNAs, other common types of epigenetic alterations in cancers that change gene expression levels include direct hypermethylation or hypomethylation of CpG islands of protein-encoding genes and alterations in histones and chromosomal architecture that influence gene expression. As an example, 147 hypermethylations and 27 hypomethylations of protein coding genes were frequently associated with colorectal cancers. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers. In addition, 11 hypermethylations and 96 hypomethylations of miRNAs were also associated with colorectal cancers. Recent evidence indicates that early epigenetic reductions of DNA repair enzyme expression likely lead to the genomic and epigenomic instability characteristic of cancer. As summarized in the articles Carcinogenesis and Neo-plasm, for sporadic cancers in general, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but is much more frequently due to epigenetic alterations that reduce or silence expression of DNA repair genes.

DIAGNOSIS Colorectal cancer diagnosis is performed by sampling of areas of the colon suspicious for possible tumor development, typically during colonoscopy or sigmoidoscopy, depending on the location of the lesion. It is confirmed by microscopical examination of a tissue sample. Disease extent is usually determined by a CT scan of the chest, abdomen and pelvis. Other potential imaging tests such as PET and MRI may be used in certain cases. Colon cancer staging is done next and is based on radiology and pathology. As for all other forms of cancer, tumor staging is based on the TNM system which considers how much the initial tumor has spread, if and where there are lymph node metastasis and if there are metastases in more distant organs, usually liver. The microscopic cellular characteristics of the tumor are reported from the analysis of tissue taken from a biopsy or surgery. A pathology report contains a description of the microscopical characteristics of the tumor tissue,

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including both tumor cells and how the tumor invades into healthy tissues and finally if the tumor appears to be completely removed. The most common form of colon cancer is adenocarcinoma (98% of cases). Other, rarer types include lymphoma, adenosquamous and squamous cell carcinoma. Some subtypes have been found to be more aggressive.

Macroscopy Cancers on the right side of the large intestine (ascending colon and cecum) tend to be exophytic, that is, the tumor grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumors tend to be circumferential, and can obstruct the bowel lumen, much like a napkin ring, and results in thinner calibre stools.

Microscopy Adenocarcinoma is a malignant epithelial tumor, originating from superficial glandular epithelial cells lining the colon and rectum. It invades the wall, infiltrating the muscularis mucosae layer, the submucosa, and then the muscularis propria. Tumor cells describe irregular tubular structures, harbouring pluristratification, multiple lumens, reduced stroma (“back to back” aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus. This occurs in mucinous adenocarcinoma, in which cells are poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery, this occurs in “signet-ring cell.” Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated.

Immunochemistry In cases where a metastasis from colorectal cancer is suspected, immunohistochemistry is used to ascertain correct diagnosis. Proteins that are more specifically expressed in colorectal cancer and can be used as diagnostic markers are cytokeratin 20, CDX2, SATB2 and CDH17. Most (50%) colorectal adenomas and (80–90%) colorectal cancer tumors are thought to over express the cyclooxygenase-2 (COX-2) enzyme. This enzyme is generally not found in healthy colon tissue, but is thought to fuel abnormal cell growth.

Tumor Budding Tumor budding in colorectal cancer is loosely defined by the presence of individual cells and small clusters of tumor cells at the invasive front of carcinomas. It has been postulated to represent an epithelial–mesenchymal transition (EMT). Tumor budding is a well-established independent marker of a potentially poor outcome in colorectal carcinoma that may allow for dividing people into risk categories more meaningful than those defined by TNM staging, and also potentially guide treatment decisions, especially in T1 and T3 N0 (Stage II, Dukes’ B) colorectal carcinoma. Unfortunately, its universal acceptance as a reportable factor has been held back by a lack of definitional uniformity with respect to both qualitative and quantitative aspects of tumor budding.

PREVENTION It has been estimated that about half of colorectal cancer cases are due to lifestyle factors and about a quarter of all cases are preventable. Increasing surveillance, engaging in physical activity, consuming a diet high in fibre, and reducing smoking and alcohol consumption decrease the risk.

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Lifestyle Current dietary recommendations to prevent colorectal cancer include increasing the consumption of whole grains, fruits and vegetables, and reducing the intake of red meat and processed meats. Higher physical activity is also recommended. Physical exercise is associated with a modest reduction in colon but not rectal cancer risk. High levels of physical activity reduce the risk of colon cancer by about 21%. Sitting regularly for prolonged periods is associated with higher mortality from colon cancer. The risk is not negated by regular exercise, though it is lowered. The evidence for any protective effect conferred by fibre and fruits and vegetables is, however, poor. The risk of colon cancer can be reduced by maintaining a normal body weight.

Medication Aspirin and celecoxib appear to decrease the risk of colorectal cancer in those at high risk. Aspirin is recommended in those who are 50 to 60 years old, do not have an increased risk of bleeding, and are at risk for cardiovascular disease to prevent colorectal cancer. It is not recommended in those at average risk. There is tentative evidence for calcium supplementation, but it is not sufficient to make a recommendation. Vitamin D intake and blood levels are associated with a lower risk of colon cancer.

Screening As more than 80% of colorectal cancers arise from adenomatous polyps, screening for this cancer is effective not only for early detection but also for prevention. Diagnosis of cases of colorectal cancer through screening tends to occur 2–3 years before diagnosis of cases with symptoms. Any polyps that are detected can be removed, usually by colonoscopy or sigmoidoscopy, and thus prevent them from turning cancerous. Screening has the potential to reduce colorectal cancer deaths by 60%. The three main screening tests are colonoscopy, fecal occult blood testing, flexible sigmoidoscopy. Of the three, only sigmoidoscopy cannot screen the right side of the colon where 42% of malignancies are found. Flexible sigmoidoscopy however has the best evidence for decreasing the risk of death from any cause. Other options may include virtual colonoscopy and stool DNA screening testing. Virtual colonoscopy via a CT scan appears as good as standard colonoscopy for detecting cancers and large adenomas but is expensive, associated with radiation exposure, and cannot remove any detected abnormal growths like standard colonoscopy can. Fecal occult blood testing (FOBT) of the stool is typically recommended every two years and can be either guaiac-based or immunochemical. If abnormal FOBT results are found, participants are typically referred for a follow-up colonoscopy examination. Yearly to every two year FOBT screening reduces colorectal cancer deaths by 16% and among those participating in screening colorectal cancer deaths can be reduced up to 23%, although it has not been proven to reduce all-cause mortality. Immunochemical tests are accurate and do not require dietary or medication changes before testing. The stool DNA screening test looks for biomarkers associated with colorectal cancer and precancerous lesions, including altered DNA and blood hemoglobin. A positive result should be followed by colonoscopy. If used, screening is recommended every 3 years, starting at age 50.

Recommendations In the United States, screening is typically recommended between ages 50 to 75 years. For those between 76 and 85 years old, the decision to screen should be individualized. Several screening methods can be used, including stool based tests every 3 years, sigmoidoscopy every 5 years and colonoscopy every 10 years. For those at high risk, screenings usually begin at around 40. It is unclear which of these two methods is better. Colonoscopy may find more cancers in the first part of the colon, but is associated with greater cost and more

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complications. For people with average risk who have had a high-quality colonoscopy with normal results, the American Gastroenterological Association does not recommend any type of screening in the 10 years following the colonoscopy. For people over 75 or those with a life expectancy of less than 10 years, screening is not recommended. It takes about 10 years after screening for one out of a 1000 people to benefit. In Canada, among those 50 to 75 years old at normal risk, fecal immunochemical testing or FOBT is recommended every two years or sigmoidoscopy every 10 years. Colonoscopy is less preferred. Some countries have national colorectal screening programmes which offer FOBT screening for all adults within a certain age group, typically starting between ages 50 to 60. Examples of countries with organised screening include the United Kingdom, Australia, and the Netherlands.

TREATMENT The treatment of colorectal cancer can be aimed at cure or palliation. The decision on which aim to adopt depends on various factors, including the person’s health and preferences, as well as the stage of the tumor. When colorectal cancer is caught early, surgery can be curative. However, when it is detected at later stages (for which metastases are present), this is less likely and treatment is often directed at palliation, to relieve symptoms caused by the tumour and keep the person as comfortable as possible.

Surgery If the cancer is found at a very early stage, it may be removed during a colonoscopy. For people with localized cancer, the preferred treatment is complete surgical removal with adequate margins, with the attempt of achieving a cure. This can either be done by an open laparotomy or sometimes laparoscopically. The colon may then be reconnected or a person may have a colostomy. If there are only a few metastases in the liver or lungs they may also be removed. Sometimes chemotherapy is used before surgery to shrink the cancer before attempting to remove it. The two most common sites of recurrence of colorectal cancer are the liver and lungs.

Chemotherapy In both cancer of the colon and rectum, chemotherapy may be used in addition to surgery in certain cases. The decision to add chemotherapy in management of colon and rectal cancer depends on the stage of the disease. In Stage I colon cancer, no chemotherapy is offered, and surgery is the definitive treatment. The role of chemotherapy in Stage II colon cancer is debatable, and is usually not offered unless risk factors such as T4 tumor or inadequate lymph node sampling is identified. It is also known that the people who carry abnormalities of the mismatch repair genes do not benefit from chemotherapy. For stage III and Stage IV colon cancer, chemotherapy is an integral part of treatment. If cancer has spread to the lymph nodes or distant organs, which is the case with stage III and stage IV colon cancer respectively, adding chemotherapy agents fluorouracil, capecitabine or oxaliplatin increases life expectancy. If the lymph nodes do not contain cancer, the benefits of chemotherapy are controversial. If the cancer is widely metastatic or unresectable, treatment is then palliative. Typically in this setting, a number of different chemotherapy medications may be used. Chemotherapy drugs for this condition may include capecitabine, fluorouracil, irinotecan, oxaliplatin and UFT. The drugs capecitabine and fluorouracil are interchangeable, with capecitabine being an oral medication while fluorouracil being an intravenous medicine. Some specific regimens used for CRC are FOLFOX, FOLFOXIRI, and FOLFIRI. Antiangiogenic drugs such as bevacizumab are often added in first line therapy. Another class of drugs used in the second line setting are epidermal growth factor receptor inhibitors, of which the two FDA approved ones are cetuximab and panitumumab. The primary difference in the approach to low stage rectal cancer is the

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incorporation of radiation therapy. Often, it is used in conjunction with chemotherapy in a neo-adjuvant fashion to enable surgical resection, so that ultimately as colostomy is not required. However, it may not be possible in low lying tumors, in which case, a permanent colostomy may be required. Stage IV rectal cancer is treated similar to stage IV colon cancer.

Radiation Therapy While a combination of radiation and chemotherapy may be useful for rectal cancer, its use in colon cancer is not routine due to the sensitivity of the bowels to radiation. Just as for chemotherapy, radiotherapy can be used in the neo-adjuvant and adjuvant setting for some stages of rectal cancer.

Immunotherapy Immunotherapy with immune checkpoint inhibitors has been found to be useful for a type of colorectal cancer with mismatch repair deficiency and microsatellite instability. Most people who do improve, however, still worsen after months or years. Other types of colorectal cancer as of 2017 is still being studied.

Palliative Care Palliative care is medical care which focuses on treatment of symptoms from serious illness, like cancer, and improving quality of life. Palliative care is recommended for any person who has advanced colon cancer or has significant symptoms. Involvement of palliative care may be beneficial to improve the quality of life for both the person and his or her family, by improving symptoms, anxiety and preventing admissions to the hospital. In people with incurable colorectal cancer, palliative care can consist of procedures that relieve symptoms or complications from the cancer but do not attempt to cure the underlying cancer, thereby improving quality of life. Surgical options may include non-curative surgical removal of some of the cancer tissue, bypassing part of the intestines, or stent placement. These procedures can be considered to improve symptoms and reduce complications such as bleeding from the tumor, abdominal pain and intestinal obstruction. Non-operative methods of symptomatic treatment include radiation therapy to decrease tumor size as well as pain medications.

Follow-up The aims of follow-up are to diagnose, in the earliest possible stage, any metastasis or tumors that develop later, but did not originate from the original cancer (metachronous lesions). The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon cancer. A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for people with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for people who are at high risk of recurrence (for example, those who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, a polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year. Routine PET or ultrasound scanning, chest X-rays, complete blood count or liver function tests are not recommended. A 2016 systematic review concluded that more intense surveillance and close follow-up does not provide additional survival benefits in non-metastatic colorectal cancers.

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Exercise Exercise may be recommended in the future as secondary therapy to cancer survivors. In epidemiological studies, exercise may decrease colorectal cancer-specific mortality and all-cause mortality. Results for the specific amounts of exercise needed to observe a benefit were conflicting. These differences may reflect differences in tumour biology and expression of biomarkers. Patients with tumors that lacked CTNNB1 expression (β-catenin), involved in Wnt signalling pathway, required more than 18 Metabolic equivalent (MET) hours per week, a measure of exercise, to observe a reduction in colorectal cancer mortality. The mechanism of how exercise benefits survival may be involved in immune surveillance and inflammation pathways. In clinical studies, a pro-inflammatory response was found in patients with stage II-III colorectal cancer who underwent 2 weeks of moderate exercise after completing their primary therapy. Oxidative balance may be another possible mechanism for benefits observed. A significant decrease in 8-oxo-dG was found in the urine of patients who underwent 2 weeks of moderate exercise after primary therapy. Other possible mechanisms may involve metabolic hormone and sex-steroid hormones, although these pathways may be involved in other types of cancers. Another potential biomarker may be p27. Survivors with tumors that expressed p27 and performed greater and equal to 18 MET hours per week were found to have reduced colorectal-cancer mortality survival compared to those with less than 18 MET hours per week. Survivors without p27 expression who exercised were shown to have worse outcomes. The constitutive activation of PI3K/AKT/mTOR pathway may explain the loss of p27 and excess energy balance may up-regulate p27 to stop cancer cells from dividing.

PROGNOSIS In Europe the five-year survival rate for colorectal cancer is less than 60%. In the developed world about a third of people who get the disease die from it. Survival is directly related to detection and the type of cancer involved, but overall is poor for symptomatic cancers, as they are typically quite advanced. Survival rates for early stage detection are about five times that of late stage cancers. People with a tumor that has not breached the muscularis mucosa (TNM stage Tis, N0, M0) have a five-year survival rate of 100%, while those with invasive cancer of T1 (within the submucosal layer) or T2 (within the muscular layer) have an average five-year survival rate of approximately 90%. Those with a more invasive tumor yet without node involvement (T3-4, N0, M0) have an average five-year survival rate of approximately 70%. Patients with positive regional lymph nodes (any T, N1-3, M0) have an average five-year survival rate of approximately 40%, while those with distant metastases (any T, any N, M1) have an average five-year survival rate of approximately 5%. According to American Cancer Society statistics in 2006, over 20% of people with colorectal cancer come to medical attention when the disease is already advanced (stage IV), and up to 25% of this group will have isolated liver metastasis that is potentially resectable. In this selective group, those who undergo curative resection experience a fiveyear survival outcome in a third of the cases. Less than 600 genes are linked to outcomes in colorectal cancer. These include both unfavourable genes, where high expression is related to poor outcome, for example the heat shock 70 kDa protein 1 (HSPA1A), and favourable genes where high expression is associated with better survival, for example the putative RNA-binding protein 3 (RBM3).

RECT AL C ANCER RECTAL CANCER The rectum is the last several inches of the large intestine. It starts at the end of the final segment of your colon and ends when it reaches the short, narrow passage leading to the anus. Cancer inside the rectum (rectal cancer) and cancer inside the colon (colon cancer) are often referred to together as “colorectal cancer.” While rectal and colon cancers are similar in many ways, their treatments are quite different. This is mainly because the rectum sits in a tight space, barely separated from other organs and structures in the pelvic cavity. As a

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result, complete surgical removal of rectal cancer is challenging and highly complex. Additional treatment is often needed before or after surgery — or both — to reduce the chance that the cancer will return. In the past, long-term survival was uncommon for people with rectal cancer, even after extensive treatment. Thanks to treatment advances over the past 30 years, rectal cancer can now, in many cases, be cured.

SYMPTOMS Common symptoms include: • A change in your bowel habits, such as diarrhea, constipation or more-frequent bowel movements • Dark or red blood in stool • Mucus in stool • Narrow stool • Abdominal pain • Painful bowel movements • Iron deficiency anemia • A feeling that your bowel doesn’t empty completely • Unexplained weight loss • Weakness or fatigue.

CAUSES Rectal cancer occurs when healthy cells in the rectum develop errors in their DNA. In most cases, the cause of these errors is unknown. Healthy cells grow and divide in an orderly way to keep your body functioning normally. But when a cell’s DNA is damaged and becomes cancerous, cells continue to divide — even when new cells aren’t needed. As the cells accumulate, they form a tumor. With time, the cancer cells can grow to invade and destroy normal tissue nearby. And cancerous cells can travel to other parts of the body. Inherited gene mutations that increase the risk of colon and rectal cancer In some families, gene mutations passed from parents to children increase the risk of colorectal cancer. These mutations are involved in only a small percentage of rectal cancers. Some genes linked to rectal cancer increase an individual’s risk of developing the disease, but they don’t make it inevitable. Two well-defined genetic colorectal cancer syndromes are: • Hereditary non-polyposis colorectal cancer (HNPCC). HNPCC, also called Lynch syndrome, increases the risk of colon cancer and other cancers. People with HNPCC tend to develop colon cancer before age 50. • Familial adenomatous polyposis (FAP). FAP is a rare disorder that causes you to develop thousands of polyps in the lining of your colon and rectum. People with untreated FAP have a greatly increased risk of developing colon or rectal cancer before age 40. FAP, HNPCC and other, rarer inherited colorectal cancer syndromes can be detected through genetic testing. If you’re concerned about your family’s history of colon cancer, talk to your doctor about whether your family history suggests you have a risk of these conditions.

RISK FACTORS The characteristics and lifestyle factors that increase your risk of rectal cancer are the same as those that increase your risk of colon cancer. They include: • Older age. The great majority of people diagnosed with colon and rectal cancer are older than 50. Colorectal cancer can occur in younger people, but it occurs much less frequently.

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African-American descent. People of African ancestry born in the United States have a greater risk of colorectal cancer than do people of European ancestry. A personal history of colorectal cancer or polyps. If you’ve already had rectal cancer, colon cancer or adenomatous polyps, you have a greater risk of colorectal cancer in the future. Inflammatory bowel disease. Chronic inflammatory diseases of the colon and rectum, such as ulcerative colitis and Crohn’s disease, increase your risk of colorectal cancer. Inherited syndromes that increase colorectal cancer risk. Genetic syndromes passed through generations of your family can increase your risk of colorectal cancer. These syndromes include FAP and HNPCC. Family history of colorectal cancer. You’re more likely to develop colorectal cancer if you have a parent, sibling or child with the disease. If more than one family member has colon cancer or rectal cancer, your risk is even greater. Dietary factors. Colorectal cancer may be associated with a diet low in vegetables and high in red meat, particularly when the meat is charred or well-done. A sedentary lifestyle. If you’re inactive, you’re more likely to develop colorectal cancer. Getting regular physical activity may reduce your risk of colon cancer. Diabetes. People with poorly controlled type 2 diabetes and insulin resistance may have an increased risk of colorectal cancer. Obesity. People who are obese have an increased risk of colorectal cancer and an increased risk of dying of colon or rectal cancer when compared with people considered normal weight. Smoking. People who smoke may have an increased risk of colon cancer. Alcohol. Regularly drinking more than three alcoholic beverages a week may increase your risk of colorectal cancer. Radiation therapy for previous cancer. Radiation therapy directed at the abdomen to treat previous cancers may increase the risk of colorectal cancer.

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PREVENTION Talk to your doctor about when you should start getting screened for colorectal cancer. Guidelines generally recommend having your first colorectal cancer screening test at age 50. Your doctor may recommend more-frequent or earlier screening if you have other risk factors, such as a family history of colon or rectal cancer. The most accurate screening test is a colonoscopy. In this test, a doctor examines the lining of your rectum and large intestine using a long, flexible tube with a tiny video camera at its tip (colonoscope). The colonoscope is inserted in the anus and advanced through the rectum and colon. As the scope’s camera moves through the bowel, it sends a video of the rectal and colonic lining to a monitor the doctor sees. If a polyp or suspiciouslooking area of tissue is found, the doctor can also take samples of tissue from these areas with instruments inserted in the colonoscope.

SUR GIC AL MANA GEMENT OF LIVER MET AST ASES FR OM COL ORECT AL CANCER SURGIC GICAL MANAGEMENT METAST ASTASES FROM COLORECT ORECTAL Colorectal cancer is the third most common cancer and the third leading cause of mortality among men and women. In 2015, there will be an estimated 132,700 new cases and an estimated 49,700 deaths from colorectal cancer. Approximately 30% to 50% of patients with this disease will develop liver metastases at the time of presentation or later during the course of their disease. The focus of this article is to discuss the surgical management of liver metastases in the context of other treatment options available to these patients. Surgical resection can be curative in a subset of patients with limited disease and favourable biology.

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TREATMENT OPTIONS The treatment of patients with metastatic colorectal cancer is multidisciplinary, involving surgeons (surgical oncologist, hepatobiliary surgeons, and colorectal surgeons), medical oncologists, radiation oncologists, radiology, interventional radiologists and oncologists, gastroenterologists, and ancillary staff. These patients should be discussed in a tumor-board fashion and surgeons should be involved early in their care. Several treatment options are available for patients with colorectal liver metastases, with chemotherapy and surgical resection forming the backbone of treatment in these patients. There have been several advancements in the field of chemotherapy, with three major classes of drugs being used: cytotoxic chemotherapy, including fluorouracil with leucovorin, capecitabine, irinotecan, and oxaliplatin; angiogenesis inhibitors, including bevacizumab, zivaflibercept, and regorafenib; and epidermal growth factor receptor (EGFR) inhibitors, including cetuximab and panitumumab. These drugs have been studied extensively in phase III randomized clinical trials. In the United States, unless otherwise contraindicated, patients receive multidrug regimens, including infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without angiogenesis inhibitors or EGFR inhibitors, on the basis of their expanded RAS (KRAS/NRAS/HRAS/BRAF) mutational profile, as first-line therapy. Given its increased toxicity, fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) may be considered in highly select patients in whom a high response rate is desired and an aggressive approach is warranted. Recent trials, including FIRE-3, PEAK, and Cancer and Leukemia Group B (CALGB)/Southwest Oncology Group (SWOG) 80405, have attempted to compare anti-EGFR regimens with anti–vascular endothelial growth factor (VEGF) regimens. Anti-EGFR regimens were associated with higher response rates in the FIRE-3 and PEAK trials and a statistically significant increase in median overall survival (OS) in the first-line setting (anti-EGFR v anti-VEGF OS: FIRE-3, 28.7 months v 25 months; PEAK, 34.2 months v 24.3 months).

SURGICAL TREATMENT

Hepatic Resection Hepatic resection remains one of the major curative treatment options available to patients with liver metastases. Decision making for these patients can be complex and several factors must be considered, including medical tolerability and technical and oncologic feasibility. Evaluation for medical fitness remains paramount before embarking on any treatment option in these patients.

Preoperative Imaging to Evaluate the Extent of Disease A high-quality, preoperative, triple-phase computed tomography (CT) scan with thin cuts or a contrastenhanced dynamic magnetic resonance imaging (MRI), preferably with liver-specific contrast agents such as gadoxetate disodium, is paramount to preoperative evaluation of liver metastases in these patients. In addition, a complete staging work-up, including colonoscopy and chest CT in patients who had CT of the abdomen and pelvis, or chest, abdomen, and pelvis CT in patients who were evaluated by liver MRI, is essential for evaluation of extrahepatic disease. The role of positron emission tomography/CT in colorectal liver metastases remains controversial, and recent studies have questioned its routine use. The two goals of preoperative imaging are to identify the extent of liver metastasis, and to determine the presence of any extrahepatic disease. Figure shows how proper imaging can improve the detection of liver metastases.

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Fig. Role of appropriate imaging. An appropriately timed computed tomography (CT) scan with thin slices can enhance the detection of liver metastases. (A) Regular CT scan with thick slices. (B) Thin-cut CT scan with enhanced visualization of segment 7 lesion (arrow).

Limits of Resection Historically, several criteria, which were based on size and number of metastases, expected margin of resection, and presence of extrahepatic disease, excluded patients from undergoing liver resection. However, the availability of portal vein embolization, ablation techniques, two-stage hepatectomies, preoperative chemotherapy, and resections in the setting of extrahepatic metastases have led to a paradigm shift and an increase in number of complex resections. In simplified terms, the focus of surgical resection has shifted from what is being removed to what is being left behind. The limits of technical resection include leaving behind at least two contiguous liver segments with adequate vascular inflow and outflow, adequate biliary drainage, and an adequate future liver remnant. The terminology used for hepatic resection has been standardized. Most experts consider removal of three or more segments as major hepatectomy. Decision making before surgery involves evaluation for the following: number, size, and location of lesions and their relationship to inflow and outflow vessels; subtle radiologic signs such as fatty liver disease and signs of portal hypertension such as splenomegaly (low platelet count and impaired liver function tests can be an indicator of underlying liver damage); portal and retroperitoneal lymphadenopathy; peritoneal carcinomatosis; other areas of metastases, including lung, mediastinum, bone, etc; and size and function of the future liver remnant.

Evaluation of Future Liver Remnant Volume Major or extended hepatectomy may lead to an inadequate future liver remnant that can be associated with significant risk of hepatic insufficiency and subsequent mortality. Although the risk of hepatic insufficiency is determined by several factors, the size of the future liver remnant continues to be one of the major determinants of postoperative hepatic failure. Precise measurements of hepatic volume are needed before operating on any patient who is likely to be left with an inadequate future liver remnant, because the size of the right and left hemilivers varies considerably among the patients. The size of the future liver remnant can be calculated using three-dimensional CT volumetry. The size of the future liver remnant has been used as a surrogate to predict postoperative outcomes. In patients with normal liver function, a future liver remnant of at least 20% is recommended. For patients with cirrhosis and for those treated with systemic chemotherapy because of the underlying liver dysfunction, a larger future liver remnant size is recommended (40% for cirrhosis, 30% after systemic chemotherapy).

Portal Vein Embolization A small future liver remnant may increase the risk of posthepatectomy liver failure; however, this can be avoided by inducing ipsilateral atrophy of the tumor-bearing liver and compensatory hypertrophy of the future

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liver remnant by selectively occluding the blood flow to the tumor-bearing part of the liver. Portal vein embolization is offered to patients with normal liver function and a future liver remnant of 25% to 30% and to those with compromised liver function, such as postchemotherapy liver damage, cirrhosis/fibrosis, and cholestasis and a future liver remnant of 35% to 40%. In the post–portal vein embolization period, the future liver remnant undergoes rapid hypertrophy in the ensuing 3 to 4 weeks. In patients who have diabetes and cirrhosis, the hypertrophy may be delayed, and an additional 3 to 4 weeks may be required to assess the complete response. Figure shows the increase in the volume of the remnant liver after portal vein embolization.

Fig. Liver hypertrophy after portal vein embolization (PVE). (A, before; B, after) Shaded area in green depicts increase in volume of the left lateral segment after PVE of the right side.

A recent meta-analysis by van Lienden et al has shown that the mean technical success rate of the procedure is 99.3% and that 96.1% of patients undergo sufficient hypertrophy of the future liver remnant to allow resection. The mean increase in future liver remnant size is 37.9% (range, 20.5% to 69.4%). Chemotherapy does not seem to affect the hypertrophy, whereas patients with cirrhosis and fibrosis tend to undergo less hypertrophy than do patients with normal livers. Less than 1% of patients may develop severe complications in the form of severe cholangitis, liver abscesses, sepsis, or portal venous or mesentericoportal venous thrombosis precluding liver resection. The originally planned liver resection may not be possible in approximately 20% of patients because of intrahepatic tumor progression, extrahepatic tumor spread, insufficient hypertrophy, major complications, or preoperative mortality or if the patient refuses. Portal vein embolization can be used as a stress test for the liver. Patients who undergo sufficient hypertrophy may do well with resection, whereas those with insufficient hypertrophy are more likely to experience complications and posthepatectomy liver failure. Similarly, any disease progression seen during the period of portal vein embolization indicates aggressive tumors to begin with, and resection may not change the course of the disease. Technical factors that can enhance hypertrophy after portal vein embolization include embolization of segment 4 branches during right portal vein embolization and the use of small spherical particles. All three of the following criteria should be taken into consideration to prevent posthepatectomy liver failure: absolute increase of 5%; kinetic growth rate of ≥ 2% per week of the future liver remnant; and overall size of future liver remnant (> 30% after chemotherapy, > 40% for early cirrhosis or fibrosis).

Margins of Resection R0 resection margins are the goal of surgical resection. A positive margin increases the risk of local recurrence and compromises long-term survival. Older studies showed an advantage of a 1-cm resection margin over just achieving a negative margin; however, studies performed in the era of modern chemotherapy argue that the extent of the negative margin has minimal impact on the outcome. In addition, as more and more complex resections are being undertaken, a 1-cm margin is not always feasible. The goal of surgery is to achieve an R0 resection margin.

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Chemotherapy: Resectable Versus Unresectable Disease The role of adjuvant therapy in patients with resectable liver metastases is controversial. EORTC 40983 randomly assigned patients with resectable liver metastases to perioperative chemotherapy (FOLFOX4) versus surgery alone. The use of perioperative chemotherapy resulted in an improvement in progression-free survival; however, long-term data did not show any statistically significant benefit in OS. The advantages of chemotherapy in patients with resectable disease remain controversial; however, most surgical oncologists recommend a short course of chemotherapy 2 to 3 months before surgical resection to assess tumor response to systemic therapy. Long periods of systemic therapy before resection can lead to two issues: chemotherapy-induced liver injury or steatohepatitis, and disappearing colorectal liver metastases. In contrast to the treatment of resectable liver metastases, chemotherapy remains the mainstay of therapy for patients with unresectable liver metastases. With the advent of modern chemotherapy regimens, response rates to first-line chemotherapy using FOLFOX/ FOLFIRI and biologic agents, such as VEGF inhibitor or EGFR inhibitors, are up to 60% to 70%, and median survival is up to 34 months in patients with metastases. However, progression-free survival still averages 10 months, and response rates in the second-line setting average only 30%. With modern chemotherapy, a subset of patients (approximately 15% to 40%) with unresectable disease may convert to resectable disease, and these patients have a long-term outcome comparable to those with an original diagnosis of resectable disease (ie, a 5year survival of 30% to 40%). Patients receiving chemotherapy who continue to have unresectable disease either because of lack of adequate response or because of progression of disease have a poor prognosis. In addition to the improved efficacy of systemic chemotherapy, factors that have contributed to the increase in secondary resection rates include portal vein embolization, two-stage hepatectomies, ablation techniques, expanding criteria for resection, and improved surgical and parenchymal transection techniques.

Two-stage Hepatectomy In patients presenting with unresectable bilobar liver metastases who respond to systemic chemotherapy, a two-stage hepatectomy approach has been proposed. Most of these patients have synchronous metastases at the time of presentation.

Fig. Two-stage hepatectomy. Minor disease is resected first, followed by contralateral portal vein embolization to maximize future liver remnant before major hepatectomy.

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In addition, one side of the liver is less affected than the other. In these patients, a limited resection could clear the less affected side of the liver before the patient undergoes a future contralateral liver resection. In the majority of these patients, systemic chemotherapy is administered initially, followed by a limited resection of the left side. Right portal vein and segment 4 branch embolization is used next to increase the size of the left lateral sector, and these patients then undergo an extended right hepatectomy. Figure depicts an example of a patient who underwent this approach. Brouquet et al reported that 72% of the patients selected for this approach were able to complete the second stage of the procedure. Progression of the disease was the main cause (61%) for non-completion of the second stage. After a median follow-up of 50 months, 5-year survival was 51% in the two-stage hepatectomy group compared with 15% in those treated by chemotherapy alone. Lam et al performed a systematic review on the topic and included 10 studies with a total of 459 patients in their quantitative analysis. Seventy-seven percent of the patients were able to undergo the planned second stage, and the median survival of this cohort was 37 months. In selected patients with unresectable bilobar colorectal liver metastases, a two-stage hepatectomy seems to be safe. The duration of preoperative and interval chemotherapy between the two stages varies among institutions and must be decided on a case-by-case basis. There are several different possibilities for treatment sequencing: • Chemotherapy, hepatectomy (first stage), hepatectomy (second stage), then chemotherapy; • Chemotherapy, hepatectomy (first stage), portal vein embolization, hepatectomy (second stage), then chemotherapy; and • Chemotherapy, hepatectomy (first stage), portal vein embolization, chemotherapy (second stage), hepatectomy, then chemotherapy.

Chemotherapy-associated Liver Injury or Steatohepatitis The majority of patients receive chemotherapy before liver resection, with FOLFOX and FOLFIRI forming the backbone of modern-day chemotherapy. Longer durations of chemotherapy are being used to increase cure rates in resectable cases and for conversion therapy (ie, to convert unresectable to resectable disease); however, the use of more than eight cycles of chemotherapy leads to chemotherapy-associated liver injury, without increasing response rates. Therefore, longer durations of chemotherapy should be avoided, and liver surgeons should be involved from the beginning in the multidisciplinary care of patients with colorectal liver metastases. The goal of chemotherapy should be to facilitate resection rather than to maximize the response before resection. Oxaliplatin is associated with sinusoidal damage, which can appear as blue liver intraoperatively. Therefore, a longer duration of oxaliplatin therapy can give rise to portal hypertension, often noted on the preoperative CT scan as splenomegaly and ascites. In addition, blue liver leads to increased perioperative blood loss without increasing mortality. Irinotecan is associated with steatohepatitis, especially in patients with obesity and diabetes, resulting in yellow liver. Irinotecan-associated steatohepatitis has been shown to increase the risk of posthepatectomy liver failure; however, more recent data suggest that morbidity is not influenced by the type of chemotherapy used.

Disappearing Liver Metastases The response rates to modern chemotherapy have increased, resulting in complete radiographic response in some patients; the lesions in these cases are termed disappearing liver metastases. The incidence of disappearing liver metastases varies from 7% to 24%. Approximately 10% to 50% of these lesions can be detected in the operating room. Disappearing liver metastases are more likely to occur in patients with smaller tumors or multiple tumors and in those undergoing an increasing number of cycles of chemotherapy. The incidence of

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disappearing liver metastases varies with the imaging modality used. MRI with the appropriate contrast medium has the highest sensitivity and specificity. Limiting the duration of chemotherapy to less than 3 months also helps limit the number of disappearing liver metastases. Complete pathologic response is seen in approximately two thirds of resected disappearing liver metastases. However, if left in situ, more than one half of these lesions will recur. Factors associated with true pathologic response are seen in patients who undergo hepatic artery infusion therapy, have normalization of carcinoembryonic antigen (CEA), underwent MRI as preoperative imaging, have no steatosis, and have a body mass index less than 30. Rubbia-Brandt et al reported that pathologic tumor regression corresponds to fibrosis overgrowth and a decrease in necrosis. The degree of tumor regression predicts disease-free survival and OS, independent of the neo-adjuvant chemotherapy used. Oxaliplatin-containing regimens are associated with higher tumor regression compared with irinotecan-containing regimens. However, complete sterilization of the tumor after chemotherapy is rare (< 5%), which further supports the notion of the resection of disappearing liver metastases. The management of disappearing liver metastases remains controversial. Resection is the usual recommended treatment, if resection of all original sites of disappearing liver metastases is feasible. If the original sites cannot be resected, it is reasonable to resect macroscopic disease and leave disappearing liver metastases in situ because more than one half of these tend to recur within a year. A recent study suggests that surveillance of disappearing liver metastases after systemic chemotherapy was more beneficial and cost effective among patients older than 60 years and with multiple factors predictive of true complete, pathologic response, such as normalization of CEA, hepatic artery infusion therapy, body mass index ≤ 30 kg/m, and diagnosis of disappearing liver metastases made through MRI.

Survival Overall, 5-year survival after resection in patients with colorectal liver metastases varies from 40% to 60% in large series, and 10-year survival is up to 30% in some series. Two large series of more than 2,000 patients reported a 5-year survival of approximately 40%. Resection can be curative in a subset of patients with limited disease and favourable biology; however, more than two thirds of these patients will have recurrences, and most of these tend to occur within the first 2 years. Patient selection is the key. Several prognostic models have been devised to act as adjunctive tools for patient selection, postoperative prognostication, and further substratification for use of adjuvant therapy. The clinical risk score proposed by Fong et al in 1999 remains one of the most commonly used prognostic scoring systems for resection of colorectal liver metastases. Some of the scoring systems proposed by others have been discussed in detail elsewhere. Nodal status of the primary tumor, disease-free interval, CEA levels, liver tumor burden, and the presence of extrahepatic disease remain some of the common factors included in these scoring systems. Poor predictors include an increasing number and size of the metastatic tumors, positive nodal status of the primary tumor, short disease-free interval, and high CEA. Lack of tumor regression after chemotherapy also portends poor prognosis. Recently, molecular factors, such as the presence of KRAS mutation and BRAF mutation, have been associated with poor prognosis.

HEREDIT AR YC OL ORECT AL C ANCER AND POL YPOSIS SYNDR OMES HEREDITAR ARY COL OLORECT ORECTAL CANCER POLYPOSIS SYNDROMES HEREDITARY COLORECTAL SYNDROMES The following rare hereditary colorectal syndromes are precancerous conditions of the colon or rectum. They cause many polyps to develop in the colon and rectum. These syndromes are caused by a mutated, or changed, gene that can be passed from parents to children. They increase the risk of developing colorectal cancer.

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Lynch syndrome is also called hereditary non-polyposis colorectal cancer (HNPCC). It is the most common type of hereditary colorectal syndrome. Most people with Lynch syndrome do not have an unusual number of polyps, which are small growths on a mucous membrane. If they do have polyps, they occur at an earlier age than in the general population and are more likely to become cancerous. Familial adenomatous polyposis (FAP) causes hundreds to thousands of polyps to develop on the lining of the colon and rectum. Peutz-Jeghers syndrome causes many hamartomas, or hamartomatous polyps, to grow in the digestive tract, including the colon and rectum. Juvenile polyposis syndrome causes hamartomas to grow in the digestive tract, including the colon and rectum. These hamartomas usually form before age 20. Some people with this syndrome develop only a few hamartomas in the digestive tract. Other people can have over 100 hamartomas.

Risk Factors Your risk of having a hereditary colorectal syndrome depends on if family members have one of the mutated genes linked to the syndrome.

Symptoms The symptoms of a hereditary colorectal syndrome depend on the type of syndrome and the number of polyps in the colon and rectum. You may not have any symptoms. When there are many polyps, they can cause: • Changes in bowel habits • Bleeding from the rectum • Pain or discomfort in the abdomen • Anemia • Blockage in the intestine (called bowel obstruction) • Part of the intestine slides into another nearby part of the intestine.

Diagnosis If you have symptoms or your doctor thinks you might have a hereditary colorectal syndrome, you will be sent for tests. Tests used to diagnose a hereditary colorectal syndrome may include: • Gastroscopy (a type of endoscopy that looks at the inside of the esophagus and stomach) • Colonoscopy • Biopsy • Genetic testing.

Treatment and Follow-up Treatments offered for hereditary colorectal syndromes depend on the number of polyps and if you have symptoms. Treatments may include: • Removal of polyps (called polypectomy) • Bowel resection with total colectomy or proctocolectomy. You will have regular screening with colonoscopy or sigmoidoscopy, as well as other tests. These tests are done to check the polyps and find cancer if it develops.

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CY TOREDUCTIVE SUR GER Y AND HYPER THERMIC INTR APERIT ONEAL CYT SURGER GERY HYPERTHERMIC INTRAPERIT APERITONEAL CHEMO THER APY CHEMOTHER THERAPY In Peritoneal surface malignancies (PSM), tumor location is restricted to the abdominal cavity as opposed to systemic metastatic disease. In the past, the majority of PSM patients underwent systemic chemotherapy which was associated with poor quality of life and was ineffective with respect to prolonging survival. Thanks to the pioneer work of Professor Paul Sugarbaker, a proactive surgical approach termed cytoreductive surgery (CRS), aiming for maximal tumor resection, along with hyperthermic intraperitoneal chemotherapy (HIPEC) evolved into a highly relevant treatment option for selected patients with limited peritoneal spread of various tumor entities. The rationale for this particular approach is the restriction of tumor dissemination to the peritoneal compartment justifying a radical surgical procedure followed by HIPEC. Although there is now evidence for the superiority of CRS and HIPEC to systemic chemotherapy, this strategy has not made its way into clinical routine since peritoneal spread is still considered as stage IV cancer when surgical resection is not an option any more. However, there was a similar thinking for colorectal liver metastasis for a long time. Now, surgery represents the main strategy even though its superiority has never been proven in a randomized phase III trial. If cytoreductive surgery is scheduled, proactive surgery achieving total or almost total (remaining nodules < 2.5 mm) cytoreduction has to be the main aim In addition, hyperthermic intraperitoneal chemotherapy is administered for eradication of microscopic residual disease. The most frequently cited paper on this topic was published by Verwaal et al who first proved the benefit of this multimodal approach in a phase III trial comparing patients with colorectal cancer undergoing CRS and HIPEC followed by systemic chemotherapy with systemic chemotherapy. Up to now, there are several reports on long term survival if radical resection was performed. Other entities for which this treatment is accepted are pseudomyxoma peritonei and mesothelioma. For selected patients with ovarian and gastric cancer this option can be offered with good results. Since survival does not significantly differ between completeness of cytoreduction CC0 or CC1, an oncologic resection with wide resection margins seems not necessary in this content except for primary gastrointestinal cancer with peritoneal carcinomatosis PC.

INTERDISCIPLINARY CONCEPT The implementation of many new centers for PSM could mean that more and more patients are asking for this therapeutic option. However, the perioperative setting has to be established first rather than the surgical one. An experienced radiologist is mandatory to assess preoperative tumor load and to rule out contraindications such as diffuse infiltration of the small bowel or extraperitoneal disease. The anaesthesiologists, nurses and HIPEC technicians should visit centers and participate in workshops for HIPEC before initiating the programme. Lastly, the medical oncologist becomes more and more important because there are numerous different intraperitoneal as well as pre- and postoperative chemotherapy regimens. The founding of a peritoneal surface malignancy group which meets regularly has had a great impact on scientific discussion between surgeons, radiologists, anaesthesiologists. In addition, this facilitates the initiation of clinical multi-center and experimental studies.

HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY In most cases, intraperitoneal chemotherapy is administered after cytoreductive surgery and completion of intestinal anastomoses, either immediately intraoperatively (HIPEC) or early postoperatively (EPIC). Technically, this chemotherapy can be applied to an open or closed abdomen which varies between the different centers. The rationale of HIPEC is the synergistic cytotoxic effect of heat, ideally 42-43 degree Celcius, and the chemotherapeutic agent itself on tumor cells. There are various concepts varying in duration of exposition, in

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combination with for example intraoperative intravenous therapy and in type of the administered chemotherapy. The effect of hyperthermic intraperitoneal chemotherapy itself has never been proven in a randomized controlled trial and is still the focus of ongoing investigations. Nevertheless, there are numerous data of how HIPEC might work and most surgeons, medical oncologists and last but not least patients believe in the effect of local chemotherapy. The rationale for applying intraoperative chemotherapy under hyperthermic conditions is improving both tissue as well as tumor oxygenation by vasodilation enhancing the cytotoxic effect of chemotherapeutic agents. So far, however, nobody has demonstrated an effect on hyperthermia on tissue oxygenation and there is no data whether this putative effect on pO2 (oxygen) might be sustained throughout the entire HIPEC period. As learned from wound healing research, supplemental oxygen during HIPEC might further enhance cytotoxicity since it has been shown to increase tissue oxygen tension. In addition of thinking about the best timing for HIPEC, HIPEC in combination with supplemental oxygen could be a worthwhile option in the future. Another future important issue could be testing chemotherapeutic sensitivity to improve the cytotoxic effect of HIPEC. Such particular tests already exist for ovarian cancer with respect to platinum resistance. This further strengthens the need for personalized intraoperative chemotherapy regimens.

NEO-ADJUVANT CHEMOTHERAPY A quite high percentage of patients is not eligible for cytoreductive surgery at the time of surgical exploration. Therefore, tumor downsizing by systemic chemotherapy and subsequent surgery might be an option. In liver surgery, the concept of secondary resection after chemotherapy, both intravenous as well as regionally, is accepted and response to preoperative chemotherapy can be considered as a prognostic factor. In PSM, neo-adjuvant chemotherapy might also aid in categorizing patients in responders and non-responders with responders being more likely to profit from CRS and HIPEC. One limitation is the difficulty to evaluate response to chemotherapy since computed tomography (CT) or positron emission tomography (PET)/CT often do not sufficiently show tumor spread. One ongoing phase II trial in Germany addressing perioperative chemotherapy is the COMBATAC trial (multimodality treatment including neo-adjuvant and adjuvant chemotherapy with cetuximab and CRS and HIPEC).

ORGAN PRESERVING CYTOREDUCTIVE SURGERY Radical cytoreduction is many times associated with multivisceral resection because of diffuse organ infiltration. When performing cytoreductive surgery, the surgeon should, however, aim for preserving as many organs as possible. Moreover, the surgeon should leave as much as possible behind but without any oncological compromise. This approach seems quite unfamiliar to surgeons who do not deal with peritoneal metastases. In many cases, the small/large bowel can be preserved when addressed with patience for meticulous tumor resection since tumor nodules are mainly located on the peritoneal surface and can be removed without opening the bowel in most cases unless there is infiltrative growth. From an oncologic point of view, a radical oncologic colon resection, except in primary colorectal cancer with peritoneal spread is not necessary in our opinion. The surgical expertise should ideally include a broad surgical spectrum especially colorectal surgery. One technical challenge is certainly the liver hilus with the sulcus rex, sulcus arancii and segment 1 region which is very demanding to dissect with the risk of biliary or vascular damage when a certain experience in liver surgery is helpful.

SECOND LOOK SURGERY Peritoneal carcinomatosis index (PCI), representing intraabdominal tumor load is a prognostic factor for survival. The lower the PCI, the better the prognosis maybe also due to the fact that a complete cytoreduction

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becomes more likely. Clinical signs of peritoneal metastases are often not specific and current imaging methods often do not detect small tumor nodules. Given these findings, a second look protocol with a relaparotomy within one year of colorectal surgery in high risk patients was proposed. The high risk patient for developing PSM suffers from either a perforated tumor or a local peritoneal spread at the time of primary surgery. Current data revealed quite a high percentage of PSM in those patients. The second look protocol was firstly described by Elias et al. Predicting the development of PSM in high risk patients is certainly a mile stone in the treatment of peritoneal metastases. Although this approach is pro-active, it may further prolong survival in those patients. The administration of HIPEC even in a patient without macroscopic peritoneal disease needs further to be elucidated in randomized trials but seems to be promising so far. The “ProphyloCHIP” trial (Trial Comparing Simple Follow-up to Exploratory Laparotomy Plus “in Principle” HIPEC in Colorectal Patients) run by Prof Elias is addressing this particular point. In this randomised phase III trial, colorectal cancer patients at risk to develop PC receive standard adjuvant chemotherapy after curative resection. After having excluded recurrent disease within 6 mo of follow-up they are randomised to either surveillance alone or explorative laparotomy and HIPEC. With this proactive approach, disease free and overall survival may be increased.

SQU AMOUS CELL CAR CINOMA OF THE ANAL MAR GIN SQUAMOUS CARCINOMA MARGIN Squamous cell carcinoma of the anal margin or perianal skin is relatively uncommon, and most physicians, even those practicing at large referral centers, encounter very few patients with this entity. The goal of treatment is to cure the patient while preserving anal function, thus avoiding a permanent colostomy. Traditionally, treatment has consisted of either local excision or, in advanced cases, abdominoperineal resection (APR). In recent years, a few centers have reported promising results with radiotherapy alone or combined with concomitant chemotherapy. The purpose of this paper is to review the epidemiology, diagnosis, staging, natural history, and results of treatment for this disease. Squamous cell carcinoma of the anal margin is defined as a lesion originating between the dentate line and the outer limit of the perianal skin, defined to be 5 cm from the anal verge in any direction. These lesions represent only one-fourth to one-third of all squamous cell carcinomas of the anus and should be distinguished from squamous cell carcinoma of the anal canal, which has a different natural history and a less favourable prognosis. Most patients with anal margin carcinoma are 60 to 70 years old, but the age range of affected individuals is wide (approximately 25 to 90 years). Although some authors have observed a slight female preponderance, others have reported that the disease is more likely to occur in men.

DIAGNOSIS AND STAGING Jensen et al observed the following symptoms in 76 patients with squamous cell carcinoma of the anal margin treated in Denmark: palpable mass (100%), bleeding (78%), pain (70%), change in bowel habits (29%), discharge (20%), and pruritus ani (20%). The median duration of symptoms was 6 months (range, 2 to 60 months). Associated condylomata and chronic fistulae are observed in approximately 15% of patients. Jensen et al observed that an erroneous diagnosis was made at the first physician visit in 29% of patients with squamous cell carcinoma of the anal margin, as compared with 55% of 125 patients with squamous cell carcinoma of the anal canal. The majority of anal margin tumors tend to be well- or moderately differentiated keratinizing squamous cell carcinomas; less than 10% of lesions are poorly differentiated or cloacogenic carcinomas. Squamous cell carcinoma of the anal margin is staged according to either the American Joint Committee on Cancer (AJCC) or Union Internationale Contre le Cancer (UICC) staging system. The AJCC staging system for anal margin carcinoma is the same one used for other skin cancers (Table) and differs from the staging system used for the anal canal. The AJCC and UICC systems for anal margin carcinoma are virtually identical.

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NATURAL HISTORY AND SPREAD PATTERNS The primary tumor usually starts as a slow-growing nodule that remains localized to the perianal skin until late in the course of the disease, when it may invade the anal canal. The lesion is usually ulcerated and may have a significant palpable subcutaneous component. The sphincter muscle is rarely invaded. The distribution of primary tumor size varies, depending on referral patterns. Pinna Pintor et al found the following UICC T-stage distribution in 83 patients treated at St. Mark’s Hospital for Diseases of the Colon and Rectum in London: stage T1, 14%; stage T2, 50%; stage T3, 32%; and stage T4, 4%. The medial inguinal nodes are the first-echelon lymph node drainage for the anal margin, whereas the perirectal nodes are the first-echelon drainage for the anal canal. The iliac nodes are also occasionally involved. The incidence of inguinal lymph node involvement is approximately 15% to 25%, and is related to the size and histologic differentiation of the primary tumor. Cummings et al reported on the relationship between primary tumor diameter and the risk of inguinal lymph node invasion at diagnosis in a series of 29 patients treated at the Princess Margaret Hospital, Toronto. They found inguinal node invasion in 0 of 13 (0%) of patients with tumors less than 5 cm in diameter, as compared with 4 of 16 (25%) of those with tumors 5 cm or more. In 57 patients, Papillon and Chassard documented the following rates of inguinal lymph node involvement, according to primary tumor size: less than 2 cm, 0 of 10 (0%); 2 to 5 cm, 9 of 38 (24%); and 5 cm or more, 6 of 9 (67%). Distant metastases are rare at presentation. The pretreatment evaluation of the patient should take into account the spread patterns of the disease and should include a chest roentgenogram and CT scan of the abdomen and pelvis. Computed tomography is obtained to evaluate the presence and extent of lymph node metastases, exclude the unlikely possibility of liver metastases, and complement the physical examination of the primary lesion.

SURGICAL MANAGEMENT Early lesions of the anal margin may be successfully treated with local excision; a skin graft may be necessary if the surgical defect cannot be closed primarily or healed by secondary intention. An APR is necessary for resection of more advanced lesions. The inguinal lymph nodes are not dissected unless they are deemed to harbour metastatic disease. Greenall et al reported on 31 patients treated with local excision alone at Memorial Sloan-Kettering Cancer Center between 1950 and 1978. Local recurrence alone developed in nine patients (29%), one patient had recurrences at both the primary site and the inguinal lymph nodes, and isolated inguinal node metastases developed in three patients. Of the nine patients who experienced a local recurrence alone, eight underwent a second local excision and one required an APR. The 5-year absolute and cause-specific survival rates were 68% and 88%, respectively. Greenall et al described an additional 11 patients who underwent a primary APR; one patient died postoperatively and two patients died secondary to recurrence. Seven patients (64%) were alive and disease-free 5 years or more after surgery. At the Cleveland Clinic, 10 patients were treated with local excision between 1951 and 1971, as reported by Al-Jurf et al. Local recurrence developed in 3 patients (30%), 2 of whom were salvaged by a second local excision. Seven patients were alive and diseasefree at 5 years or more, one patient died of intercurrent disease at 15 months, one patient was alive with disease at 6 years, and one patient died of disease at 8 years. Schraut et al reported on 16 patients treated surgically at the University of Chicago. The disease was controlled in 9 of 11 patients after a local excision and in 4 of 5 after an APR. Beahrs and Wilson described 27 patients treated with local excision for in situ or superficial squamous cell carcinoma of the anal margin at the Mayo Clinic between 1950 and 1970. The local control rate was not stated; all patients apparently survived 5 years. In a series of 49 patients who underwent local excision alone or combined with radiotherapy at St. Mark’s Hospital for Diseases of the Colon and Rectum, London, the 5-year absolute and cause-specific survival rates were 65% and 68%, respectively. An additional 16 patients underwent an APR alone or combined with radiotherapy; 5-year absolute and cause-specific survival rates were 38% and 40%, respectively. Local control rates after surgery were not presented.

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RADIATION THERAPY Superficial, well-differentiated T1 and early T2 lesions may be irradiated through a perineal field alone using either cobalt-60 or an electron beam. The inguinal nodes should be electively irradiated in patients with more advanced and/or poorly differentiated lesions. In patients presenting with inguinal lymph node metastases and/or advanced T3 and T4 primary lesions, the pelvic lymph nodes are also treated.

ADJUVANT CHEMOTHERAPY Very limited data are available on the role of adjuvant chemotherapy in squamous cell carcinoma of the anal margin. In addition to these data, one may extrapolate information on anal canal carcinoma, for which the value of chemotherapy is better defined. In a study by Cummings et al, local control was obtained in 7 of 11 patients (64%) treated with radiotherapy alone, as compared with 15 of 17 patients (88%) treated with radiotherapy and concomitant fluorouracil and mitomycin. Adjuvant concomitant chemotherapy is probably indicated for patients with tumors that are poorly differentiated, 5 cm or more, and/or associated with inguinal node metastases. Currently, the optimal chemotherapy regimen consists of two cycles of fluorouracil and mitomycin, although it may be possible to substitute cisplatin for mitomycin to decrease toxicity without sacrificing efficacy.

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Chapter 4

Endocrine THYR OID CANCER THYROID Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck. Cancer can also occur in the thyroid after spread from other locations, in which case it is not classified as thyroid cancer. Risk factors include radiation exposure at a young age, having an enlarged thyroid, and family history. There are four main types – papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer. Diagnosis is often based on ultrasound and fine needle aspiration. Screening people without symptoms and at normal risk for the disease is not recommended as of 2017. Treatment options may include surgery, radiation therapy including radioactive iodine, chemotherapy, thyroid hormone, targeted therapy, and watchful waiting. Surgery may involve removing part or all of the thyroid. Five year survival rates are 98% in the United States. Globally as of 2015 3.2 million people have thyroid cancer. In 2012, 298,000 new cases occurred. It most commonly occurs between the ages of 35 and 65. Women are affected more often than men. Those of Asian descent are more commonly affected. Rates have increased in the last few decades which is believed to be due to better detection. In 2015 it resulted in 31,900 deaths.

SIGNS AND SYMPTOMS Most often the first symptom of thyroid cancer is a nodule in the thyroid region of the neck. However, many adults have small nodules in their thyroids, but typically under 5% of these nodules are found to be cancerous. Sometimes the first sign is an enlarged lymph node. Later symptoms that can be present are pain in the anterior region of the neck and changes in voice due to an involvement of the recurrent laryngeal nerve. Thyroid cancer is usually found in a euthyroid patient, but symptoms of hyperthyroidism or hypothyroidism may be associated with a large or metastatic well-differentiated tumor. Thyroid nodules are of particular concern when they are found in those under the age of 20. The presentation of benign nodules at this age is less likely, and thus the potential for malignancy is far greater.

CAUSES Thyroid cancers are thought to be related to a number of environmental and genetic predisposing factors, but significant uncertainty remains regarding their causes. Environmental exposure to ionizing radiation from both natural background sources and artificial sources is suspected to play a significant role, and there are significant increased rates of thyroid cancer in those exposed to mantlefield radiation for lymphoma, and those exposed to iodine-131 following the Chernobyl, Fukushima, Kyshtym, and Windscale nuclear disasters.

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Thyroiditis and other thyroid diseases also predispose to thyroid cancer. Genetic causes include multiple endocrine neo-plasia type 2 which markedly increases rates, particularly of the rarer medullary form of the disease.

DIAGNOSIS After a thyroid nodule is found during a physical examination, a referral to an endocrinologist or a thyroidologist may occur. Most commonly an ultrasound is performed to confirm the presence of a nodule and assess the status of the whole gland. Measurement of thyroid stimulating hormone and anti-thyroid antibodies will help decide if there is a functional thyroid disease such as Hashimoto’s thyroiditis present, a known cause of a benign nodular goiter. Measurement of calcitonin is necessary to exclude the presence of medullary thyroid cancer. Finally, to achieve a definitive diagnosis before deciding on treatment, a fine needle aspiration cytology test is usually performed and reported according to the Bethesda system. In adults without symptoms screening for thyroid cancer is not recommended.

Classification Thyroid cancers can be classified according to their histopathological characteristics. The following variants can be distinguished (distribution over various subtypes may show regional variation): • Papillary thyroid cancer (75% to 85% of cases) – often in young females – excellent prognosis. May occur in women with familial adenomatous polyposis and in patients with Cowden syndrome. • Newly reclassified variant: non-invasive follicular thyroid neo-plasm with papillary-like nuclear features is considered an indolent tumor of limited biologic potential. • Follicular thyroid cancer (10% to 20% of cases) – occasionally seen in people with Cowden syndrome. Some include Hürthle cell carcinoma as a variant and others list it as a separate type. • Medullary thyroid cancer (5% to 8% of cases) – cancer of the parafollicular cells, often part of multiple endocrine neo-plasia type 2. • Poorly differentiated thyroid cancer • Anaplastic thyroid cancer (less than 5% of cases) is not responsive to treatment and can cause pressure symptoms. • Others a. Thyroid lymphoma b. Squamous cell thyroid carcinoma c. Sarcoma of thyroid. The follicular and papillary types together can be classified as “differentiated thyroid cancer”. These types have a more favourable prognosis than the medullary and undifferentiated types. • Papillary microcarcinoma is a subset of papillary thyroid cancer defined as measuring less than or equal to 1 cm. The highest incidence of papillary thyroid microcarcinoma in autopsy series was reported by Harach et al. in 1985, who found 36 of 101 consecutive autopsies were found to have an incidental microcarcinoma. Michael Pakdaman et al. report the highest incidence in a retrospective surgical series at 49.9% of 860 cases. Management strategies for incidental papillary microcarcinoma on ultrasound (and confirmed on FNAB) range from total thyroidectomy with radioactive iodine ablation to observation alone. Harach et al. suggest using the term “occult papillary tumor” to avoid giving patients distress over having cancer. It was Woolner et al. who first arbitrarily coined the term “occult papillary carcinoma” in 1960, to describe papillary carcinomas ≤ 1.5 cm in diameter.

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Staging Cancer staging is the process of determining the extent of the development of a cancer. The TNM staging system is usually used to classify stages of cancers but not of the brain.

Thyroid

Cancer has spread to the lungs and bone

Fig. Stage M1 thyroid cancer

Tumour Cancer cells in lymph nodes close to the thyroid

Thyroid Windpipe

Fig. Stage N1a thyroid cancer

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Fig. Stage N1b thyroid cancer

Fig. Stage T1a thyroid cancer

Thyroid

Tumour is between 1 and 2cm

Windpipe

Fig. Stage T1b thyroid cancer

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Fig. Stage T2 thyroid cancer

Thyroid

Tumour is larger than 4cm

Windpipe

Fig. Stage T3 thyroid cancer

Tumour has grown into a nearby structure

Thyroid Windpipe

Fig. Stage T4a thyroid cancer

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Tumour has grown into a blood vessel or the bones of the spine

Thyroid Windpipe

Fig. Stage T4b thyroid cancer

Metastases Detection of any metastases of thyroid cancer can be performed with a full body scintigraphy using iodine131.

TREATMENT Thyroidectomy and dissection of central neck compartment is initial step in treatment of thyroid cancer in majority of cases. Thyroid-preserving operation may be applied in cases, when thyroid cancer exhibits low biological aggressiveness (e.g. well-differentiated cancer, no evidence of lymph node metastases, low MIB-1 index, no major genetic alterations like BRAF mutations, RET/PTC rearrangements, p53 mutations etc.) in patients younger than 45 years. If the diagnosis of well-differentiated thyroid cancer (e.g. papillary thyroid cancer) is established or suspected by FNA the surgery is indicated, whereas watchful waiting strategy is not recommended in any evidence-based guidelines. Watchful waiting reduces overdiagnosis and overtreatment of thyroid cancer among old patients. Radioactive Iodine-131 is used in patients with papillary or follicular thyroid cancer for ablation of residual thyroid tissue after surgery and for the treatment of thyroid cancer. Patients with medullary, anaplastic, and most Hurthle cell cancers do not benefit from this therapy. External irradiation may be used when the cancer is unresectable, when it recurs after resection, or to relieve pain from bone metastasis. Sorafenib and lenvatinib, are approved for advanced metastatic thyroid cancer. Numerous agents are in phase II and III clinical trials.

PROGNOSIS The prognosis of thyroid cancer is related to the type of cancer and the stage at the time of diagnosis. For the most common form of thyroid cancer, papillary, the overall prognosis is excellent. Indeed, the increased incidence of papillary thyroid carcinoma in recent years is likely related to increased and earlier diagnosis. One can look at the trend to earlier diagnosis in two ways. The first is that many of these cancers are small and not likely to develop into aggressive malignancies. A second perspective is that earlier diagnosis removes these cancers at a time when they are not likely to have spread beyond the thyroid gland, thereby improving the long-term outcome for the patient. There is no consensus at present on whether this trend towards earlier diagnosis is beneficial or unnecessary.

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The argument against early diagnosis and treatment is based on the logic that many small thyroid cancers (mostly papillary) will not grow or metastasize. This viewpoint holds the overwhelming majority of thyroid cancers are over diagnosed (that is, will never cause any symptoms, illness, or death for the patient, even if nothing is ever done about the cancer). Including these over diagnosed cases skews the statistics by lumping clinically significant cases in with apparently harmless cancers. Thyroid cancer is incredibly common, with autopsy studies of people dying from other causes showing that more than one-third of older adults technically have thyroid cancer, which is causing them no harm. It is easy to detect nodules that might be cancerous, simply by feeling the throat, which contributes to the level of over diagnosis. Benign (non-cancerous) nodules frequently co-exist with thyroid cancer; sometimes, it is a benign nodule that is discovered but surgery uncovers an incidental small thyroid cancer. Increasingly, small thyroid nodules are discovered as incidental findings on imaging (CT scan, MRI, ultrasound) performed for another purpose; very few of these people with accidentally discovered, symptom-free thyroid cancers will ever have any symptoms, and treatment in such patients has the potential to cause harm to them, not to help them. Thyroid cancer is three times more common in women than in men, but according to European statistics, the overall relative 5-year survival rate for thyroid cancer is 85% for females and 74% for males. The table below highlights some of the challenges with decision making and prognostication in thyroid cancer. While there is general agreement that stage I or II papillary, follicular or medullary cancer have a good prognosis, it is not possible when evaluating a small thyroid cancer to determine which ones will grow and metastasize and which will not. As a result, once a diagnosis of thyroid cancer has been established (most commonly by a fine needle aspiration), it is likely that a total thyroidectomy will be performed. This drive to earlier diagnosis has also manifested itself on the European continent by the use of serum calcitonin measurements in patients with goiter to identify patients with early abnormalities of the parafollicular or calcitonin-producing cells within the thyroid gland. As multiple studies have demonstrated, the finding of an elevated serum calcitonin is associated with the finding of a medullary thyroid carcinoma in as high as 20% of cases. In Europe where the threshold for thyroid surgery is lower than in the United States, an elaborate strategy that incorporates serum calcitonin measurements and stimulatory tests for calcitonin has been incorporated into the decision to perform a thyroidectomy; thyroid experts in the United States, looking at the same data sets have, for the most part, not incorporated calcitonin testing as a routine part of their evaluation, thereby eliminating a large number of thyroidectomies and the consequent morbidity. The European thyroid community has focused on prevention of metastasis from small medullary thyroid carcinomas; the North American thyroid community has focused more on prevention of complications associated with thyroidectomy. It is not clear at this time who is correct. As demonstrated in the Table below, individuals with stage III and IV disease have a significant risk of dying from thyroid cancer. While many present with widely metastatic disease, an equal number evolve over years and decades from stage I or II disease. Physicians who manage thyroid cancer of any stage recognize that a small percentage of patients with low-risk thyroid cancer will progress to metastatic disease. Fortunately for those with metastatic thyroid cancer, the last 5 years has brought about a renaissance in thyroid cancer treatment. The identification of some of the molecular or DNA abnormalities for thyroid cancer has led to the development of therapies that target these molecular defects. The first of these agents to negotiate the approval process is vandetanib, a tyrosine kinase inhibitor that targets the RET proto-oncogene, 2 subtypes of the vascular endothelial growth factor receptor, and the epidermal growth factor receptor. More of these compounds are under investigation and are likely to make it through the approval process. For differentiated thyroid carcinoma, strategies are evolving to use selected types of targeted therapy to increase radioactive iodine uptake in papillary thyroid carcinomas that have lost the ability to concentrate iodide. This strategy would make it possible to use radioactive iodine therapy to treat “resistant” thyroid cancers. Other targeted therapies are being evaluated, making it possible that life will be extended over the next 5–10 years for those with stage III and IV thyroid cancer.

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Prognosis is better in younger people than older ones. Prognosis depends mainly on the type of cancer and cancer stage. Thyroid cancer type Papillary Follicular Medullary Anaplastic

5-year survival Stage I Stage II 100% 100% 100% 100% 100% 98% (always stage IV)

Stage III 93% 71% 81%

Stage IV 51% 50% 28% 7%

Overall 96% or 97% 91% 80%, 83% or 86% 7% or 14%

10-year survival Overall 93% 85% 75% (no data)

PANCREA TIC NEUR OENDOCRINE TUMORS (PNETS) PANCREATIC NEUROENDOCRINE Pancreatic neuroendocrine tumors (PanNETs, PETs, or PNETs), often referred to as “islet cell tumors”, or “pancreatic endocrine tumors” are neuroendocrine neo-plasms that arise from cells of the endocrine (hormonal) and nervous system within the pancreas. PanNETs are a type of neuroendocrine tumor, representing about one third of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Many PanNETs are benign, while some are malignant. Aggressive PanNET tumors have traditionally been termed “islet cell carcinoma”. PanNETs are quite distinct from the usual form of pancreatic cancer, the majority of which are adenocarcinomas, which arises in the exocrine pancreas. Only 1 or 2% of clinically significant pancreas neoplasms are PanNETs.

TYPES The majority of PanNETs are benign, while some are malignant. The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor grade rather than the anatomical origin. In practice, those tumors termed well or intermediately differentiated PanNETs in the WHO scheme are sometimes called “islet cell tumors.” The high grade subtype, termed neuroendocrine cancer (NEC) in the WHO scheme, is synonymous with “islet cell carcinoma”. Types of PNET based on hormones produced Type Insulinoma Gastrinoma VIPoma Glucagonoma Somatostatinoma PPoma

Location of tumor Head, body, tail of pancreas Gastrinoma triangle Distal pancreas (body and tail) Body and tail of pancreas Pancreatoduodenal groove, ampullary, periampullary Head or pancreas

Biomarkers insulin, proinsulin, C-peptide gastrin, PP VIP glucagon, glycentin somatostatin pancreatic polypeptide

SIGNS AND SYMPTOMS Some PanNETs do not cause any symptoms, in which case they may be discovered incidentally on a CT scan performed for a different purpose. Symptoms such as abdominal or back pain or pressure, diarrhea, indigestion, or yellowing of the skin and whites of the eyes can arise from the effects of a larger PanNET tumor, either locally or at a metastasis. About 40% of PanNETS have symptoms related to excessive secretion of hormones or active polypeptides and are accordingly labeled as “functional”; the symptoms reflect the type of hormone secreted, as discussed below. Up to 60% of PanNETs are non-secretory or non-functional, in which there is no secretion, or the quantity or type of products, such as pancreatic polypeptide (PPoma), chromogranin A, and neurotensin, do not cause a clinical syndrome although blood levels may be elevated. In total, 85% of PanNETs have an elevated blood marker. Functional tumors are often classified by the hormone most strongly secreted, for example: • Gastrinoma: the excessive gastrin causes Zollinger–Ellison syndrome (ZES) with peptic ulcers and diarrhea

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Insulinoma: hypoglycemia occurs with concurrent elevations of insulin, proinsulin and C peptide Glucagonoma: the symptoms are not all due to glucagon elevations, and include a rash, sore mouth, altered bowel habits, venous thrombosis, and high blood glucose levels • VIPoma, producing excessive vasoactive intestinal peptide, which may cause profound chronic watery diarrhea and resultant dehydration, hypokalemia, and achlorhydria (WDHA or pancreatic cholera syndrome) • Somatostatinoma: these rare tumors are associated with elevated blood glucose levels, achlorhydria, cholelithiasis, and diarrhea • Less common types include ACTHoma, CRHoma, calcitoninoma, GHRHoma, GRFoma, and parathyroid hormone–related peptide tumor. In these various types of functional tumors, the frequency of malignancy and the survival prognosis have been estimated dissimilarly, but a pertinent accessible summary is available.

DIAGNOSIS Because symptoms are non-specific, diagnosis is often delayed. Measurement of hormones including pancreatic polypeptide, gastrin, proinsulin, insulin, glucagon, and vasoactive intestinal peptide can determine if a tumor is causing hypersecretion. CT and MRI may be used to determine location and size of PNET.

STAGING The 2010 WHO classification of tumors of the digestive system grades all the neuroendocrine tumors into three categories, based on their degree of cellular differentiation (from well-differentiated “NET G1” through to poorly-differentiated “NET G3”). The NCCN recommends use of the same AJCC-UICC staging system as pancreatic adenocarcinoma. Using this scheme, the stage by stage outcomes for PanNETs are dissimilar to pancreatic exocrine cancers. A different TNM system for PanNETs has been proposed by The European Neuroendocrine Tumor Society. The cancer is no more than 2cm in size

Bowel

Pancreas Fig. Stage T1

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The cancer is more than 2cm in size

Bowel

Pancreas Fig. Stage T2

The cancer has grown into the tissues outside the pancreas

Bowel

Pancreas Fig. Stage T3

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The cancer has grown outside the pancreas and into one of the blood vessels

Bowel

Pancreas Fig. Stage T4

Cancer

Bowel

There is cancer in the lymph nodes

Pancreas Fig. Involvement of nearby lymph nodes – Stage N1

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Cancer has spread to the liver

Fig. Metastasis – stage M1

TREATMENT In general, treatment for PanNET encompasses the same array of options as other neuroendocrine tumors, as discussed in that main article. However, there are some specific differences, which are discussed here. In functioning PanNETs, octreotide is usually recommended prior to biopsy or surgery but is generally avoided in insulinomas to avoid profound hypoglycemia. PanNETs in Multiple endocrine neo-plasia type 1 are often multiple, and thus require different treatment and surveillance strategies. Some PanNETs are more responsive to chemotherapy than are gastroenteric carcinoid tumors. Several agents have shown activity. In well differentiated PanNETs, chemotherapy is generally reserved for when there are no other treatment options. Combinations of several medicines have been used, such as doxorubicin with streptozocin and fluorouracil (5-FU) and capecitabine with temozolomide. Although marginally effective in well-differentiated PETs, cisplatin with etoposide has some activity in poorly differentiated neuroendocrine cancers (PDNECs), particularly if the PDNEC has an extremely high Ki-67 score of over 50%. Several targeted therapy agents have been approved in PanNETs by the FDA based on improved progressionfree survival (PFS): • Everolimus (Afinitor) is labeled for treatment of progressive neuroendocrine tumors of pancreatic origin in patients with unresectable, locally advanced or metastatic disease. The safety and effectiveness of everolimus in carcinoid tumors have not been established. • Sunitinib (Sutent) is labeled for treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease. Sutent also has approval from the European Commission for the treatment of ‘unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults’. A phase III study of sunitinib treatment in well differentiated pNET that had worsened within the past 12 months (either advanced or metastatic disease) showed that sunitinib treatment improved progression-free survival (11.4 months vs. 5.5 months), overall survival, and the objective response rate (9.3% vs. 0.0%) when compared with placebo.

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GENETICS Pancreatic neuroendocrine tumors may arise in the context of multiple endocrine neo-plasia type 1or Von Hippel–Lindau disease. Analysis of somatic DNA mutations in well-differentiated pancreatic neuroendocrine tumors identified four important findings: • As expected, the genes mutated in NETs, MEN1, ATRX, DAXX, TSC2, PTEN and PIK3CA, are different from the mutated genes previously found in pancreatic adenocarcinoma. • One in six well-differentiated pancreatic NETs have mutations in mTOR pathway genes, such as TSC2, PTEN and PIK3CA. The sequencing discovery might allow selection of which NETs would benefit from mTOR inhibition such as with everolimus, but this awaits validation in a clinical trial. • Mutations affecting a new cancer pathway involving ATRX and DAXX genes were found in about 40% of pancreatic NETs. The proteins encoded by ATRX and DAXX participate in chromatin remodeling of telomeres; these mutations are associated with a telomerase-independent maintenance mechanism termed ALT (alternative lengthening of telomeres) that results in abnormally long telomeric ends of chromosomes. • ATRX/DAXX and MEN1 mutations were associated with a better prognosis.

MUL TIPLE ENDOCRINE NEO-PL ASIA (MEN) SYNDR OMES MULTIPLE NEO-PLASIA SYNDROMES The term multiple endocrine neo-plasia (MEN) encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes. MEN syndromes are inherited as autosomal dominant disorders.

TERMINOLOGY The older names, “multiple endocrine adenomas” and “multiple endocrine adenomatosis” (MEA), have been replaced by the current terminology. The term multiple endocrine neo-plasia is used when two or more endocrine tumor types, known to occur as a part of one of the defined MEN syndromes, occurs in a single patient and there is evidence for either a causative mutation or hereditary transmission. The presence of two or more tumor types in a single patient does not automatically designate that individual as having MEN because there is a small statistical chance that development of two “sporadic” tumors that occur in one of the MEN syndromes could occur by chance. The term “multiple endocrine neo-plasia” was introduced in 1968, but descriptions of the condition date back to 1903.

RELATED CONDITIONS Although not officially categorized as multiple endocrine neo-plasia syndromes, Von Hippel-Lindau disease and Carney complex are two other autosomal dominant endocrine tumor syndromes with features that overlap the clinical features of the MEN syndromes. Although not transmitted in the germline, McCune-Albright syndrome is a genetic disorder characterized by endocrine neo-plastic features involving endocrine glands that overlap with those involved in MEN1 or MEN2.

HISTORY •

In 1903 Erdheim described the case of an acromegalic patient with a pituitary adenoma and three enlarged parathyroid glands.

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•

In 1953 Underdahl et al. reported a case series of 8 patients with a syndrome of pituitary, parathyroid, and pancreatic islet adenomas. In 1954 Wermer noted that this syndrome was transmitted as a dominant trait. In 1959 Hazard et al. described medullary (solid) thyroid carcinoma. In 1961 Sipple described a combination of a pheochromocytoma, medullary thyroid carcinoma and parathyroid adenoma. In 1966 Williams et al. described the combination of mucosal neuromas, pheochromocytoma and medullary thyroid carcinoma. In 1968 Steiner et al. introduced the term “multiple endocrine neo-plasia” (MEN) to describe disorders featuring combinations of endocrine tumors and proposed the terms ‘Wermer syndrome’ for MEN 1 and ‘Sipple syndrome’ for MEN 2. In 1974 Sizemore et al. showed that the MEN 2 category included two groups of patients with MTC and pheochromocytoma: one with parathyroid disease and a normal appearance (MEN 2A) and the other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B). In 1988 the MEN1 locus was assigned to Chromosome 11 (11q13). In 1993 mutations in the RET oncogene were shown to be the cause of MEN 2A by Lois Mulligan, working in the laboratory of Bruce Ponder in Cambridge. In 1998 the MEN1 gene was cloned.

• • • • •

•

• • •

COMPARISON Percentages in table below refer to how large fraction of people with the MEN type develop the neo-plasia type. Feature

MEN 1

Eponym OMIM Pancreatic tumors

Wermer syndrome 131100 gastrinoma (50%), insulinoma (20%), VIPoma, glucagonoma, PPoma 66% 64%* 17%* 90% MEN1 (131100)

Pituitary adenoma Angiofibroma Lipoma Parathyroid hyperplasia Medullary thyroid carcinoma Pheochromocytoma Marfanoid body habitus Mucosal neuroma Gene(s) Approx. prevalence

Initial description (year)

1 in 35,000 (1 in 20,000 to 1 in 40,000) 1954

MEN 2 MEN 2A Sipple syndrome 171400 -

MEN 2B (multiple) 162300 -

FMTC (none) 155240 -

50% 100% >33% RET (164761)

85% 50% 80% 100% RET (164761)

100% RET (164761), NTRK1 (191315)

1 in 40,000

1 in 1,000,000 (1 in 600,000 to 1 in 4,000,000) 1965

1961

*- of patients with MEN1 and gastrinoma FMTC = familial medullary thyroid cancer MEN 2B is sometimes known as MEN 3 and the designation varies by institution (c.f. www.ClinicalReview.com). Although a variety of additional eponyms have been proposed for MEN2B (e.g. Williams-Pollock syndrome, Gorlin-Vickers syndrome, and Wagenmann–Froboese syndrome), none ever gained sufficient traction to merit continued use and, indeed, are all but abandoned in the medical literature. Another

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early report was Schimke et al. in 1968. OMIM also includes a fourth form of multiple endocrine neo-plasia (“MEN4”), associated with CDKN1B. The presentation is believed to overlap that of MEN1 and MEN2.

MULTIPLE ENDOCRINE NEO-PLASIA TYPE 1 (MEN1)

The MEN1 Gene The MEN1 gene consists of ten exons, spanning about 10 kb, and encodes a 610 amino acid protein named menin. The first exon and the last part of exon 10 are not translated. A main transcript of 2.8 kb has been described in a large variety of human tissues (pancreas, thymus, adrenal glands, thyroid, testis, leukocytes, heart, brain, lung, muscle, small intestine, liver, and kidney); an additional transcript of approximately 4 kb has been detected in pancreas and thymus, suggesting a tissue-specific alternative splicing.

The Menin Protein Menin is a 610 amino acid (67Kda) nuclear protein, highly conserved from mouse (98%), rat (97%) and, more distantly, zebrafish (75%) and Drosophila (47%) (47-51). Human and mouse MEN1 amino acid sequences share 95.8% identity and 98.4% similarity. Analysis of menin amino acid sequence did not reveal homologies to any other known human or mammalian protein, sequence motif, or signal peptide. The absence of significant homology to any other protein complicates efforts to elucidate the functions of menin.

Pathophysiology MEN1 follows Knudson’s “two-hit” model for tumor suppressor gene carcinogenesis (30). The first hit is a heterozygous MEN1 germline mutation, inherited from one parent (familial cases) or developed in an early embryonic stage (sporadic cases) and present in all cells at birth. The second hit is a MEN1 somatic mutation, usually a large deletion, that occurs in the predisposed endocrine cell as loss of the remaining wild-type allele and gives cells the survival advantage needed for tumor development.

Mnemonic A useful mnemonic to remember the associated neo-plasias is below: MEN I (3 Ps) - Pituitary, Parathyroid, Pancreatic MEN IIa (2Ps, 1M) - Pheochromocytoma, Parathyroid, Medullary Thyroid Ca MEN IIb (1P, 2Ms) - Pheochromocytoma, Medullary Thyroid Ca, Marfanoid habitus/mucosal neuroma

MEN1 Mutations in Multiple Endocrine Neo-plasia Patients and Clinical Genetics MEN1 gene mutations can be identified in 70-95% of MEN1 patients and in about 20% of familial isolated hyperparathyroidism cases. Almost all patients are heterozygous for mutations. One affected family has been identified with individuals both homozygous and heterozygous for MEN1 mutations. In this family, there was no difference in disease history between the homozygous and heterozygous mutation carriers. Fifty percent of patients develop signs and symptoms by 20 years of age and more than 95% have symptoms by 40 years of age. There is significant intra- and inter-familial variability in the age of onset, severity of disease, and tumor types. Despite numerous studies, no genotype-phenotype correlations have been established, suggesting that unknown genetic and environmental modifiers are involved in the expression of the MEN1 phenotype.

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Manifestations Multiple Endocrine Neo-plasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterized primarily by tumors of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic (GEP) tract (30-80% of cases), and anterior pituitary (15-90% of cases). Other endocrine and non-endocrine neo-plasms including adrenocortical and thyroid tumors, visceral and cutaneous lipomas, meningiomas, facial angiofibromas and collagenomas, and thymic, gastric, and bronchial carcinoids also occur. The phenotype of MEN1 is broad, and over 20 different combinations of endocrine and non-endocrine manifestations have been described. MEN1 should be suspected in patients with an endocrinopathy of two of the three characteristic affected organs, or with an endocrinopathy of one of these organs plus a first-degree relative affected by MEN1 syndrome. MEN1 patients usually have a family history of MEN1. Inheritance is autosomal dominant; any affected parent has a 50% chance to transmit the disease to his or her progeny. MEN1 gene mutations can be identified in 70-95% of MEN1 patients. Many endocrine tumors in MEN1 are benign and cause symptoms by overproduction of hormones or local mass effects, while other MEN1 tumors are associated with an elevated risk for malignancy. About one third of patients affected with MEN1 will die early from an MEN1-related cancer or associated malignancy. Entero-pancreatic gastrinomas and thymic and bronchial carcinoids are the leading cause of morbidity and mortality. Consequently, the average age of death in untreated individuals with MEN1 is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.

Recommended Cancer Surveillance A recommend surveillance programme for Multiple Endocrine Neo-plasia Type 1 has been suggested by the International Guidelines for Diagnosis and Therapy of MEN syndromes group.

CAR CINOID TUMORS CARCINOID Carcinoid (also carcinoid tumor) is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut (jejunum, ileum, appendix, and cecum) are associated with carcinoid syndrome. Carcinoid tumors are the most common malignant tumor of the appendix, but they are most commonly associated with the small intestine, and they can also be found in the rectum and stomach. They are known to grow in the liver, but this finding is usually a manifestation of metastatic disease from a primary carcinoid occurring elsewhere in the body. They have a very slow growth rate compared to most malignant tumors. The median age at diagnosis for all patients with neuroendocrine tumors is 63 years.

SIGNS AND SYMPTOMS While most carcinoids are asymptomatic through the natural lifetime and are discovered only upon surgery for unrelated reasons (so-called coincidental carcinoids), all carcinoids are considered to have malignant potential. About 10% of carcinoids secrete excessive levels of a range of hormones, most notably serotonin (5-HT), causing: • Flushing (serotonin itself does not cause flushing). Potential causes of flushing in carcinoid syndrome include bradykinins, prostaglandins, tachykinins, substance P, and/or histamine, diarrhea, and heart problems. Because of serotonin’s growth-promoting effect on cardiac myocytes, a serotonin-secreting carcinoid tumour may cause a tricuspid valve disease syndrome, due to the proliferation of myocytes onto the valve.

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• Diarrhea • Wheezing • Abdominal cramping • Peripheral edema The outflow of serotonin can cause a depletion of tryptophan leading to niacin deficiency. Niacin deficiency, also known as pellagra, is associated with dermatitis, dementia, and diarrhea. This constellation of symptoms is called carcinoid syndrome or (if acute) carcinoid crisis. Occasionally, haemorrhage or the effects of tumor bulk are the presenting symptoms. The most common originating sites of carcinoid is the small bowel, particularly the ileum; carcinoid tumors are the most common malignancy of the appendix. Carcinoid tumors may rarely arise from the ovary or thymus. They are most commonly found in the midgut at the level of the ileum or in the appendix. The next most common affected area is the respiratory tract, with 28% of all cases—per PAN-SEER data (1973–1999). The rectum is also a common site.

Gastrointestinal Carcinoid tumors are apudomas that arise from the enterochromaffin cells throughout the gut. Over twothirds of carcinoid tumors are found in the gastrointestinal tract.

Lung Carcinoid tumors are also found in the lungs.

Other Sites/ Metastases Metastasis of carcinoid can lead to carcinoid syndrome. This is due to the over-production of many substances, including serotonin, which are released into the systemic circulation, and which can lead to symptoms of cutaneous flushing, diarrhea, bronchoconstriction, and right-sided cardiac valve disease. It is estimated that less than 6% of carcinoid patients will develop carcinoid syndrome, and of these, 50% will have cardiac involvement.

CAUSE Carcinoid syndrome involves multiple tumors in 1/5 of cases. The incidence of gastric carcinoids is increased in achlorhydria, Hashimoto’s thyroiditis, and pernicious anemia.

TREATMENT Surgery, if feasible, is the only curative therapy. If the tumor has metastasized (most commonly, to the liver) and is considered incurable, there are some promising treatment modalities, such as radiolabeled octreotide (e.g. Lutetium (Lu) DOTA-octreotate) or the radiopharmaceutical 131I-mIBG (meta iodo benzyl guanidine) for arresting the growth of the tumors and prolonging survival in patients with liver metastases, though these are currently experimental. Chemotherapy is of little benefit and is generally not indicated. Octreotide or Lanreotide (somatostatin analogues) may decrease the secretory activity of the carcinoid, and may also have an anti-proliferative effect. Interferon treatment is also effective, and usually combined with somatostatin analogues. As the metastatic potential of a coincidental carcinoid is probably low, the current recommendation is for follow up in 3 months with CT or MRI, labs for tumor markers such as serotonin, and a history and physical, with annual physicals thereafter.

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GOBLET CELL CARCINOID This is considered to be a hybrid between an exocrine and endocrine tumor derived from crypt cells of the appendix. Histologically, it forms clusters of goblet cells containing mucin with a minor admixture of Paneth cells and endocrine cells. The growth pattern is distinctive: typically producing a concentric band of tumor nests interspersed among the muscle and stroma of the appendiceal wall extending up the shaft of the appendix. This makes the lesion difficult to suspect grossly and difficult to measure. Small tumor nests may be camouflaged amongst the muscle or in periappendiceal fat; cytokeratin preparations best demonstrate the tumor cells; mucin stains are also helpful in identifying them. They behave in a more aggressive manner than do classical appendiceal carcinoids. Spread is usually to regional lymph nodes, peritoneum, and particularly the ovary. They do not produce sufficient hormonal substances to cause the carcinoid or other endocrine syndromes. In fact, they more closely resemble exocrine than endocrine tumors. The term ‘crypt cell carcinoma’ has been used for them, and though perhaps more accurate than considering them carcinoids, has not been a successful competitor.

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Chapter 5

Sarcoma INTR ODUCTION INTRODUCTION A sarcoma is a cancer that arises from transformed cells of mesenchymal origin. Thus, malignant tumors made of cancellous bone, cartilage, fat, muscle, vascular, or hematopoietic tissues are, by definition, considered sarcomas. This is in contrast to a malignant tumor originating from epithelial cells, which are termed carcinoma. Human sarcomas are quite rare. Common malignancies, such as breast, colon, and lung cancer, are almost always carcinoma. The term is from the Greek óÜñî sarx meaning “flesh”.

DIAGNOSIS

Classification Tissue Sarcomas are given a number of different names based on the type of tissue that they most closely resemble. For example, osteosarcoma resembles bone, chondrosarcoma resembles cartilage, liposarcoma resembles fat, and leiomyosarcoma resembles smooth muscle.

GRADE In addition to being named based on the tissue of origin, sarcomas are also assigned a grade (low, intermediate, or high) based on the presence and frequency of certain cellular and subcellular characteristics associated with malignant biological behaviour. Low grade sarcomas are usually treated surgically, although sometimes radiation therapy or chemotherapy are used. Intermediate and high grade sarcomas are more frequently treated with a combination of surgery, chemotherapy and/or radiation therapy. Since higher grade tumors are more likely to undergo metastasis (invasion and spread to locoregional and distant sites), they are treated more aggressively. The recognition that many sarcomas are sensitive to chemotherapy has dramatically improved the survival of patients. For example, in the era before chemotherapy, long-term survival for patients with localized osteosarcoma was only approximately 20%, but now has risen to 60–70%.

AWARENESS In the US, July is widely recognized as Sarcoma Awareness Month. The UK has a Sarcoma Awareness Week July led by Sarcoma UK:the bone and soft tissue cancer charity. In December 2016, British medical company

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MidMeds launched Sarcoma Awareness Day in the UK, with the sole aim of raising awareness of the cancer. The event gained both local and national press attention.

CHONDR OSAR COMA CHONDROSAR OSARC Chondrosarcoma is a cancer composed of cells derived from transformed cells that produce cartilage. Chondrosarcoma is a member of a category of tumors of bone and soft tissue known as sarcomas. About 30% of skeletal system cancers are chondrosarcomas. It is resistant to chemotherapy and radiotherapy. Unlike other primary bone cancers that mainly affect children and adolescents, chondrosarcoma can present at any age. It more often affects the axial skeleton than the appendicular skeleton.

CLASSIFICATION AND GRADING Physicians grade chondrosarcoma using several criteria, but particularly on how abnormal the cancerous cells appear under the microscope, and the growth rate of the tumors themselves, both of which are directly linked to the propensity of the cancer to invade locally, and to spread widely to distant organs and sites in the body (called metastasis). Grade 1 chondrosarcoma grows relatively slowly, has cells whose histological appearance is quite similar to cells of normal cartilage, and have much less aggressive invasive and metastatic properties. Grades 2 and 3 are increasingly faster-growing cancers, with more varied and abnormal-looking cells, and are much more likely to infiltrate surrounding tissues, lymph nodes, and organs. Some, but not all, authorities and medical facilities assign a “Grade 4” to the most anaplastic, undifferentiated cartilage-derived tumors. The most common sites for chondrosarcoma to grow are the pelvis and shoulder, along with the superior metaphyseal and diaphyseal regions of the arms and legs. However, chondrosarcoma may occur in any bone, and are sometimes found in the skull, particularly at its base. ICD-O codes provide a more precise classification of chondrosarcoma. These “subtypes” are derived from, and reflect, both (a) the topographical location of the tumor, (b) the histological characteristics of the cancerous cartilage cells, and (c) the makeup of the surrounding matrix material associated with the tumor: ICD-O 9220 9221 9231 9240 9242 9243

Classification Chondrosarcoma NOS (“Not Otherwise Specified”) Juxtacortical chondrosarcoma Myxoid chondrosarcoma Mesenchymal chondrosarcoma Clear cell chondrosarcoma Dedifferentiated chondrosarcoma

SYMPTOMS • • • •

Back or thigh pain Sciatica Bladder Symptoms Unilateral edema.

CAUSES The cause is unknown. Patients may have a history of enchondroma or osteochondroma. A small minority of secondary chondrosarcomas occur in patients with Maffucci syndrome and Ollier disease. It has been associated with faulty isocitrate dehydrogenase 1 and 2 enzymes, which are also associated with gliomas and leukemias.

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DIAGNOSIS File:Metastatic chondrosarcoma at the lower lip.jpgFile:Metastatic chondrosarcoma at the lower lip.jpg Imaging studies - including radiographs (“x-rays”), computerized tomography (CT), and magnetic resonance imaging (MRI) - are often used to make a presumptive diagnosis of chondrosarcoma. However, a definitive diagnosis depends on the identification of malignant cancer cells producing cartilage in a biopsy specimen that has been examined by a pathologist. In a few cases, usually of highly anaplastic tumors, immunohistochemistry (IHC)is required. There are no blood tests currently available to enable an oncologist to render a diagnosis of chondrosarcoma. The most characteristic imaging findings are usually obtained with CT. Nearly all chondrosarcoma patients appear to be in good health. Often, patients are not aware of the growing tumor until there is a noticeable lump or pain. Earlier diagnosis is generally accidental, when a patient undergoes testing for another problem and physicians discover the cancer. Occasionally the first symptom will be a broken bone at the cancerous site. Any broken bone that occurs from mild trauma warrants further investigation, although there are many conditions that can lead to weak bones, and this form of cancer is not a common cause of such breaks.

TREATMENT Treatment depends on the location of the disease and the aggressiveness of the tumors. Because chondrosarcomas are rare, they are treated at specialist hospitals with Sarcoma Centers. Surgery is the main form of treatment for chondrosarcoma. Musculoskeletal tumor specialists or orthopedic oncologists are usually chosen to treat chondrosarcoma, unless it is located in the skull, spine, or chest cavity, in which case, a neurosurgeon or thoracic surgeon experienced with sarcomas is chosen. Often, a limb-sparing operation can be performed, but in some cases amputation is unavoidable. Amputation of the arm, leg, jaw, or half of the pelvis (called a hemipelvectomy) may be necessary in some cases. There are two kinds of hemipelvectomy - internal and external. • External hemipelvectomy - is removal of that half of the pelvis with the amputation of the leg. It is also called the hindquarter amputation. • Internal hemipelvectomy - is removal of that half of the pelvis, but the leg is left intact. Amputation at the hip is called hip disarticulation and amputees who have had this amputation are also called hip disartics. Chemotherapy or traditional radiotherapy are not very effective for most chondrosarcomas, although proton therapy is showing promise with local tumor control at over 80%. Complete surgical ablation is the most effective treatment, but sometimes this is difficult. Proton therapy radiation can be useful in awkward locations to make surgery more effective. Recent studies have shown that induction of apoptosis in high-grade chondrosarcoma, both directly and by enhancement of response to chemotherapy and radiation, is a valid therapeutic strategy.

PROGNOSIS Prognosis depends on how early the cancer is discovered and treated. For the least aggressive grade, about 90% of patients survive more than five years after diagnosis. People usually have a good survival rate at the low grade volume of cancer. For the most aggressive grade, only 10% of patients will survive one year. Tumors may recur in the future. Follow up scans are extremely important for chondrosarcoma to make sure there has been no recurrence or metastasis, which usually occurs in the lungs.

EWING ’S SAR COMA EWING’S SARC Ewing’s sarcoma or Ewing sarcoma is a malignant small, round, blue cell tumor. It is a rare disease in which cancer cells are found in the bone or in soft tissue. The most common areas in which it occurs are the pelvis, the

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femur, the humerus, the ribs and clavicle (collar bone). Since a common genetic locus is responsible for a large percentage of Ewing sarcoma and primitive neuroectodermal tumors, these are sometimes grouped together in a category known as the Ewing family of tumors. Ewing’s sarcoma occurs most frequently in teenagers and young adults, with a male/female ratio of 1.6:1. Although usually classified as a bone tumor, Ewing’s sarcoma can have characteristics of both mesodermal and ectodermal origin, making it difficult to classify. James Ewing (1866–1943) first described the tumour, establishing that the disease was separate from lymphoma and other types of cancer known at that time.

PRESENTATION Ewing’s sarcoma is more common in males (1.6 male:1 female) and usually presents in childhood or early adulthood, with a peak between 10 and 20 years of age. It can occur anywhere in the body, but most commonly in the pelvis and proximal long tubular bones, especially around the growth plates. The diaphyses of the femur are the most common sites, followed by the tibia and the humerus. Thirty percent are overtly metastatic at presentation. Patients usually experience extreme bone pain. Rarely, it can develop in the vagina. Signs and symptoms include: intermittent fevers, anemia, leukocytosis, increased sedimentation rate, and other symptoms of inflammatory systemic illness. Also, depending on the type, progression, and location of the tumor, great pain may occur. According to the Bone Cancer Research Trust (BCRT), the most common symptoms are: localized pain, swelling, and sporadic bone pain with variable intensity. The swelling is most likely to be visible if the sarcoma is located on a bone near the surface of the body, but when it occurs in other places deeper in the body, like on the pelvis, it may not be visible.

CAUSES Genetic exchange between chromosomes can cause cells to become cancerous. Most cases of Ewing’s sarcoma (85%) are the result of a translocation between chromosomes 11 and 22, which fuses the EWS gene of chromosome 22 to the FLI1 gene of chromosome 11. EWS/FLI functions as the master regulator. Other translocations are at t(21;22) and t(7;22). Ewing’s sarcoma cells are positive for CD99 and MIC2, and negative for CD45.

DIAGNOSIS The definitive diagnosis is based on histomorphologic findings, immunohistochemistry and molecular pathology. Ewing’s sarcoma is a small-blue-round-cell tumor that typically has a clear cytoplasm on H&E staining, due to glycogen. The presence of the glycogen can be demonstrated with positive PAS staining and negative PAS diastase staining. The characteristic immunostain is CD99, which diffusely marks the cell membrane. Morphologic and immunohistochemical findings are corroborated with an associated chromosomal translocation, of which several occur. The most common translocation, present in about 90% of Ewing sarcoma cases, is t(11;22)(q24;q12), which generates an aberrant transcription factor through fusion of the EWSR1 gene with the FLI1 gene. The pathologic differential diagnosis is the grouping of small-blue-round-cell tumors, which includes lymphoma, alveolar rhabdomyosarcoma, and desmoplastic small round cell tumor, among others.

Differential Diagnosis Other entities with similar clinical presentations include osteomyelitis, osteosarcoma (especially telangiectatic osteosarcoma), and eosinophilic granuloma. Soft-tissue neo-plasms such as pleomorphic undifferentiated sarcoma (malignant fibrous histiocytoma) that erode into adjacent bone may also have a similar appearance.

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Imaging Findings On conventional radiographs, the most common osseous presentation is a permeative lytic lesion with periosteal reaction. The classic description of lamellated or “onion-skin” type periosteal reaction is often associated with this lesion. Plain films add valuable information in the initial evaluation or screening. The wide zone of transition (e.g. permeative) is the most useful plain film characteristic in differentiation of benign versus aggressive or malignant lytic lesions. Magnetic resonance imaging (MRI) should be routinely used in the work-up of malignant tumors. It will show the full bony and soft tissue extent and relate the tumor to other nearby anatomic structures (e.g. vessels). Gadolinium contrast is not necessary as it does not give additional information over non-contrast studies, though some current researchers argue that dynamic, contrast-enhanced MRI may help determine the amount of necrosis within the tumor, thus help in determining response to treatment prior to surgery. Computed axial tomography(CT) can also be used to define the extraosseous extent of the tumor, especially in the skull, spine, ribs, and pelvis. Both CT and MRI can be used to follow response to radiation and/or chemotherapy. Bone scintigraphy can also be used to follow tumor response to therapy. In the group of malignant small round cell tumors which include Ewing’s sarcoma, bone lymphoma, and small cell osteosarcoma, the cortex may appear almost normal radiographically, while permeative growth occurs throughout the Haversian channels. These tumours may be accompanied by a large soft-tissue mass while almost no bone destruction is visible. The radiographs frequently do not shown any signs of cortical destruction. Radiographically, Ewing’s sarcoma presents as “moth-eaten” destructive radiolucencies of the medulla and erosion of the cortex with expansion.

TREATMENT Almost all patients require multidrug chemotherapy (often including ifosfamide and etoposide), as well as local disease control with surgery and/or radiation. An aggressive approach is necessary because almost all patients with apparently localized disease at the time of diagnosis actually have asymptomatic metastatic disease. Treatment often consists of neo-adjuvant chemotherapy, which may include vincristine, doxorubicin, and cyclophosphamide with ifosfamide and etoposide. After about three months of chemotherapy, the remaining tumor is surgically resected, irradiated, or both. The surgical resection may involve limb salvage or amputation. Complete excision at the time of biopsy may be performed if malignancy is confirmed at the time it is examined. Treatment lengths vary depending on location and stage of the disease at diagnosis. Radical chemotherapy may be as short as six treatments at 3-week cycles, but most patients undergo chemotherapy for 6–12 months and radiation therapy for 5–8 weeks. Radiotherapy has been used for localized disease. The tumor has a unique property of being highly sensitive to radiation, sometimes acknowledged by the phrase “melting like snow”, but the main drawback is that it recurs dramatically after some time. Antisense oligodeoxynucleotides have been proposed as possible treatment by down-regulating the expression of the oncogenic fusion protein associated with the development of Ewing’s sarcoma resulting from the EWS-ETS gene translocation. In addition, the synthetic retinoid derivative fenretinide (4-hydroxy(phenyl)retinamide) has been reported to induce high levels of cell death in Ewing’s sarcoma cell lines in vitro and to delay growth of xenografts in in vivo mouse models.

Fertility Preservation In women, chemotherapy may damage the ovaries and cause infertility. To avail future pregnancies, the woman may preserve oocytes or ovarian tissue by oocyte cryopreservation or ovarian tissue cryopreservation prior to starting chemotherapy. However, the latter may reseed the cancer upon reinsertion of the ovarian tissue.

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If it is performed, the ovarian tissue should be examined for traces of malignancy at both the pathological and molecular levels prior to the grafting of the cryopreserved tissue.

PROGNOSIS Staging attempts to distinguish patients with localized from those with metastatic disease. Most commonly, metastases occur in the chest, bone and/or bone marrow. Less common sites include the central nervous system and lymph nodes. Five-year survival for localized disease is 70% to 80% when treated with chemotherapy. Prior to the use of multi-drug chemotherapy, long-term survival was less than 10%. The development of multi-disciplinary therapy with chemotherapy, irradiation, and surgery has increased current long-term survival rates in most clinical centers to greater than 50%. However, some sources state it is 25–30%. Retrospective research in patients led by Idriss M. Bennani-Baiti (Cancer Epigenetics Society) showed that two chemokine receptors, CXCR4 and CXCR7, can be used as molecular prognosis factors. Patients who express low levels of both chemokine receptors have the highest odds of long-term survival with >90% survival at 5 years post-diagnosis versus 90%) with wide resection. • Stage II prognosis depends on the site of the tumor (proximal tibia, femur, pelvis, etc.), size of the tumor mass, and the degree of necrosis from neo-adjuvant chemotherapy. Other pathological factors such as the degree of p-glycoprotein, whether the tumor is cxcr4-positive, or Her2-positive are also important, as these are associated with distant metastases to the lung. The prognosis for patients with metastatic osteosarcoma improves with longer times to metastases, (more than 12 months to 4 months), a smaller number of metastases, and their resectability. It is better to have fewer metastases than longer time to metastases. Those with a longer length of time (more than 24 months) and few nodules (two or fewer) have the best prognosis, with a two-year survival after the metastases of 50%, five-year of 40%, and 10-year of 20%. If metastases are both local and regional, the prognosis is worse. • Initial presentation of stage III osteosarcoma with lung metastases depends on the resectability of the primary tumor and lung nodules, degree of necrosis of the primary tumor, and maybe the number of metastases. Overall survival prognosis is about 30%. Deaths due to malignant neo-plasms of the bones and joints account for an unknown number of childhood cancer deaths. Mortality rates due to osteosarcoma have been declining at about 1.3% per year. Long-term survival probabilities for osteosarcoma have improved dramatically during the late 20th century and approximated 68% in 2009.

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SAR COMA BO TR Y SARC BOTR TRY YOIDES Sarcoma botryoides or botryoid sarcoma or botryoid rhabdomyosarcoma is a subtype of embryonal rhabdomyosarcoma, that can be observed in the walls of hollow, mucosa lined structures such as the nasopharynx, common bile duct, urinary bladder of infants and young children or the vagina in females, typically younger than age 8. The name comes from the gross appearance of “grape bunches” (botryoid in Greek).

CLINICAL CHARACTERISTICS For botryoid rhabdomyosarcoma of the vagina, the most common clinical finding is vaginal bleeding but vaginal bleeding is not specific for sarcoma botryoides: other vaginal cancers are possible. They may appear as a polypoid mass, somewhat yellow in colour and are friable: thus, they (possibly) may break off, leading to vaginal bleeding or infections.

HISTOLOGY Under the microscope one can see rhabdomyoblasts that may contain cross-striations. Tumor cells are crowded in a distinct layer beneath the vaginal epithelium ( cambium layer). Spindle-shaped tumor cells that are desmin positive.

TREATMENT AND PROGNOSIS The disease used to be uniformly fatal, with a 5-year survival rate between 10 and 35%. As a result, treatment was radical surgery. New multidrug chemotherapy regimens with or without radiation therapy are now used in combination with less radical surgery with good results, although outcome data are not yet available.

EPIDEMIOLOGY Sarcoma botryoides normally is found in children under 8 years of age. Onset of symptoms occurs at age 3 years (38.3 months) on average. Cases of older women with this condition have also been reported.

SOFT-TISSUE SAR COMA SARC A soft-tissue sarcoma is a form of sarcoma that develops in connective tissue, though the term is sometimes applied to elements of the soft tissue that are not currently considered connective tissue.

SIGNS AND SYMPTOMS In their early stages, soft-tissue sarcomas usually do not cause symptoms. Because soft tissue is relatively elastic, tumors can grow rather large, pushing aside normal tissue, before they are felt or cause any problems. The first noticeable symptom is usually a painless lump or swelling. As the tumor grows, it may cause other symptoms, such as pain or soreness, as it presses against nearby nerves and muscles. If in the abdomen it can cause abdominal pains commonly mistaken for menstrual cramps, indigestion, or cause constipation.

RISK FACTORS Most soft-tissue sarcomas are not associated with any known risk factors or identifiable cause. There are some exceptions: • Studies suggest that workers who are exposed to chlorophenols in wood preservatives and phenoxy herbicides may have an increased risk of developing soft-tissue sarcomas. An unusual percentage of

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•

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patients with a rare blood vessel tumor, angiosarcoma of the liver, have been exposed to vinyl chloride in their work. This substance is used in the manufacture of certain plastics, notably PVC. In the early 1900s, when scientists were just discovering the potential uses of radiation to treat disease, little was known about safe dosage levels and precise methods of delivery. At that time, radiation was used to treat a variety of non-cancerous medical problems, including enlargement of the tonsils, adenoids, and thymus gland. Later, researchers found that high doses of radiation caused soft-tissue sarcomas in some patients. Because of this risk, radiation treatment for cancer is now planned to ensure that the maximum dosage of radiation is delivered to diseased tissue while surrounding healthy tissue is protected as much as possible. Kaposi’s sarcoma, a rare cancer of the cells that line blood vessels in the skin and mucus membranes, is caused by Human herpesvirus 8. Kaposi’s sarcoma often occurs in patients with AIDS (acquired immune deficiency syndrome). Kaposi’s sarcoma, however, has different characteristics than typical soft-tissue sarcomas and is treated differently. In a very small fraction of cases, sarcoma may be related to a rare inherited genetic alteration of the p53 gene and is known as Li-Fraumeni syndrome. Certain other inherited diseases are associated with an increased risk of developing soft-tissue sarcomas. For example, people with neurofibromatosis type I (also called von Recklinghausen’s disease, associated with alterations in the NF1 gene) are at an increased risk of developing soft-tissue sarcomas known as malignant peripheral nerve sheath tumors. Patients with inherited retinoblastoma have alterations in the RB1 gene, a tumor suppressor gene, and are likely to develop soft-tissue sarcomas as they mature into adulthood.

DIAGNOSIS The only reliable way to determine whether a soft-tissue tumour is benign or malignant is through a biopsy. There are two methods for acquisition of tumour tissue for cytopathological analysis; • Needle Aspiration, via biopsy needle • Surgically, via an incision made into the tumour. A pathologist examines the tissue under a microscope. If cancer is present, the pathologist can usually determine the type of cancer and its grade. Here, ‘grade’ refers to a scale used to represent concisely the predicted growth rate of the tumour and its tendency to spread, and this is determined by the degree to which the cancer cells appear abnormal when examined under a microscope. Low-grade sarcomas, although cancerous, are defined as those that are less likely to metastasise. High-grade sarcomas are defined as those more likely to spread to other parts of the body. For soft-tissue sarcoma there are two histological grading systems: the National Cancer Institute (NCI) system and the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system. Soft tissue sarcomas commonly originate in the upper body, in the shoulder or upper chest. Some symptoms are uneven posture, pain in the trapezius muscle and cervical inflexibility [difficulty in turning the head]. The most common site to which soft tissue sarcoma spreads is the lungs.

TREATMENT In general, treatment for soft-tissue sarcomas depends on the stage of the cancer. The stage of the sarcoma is based on the size and grade of the tumor, and whether the cancer has spread to the lymph nodes or other parts of the body (metastasized). Treatment options for soft-tissue sarcomas include surgery, radiation therapy, and chemotherapy. • Surgery is the most common treatment for soft-tissue sarcomas. If possible, the doctor will remove the cancer and a safe margin of the healthy tissue around it. It is important to obtain a margin free of tumor to decrease the likelihood of local recurrence and give the best chance for eradication of the

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tumor. Depending on the size and location of the sarcoma, it may, rarely, be necessary to remove all or part of an arm or leg. • Radiation therapy may be used either before surgery to shrink tumors or after surgery to kill any cancer cells that may have been left behind. In some cases, it can be used to treat tumours that cannot be surgically removed. In multiple studies, radiation therapy has been found to improve the rate of local control, but has not had any influence on overall survival. • Chemotherapy may be used with radiation therapy either before or after surgery to try to shrink the tumor or kill any remaining cancer cells. The use of chemotherapy to prevent the spread of softtissue sarcomas has not been proven to be effective. If the cancer has spread to other areas of the body, chemotherapy may be used to shrink tumors and reduce the pain and discomfort they cause, but is unlikely to eradicate the disease. A combination of Taxotere and Gemzar could be an effective chemotherapy regimen in patients with advanced soft-tissue sarcoma.

EPIDEMIOLOGY Soft-tissue sarcomas are relatively uncommon cancers. They account for less than 1% of all new cancer cases each year. This may be because cells in soft tissue, in contrast to tissues that more commonly give rise to malignancies, are not continuously dividing cells. In 2006, about 9,500 new cases were diagnosed in the United States. Soft-tissue sarcomas are more commonly found in older patients (>50 years old) although in children and adolescents under age 20, certain histologies are common (rhabdomyosarcoma, synovial sarcoma). Around 3,300 people were diagnosed with soft tissue sarcoma in the UK 2011.

TABLES Table. Major Types of Soft-Tissue Sarcomas in Adults Tissue of Origin

Type of Cancer

Usual Location in the Body

Fibrous tissue

Fibrosarcoma Malignant fibroushystiocytoma Dermatofibrosarcoma Liposarcoma

Arms, legs, trunk Legs Trunk Arms, legs, trunk

Rhabdomyosarcoma Leiomyosarcoma Hemangiosarcoma Kaposi’s sarcoma Lymphangiosarcoma Synovial sarcoma

Arms, legs Uterus, digestive tract Arms, legs, trunk Legs, trunk Arms Legs

Malignant peripheral nerve sheath tumour/Neurofibrosarcoma Extraskeletal chondrosarcoma Extraskeletal osteosarcoma

Arms, legs, trunk

Fat Muscle Striated muscle Smooth muscle Blood vessels Lymph vessels Synovial tissue(linings of joint cavities, tendon sheaths) Peripheral nerves Cartilage and bone-forming tissue

Legs Legs, trunk (not involving the bone)

Table. Major Types of Soft-Tissue Sarcomas in Children Tissue of Origin Muscle Striated muscle

Smoothmuscle Fibrous tissue

Type of Cancer

Usual Location in the Body

Rhabdomyosarcoma Embryonal Alveolar soft part sarcoma Leiomyosarcoma Fibrosarcoma Malignant fibroushistiocytoma

Head and neck, genitourinary tract Arms, legs, head, and neck Trunk Arms and legs Legs

Most common ages

Infant–4 Infant–19 15–19 15–19 15–19

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Fat Blood vessels Synovial tissue(linings of joint cavities, tendon sheaths) Peripheral nerves

Muscular nerves Cartilage and boneforming tissue

Dermatofibrosarcoma Liposarcoma Infantile hemangio-pericytoma Synovial sarcoma

Trunk Arms and Legs Arms, legs, trunk, head, and neck Legs, arms, and trunk

15–19 15–19 Infant–4 15–19

Malignant peripheral nerve sheath tumors (also called neurofibrosarcomas, malignant schwannomas, and neurogenic sarcomas) Alveolar soft part sarcoma Extraskeletal myxoid chondrosarcoma Extraskeletal mesenchymal

Arms, legs, and trunk

15–19

Arms and legs Legs

Infant–19 10–14

Legs

10–14

An earlier version of this article was taken from the US National Cancer Center’s Cancer Information Service.

ALVEOLAR SOFT PART SARCOMA Alveolar soft part sarcoma, abbreviated ASPS, is a very rare type of soft-tissue sarcoma, that grows slowly and whose cell of origin is unknown. It arises mainly in children and young adults. ASPS can migrate (metastasize) into other parts of the body, typically the lungs and the brain. ASPS is a sarcoma, and that indicates that this cancer initially arises from tissue of embryonic mesenchymal origin. (The fertilized egg divides and redivides forming a sphere. Early in embryogenesis, dimples appear in the poles of the sphere and burrow through the sphere forming an inner passage that will ultimately form the gut. Malignancies arising from cells that were originally part of the outer layer of the sphere and those that were part of the embryonic tunnel are termed carcinomas; malignancies arising from the cells between the outer layer and the inner burrow are termed sarcomas.) Typically, ASPS arises in muscles and deep soft tissue of the thigh or the leg (lower extremities), but can also appear in the upper extremities (hands, neck, and head). While ASPS is a soft tissue sarcoma, it can also spread and grow inside the bones. The term alveolar comes from the microscopic pattern, visible during the analysis of slides of ASPS under the microscope in histopathology. The tumor cells seem to be arranged in the same pattern as the cells of the small air sacks (alveoli) in the lungs. However, this is just a structural similarity. ASPS was first described and characterized in 1952.

Causes Chromosomal analysis of ASPS shows the breaking and joining of two chromosomes in the tumor cells. A piece of chromosome X breaks and is joined to chromosome 17. This translocation creates a fusion between two genes named ASPL and TFE3, which results in the formation of an aberrant protein (termed fusion protein) that is not found in normal cells. Two sorts of fusions between chromosome X and chromosome 17 are found in different ASPS tumors: Type one, and type two. Dr. Ladanyi at Memorial Sloan-Kettering Cancer Center, in New York City, has pioneered this work. The first xenograft model of ASPS (for type one) was established in mice by David Vistica at the National Cancer Institute in Frederick, MD in 2009.

Primary Diagnosis ASPS may exist in the patient’s body for a long time before being diagnosed. It can grow large and push aside surrounding tissues for a long time before causing any discomfort. Therefore, ASPS symptoms may either be a painless swelling, or a soreness caused by compressed nerves or muscles, affecting the range of motion in the area.

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Pathology The definitive diagnosis of ASPS is based on its appearance under the microscope, i.e. its histomorphology, and presence of the characteristic chromosomal translocation. ASPS’ histomorphologic features include an alveolar-like pattern at low magnification and the presence of large cells with abundant eosinophilic cytoplasm and eccentric nuclei. Calcifications are commonly present, as may be seen with slow growing neo-plasms.

Prognosis Although ASPS displays a relatively indolent course, the ultimate prognosis is poor and is often characterized by late metastases.

Epidemiology ASPS is an extremely rare cancer. While sarcomas comprise about 1% of all newly diagnosed cancers, and 15% of all childhood cancers, ASPS comprises less than 1% of sarcomas. According to the American Cancer Society, about 9530 new cases of soft tissue sarcoma will be diagnosed in the USA in 2006. This predicts under 100 new cases of ASPS. Such low numbers of occurrence seriously impede the search for a cure by making it hard to gather any meaningful statistics about the disease. As a result, finding the best treatment option often involves making a lot of educated guesses.

Research • •

Sunitinib Cediranib new trial from England; adult doses have already been established, NCI is currently working on doses for children. Work out of Huntsman Cancer Institute (HCI) in Utah has demonstrated that ASPS might be driven in part by lactate both being used as a fuel and driving angiogenesis.

ANGIOSARCOMA Angiosarcoma is a cancer of the cells that line the walls of blood vessels or lymphatic vessels. The lining of the vessel walls is called the endothelium. However, they should not be confused with cherry hemangiomas. Most tumors of visceral blood and lymphatic vessel walls are cancerous (malignant). Because these cancers are carried by the blood flow or lymphatic flow, they can more easily metastasize to distant sites, particularly the liver and lungs. Angiosarcomas show signs of hemorrhage and necrosis. Pathologically, tumor cells show increased nuclear to cytoplasm ratio, nuclear hyperchromasia, nuclear pleomorphism and high mitotic activity. In dogs, hemangiosarcoma is relatively common, especially in larger breeds such as golden retrievers and Labrador retrievers. In humans, hemangiosarcomas and lymphangiosarcomas of the skin are uncommon. Angiosarcoma of the liver, a rare fatal tumor, has been seen in workers intensively exposed to the gas vinyl chloride monomer (VCM) for prolonged periods while working in polyvinyl chloride (PVC) polymerization plants. It has also been associated with individuals exposed to arsenic-containing insecticides and Thorotrast.

PHYLLODES TUMOR Phyllodes tumors also cystosarcoma phyllodes, cystosarcoma phylloides and phylloides tumor, are typically large, fast-growing masses that form from the periductal stromal cells of the breast. They account for less than 1% of all breast neo-plasms.

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Classification Phyllodes tumors are a fibroepithelial tumor composed of an epithelial and a cellular stromal component. They may be considered benign, borderline, or malignant depending on histologic features including stromal cellularity, infiltration at the tumor’s edge, and mitotic activity. All forms of phyllodes tumors are regarded as having malignant potential. A large series from the M.D. Anderson Cancer Centre reported the incidence of each as benign (58%), borderline (12%), and malignant (30%). Malignant phyllodes tumours behave like sarcomas and can develop blood-borne metastases. Approximately 10% of patients with phyllodes tumours develop distant metastases and this can go up to 20% in patients with histologically malignant tumours. The commonest sites for distant metastases are the lung, bone, and abdominal viscera. Rare sites of metastasis like to parotid region have also been described. They are classified as a fibroepithelial tumor by ICD-O, but not by MeSH. Younger women have a higher chance of having a benign phyllodes tumor.

Presentation This is predominantly a tumor of adult women, with very few examples reported in adolescents. Patients typically present with a firm, palpable mass. These tumors are very fast-growing, and can increase in size in just a few weeks. Occurrence is most common between the ages of 40 and 50, prior to menopause. This is about 15 years older than the typical age of patients with fibroadenoma, a condition with which phyllodes tumors may be confused. They have been documented to occur at any age above 12 years.

Treatment The common treatment for phyllodes is wide local excision. Other than surgery, there is no cure for phyllodes, as chemotherapy and radiation therapy are not effective. The risk of developing local recurrence or metastases is related to the histologic grade, according to the above-named features. Despite wide excision, a very high percentage of surgeries yielded incomplete excision margins that required revision surgery. Radiation treatment after breast-conserving surgery with negative margins may significantly reduce the local recurrence rate for borderline and malignant tumors. The authors of a 2012 study have derived a risk calculator for relapse risk of phyllodes tumors after surgery.

Spectrum Phyllodes tumors are considered to be on a spectrum of disease that consists of fibroadenoma, fibroadenoma variant and benign phyllodes. Some would extend the spectrum to include malignant phyllodes tumors and frank sarcoma.

DERMATOFIBROSARCOMA PROTUBERANS Dermatofibrosarcoma protuberans (DFSP) is a rare tumor. It is a rare neo-plasm of the dermis layer of the skin, and is classified as a sarcoma. There is only about one case per million per year. DFSP is a fibrosarcoma, more precisely a cutaneous soft tissue sarcoma. In many respects, the disease behaves as a benign tumor, but in 2–5% of cases it can metastasize, so it should be considered to have malignant potential. It occurs most often in adults in their thirties; it has been described congenitally, in children, and the elderly. It accounts for approximately 2–6% of soft tissue sarcoma cancers.

Presentation Dermatofibrosarcoma protuberans can begin as a minor firm area of skin most commonly about to 1 to 5 cm in diameter. It can resemble a bruise, birthmark, or pimple. It is a slow growing tumor and is usually found on

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the torso but can also be found on the arms, legs, head and neck. About 90% of DFSPs are low grade sarcomas. About 10% are mixed; they contain a high-grade sarcomatous component (DFSP-FS); therefore, they are considered to be intermediate-grade sarcomas. DFSPs rarely lead to a metastasis (fewer than 5% do metastasise), but DFSPs can recur locally. DFSPs most often arise in patients who are in their thirties, but sometimes have been described in children or the elderly.

Pathophysiology More than 90% of DFSP tumors have the chromosomal translocation t(17;22). The translocation fuses the collagen gene (COL1A1) with the platelet-derived growth factor (PDGF) gene. The fibroblast, the cell of origin of this tumor, expresses the fusion gene in the belief that it codes for collagen. However the resulting fusion protein is processed into mature platelet-derived growth factor which is a potent growth factor. Fibroblasts contain the receptor for this growth factor. Thus the cell “thinks” it is producing a structural protein, but it actually produces a self-stimulatory growth signal. The cell divides rapidly and a tumor forms. The tissue is often positive for CD34.

Diagnosis Dermatofibrosarcoma protuberans is diagnosed with a biopsy, when a portion of the tumor is removed for examination. In order to ensure that enough tissue is removed to make an accurate diagnosis, the initial biopsy of a suspected DFSP is usually done with a core needle or a surgical incision.

Treatment Treatment is primarily surgical, with chemotherapy and radiation therapy sometimes used. The NCCN guideline recommends CCPDMA or Mohs surgery for the best cure rate of DFSP. Mohs surgery can be extremely effective. It will remove the tumor and all related pathological cells without a wide-area excision that may overlook sarcoma cells that have penetrated muscle tissue. The standard of care for patients with DFSP is surgery. Usually, complete surgical resection with margins of 2 to 4 cm (recommended) is performed. The addition of adjuvant radiotherapy (irradiation) improves local control in patients with close or positive margins during the surgery. A special surgical technique, the “Mohs micrographic surgery” (MMS), can be employed in patients with DFSP. MMS is technically possible if the DFSP is in an anatomically confined area. A high probability of cure of DFSP can be attained with MMS as long as the final margins are negative. Patients who have a recurrent DFSP can have further surgery, but the probability of adverse effects of surgery and/or metastasis is increased in these patients. The Mohs surgery is highly successful. Imatinib is approved for treatment. As is true for all medicinal drugs that have a name that ends in “ib,” imatinib is a small molecular pathway inhibitor; imatinib inhibits tyrosine kinase. It may be able to induce tumor regression in patients with recurrent DFSP, unresectable DFSP or metastatic DFSP. There is clinical evidence that imatinib, which inhibits PDGF-receptors, may be effective for tumors positive for the t(17;22) translocation.

AGGRESSIVE FIBROMATOSIS Aggressive fibromatosis is a rare condition marked by the presence of desmoid tumors. Desmoid tumors can arise in virtually any part of the body, and are tumors that arise from cells called fibroblasts, which are found throughout the body and provide structural support, protection to the vital organs, and play a critical role in wound healing. These tumors tend to occur in women in their thirties, but can occur in anyone at any age. They

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can be either relatively slow-growing or malignant. However, aggressive fibromatosis is locally aggressive. When they are aggressive they can cause life-threatening problems or even death when they compress vital organs such as intestines, kidney, lungs, blood vessels, nerves etc. Most cases are sporadic, but some are associated with familial adenomatous polyposis (FAP). Approximately 10% of individuals with Gardner’s syndrome, a type of FAP with extracolonic features, have desmoid tumors. Histologically they resemble very low-grade fibrosarcomas, but they are very locally aggressive and tend to recur even after complete resection. There is a tendency for recurrence in the setting of prior surgery; in one study, two-thirds of patients with desmoid tumors had a history of prior abdominal surgery. Risk factors for desmoid disease amongst FAP patients include female sex, a 3' APC mutation, a positive family history and a history of previous abdominal surgery.

Classification Desmoid tumors may be classified as extra-abdominal, abdominal wall, or intra-abdominal (the last is more common in patients with FAP). It is thought that the lesions may develop in relation to estrogen levels or trauma/operations. A 3' APC mutation is the most significant risk factor for intra-abdominal desmoid development amongst FAP patients. FAP patients presenting with an abdominal wall desmoid pre-operatively are at an increased risk of developing an intra-abdominal desmoid post-operatively. Desmoid tumours of the breast are rare. Although benign, they can mimic breast cancer on physical examination, mammography and breast ultrasound and can also be locally invasive. Even though they occur sporadically, they can also be seen as a part of Gardner’s syndrome. A high index of suspicion and a thorough triple examination protocol is necessary to detect rare lesions like a desmoid tumour which can masquerade as breast carcinoma. Desmoid tumour of the breast may present a difficulty in the diagnosis especially where imaging studies are not conclusive and suggest a more ominous diagnosis.

Treatment Treatment may consist of watching and waiting, complete surgical removal, radiation therapy, antiestrogens (ex. Tamoxifen), NSAIDs, chemotherapy or microwave ablation. Patients with desmoid tumors should be evaluated by a multi-disciplinary team of surgeons, medical oncologists, radiation oncologists, geneticists and nurses. There is no cure for desmoid tumors and when possible patients are encouraged to enlist in clinical trials. A biopsy is always indicated as the definitive method to determine nature of the tumour. Management of these lesions is complex, the main problem being the high rates of recurrence in FAP associated disease. Conversely, for intra-abdominal fibromatosis without evidence of FAP, although extensive surgery may still be required for local symptoms, the risk of recurrence appears to be lower. Wide surgical resection with clear margins is the most widely practiced technique with radiation, chemotherapy, or hormonal therapy being used to reduce the risk of recurrence. Current experimental studies are being done with Gleevec (Imatinib) and Nexavar (sorafenib) for treatment of desmoid tumors, and show promising success rates.

DESMOPLASTIC SMALL-ROUND-CELL TUMOR Desmoplastic small-round-cell tumor is an aggressive and rare cancer that primarily occurs as masses in the abdomen. Other areas affected may include the lymph nodes, the lining of the abdomen, diaphragm, spleen, liver, chest wall, skull, spinal cord, large intestine, small intestine, bladder, brain, lungs, testicles, ovaries, and the pelvis. Reported sites of metastatic spread include the liver, lungs, lymph nodes, brain, skull, and bones. The tumor is classified as a soft tissue sarcoma. It is considered a childhood cancer that predominantly strikes boys and young adults. The disease rarely occurs in females, but when it does the tumors can be mistaken for ovarian cancer. In dogs, mast cell tumors are the most frequent round cell tumor.

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Symptoms There are few early warning signs that a patient has a DSRCT. Patients are often young and healthy as the tumors grow and spread uninhibited within the abdominal cavity. These are rare tumors and symptoms are often misdiagnosed by physicians. The abdominal masses can grow to enormous size before being noticed by the patient. The tumors can be felt as hard, round masses by palpating the abdomen. First symptoms of the disease often include abdominal distention, abdominal mass, abdominal or back pain, gastrointestinal obstruction, lack of appetite, ascites, anemia, and/or cachexia. Other reported symptoms include unknown lumps, thyroid conditions, hormonal conditions, blood clotting, kidney or urological problems, testicle, breast, uterine, vaginal, or ovarian masses.

Causes There are no known risk factors that have been identified specific to the disease. The tumor appears to arise from the primitive cells of childhood, and is considered a childhood cancer. Research has indicated that there is a chimeric relationship between desmoplastic small-round-cell tumor (DSRCT) and Wilms’ tumor and Ewing’s sarcoma. Together with neuroblastoma and non-Hodgkin’s lymphoma, they form the small cell tumors. DSRCT is associated with a unique chromosomal translocation t(11;22)(p13:q12) resulting in an EWS/WT1 transcript that is diagnostic of this tumor. This transcript codes for a protein that acts as a transcriptional activator that fails to suppress tumor growth. The EWS/WT1 translocation product targets ENT4. ENT4 is also known as PMAT.

Pathology The entity was first described by pathologists William L. Gerald and Juan Rosai in 1989. Pathology reveals well circumscribed solid tumor nodules within a dense desmoplastic stroma. Often areas of central necrosis are present. Tumor cells have hyperchromatic nuclei with increased nuclear/cytoplasmic ratio. On immunohistochemistry, these cells have trilinear coexpression including the epithelial marker cytokeratin, the mesenchymal markers desmin and vimentin, and the neuronal marker neuron-specific enolase. Thus, although initially thought to be of mesothelial origin due to sites of presentation, it is now hypothesized to arise from a progenitor cell with multiphenotypic differentiation.

Diagnosis Differential Diagnosis Because this is a rare tumor, not many family physicians or oncologists are familiar with this disease. DSRCT in young patients can be mistaken for other abdominal tumors including rhabdomyosarcoma, neuroblastoma, and mesenteric carcinoid. In older patients DSRCT can resemble lymphoma, peritoneal mesothelioma, and peritoneal carcinomatosis. In males DSRCT may be mistaken for germ cell or testicular cancer while in females DSRCT can be mistaken for Ovarian cancer. DSRCT shares characteristics with other small-round blue cell cancers including Ewing’s sarcoma, acute leukemia, small cell mesothelioma, neuroblastoma, primitive neuroectodermal tumor, rhabdomyosarcoma, and Wilms’ tumor.

Treatment DSRCT is frequently misdiagnosed. Adult patients should always be referred to a sarcoma specialist. This is an aggressive, rare, fast spreading tumor and both pediatric and adult patients should be treated at a sarcoma center. There is no standard protocol for the disease; however, recent journals and studies have reported that

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some patients respond to high-dose (P6 Protocol) chemotherapy, maintenance chemotherapy, debulking operation, cytoreductive surgery, and radiation therapy. Other treatment options include: hematopoietic stem cell transplantation, intensity-modulated radiation Therapy, radiofrequency ablation, stereotactic body radiation therapy, intraperitoneal hyperthermic chemoperfusion, and clinical trials.

Prognosis The prognosis for DSRCT remains poor. Prognosis depends upon the stage of the cancer. Because the disease can be misdiagnosed or remain undetected, tumors frequently grow large within the abdomen and metastasize or seed to other parts of the body. There is no known organ or area of origin. DSRCT can metastasize through lymph nodes or the blood stream. Sites of metastasis include the spleen, diaphragm, liver, large and small intestine, lungs, central nervous system, bones, uterus, bladder, genitals, abdominal cavity, and the brain. A multi-modality approach of high-dose chemotherapy, aggressive surgical resection, radiation, and stem cell rescue improves survival for some patients. Reports have indicated that patients will initially respond to first line chemotherapy and treatment but that relapse is common. Some patients in remission or with inoperable tumor seem to benefit from long term low dose chemotherapy, turning DSRCT into a chronic disease.

Research The Stehlin Foundation currently offers DSRCT patients the opportunity to send samples of their tumors free of charge for testing. Research scientists are growing the samples on nude mice and testing various chemical agents to find which are most effective against the individual’s tumor. Patients with advanced DSRCT may qualify to participate in clinical trials that are researching new drugs to treat the disease.

Alternative Names This disease is also known as: desmoplastic small round blue cell tumor; intraabdominal desmoplastic small round blue cell tumor; desmoplastic small cell tumor; desmoplastic cancer; desmoplastic sarcoma; DSRCT. There is no connection to peritoneal mesothelioma which is another disease sometimes described as desmoplastic.

EPITHELIOID SARCOMA Epithelioid sarcoma is a rare soft tissue sarcoma arising from mesenchymal tissue and characterized by epithelioid-like features. It accounts for less than 1% of all soft tissue sarcomas. It was first clearly characterized by F.M. Enzinger in 1970. It commonly presents itself in the distal limbs (fingers, hands, forearms, or feet) of young adults as a small, soft mass or a series of bumps. A proximal version has also been described, frequently occurring in the upper extremities. Rare cases have been reported in the pelvis, vulva, penis, and spine. Histologically, epithelioid sarcoma forms nodules with central necrosis surrounded by bland, polygonal cells with eosinophilic cytoplasm and peripheral spindling. Epithelioid sarcomas typically express vimentin, cytokeratins, epithelial membrane antigen, and CD34, whereas they are usually negative for S100, desmin, and FLI-1. They typically stain positive for CA125. Epithelioid sarcoma most commonly strikes young adults, yet no age group is immune. The disease has a tendency to develop local recurrences and metastasis thereafter to regional lymph nodes, lung, bone, brain, and other locations, including the scalp. Generally speaking, epithelioid sarcoma has a high rate of relapse after initial treatment and tends to recur locally (at or near the original tumor site). Epithelioid sarcoma also demonstrates lymphatic spread (in 22-48% of cases), and metastasis (in 21-63% of cases). These events, as well as advanced stage (progression) and grade (aggressiveness), are predictive of an overall worse outcome. The overall five-year survival rate for epithelioid sarcoma is anywhere from 25 to 78%.

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Importantly, the 10-year and 15-year survival rate drops off significantly. Associated with a more positive outcome are younger age, female vs. male sex, distal vs. proximal location, smaller tumor size, and negative margins upon tumor resection.

Signs and Symptoms In general, epithelioid sarcoma is a slow-growing and relatively painless tumor, often resulting in a lengthy period of time between presentation and diagnosis. Due to its ambiguity, it is often misdiagnosed, mistaken as a persistent wart or cyst. It most commonly presents itself in the distal limbs (fingers, hands, forearms, or feet) as a small, soft mass or a series of bumps. It is most often described as a firm-to-hard palpable mass, either in the deep soft tissue or in the dermis. Often, superficial lesions will ulcerate causing a mistaken diagnosis of a poorly healing traumatic wound or wart. About 13% of patients will present with multifocal tumors, and about 13% of patients will present with metastatic disease.

Genetics The most common genetic mutation (found in 80-90% of epithelioid sarcomas) is the inactivation of the SMARCB1 gene, or the loss of INI-1 function, which is thought to be a major contributor to disease progression. Epithelioid sarcoma typically contains chromosome 22q11.2 mutations or deletions and 8q gains, particularly i(8) (>q10). Aberrations of 18q and 8q, as well as recurrent gains at 11q13, have also been observed. The SMARCB1 gene (also termed BAF47, INI1, or hSNF5) is located on chromosome 22q11.2 and codes for a member of the SWI/SNF chromatin remodeling complex. Loss of SMARCB1 function is the most common genetic mutation observed in epithelioid sarcoma, and this dysfunction is likely a major driver of disease progression. SMARCB1 is a core protein subunit of the 15 subunit SWI/SNF (or BAF) complex involved in regulating the nucleosome architecture of our genome and has been shown to be a potent tumor suppressor gene, meaning that its primary role is to control cell division and to even halt division under appropriate circumstances (i.e. signals to over-replicate). As this tumor suppressor is commonly inactivated in epithelioid sarcoma, cell division can fail to appropriately halt, resulting in unregulated cellular growth and the formation of cancer tumors. Several research teams are currently developing techniques to reverse this loss of genetic function characteristic of epithelioid sarcoma.

Molecular Biology VEGF VEGF (vascular endothelial growth factor) is often over-expressed in epithelioid sarcoma. This is a critical pathway in angiogenesis, a process that cancer cells use to form new blood vessels, which provide necessary elements to the tumor for tumor survival. Anti-VEGF agents such as pazopanib have shown promise across several different carcinomas and in soft tissue sarcomas. In one case study, a patient with advanced metastatic vulvar epithelioid sarcoma showed a partial resolution of both lung and pleural metastases when pazopanib was administered, whereas all other therapies had failed

MET MET (mesenchymal to epithelial transition) is another biological pathway that is likely involved in the development and progression of epithelioid sarcoma. c-MET is a tyrosine kinase oncogene, and its signaling pathway has been implicated in a variety of malignancies, including many cancers.

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Sonic Hedgehog and Notch The Sonic hedgehog and Notch signaling pathways are also suspected to be up-regulated in epithelioid sarcoma. These cell signaling pathways control cellular proliferation and differentiation. They are also involved in cancer stem cell coordination and disease invasiveness and metastasis. Hhat inhibitors (such as RU-SKI 43) block the Sonic hedgehog signaling pathway by inhibiting hedgehog palmitoyl acytl-transferase. Current trials are investigating Notch inhibitors against epithelioid sarcoma.

mTOR The frequent hyperactivation of mTOR (mammalian target of rapamycin) signaling has also been observed in epithelioid sarcoma. The mTOR pathway has been described as a “master switch” for cellular catabolism and anabolism, and it can enhance cell cycle progression, cell survival, and block normal cell death (apoptosis). Interestingly, it has been demonstrated that simply blocking mTOR signaling can result in the reactivation of the AKT pathway, negating much of the anti-mTOR’s efficacy. This reactivation of AKT has been shown to be c-MET-dependent, resulting in the rationale that blocking both mTOR and c-MET concurrently would show increased efficacy.

EGFR The over-expression of epidermal growth factor receptor (EGFR) has been reported in a majority of epithelioid sarcomas. EGFR is a member of the HER receptor family. Upon ligand binding, EGFR phosphorylation triggers the activation of downstream signaling pathways involved in critical cellular functions such as proliferation, survival, and angiogenesis. In-vitro and in-vivo laboratory experiments have demonstrated that the blockade of EGFR in epithelioid sarcoma results in decreased cell proliferation, increased apoptosis, and abrogated invasion and migration capacities. Of interest, while the simple blockade of EGFR with a single agent has shown limited results in the clinical setting, when used as part of a combination regime (where an EGFR inhibitor is combined with an mTOR inhibitor), a synergism has been observed, and superior tumor growth inhibition has been demonstrated.

CD109 CD109 is often expressed in advanced epithelioid sarcoma and is thought to mark the cancer stem cell (or cancer initiating cell) of the disease. Its level of expression has also been shown to be predictive of outcome. Cancer stem cells are a small population of tumor cells characterized by general chemo-resistance, the ability to self-renew, multi-differentiation potential, dormancy capabilities, and tumorigenesis. Therefore, cancer stem cells are thought to play key roles in the progression and relapse of cancer.

Cyclin D1 Cyclin D1 is a protein requisite for cell cycle progression and has been shown to be up-regulated in epithelioid sarcoma. Cyclin D-1 is a regulator of cyclin-dependent kinases (CDK4 and CDK6). It has been shown to interact with the retinoblastoma protein (a tumor suppressor gene), CDK4 and CDK6, thyroid hormone receptor beta, and nuclear receptor coactivator 1, among others. Cyclin D and CDKs promote cell cycle progression by releasing transcription factors that are important for the initiation of DNA replication. Abnormal levels of cyclin D-1 may promote rapid cell division in epithelioid sarcoma.

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Diagnosis Tissue biopsy is the diagnostic modality of choice. Due to a high incidence of lymph node involvement, a sentinel lymph node biopsy is often performed. A common characteristic of epithelioid sarcoma (observed in 80% of all cases) is the loss of function of the SMARCB1 gene (also termed BAF47, INI1, or hSNF5). Immunohistochemical staining of INI1 is available and can be used for the diagnosis of epithelioid sarcoma. MRI is the diagnostic modality of choice for imaging prior to biopsy and pathologic diagnosis, with the primary role being the determination of anatomic boundaries.

Staging The staging for epithelioid sarcoma takes into account size and location of the primary tumor, lymph node involvement, presence and location of metastasis, and histologic grade (a measure of disease aggressiveness).

Treatment Surgical resection of the tumor with wide margins remains the preferred method of treatment, and has shown the most success against the disease. Recently, limb-sparing surgery has been explored with moderate success. In cases of advanced, recurrent, or metastasized disease, or if the tumor is inoperable, chemotherapy and radiation are the standard of care, although the overall success rates with these remains low.

Prognosis The 5-year survival rate for epithelioid sarcoma patients is 50-70%, and the 10-year survival rate is 42-55%. Children with epithelioid sarcoma tend to have slightly better outcomes than adults, with 5 year survival rates around 65%. Pediatric patients also tend to display less lymphatic spread and metastasis. In addition to stage and grade of the tumor, gender, site, age at diagnosis, tumor size and microscopic pathology have all been shown to affect prognosis. Advanced stage and grade are associated with worse outcomes. Females tend to have more favourable outcomes than males, proximal cases show worse outcomes than distal cases, and younger age is associated with more positive outcomes. Tumors more than 2 cm in diameter and tumors with necrosis and vascular invasion have been correlated with a worse outcome. The gold standard for chemotherapy is a combination of doxorubicin and ifosfamide. However, recent studies have suggested that the addition of ifosfamide to doxorubicin does not necessarily lead to an increase in overall survival. Etoposide, vincristine, dactinomycin, and cyclophosphamide have also traditionally been given. Newer chemotherapies, such as gemcitabine and pazopanib, are currently being tested in clinical trials. Radiation therapy is also a treatment option when tumors are deemed inoperable or wide surgical margins are not achievable. Radiation therapy in combination with chemotherapy has so far resulted in only minimal improvements to response rates. Trials with brachytherapy (an internal radiation treatment that delivers a high dose of radiation directly to the tumor and is thought to have fewer long-term side effects) have produced some positive results.

New Therapeutic Strategies Epithelioid sarcoma (especially advanced stage, recurrent, or metastasized disease) has been shown to be resistant to traditional cancer therapies, necessitating further exploration of novel treatment methods and techniques. Because of the relatively poor response of epithelioid sarcoma to traditional cancer treatments (surgery, chemotherapy, and radiation), new treatment strategies are being looked to.

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New Chemotherapies New chemotherapies are being explored in current clinical trials for epithelioid sarcoma, although, thus far, none has shown significant improvement over the efficacy of doxorubicin/ifosfamide. These new agents include gemcitabine, pazopanib, cixutumumab, temozolomide, dasatanib, bevacizumab, taxanes, and vinorelbine. Aldoxorubicin is a new pro-drug of doxorubicin. Doxorubicin is the standard of care for advanced or metastic epithelioid sarcoma, but has dose-limiting toxicities, namely acute and chronic cardiac toxicity. Doxorubicin has achieved response rates in the 12-23% range for patients with soft tissue sarcomas. Aldoxorubicin is a new version of doxorubicin that is designed to safely deliver a higher dose of the drug directly to the tumor, resulting in increased efficacy and less toxicity. It works by entering the bloodstream, binding to the albumin in the blood, traveling throughout the body, and releasing a doxorubicin payload when it encounters the acidic microenvironment of a tumor. Several phase I and II studies are ongoing, and, thus far at least, little if any cardiac toxicity has been observed. A maximum tolerated dose of aldoxorubicin has been established at 3.5 times the MTD of doxorubicin, and studies have indicated increased response rates for patients with soft tissue sarcomas. What is unknown at this time are the potential long-term side-effects of this increased dose of doxorubicin. Several studies have shown increased risk of the development of secondary cancers associated with exposure to high-dose anthracyclines (such as doxorubicin). TH-302 is another novel prodrug in current development. It targets tumor hypoxia, a common event in tumorigenesis where the tumor microenvironment is depleted of oxygen and becomes hypoxic. Hypoxic niches in tumors tend to harbour slower-growing cancer cells, making many chemotherapies ineffective in these areas. TH-302 directly targets these deep hypoxic regions, and once within them, it releases a cytotoxic payload of bromo-isophosphoramide mustard directly to the cancer cells. Given that epithelioid sarcoma is a slow-growing tumor, it is reasonable to hypothesize that ES tumors would be highly hypoxic and show a favourable response to TH-302. Several studies have observed increased efficacy of TH-302 when the hypoxic tumor microenvironment has been exasperated. Several phase I, II, and III trials with TH-302 and TH-302 in combination with doxorubicin are ongoing, and promising results have thus far been observed. Two phase 3 trials failed in 2015.

Immunotherapies Immunotherapy is the strategy of using the body’s own immune system to fight cancer. It usually involves “training” or “tweaking” the immune system so that it can better recognize and reject cancer cells. Different immunotherapies can include manipulation of the body’s T-cells, NK cells, or Dendritic cells so they are more effective against cancer cells. They can also include the administration of laboratory-produced antibodies specific to tumor antigens to create or boost an immune response. Vaccine therapy is perhaps the immunotherapeutic strategy with the most ongoing exploration in sarcomas at the current time, although, thus far at least, little evidence has emerged indicating that active vaccination alone can lead to tumor regression. Multiple techniques and treatment strategies are currently being studied in an effort to improve the objective response rate of vaccine therapy. Vaccines can deliver various tumor-associated factors (tumor antigens) to the immune system, resulting in a natural antibody and T-cell response to the tumor. Adoptive immunotherapy seeks to expand a population of the body’s T-cells that will recognize a specific tumor antigen. T-cells can be harvested and then expanded and genetically manipulated to recognize certain tumor markers. In an interesting case study, a patient with advanced epithelioid sarcoma who had failed multiple therapies showed a strong response to expanded lymphocytes and natural killer cells. Immune checkpoint inhibitors have recently shown promise against several cancers and may hold promise against sarcomas as well. Tumors often evolve during disease progression, and they can develop an expression of inhibitory proteins that deter recognition by the immune system and allow the tumor to escape immune surveillance. By targeting these inhibitory proteins, a pathway is opened for the

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immune system to recognize the tumor. Two of these inhibitory proteins that have been studied recently are CTLA-4 and PD1, and drugs targeting these proteins are in development and showing some promise.

Anti-angiogenic Therapies Several anti-angiogenic agents are being explored in epithelioid sarcoma, a cancer that likely relies on angiogenesis for survival and progression. These agents interfere with various pro-angiogenic factors, several of which are known to be over-expressed in epithelioid sarcoma (VEGF and EGFR for example). Tumors require a blood supply to provide them with oxygen and nutrients necessary for their survival. As tumors expand and grow, they send out various signals (such as HIF1) that encourage new blood vessel development to the tumor. Anti-angiogenic agents, such as bevacizumab, pazopanib, and sunitinib, attempt to slow or block the growth of tumors by essentially cutting off their blood supply.

Targeted Therapies Given the multiple genetic abnormalities and disrupted biological pathways observed in epithelioid sarcoma, drugs targeting these unique tumor characteristics are being looked at for more effective treatments.

Tyrosine Kinase Inhibitors Stromal tumors (GISTs). Tyrosine kinase (a subclass of protein kinases) is an enzyme that transfers a phosphate group from an ATP molecule to a protein in a cell. It functions as an “on” or “off” switch for many cellular functions, including signaling within the cell, and cell division. Tyrosine kinases can contain mutations that cause them to become constitutively active, or stuck in the “on” position, resulting in unregulated cell division (a hallmark of cancer). Tyrosine kinase Inhibitors block the action of these enzymes. Tyrosine kinase inhibitors have been shown to inhibit the VEGF, EGFR, and MET, pathways that are frequently over-expressed in epithelioid sarcoma. They also can be used against the c-KIT and JAK-STAT signaling pathways, which are involved in many cancers and may be involved in epithelioid sarcoma. Temsirolimus is a tyrosine kinase inhibitor that blocks the effects of the mTOR protein and inhibits the mTOR pathway. Interestingly, because of crosstalk between cell signaling pathways, it has been shown that, while interfering with the mTOR pathway alone produces only limited results in halting tumorigenesis, inhibiting both the mTOR and the EGFR pathways concurrently shows an increased effect.

SINE Selective inhibitors of nuclear export (SINE) compounds, such as selinexor and CBS9106, are being investigated in several sarcomas and have recently shown promising results across a broad spectrum of both hematological malignancies and solid tumors. These compounds work by blocking the export of tumor suppressor genes from the cell’s nucleus to the cell’s cytoplasm, where they are rendered non-functional. Exportin 1 (a.k.a. XPO1 or CRM1) is a nuclear export protein responsible for the export of over 200 proteins, including the vast majority of tumor suppressor proteins. For tumor suppressor genes to carry out their normal function (appropriately initiating apoptosis), they must be located in the nucleus of the cell. Many cancer cells have been shown to express high levels of exportin1, resulting in the increased export of tumor suppressor proteins out of the nucleus and therefore counteracting the natural apoptic processes that protect the body from cancer. SINE compounds prevent the transport of these tumor suppressor proteins out of the nucleus, allowing them to function normally and encourage apoptosis. Recently, researchers have observed a synergistic effect when using SINE compounds in combination with traditional chemotherapies (such as doxorubicin). Of interest with respect to epithelioid sarcoma and other diseases characterized by the loss of INI1 function, it has been demonstrated that a loss of INI1 expression can result in the “unmasking” of a nuclear export signal, resulting in the transport of

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tumor suppressor proteins out of the nucleus of the cell, thus favouring tumorigenesis. It is therefore reasonable to suspect that a SINE inhibitor would show efficacy against epithelioid sarcoma, as the disease is characterized by a loss of INI1 function.

HDAC Inhibitors Histone deacetylase (HDAC) inhibitors, such as vorinostat, have shown some promise in epithelioid sarcoma. Researchers in Texas are investigating whether or not HDAC inhibitors can reverse the loss of INI1 function that is characteristic of epithelioid sarcoma. HDAC inhibitors work by blocking events involved in DNA replication and, therefore, in cell division. Blocking HDAC has been shown to encourage cancer cells to enter apoptosis. Interestingly, several dietary phytochemicals have been shown to be effective HDAC inhibitors. These include sulphorphane, indole-3-carbinol, and phenethyl isothiocyanates, found in broccoli, kale, and watercress, and epigallocatecehin-3-gallate, found in green tea.

CDK Inhibitors Because of the association with cyclin D1 CDK inhibitors are being studied. palbociclib is a CDK inhibitor (approved for some breast cancer). Other experimental CDK inhibitors include abemaciclib and ribociclib.

Targeting the Cancer Stem Cell Cancer stem cells (or cancer-initiating cells) are thought to be a small population of cells within the tumor that are directly responsible for tumor formation. They are thought to be resistant to treatment and to have the ability to form all the cells needed for tumor development. They are suspected to be a major contributing factor in cancer progression and relapse after treatment. Certain “stem-like” cells have been found in epithelioid sarcoma that are marked by CD109 (cluster of differentiation 109), providing a potentially drug-able target on the cancer stem cell for the disease. Certain challenges to targeting CD109 do exist, however, as CD109 is expressed in other areas of the body and not only in tumor cells.

Oncolytic Viral Therapy Oncolytic viral therapy is an emerging cancer therapy that attempts to infect cancer cells with a genetically engineered virus that can penetrate the DNA of the cell. The virus then • Does direct damage to the cancer cell, • Is spread throughout the cells of the tumor via cellular (DNA) multiplication (tumor cell division and replication), and • Provides a target for a direct immune response from the patient. It has been noted that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect but strongly relies on the induction of an endogenous immune response against transformed cells. Superior anticancer effects have been observed when oncolytic viruses are engineered to express (or be co-administered with) immunostimulatory molecules such as GM-CSF. Telomelysin (OBP-301) is an adenovirus that targets telomerase, an enzyme that is expressed in practically all cancer cells but not in normal cells. OBP301 has been studied in epithelioid sarcoma and shown to promote apoptosis and cell death.

CGTG-102 CGTG-102 (developed by Oncos Therapeutics) is an adenovirus currently in orphan drug status for soft tissue sarcomas. It is modified to selectively replicate in p16/Rb-defective cells, which include most human cancer cells. In addition, CGTG-102 codes for the granulocyte–macrophage colony-stimulating factor (GMCSF), a potent immunostimulatory molecule. While the CGTG-102 oncolytic adenovirus has shown efficacy as

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a single agent against several soft tissue sarcomas, it would also be appealing to use in combination with other regimes, as oncolytic viruses have demonstrated very little overlap in side effects with traditional therapies such as chemotherapy and radiation. CGTG-102 has recently been studied in combination with doxorubicin, and a synergistic effect was observed. At least part of doxorubicin’s mechanism of action is as an inducer of immunogenic cell death, and it has been suggested that immune response contributes to its overall anti-tumor activity. Doxorubicin has been shown to increase adenoviral replication in soft tissue sarcoma cells as well, potentially contributing to the observed synergistic effect in the virus/doxorubicin combination.

FIBROSARCOMA Fibrosarcoma (fibroblastic sarcoma) is a malignant mesenchymal tumour derived from fibrous connective tissue and characterized by the presence of immature proliferating fibroblasts or undifferentiated anaplastic spindle cells in a storiform pattern. It is usually found in males aged 30 to 40. It originates in fibrous tissues of the bone and invades long or flat bones such as femur, tibia, and mandible. It also involves periosteum and overlying muscle.

Pathology The tumor may present different degrees of differentiation: low grade (differentiated), intermediate malignancy and high malignancy (anaplastic). Depending on this differentiation, tumour cells may resemble mature fibroblasts (spindle-shaped), secreting collagen, with rare mitoses. These cells are arranged in short fascicles which split and merge, giving the appearance of “fish bone” known as a herringbone pattern. Poorly differentiated tumors consist in more atypical cells, pleomorphic, giant cells, multinucleated, numerous atypical mitoses and reduced collagen production. Presence of immature blood vessels (sarcomatous vessels lacking endothelial cells) favours the bloodstream metastasizing. There are many tumors in the differential diagnosis, including spindle cell melanoma, spindle cell squamous cell carcinoma, synovial sarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor and biphenotypic sinonasal sarcoma.

Clinical Presentation in Humans Adult-type Individuals presenting with fibrosarcoma are usually adults aged thirty to fifty five years, often presenting with pain. In adults, males have a higher incidence for fibrosarcoma than females.

Infantile-type In infants, fibrosarcoma (often termed congenital infantile fibrosarcoma) is usually congenital. Infants presenting with this fibrosarcoma usually do so in the first two years of their life. Cytogenetically, congenital infantile fibrosarcoma is characterized by the majority of cases having a translocation between chromosomes 12 and 15 (notated as t(12;15)(p13;q25)) that results in formation of the fusion gene, ETV6-NTRK3, plus individual cases exhibiting trisomy for chromosomes 8, 11, 17, or 20. The histology, association with the ETV6-NRTK3 fusion gene as well as certain chromosome trisomies, and the distribution of markers for cell type (i.e. cyclin D1 and Beta-catenin) within this tumor are similar to those found in the cellular form of mesoblastic nephroma. Indeed, mesoblastic nephroma and congenital infantile sarcoma appear to be the same disease with the exception that mesoblastic lymphoma originates in the kidney whereas congenital infantile sarcoma originates in nonrenal tissues.

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Ancillary Testing Ancillary testing for fibrosarcoma includes IHC, where vimentin is positive, cytokeratin and S100 are negative, and actin is variable.

HEMANGIOPERICYTOMA A hemangiopericytoma (HPC) is a type of soft tissue sarcoma that originates in the pericytes in the walls of capillaries. When inside the nervous system, although not strictly a meningioma tumor, it is a meningeal tumor with a special aggressive behaviour. It was first characterized in 1942.

Description Hemangiopericytoma located in the cerebral cavity is an aggressive tumor of the Mesenchyme with oval nuclei with scant cytoplasm. “There is dense intercellular reticulin staining. Tumor cells can be fibroblastic, myxoid, or pericytic. These tumors, in contrast to meningiomas, do not stain with epithelial membrane antigen. They have a grade 2 or 3 biological behaviour, and need to be distinguished from benign meningiomas because of their high rate of recurrence (68.2%) and metastases (Maier et al. 1992; Kleihues et al. 1993).”

Treatment Depending on the grade of the sarcoma, it is treated with surgery, chemotherapy and/or radiotherapy.

HEMANGIOSARCOMA Hemangiosarcoma is a rapidly growing, highly invasive variety of cancer that occurs almost exclusively in dogs, and only rarely in cats, horses, mice, or humans. It is a sarcoma arising from the lining of blood vessels; that is, blood-filled channels and spaces are commonly observed microscopically. A frequent cause of death is the rupturing of this tumor, causing the patient to rapidly bleed to death. The term “angiosarcoma”, when used without a modifier, usually refers to hemangiosarcoma. However, glomangiosarcoma (8710/3) and lymphangiosarcoma (9170/3) are distinct conditions [in humans]. Hemangiosarcomas are commonly associated with toxic exposure to thorium dioxide (Thorotrast), vinyl chloride, and arsenic.

Hemangiosarcoma in Dogs Hemangiosarcoma is quite common in dogs, and more so in certain breeds including German Shepherd Dogs and Golden Retrievers. It also occurs in cats, but much more rarely. Dogs with hemangiosarcoma rarely show clinical signs until the tumor has become very large and has metastasized. Typically, clinical signs are due to hypovolemia after the tumor ruptures, causing extensive bleeding. Owners of the affected dogs often discover that the dog has hemangiosarcoma only after the dog collapses. The tumor most often appears on the spleen, right heart base, or liver, although varieties also appear on or under the skin or in other locations. It is the most common tumor of the heart, and occurs in the right atrium or right auricular appendage. Here it can cause right-sided heart failure, arrhythmias, pericardial effusion, and cardiac tamponade. Hemangiosarcoma of the spleen or liver is the most common tumor to cause hemorrhage in the abdomen. Hemorrhage secondary to splenic and hepatic tumors can also cause ventricular arrythmias. Hemangiosarcoma of the skin usually appears as a small red or bluish-black lump. It can also occur under the skin. It is suspected that in the skin, hemangiosarcoma is caused by sun exposure. Occasionally, hemangiosarcoma of the skin can be a metastasis from visceral hemangiosarcoma. Other sites the tumor may occur include bone, kidneys, the bladder, muscle, the mouth, and the central nervous system.

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Clinical Features Presenting complaints and clinical signs are usually related to the site of origin of the primary tumor or to the presence of metastases, spontaneous tumor rupture, coagulopathies, or cardiac arrhythmias. More than 50% of patients are presented because of acute collapse after spontaneous rupture of the primary tumor or its metastases. Some episodes of collapse are a result of ventricular arrhythmias, which are relatively common in dogs with splenic or cardiac HSA. Most common clinical signs of visceral hemangiosarcoma include loss of appetite, arrhythmias, weight loss, weakness, lethargy, collapse, pale mucous membranes, and/or sudden death. An enlarged abdomen is often seen due to hemorrhage. Metastasis is most commonly to the liver, omentum, lungs, or brain. A retrospective study published in 1999 by Ware, et al., found a 5 times greater risk of cardiac hemangiosarcoma in spayed vs. intact female dogs and a 2.4 times greater risk of hemangiosarcoma in neutered dogs as compared to intact males.

Clinicopathologic Findings Hemangiosarcoma can cause a wide variety of hematologic and hemostatic abnormalities, including anemia, thrombocytopenia (low platelet count), disseminated intravascular coagulation (DIC); presence of nRBC, schistocytes, and acanthocytes in the blood smear; and leukocytosis with neutrophilia, left shift, and monocytosis. A definitive diagnosis requires biopsy and histopathology. Cytologic aspirates are usually not recommended, as the accuracy rate for a positive diagnosis of malignant splenic disease is approximately 50%. This is because of frequent blood contamination and poor exfoliation. Surgical biopsy is the typical approach in veterinary medicine.

Treatments Treatment includes chemotherapy and, where practical, removal of the tumor with the affected organ, such as with a splenectomy. Splenectomy alone gives an average survival time of 1–3 months. The addition of chemotherapy, primarily comprising the drug doxorubicin, alone or in combination with other drugs, can increase the average survival time to 2-4 months, or more. A more favourable outcome has been demonstrated in recent research conducted at University of Pennsylvania Veterinary School, in dogs treated with a compound derived from the Coriolus versicolor (commonly known as “Turkey Tail”) mushroom: • “We were shocked,” Cimino Brown said. “Prior to this, the longest reported median survival time of dogs with hemangiosarcoma of the spleen that underwent no further treatment was 86 days. We had dogs that lived beyond a year with nothing other than this mushroom as treatment.”There were not statistically significant differences in survival between the three dosage groups, though the longest survival time was highest in the 100 mg group, at 199 days, eclipsing the previously reported survival time. • The results were so surprising, in fact, that the researchers asked Penn Vet pathologists to recheck the dogs’ tissue biopsies to make sure that the dogs really had the disease. “They reread the samples and said, yes, it’s really hemangiosarcoma,” Cimino Brown said. Chemotherapy is available for treating hemangiosarcoma, but many owners opt not to pursue that treatment once their dog is diagnosed. • “It doesn’t hugely increase survival, it’s expensive and it means a lot of back and forth to the vet for the dog,” Cimino Brown said. “So you have to figure in quality of life.” This treatment does not always work. So, one should always be prepared for their pet to have the same survival time as a dog who is untreated. Visceral hemangiosarcoma is usually fatal even with treatment, and usually within weeks or, at best, months. In the skin, it can be cured in most cases with complete surgical removal as long as there is not visceral involvement.

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KAPOSI’S SARCOMA Kaposi’s sarcoma (KS) is a type of cancer that can form in the skin, lymph nodes, or other organs. The skin lesions are usually purple in colour. They can occur singularly, in a limited area, or be widespread. It may worsen either gradually or quickly. Lesions may be flat or raised. Human herpesvirus 8 (HHV8) is found in the lesions of all those who are affected. Risk factors include poor immune function, either as a result of disease or specific medications, and chronic lymphedema. Five sub-types are described: classic, endemic, immunosuppresion therapy-related, and epidemic. Classic KS tends to affect older men, be slow growing, and affect the legs. Endemic KS occurs in young adult males in Africa and can be more aggressive. Immunosuppresion therapy-related KS generally occurs in people following organ transplantation and mostly affects the skin. Epidemic KS occurs in people with AIDS and many parts of the body can be affected. The diagnosis is by tissue biopsy while the extent of disease may be determined by medical imaging. Treatment is based on the sub-type, whether the condition is localized or widespread, and the person’s immune function. Localized skin lesions may be treated by surgery, injections of chemotherapy into the lesion, or radiation therapy. Widespread disease may be treated with chemotherapy or biologic therapy. In those with HIV/AIDS highly active antiretroviral therapy (HAART) prevents and often treats KS. In certain cases the addition of chemotherapy may be required. With widespread disease, death may occur. The condition is relatively common in people with HIV/AIDS and following organ transplant as of 2017. Over 35% of people with AIDS may be affected. It was first described by Moritz Kaposi in 1872. It became more widely known as one of the AIDS-defining illnesses in the 1980s. The viral association for this cancer was discovered in 1994.

Signs and Symptoms KS lesions are nodules or blotches that may be red, purple, brown, or black, and are usually papular. They are typically found on the skin, but spread elsewhere is common, especially the mouth, gastrointestinal tract and respiratory tract. Growth can range from very slow to explosively fast, and is associated with significant mortality and morbidity.

Skin Commonly affected areas include the lower limbs, back, face, mouth, and genitalia. The lesions are usually as described above, but may occasionally be plaque-like (often on the soles of the feet) or even involved in skin breakdown with resulting fungating lesions. Associated swelling may be from either local inflammation or lymphoedema (obstruction of local lymphatic vessels by the lesion). Skin lesions may be quite disfiguring for the sufferer, and a cause of much psychosocial pathology.

Mouth The mouth is involved in about 30% of cases, and is the initial site in 15% of AIDS-related KS. In the mouth, the hard palate is most frequently affected, followed by the gums. Lesions in the mouth may be easily damaged by chewing and bleed or suffer secondary infection, and even interfere with eating or speaking.

Gastrointestinal Tract Involvement can be common in those with transplant-related or AIDS-related KS, and it may occur in the absence of skin involvement. The gastrointestinal lesions may be silent or cause weight loss, pain, nausea/ vomiting, diarrhea, bleeding (either vomiting blood or passing it with bowel motions), malabsorption, or intestinal obstruction.

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Respiratory Tract Involvement of the airway can present with shortness of breath, fever, cough, hemoptysis (coughing up blood), or chest pain, or as an incidental finding on chest x-ray. The diagnosis is usually confirmed by bronchoscopy when the lesions are directly seen, and often biopsied.

Cause Kaposi’s sarcoma-associated herpesvirus (KSHV), also called HHV-8 is present in almost 100% of Kaposi sarcoma lesions, whether HIV-related, classic, endemic, or iatrogenic.

Transmission In Europe and North America, KSHV is transmitted through saliva. Thus, kissing is a theoretical risk factor for transmission. Higher rates of transmission among gay and bisexual men have been attributed to “deep kissing” sexual partners with KSHV. Another alternative theory suggests that use of saliva as a sexual lubricant might be a major mode for transmission. Prudent advice is to use commercial lubricants when needed and avoid deep kissing with partners with KSHV infection or whose status is unknown. KSHV is also transmissible via organ transplantation and blood transfusion. Testing for the virus before these procedures is likely to effectively limit iatrogenic transmission.

Classification HHV-8, is responsible for all varieties of KS. Since Moritz Kaposi first described this cancer, the disease has been reported in five separate clinical settings, with different presentations, epidemiology, and prognoses. All of these forms are infected with KSHV and are different manifestations of the same disease but have differences in clinical aggressiveness, prognosis and treatment. • Classic Kaposi sarcoma most commonly appears early on the toes and soles as reddish, violaceous, or bluish-black macules and patches that spread and coalesce to form nodules or plaques. A small percentage of these patients may have visceral lesions. In most cases the treatment involves surgical removal of the lesion. The condition tends to be indolent and chronic, affecting elderly men from the Mediterranean region, Arabian countries or of Eastern European descent. Countries bordering the Mediterranean basin have higher rates of KSHV/HHV-8 infection than the remainder of Europe. • Endemic KS, which has two types. Although this may be present worldwide, it has been originally described later in young African people, mainly from sub-Saharan Africa. This variant is not related to HIV infection and is a more aggressive disease that infiltrates the skin extensively. a. African lymphadenopathic Kaposi sarcoma is aggressive, occurring in children under 10 years of age, presenting with lymph node involvement, with or without skin lesions. b. African cutaneous Kaposi sarcoma presents with nodular, infiltrative, vascular masses on the extremities, mostly in men between the ages of 20 and 50, and is endemic in tropical Africa. • Immunosuppression-associated Kaposi sarcoma had been described, but only rarely until the advent of calcineurin inhibitors (such as ciclosporines, which are inhibitors of T-cell function) for transplant patients in the 1980s, when its incidence grew rapidly. The tumor arises either when an HHV 8infected organ is transplanted into someone who has not been exposed to the virus or when the transplant recipient already harbours pre-existing HHV 8 infection. Unlike classic Kaposi sarcoma, the site of presentation is more variable.

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AIDS-associated Kaposi sarcoma typically presents with cutaneous lesions that begin as one or several red to purple-red macules, rapidly progressing to papules, nodules, and plaques, with a predilection for the head, back, neck, trunk, and mucous membranes. In more advanced cases, they can be found in the stomach and intestines, the lymph nodes, and the lungs. KS-AIDS stimulated the greatest interest as one of the first illnesses associated with AIDS, and was first described in 1981. It is over 300 times more common in AIDS patients than in renal transplant recipients. In this case, HHV 8 is sexually transmitted among people also at risk for sexually transmitted HIV infection.

Pathology Despite its name, in general it is not considered a true sarcoma, which is a tumor arising from mesenchymal tissue. The histogenesis of KS remains controversial. KS may arise as a cancer of lymphatic endothelium and forms vascular channels that fill with blood cells, giving the tumor its characteristic bruise-like appearance. KSHV proteins are uniformly detected in KS cancer cells. KS lesions contain tumor cells with a characteristic abnormal elongated shape, called spindle cells. The most typical feature of Kaposi sarcoma is the presence of spindle cells forming slits containing red blood cells. Mitotic activity is only moderate and pleomorphism is usually absent. The tumor is highly vascular, containing abnormally dense and irregular blood vessels, which leak red blood cells into the surrounding tissue and give the tumor its dark colour. Inflammation around the tumor may produce swelling and pain. Variously sized PAS positive hyaline bodies are often seen in the cytoplasm or sometimes extracellularly. The spindle cells of Kaposi sarcoma differentiate towards endothelial cells, probably of lymph vessel rather than blood vessel nature. The consistent immunoreactivity for podoplanin supports the lymphatic nature of the lesion.

Diagnosis Although KS may be suspected from the appearance of lesions and the patient’s risk factors, definite diagnosis can be made only by biopsy and microscopic examination. Detection of the KSHV protein LANA in tumor cells confirms the diagnosis. In differential diagnosis, arteriovenous malformations, pyogenic granuloma and other vascular proliferations can be microscopically confused with KS.

Prevention Blood tests to detect antibodies against KSHV have been developed and can be used to determine whether a person is at risk for transmitting infection to their sexual partner, or whether an organ is infected prior to transplantation. However, these tests are not available except as research tools, and, thus, there is little screening for persons at risk for becoming infected with KSHV, such as people following a transplant.

Treatment Kaposi sarcoma is not curable, but it can often be treatable for many years. In KS associated with immunodeficiency or immunosuppression, treating the cause of the immune system dysfunction can slow or stop the progression of KS. In 40% or more of peoples with AIDS-associated Kaposi sarcoma, the Kaposi lesions will shrink upon first starting highly active antiretroviral therapy (HAART). However, in a certain percentage of such people, Kaposi sarcoma may again grow after a number of years on HAART, especially if HIV is not completely suppressed. People with a few local lesions can often be treated with local measures such as radiation therapy or cryosurgery.

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Weak evidence suggests that antiretroviral therapy in combination with chemotherapy is more effective than either of those two therapies individually. Limited basic and clinical evidence suggest that topical beta-blockers, such as timolol, may induce regression of localized lesions in classic as well as HIV-associated Kaposi sarcoma. In general, surgery is not recommended, as Kaposi sarcoma can appear in wound edges. In general, more widespread disease, or disease affecting internal organs, is treated with systemic therapy with interferon alpha, liposomal anthracyclines (such as Doxil) or paclitaxel.

Awareness It has been reported that only 6% of men who have sex with men are aware that KS is caused by a virus different from HIV. Thus, there is little community effort to prevent KSHV infection. Likewise, no systematic screening of organ donations is in place. In people with AIDS, Kaposi sarcoma is considered an opportunistic infection, a disease that is able to gain a foothold in the body because the immune system has been weakened. With the rise of HIV/AIDS in Africa, where KSHV is widespread, KS has become the most frequently reported cancer in some countries. Because of their highly visible nature, external lesions are sometimes the presenting symptom of AIDS. Kaposi sarcoma entered the awareness of the general public with the release of the film Philadelphia, in which the main character was fired after his employers found out he was HIV-positive due to visible lesions. By the time KS lesions appear, it is likely that the immune system has already been severely weakened.

LEIOMYOSARCOMA Leiomyosarcoma, also referred to as LMS, is a malignant (cancerous) smooth muscle tumor. A benign tumor originating from the same tissue is termed leiomyoma. While it has been believed that leiomyosarcomas do not arise from leiomyomas, there are leiomyoma variants for which classification is evolving. About 1 person in 100,000 gets diagnosed with LMS each year. Leiomyosarcoma is one of the more common types of soft-tissue sarcoma, representing 10 percent to 20 percent of new cases. (Leiomyosarcoma of the bone is more rare.) Sarcoma is rare, consisting of only 1 percent of cancer cases in adults. Leiomyosarcomas can be very unpredictable. They can remain dormant for long periods of time and recur after years. It is a resistant cancer, meaning generally not very responsive to chemotherapy or radiation. The best outcomes occur when it can be removed surgically with wide margins early, while small and still in situ.

Mechanism Smooth muscle cells make up the involuntary muscles, which are found in most parts of the body, including the uterus, stomach and intestines, the walls of all blood vessels, and the skin. It is therefore possible for leiomyosarcomas to appear at any site in the body. They are most commonly found in the uterus, stomach, small intestine and retroperitoneum. Uterine leiomyosarcomas come from the smooth muscle in the muscle layer of the uterus. Cutaneous leiomyosarcomas derive from the pilo-erector muscles in the skin. Gastrointestinal leiomyosarcomas might come from smooth muscle in the GI tract or, alternatively, also from a blood vessel. At most other primary sites—retroperitoneal extremity (in the abdomen, behind the intestines), truncal, abdominal organs, etc.—leiomyosarcomas appear to grow from the muscle layer of a blood vessel (the tunica media). Thus a leiomyosarcoma can have a primary site of origin anywhere in the body where there is a blood vessel. The tumors are usually hemorrhagic and soft and microscopically marked by pleomorphism, abundant (15–30 per 10 high power fields) abnormal mitotic figures, and coagulative tumor cell necrosis. There is a wide differential diagnosis, which includes spindle cell carcinoma, spindle cell melanoma, fibrosarcoma, malignant peripheral nerve sheath tumor and even biphenotypic sinonasal sarcoma.

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Treatment Surgery, with as wide a margin of removal as possible, has generally been the most effective and preferred way to attack LMS. If surgical margins are narrow or not clear of tumor, however, or in some situations where tumor cells were left behind, chemotherapy or radiation has been shown to give a clear survival benefit. While LMS tends to be resistant to radiation and chemotherapy, each case is different and results can vary widely. LMS of uterine origin do frequently, but not always respond to hormonal treatments.

LIPOSARCOMA Liposarcoma is a cancer that arises in fat cells in deep soft tissue, such as that inside the thigh or in the retroperitoneum. Liposarcoma is a rare type of cancer that bears a resemblance to fat cells when examined under a microscope. They are typically large bulky tumors, and tend to have multiple smaller satellites that extend beyond the main confines of the tumor. Liposarcomas, like all sarcomas, are rare.

Signs and Symptoms Patients usually note a deep seated mass in their soft tissue. Only when the tumor is very large do symptoms of pain or functional disturbances occur. Retroperitoneal tumors may present themselves with signs of weight loss and emaciation and abdominal pain. These tumors may also compress the kidney or ureter leading to kidney failure.

Diagnosis The diagnosis is established by histologic examination of the tissue, i.e., biopsy or excision. Lipoblasts are often present; these are cells with an abundant clear multi-vacuolated cytoplasm and an eccentric darkly staining nucleus that is indented by the vacuoles.

Subtypes Several subtypes of liposarcoma exist: • Well-differentiated liposarcoma, synonymous with atypical lipomatous tumor—the former term is used almost exclusively for lesions in the retroperitoneum, while the latter is used for lesions arising elsewhere • Dedifferentiated liposarcoma—well-differentiated (high-grade) liposarcoma adjacent to a more poorly differentiated tumor • Myxoid/round cell liposarcoma. • Pleomorphic liposarcoma.

Prognosis The prognosis varies depending on the site of origin, the type of cancer cell, the tumor size, the depth, and proximity to lymph nodes. Well-differentiated liposarcomas treated with surgery, intra-operative distilled water lavage and radiation have a low recurrence rate (about 10%) and rarely metastasize. Five-year survival rates vary from 100% to 56% based on histological subtype.

Epidemiology Most frequent in middle-aged and older adults (age 40 and above), liposarcomas are the second most common of all soft-tissue sarcomas following malignant fibrous histiocytomas. Annually 2.5 cases occur per million population.

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LYMPHANGIOSARCOMA Lymphangiosarcoma is a rare malignant tumor which occurs in long-standing cases of primary or secondary lymphedema. It involves either the upper or lower lymphedematous extremities but is most common in upper extremities. Although its name implies lymphatic origin, it is believed to arise from endothelial cells and may be more accurately referred to as angiosarcoma.

Signs and Symptoms Lymphangiosarcoma may present as a purplish discoloration or a tender skin nodule in the extremity, typically on the anterior surface. It progresses to an ulcer with crusting to an extensive necrotic focus involving the skin and subcutaneous tissue. It metastasizes quickly.

Causes It was previously a relatively common complication of the massive itot itot itot itot itot lymphedema of the arm which followed removal of axillary (arm pit) lymph nodes and lymphatic channels as part of the classical Halstedian radical mastectomy, as a treatment for breast cancer. The classical radical mastectomy was abandoned in most areas of the world in the late 1960s to early 1970s, being replaced by the much more conservative modified radical mastectomy and, more recently, by segmental breast tissue excision and radiation therapy. Because of this change in clinical practice lymphedema is now a rarity following breast cancer treatment—and post-mastectomy lymphangiosarcoma is now vanishingly rare. When it occurs following mastectomy it is known as Stewart-Treves syndrome (which can be both lymphangiosarcoma and hemangiosarcoma following mastectomy). The pathogenesis of lymphangiosarcoma has not been resolved, however several vague mechanisms have been proposed. Stewart and Treves, proposed that a cancer causing agent is present in lymphedematous limbs. Schreiber et al. proposed that local immunodeficiency as a result of lymphedema results in a “immunologically privileged site” in which the sarcoma is able to develop.

Treatment The most successful treatment for lymphangiosarcoma is amputation of the affected limb if possible. Chemotherapy may be administered if there is evidence or suspicion of metastatic disease. Evidence supporting the effectiveness of chemotherapy is, in many cases, unclear due to a wide variety of prognostic factors and small sample size. However, there is some evidence to suggest that drugs such as paclitaxel, doxorubicin, ifosfamide, and gemcitabine exhibit antitumor activity.

LYMPHOMA Lymphoma is a group of blood cancers that develop from lymphocytes (a type of white blood cell). The name often refers to just the cancerous versions rather than all such tumors. Signs and symptoms may include enlarged lymph nodes, fever, drenching sweats, unintended weight loss, itching, and constantly feeling tired. The enlarged lymph nodes are usually painless. The sweats are most common at night. There are dozens of subtypes of lymphomas. The two main categories of lymphomas are Hodgkin’s lymphomas (HL) and the nonHodgkin lymphomas (NHL). The World Health Organization (WHO) includes two other categories as types of lymphoma: multiple myeloma and immunoproliferative diseases. About 90% of lymphomas are non-Hodgkin lymphomas. Lymphomas and leukemias are a part of the broader group of tumors of the hematopoietic and lymphoid tissues. Risk factors for Hodgkin lymphoma include infection with Epstein–Barr virus and a history of the disease in the family. Risk factors for common types of non-Hodgkin lymphomas include autoimmune

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diseases, HIV/AIDS, infection with human T-lymphotropic virus, immunosuppressant medications, and some pesticides. Eating large amounts of red meat and tobacco smoking may also increase the risk. Diagnosis, if enlarged lymph nodes are present, is usually by lymph node biopsy. Blood, urine, and bone marrow testing may also be useful in the diagnosis. Medical imaging may then be done to determine if and where the cancer has spread. Lymphoma most often spreads to the lungs, liver, and brain. Treatment may involve one or more of the following: chemotherapy, radiation therapy, targeted therapy, and surgery. In some non-Hodgkin lymphomas, an increased amount of protein produced by the lymphoma cells causes the blood to become so thick that plasmapheresis is performed to remove the protein. Watchful waiting may be appropriate for certain types. The outcome depends on the subtype with some being curable and treatment prolonging survival in most. The fiveyear survival rate in the United States for all Hodgkin lymphoma subtypes is 85%, while that for non-Hodgkin lymphomas is 69%. Worldwide, lymphomas developed in 566,000 people in 2012 and caused 305,000 deaths. They make up 3–4% of all cancers, making them as a group the seventh-most common form. In children, they are the third-most common cancer. They occur more often in the developed world than the developing world.

Signs and Symptoms Lymphoma may present with certain non-specific symptoms; if the symptoms are persistent, an evaluation to determine their cause, including possible lymphoma, should be undertaken. • Lymphadenopathy or swelling of lymph nodes, is the primary presentation in lymphoma. • B symptoms (systemic symptoms) – can be associated with both Hodgkin lymphoma and non-Hodgkin lymphoma. They consist of: a. Fever b. Night sweats c. Weight loss • Other symptoms: a. Loss of appetite or anorexia b. Fatigue c. Respiratory distress or dyspnea d. Itching.

Diagnosis Lymphoma is definitively diagnosed by a lymph node biopsy, meaning a partial or total excision of a lymph node examined under the microscope. This examination reveals histopathological features that may indicate lymphoma. After lymphoma is diagnosed, a variety of tests may be carried out to look for specific features characteristic of different types of lymphoma. These include: • Immunophenotyping • Flow cytometry • Fluorescence in situ hybridization testing.

Classification Lymphomas in the strict sense are any neo-plasms of the lymphatic tissues (lympho- + -oma). The main classes are malignant neo-plasms (that is, cancers) of the lymphocytes, a type of white blood cell that belongs to both the lymph and the blood and pervades both. Thus, lymphomas and leukemias are both tumors of the

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hematopoietic and lymphoid tissues, and as lymphoproliferative disorders, lymphomas and lymphoid leukemias are closely related, to the point that some of them are unitary disease entities that can be called by either name (for example adult T-cell leukemia/lymphoma). Several classification systems have existed for lymphoma, which use histological and other findings to divide lymphoma into different categories. The classification of a lymphoma can affect treatment and prognosis. Classification systems generally classify lymphoma according to: • Whether or not it is a Hodgkin lymphoma • Whether the cell that is replicating is a T cell or B cell • The site from which the cell arises. Lymphoma can also spread to the central nervous system, often around the brain in the meninges, known as lymphomatous meningitis (LM).

Hodgkin Lymphoma Hodgkin lymphoma accounts for about 15% of lymphomas. It differs from other forms of lymphoma in its prognosis and several pathological characteristics. A division into Hodgkin and non-Hodgkin lymphomas is used in several of the older classification systems. A Hodgkin lymphoma is marked by the presence of a type of cell called the Reed–Sternberg cell.

Non-hodgkin Lymphomas Non-Hodgkin lymphomas, which are defined as being all lymphomas except Hodgkin lymphoma, are more common than Hodgkin lymphoma. A wide variety of lymphomas are in this class, and the causes, the types of cells involved, and the prognosis vary by type. The incidence of non-Hodgkin lymphoma increases with age. It is further divided into several subtypes.

WHO Classification The WHO classification, published in 2001 and updated in 2008, is based upon the foundations laid within the “revised European-American lymphoma classification” (REAL). This system groups lymphomas by cell type (i.e. the normal cell type that most resembles the tumor) and defining phenotypic, molecular, or cytogenetic characteristics. The five groups are shown in the table. Hodgkin lymphoma is considered separately within the WHO and preceding classifications, although it is recognized as being a tumor of, albeit markedly abnormal, lymphocytes of mature B cell lineage. Of the many forms of lymphoma, some are categorized as indolent (e.g. small lymphocytic lymphoma), compatible with a long life even without treatment, whereas other forms are aggressive (e.g. Burkitt’s lymphoma), causing rapid deterioration and death. However, most of the aggressive lymphomas respond well to treatment and are curable. The prognosis, therefore, depends on the correct diagnosis and classification of the disease, which is established after examination of a biopsy by a pathologist (usually a hematopathologist). Lymphoma subtypes (WHO 2008) Mature B cell neo-plasms Mature T cell and natural killer (NK) cell neo-plasms Precursor lymphoid neo-plasms Hodgkin lymphoma Immunodeficiency-associated lymphoproliferative disorders

Previous Classifications Several previous classifications have been used, including Rappaport 1956, Lennert/ Kiel 1974, BNLI, Working formulation (1982), and REAL (1994). The Working formulation of 1982 was a classification of non-

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Hodgkin lymphoma. It excluded the Hodgkin lymphomas and divided the remaining lymphomas into four grades (low, intermediate, high, and miscellaneous) related to prognosis, with some further subdivisions based on the size and shape of affected cells. This purely histological classification included no information about cell surface markers, or genetics, and it made no distinction between T-cell lymphomas and B-cell lymphomas. It was widely accepted at the time of its publication, but is now obsolete. It is still used by some cancer agencies for compilation of lymphoma statistics and historical rate comparisons. In 1994, the Revised European-American Lymphoma (REAL) classification applied immunophenotypic and genetic features in identifying distinct clinicopathologic entities among all the lymphomas except Hodgkin lymphoma. For coding purposes, the ICDO (codes 9590–9999) and ICD-10 (codes C81-C96) are available.

Staging After a diagnosis and before treatment, a cancer is staged. This refers to determining if the cancer has spread, and if so, whether locally or to distant sites. Staging is reported as a grade between I (confined) and IV (spread). Staging is carried out because the stage of a cancer impacts its prognosis and treatment. The Ann Arbor staging system is routinely used for staging of both HL and NHL. In this staging system, I represents a localised disease contained within a lymph node group, II represents the presence of lymphoma in two or more lymph nodes groups, III represents spread of the lymphoma to lymph nodes groups on both sides of the diaphragm, and IV indicates spread to tissue outside the lymphatic system. Different suffixes imply involvement of different organs, for example S for the spleen and H for the liver. Extra-lymphatic involvement is expressed with the letter E. In addition, the presence of B symptoms or their absence is expressed with B and A, respectively. B symptoms are defined as the presence of one of three symptoms: Unintentional weightloss of 10% body weight in the last 6 months, night sweats, and persistent fever of 38°C or more. CT scan or PET scan imaging modalities are used to stage a cancer. PET scan is advised for FDG avid lymphomas, for example Hodgkins Lymphoma as a staging tool that can even replace bone marrow biopsy. For other lymphomas CT scan is recommended for staging. Age and poor performance status are established poor prognostic factors, as well.

Treatment Prognoses and treatments are different for HL and between all the different forms of NHL, and also depend on the grade of tumour, referring to how quickly a cancer replicates. Paradoxically, high-grade lymphomas are more readily treated and have better prognoses: Burkitt lymphoma, for example, is a high-grade tumour known to double within days, and is highly responsive to treatment. Lymphomas may be curable if detected in early stages with modern treatment.

Low-grade Lymphomas Many low-grade lymphomas remain indolent for many years. Treatment of the non-symptomatic patient is often avoided. In these forms of lymphoma, such as follicular lymphoma, watchful waiting is often the initial course of action. This is carried out because the harms and risks of treatment outweigh the benefits. If a lowgrade lymphoma is becoming symptomatic, radiotherapy or chemotherapy are the treatments of choice; although they do not cure the lymphoma, they can alleviate the symptoms, particularly painful lymphadenopathy. Patients with these types of lymphoma can live near-normal lifespans, but the disease is incurable. Some centers advocate the use of single agent rituximab in the treatment of follicular lymphoma rather than the wait and watch approach. Watchful waiting is not a good strategy for all patients, as it leads to significant distress and anxiety in some patients. It has been equated with watch and worry.

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High-grade Lymphomas Treatment of some other, more aggressive, forms of lymphoma can result in a cure in the majority of cases, but the prognosis for patients with a poor response to therapy is worse. Treatment for these types of lymphoma typically consists of aggressive chemotherapy, including the CHOP or R-CHOP regimen. A number of people are cured with first-line chemotherapy. Most relapses occur within the first two years, and the relapse risk drops significantly thereafter. For people who relapse, high-dose chemotherapy followed by autologous stem cell transplantation is a proven approach.

Hodgkin Lymphoma Hodgkin lymphoma typically is treated with radiotherapy alone, as long as it is localized. Advanced Hodgkin disease requires systemic chemotherapy, sometimes combined with radiotherapy. Chemotherapy used includes the ABVD regimen, which is commonly used in the United States. Other regimens used in the management of Hodgkin lymphoma include BEACOPP and Stanford V. Considerable controversy exists regarding the use of ABVD or BEACOPP. Briefly, both regimens are effective, but BEACOPP is associated with more toxicity. Encouragingly, a significant number of people who relapse after ABVD can still be salvaged by stem cell transplant.

Palliative Care Palliative care, a specialized medical care focused on the symptoms, pain, and stress of a serious illness, is recommended by multiple national cancer treatment guidelines as an accompaniment to curative treatments for people suffering from lymphoma. It is used to address both the direct symptoms of lymphoma and many unwanted side effects that arise from treatments. Palliative care can be especially helpful for children who develop lymphoma, helping both children and their families deal with the physical and emotional symptoms of the disease. For these reasons, palliative care is especially important for patients requiring bone marrow transplants.

Prognosis Five-year relative survival by stage at diagnosis Stage at diagnosis Localized (confined to primary site) Regional (spread to regional lymph nodes) Distant (cancer has metastasized) Unknown (unstaged)

Five-year relativesurvival (%) 82.3 78.3 62.7 68.6

Percentageof cases (%) 26 19 47 8

Epidemiology Lymphoma is the most common form of hematological malignancy, or “blood cancer”, in the developed world. Taken together, lymphomas represent 5.3% of all cancers (excluding simple basal cell and squamous cell skin cancers) in the United States and 55.6% of all blood cancers. According to the U.S. National Institutes of Health, lymphomas account for about 5%, and Hodgkin lymphoma in particular accounts for less than 1% of all cases of cancer in the United States. Because the whole system is part of the body’s immune system, patients with a weakened immune system such as from HIV infection or from certain drugs or medication also have a higher incidence of lymphoma.

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Research The two types of lymphoma research are clinical or translational research and basic research. Clinical/ translational research focuses on studying the disease in a defined and generally immediately patient-applicable way, such as testing a new drug in patients. Studies may focus on effective means of treatment, better ways of treating the disease, improving the quality of life for patients, or appropriate care in remission or after cures. Hundreds of clinical trials are being planned or conducted at any given time. Basic science research studies the disease process at a distance, such as seeing whether a suspected carcinogen can cause healthy cells to turn into lymphoma cells in the laboratory or how the DNA changes inside lymphoma cells as the disease progresses. The results from basic research studies are generally less immediately useful to patients with the disease, but can improve scientists’ understanding of lymphoma and form the foundation for future, more effective treatments.

UNDIFFERENTIATED PLEOMORPHIC SARCOMA Undifferentiated pleomorphic sarcoma (UPS), also undifferentiated pleomorphic sarcoma (PUS) and previously malignant fibrous histiocytoma (abbreviated MFH), is a type of cancer and soft tissue sarcoma. It is considered a diagnosis of exclusion for sarcomas that cannot be more precisely categorized. Other sarcomas are cancers that form in bone and soft tissues, including muscle, fat, blood vessels, lymph vessels, and fibrous tissue (such as tendons and ligaments).

Presentation UPS occurs most commonly in the extremities and retroperitoneum, but has been reported in other sites. Metastasis occurs most frequently in the lungs (90%), bones (8%), and liver (1%). In the extremities, it presents itself as a painless enlarging soft tissue mass.

Diagnosis It can be detected by magnetic resonance imaging (MRI), but a biopsy is required for the definitive diagnosis. MRI findings typically show a well-circumscribed mass that is dark on T1-weighted images and bright on T2weighted images. Central necrosis is often present and identifiable by imaging, especially in larger masses.

Pathology Undifferentiated pleomorphic sarcomas are, by definition, undifferentiated, meaning (as the name implies) that they do not bear a resemblance to any normal tissue. The histomorphology, otherwise, is characterized by high cellularity, marked nuclear pleomorphism, usually accompanied by abundant mitotic activity (including atypical mitoses), and a spindle cell morphology. Necrosis is common and characteristic of high grade lesions.

Treatment Treatment consists of surgical excision (the extent of which ranges from tumor excision to limb amputation, depending on the tumor) and in almost all cases radiation. Radiation eliminates the need for limb amputation and there is level I evidence to show that it leads to equivalent rates of survival (Rosenberg et al. NCI Canada). Radiation may be delivered either pre-op or post-op depending on surgeon and multidisciplinary tumor board’s recommendations. Radiation can be omitted for low grade, Stage I excised tumors with >1 cm margin (NCCN).

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Chemotherapy remains controversial in MFH. The usual site of metastatic disease is the lungs, and metastases should be resected if possible. Unresectable or inoperable lung metastasis may be treated with stereotactic body radiation therapy (SBRT) with excellent local control. However, neither surgery nor SBRT will prevent emergence of additional metastasis elsewhere in the lung. Therefore, role of chemotherapy needs to be further explored to address systemic metastasis.

Prognosis Prognosis depends on the primary tumor grade (appearance under the microscope as judged by a pathologist), size, resectability (whether it can be completely removed surgically), and presence of metastases. The five-year survival is 80%.

MALIGNANT PERIPHERAL NERVE SHEATH TUMOR A malignant peripheral nerve sheath tumor (MPNST) (also known as “malignant schwannoma”, “neurofibrosarcoma”, and “neurosarcoma”) is a form of cancer of the connective tissue surrounding nerves. Given its origin and behaviour it is classified as a sarcoma. About half the cases are diagnosed in people with neurofibromatosis; the lifetime risk for an MPNST in patients with neurofibromatosis type 1 is 8–13%. MPNST with rhabdomyoblastomatous component are called malignant triton tumors. The first-line treatment is surgical resection with wide margins. Chemotherapy (e.g. high-dose doxorubicin) and often radiotherapy are done as adjuvant and/or neo-adjuvant treatment.

Classification Malignant peripheral nerve sheath tumors are a rare type of cancer that arise from the soft tissue that surrounds nerves. They are a type of sarcoma. Most malignant peripheral nerve sheath tumors arise from the nerve plexuses that distribute nerves into the limbs—the brachial and lumbar plexuses—or from nerves as they arise from the trunk.

Signs and Symptoms Symptoms may include: • Swelling in the extremities (arms or legs), also called peripheral edema; the swelling often is painless. • Difficulty in moving the extremity that has the tumor, including a limp. • Soreness localized to the area of the tumor or in the extremity. • Neurological symptoms. • Pain or discomfort: numbness, burning, or “pins and needles.” • Dizzyness and/or loss of balance.

Causes Soft tissue sarcomas have been linked within families, so it is hypothesized that neurofibrosarcoma may be genetic, although researchers still do not know the exact cause of the disease. Evidence supporting this hypothesis includes loss of heterozygosity on the 17p chromosome. The p53 (a tumor suppressor gene in the normal population) genome on 17p in neurofibrosarcoma patients is mutated, increasing the probability of cancer. The normal p53 gene will regulate cell growth and inhibit any uncontrollable cell growth in the healthy population; since p53 is inactivated in neurofibrosarcoma patients, they are much more susceptible to developing tumors.

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Genetics A malignant peripheral nerve sheath tumor is rare, but is one of the most common frequent soft tissue sarcoma in the pediatrics population. About half of these cases also happen to occur along with neurofibromatosis type 1 (NF-1), which is a genetic mutation on the 17th chromosome which causes tumors along the nervous system. The lifetime risk of patients with NF-1 developing MPNST has been estimated at 8–13%, while those with only MPNST have a 0.001% in the general population. NF-1 and MPNST are categorized as autosomal dominant disorders. This means when one receives an abnormal gene from one of their parents, they will ultimately have that disorder. That person has a 50/50 chance of passing on that gene to their offspring. The pedigree to the right describes this genetic pattern.

Diagnosis The most conclusive test for a patient with a potential neurofibrosarcoma is a tumor biopsy (taking a sample of cells directly from the tumor itself). MRIs, X-rays, CT scans, and bone scans can aid in locating a tumor and/ or possible metastasis.

Treatment Treatment for neurofibrosarcoma is similar to that of other cancers. Surgery is an option; the removal of the tumor along with surrounding tissue may be vital for the patient’s survival. For discrete, localized tumors, surgery is often followed by radiation therapy of the excised area to reduce the chance of recurrence. For patients suffering from neurofibrosarcomas in an extremity, if the tumor is vascularized (has its own blood supply) and has many nerves going through it and/or around it, amputation of the extremity may be necessary. Some surgeons argue that amputation should be the procedure of choice when possible, due to the increased chance of a better quality of life. Otherwise, surgeons may opt for a limb-saving treatment, by removing less of the surrounding tissue or part of the bone, which is replaced by a metal rod or grafts. Radiation will also be used in conjunction with surgery, especially if the limb was not amputated. Radiation is rarely used as a sole treatment. In some instances, the oncologist may choose chemotherapy drugs when treating a patient with neurofibrosarcoma, usually in conjunction with surgery. Patients taking chemotherapy must be prepared for the side effects that come with any other chemotherapy treatment, such as; hair loss, lethargy, weakness, etc.

Prognosis Patient response to treatment will vary based on age, health, and the tolerance to medications and therapies. Metastasis occurs in about 39% of patients, most commonly to the lung. Features associated with poor prognosis include a large primary tumor (over 5 cm across), high grade disease, co-existent neurofibromatosis, and the presence of metastases. It is a rare tumor type, with a relatively poor prognosis in children. In addition, MPNSTs are extremely threatening in NF1. In a 10-year institutional review for the treatment of chemotherapy for MPNST in NF1, which followed the cases of 1 per 2,500 in 3,300 live births, chemotherapy did not seem to reduce mortality, and its effectiveness should be questioned. Although with recent approaches with the molecular biology of MPNSTs, new therapies and prognostic factors are being examined.

RHABDOMYOSARCOMA Rhabdomyosarcoma, or RMS, is an aggressive and highly malignant form of cancer that develops from skeletal (striated) muscle cells that have failed to fully differentiate. It is generally considered to be a disease of childhood, as the vast majority of cases occur in those below the age of 18. It is commonly described as one of

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the “small, round, blue cell tumours of childhood” due to its appearance on an H&E stain. Despite being a relatively rare cancer, it accounts for approximately 40% of all recorded soft tissue sarcomas. RMS can occur in any site on the body, but is primarily found in the head, neck, orbit, genitourinary tract, genitals, and extremities. There are no clear risk factors for RMS, but the disease has been associated with some congenital abnormalities. Signs and symptoms vary according to tumor site, and prognosis is closely tied to the location of the primary tumor. Common site of metastasis include the lungs, bone marrow, and bones. There are many classification systems for RMS and a variety of defined histological types. Embryonal rhabdomyosarcoma is the most common type and comprises about 60% of cases. Patient outcomes vary considerably, with 5 years survival rates between 35% and 95% depending on the type of RMS involved, so clear diagnosis is critical for effective treatment and management. Unfortunately, accurate and quick diagnosis is often difficult due to the heterogeneity of RMS tumors and a lack of strong genetic markers of the disease. Treatment usually involves a combination of surgery, chemotherapy, and radiation. Sixty percent to 70% of newly diagnosed patients with non-metastatic disease can be cured using this combined approach to therapy. Despite aggressive multimodality treatment, less than 20% of patients with metastatic RMS are able to be cured of their disease.

Epidemiology Rhabdomyosarcoma is the most common soft-tissue sarcoma in children as well as the third most common solid tumor in children. Recent estimates place the incidence of the disease at approximately 4.5 case per 1 million children/adolescents with approximately 250 new cases in the United States each year. With the vast majority of cases of RMS occurring in children or adolescents, two-thirds of reported cases occur in youths under the age of 10. RMS also occurs slightly more often in males than in females, with a ratio of approximately 1.3–1.5:1. In addition, slightly lower prevalence of the disease has been reported in black and Asian children relative to white children. In most cases, there are no clear predisposing risk factors for the development of RMS. It tends to occur sporadically with no obvious cause. However, RMS has been correlated with familial cancer syndromes and congenital abnormalities including neurofibromatosis type 1, Beckwith-Wiedemann syndrome, Li–Fraumeni syndrome, cardio-facio-cutaneous syndrome, and Costello syndrome. It has also been associated with parental use of cocaine and marijuana.

Signs and Symptoms RMS can occur in almost any soft-tissue site in the body; the most common primary sites are genitourinary (24%), parameningeal (16%), extremity (19%), orbit (9%), other head and neck (10%), and miscellaneous other sites (22%). RMS often presents as a mass, but signs and symptoms can vary widely depending on the site of the primary tumor. Genitourinary tumors may present with hematuria, urinary tract obstruction, and/or a scrotal or vaginal mass. Tumors that arise in the retroperitoneum and mediastinum can become quite large before producing signs and symptoms. Parameningeal tumors may present with cranial nerve dysfunction, symptoms of sinusitis, ear discharge, headaches, and facial pain. Orbital tumors often present with orbital swelling and proptosis. Extremity tumors generally present as a rapidly enlarging, firm mass in the relevant tissue. The cancer’s prevalence in the head, face, and neck will often allow for earlier signs of the disease simply due to the obvious nature of tumors in these locations. Despite the varying presentation and typically aggressive nature of the disease, RMS has the potential to be diagnosed and treated early. The fourth IRSG study found that 23% of patients were diagnosed in time for a complete resection of their cancer, and 15% had resection with only minimal remnants of the diseased cells.

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Types Given the difficulty in diagnosing rhabdomyosarcoma, definitive classification of subsets has proven difficult. As a result, classification systems vary by institute and organization. However, rhabdomyosarcoma can be generally divided into three histological subsets: • Embryonal rhabdomyosarcoma (ERMS) is the most common histological variant, comprising approximately 60–70% of childhood cases. It is most common in children 0–4 years old, with a maximum reported incidence of 4 cases per 1 million children. ERMS is characterized by spindleshaped cells with a stromal-rich appearance, and the morphology is similar to the developing muscle cells of a 6–8 week old embryo. Tumors often present in the head and neck as well as the genitourinary tract. ERMS also has two defined subtypes, botryoid and spindle cell ERMS, and these subtypes are associated with a favourable prognosis. a. Subtypes of ERMS (i) Botryoid ERMS is almost always found in mucosal lined organs including the vagina, bladder, and nasopharynx (although presentation in the nasopharynx typically affects older children). It often presents in patients or