Management of Hereditary Colorectal Cancer. A Multidisciplinary Approach 9783030262334, 9783030262341

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Management of Hereditary Colorectal Cancer A Multidisciplinary Approach Jose G. Guillem Garrett Friedman Editors

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Management of Hereditary Colorectal Cancer

Jose G. Guillem Garrett Friedman Editors

Management of Hereditary Colorectal Cancer A Multidisciplinary Approach

Editors Jose G. Guillem, MD, MPH Gastrointestinal Surgery University of North Carolina Chapel Hill, NC USA

Garrett Friedman, MD Department of Surgery Mike O’Callaghan Federal Medical Center Las Vegas, NV USA

ISBN 978-3-030-26233-4    ISBN 978-3-030-26234-1 (eBook) https://doi.org/10.1007/978-3-030-26234-1 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

1 Early-Age-of-Onset Colorectal Carcinoma: An Emerging Public Health Issue��������������������������������  1 Aung K. Win, Garrett Friedman, and Jose G. Guillem 2 Management of Hamartomatous Polyps��������������������� 11 Peter C. Ambe and Gabriela Möslein 3 Familial Adenomatous Polyposis: Prophylactic Management of the Colon and Rectum ���������������������� 41 Chady Atallah, Francis M. Giardiello, and Jonathan Efron 4 FAP Surveillance Post IPAA or IRA���������������������������� 61 Robert Gryfe and Rory Kennelly 5 Familial Adenomatous Polyposis: Management of Upper Gastrointestinal Polyps���������������������������������� 81 Jennifer K. Maratt and Elena M. Stoffel 6 Desmoids in Familial Adenomatous Polyposis������������103 Susan K. Clark 7 Hepatoblastoma in Infants Born to Parents with Familial Adenomatous Polyposis����������������������������������123 Todd E. Heaton and Michael F. Walsh 8 MYH-Associated Polyposis: Manifestations, Management, and Surveillance of the Colorectum����������������������������������������������������������137 Coen L. Klos, Farhan Quader, Dayna Early, and Paul E. Wise v

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9 Lynch Syndrome: Management of the Colon, What Operation? ����������������������������������������������������������149 William C. Cirocco and Heather Hampel 10 Lynch Syndrome: Management of Rectum, What Operation? ����������������������������������������������������������175 Y. Nancy You, Marcelli Marcante, and Thomas J. George Jr. Index����������������������������������������������������������������������������������������201

Contributors

Peter C. Ambe, MD, PhD, MBA  Department of Visceral, Minimally Invasive and Oncologic Surgery, Marien Hospital Düsseldorf, Düsseldorf, Germany University Witten/Herdecke, Witten, Germany Chady Atallah, MD  Department of Surgery, Ravitch Division of Colon and Rectal Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA William C. Cirocco, MD  Colon & Rectal Surgery Section, Banner MD Anderson Cancer Center, Phoenix, AZ, USA Susan  K.  Clark The Polyposis Registry, St Mark’s Hospital, Harrow, UK Dayna  Early, MD Division of Gastroenterology, Washington ­University School of Medicine in St. Louis, St. Louis, MO, USA Jonathan Efron, MD  Department of Surgery, Ravitch Division of Colon and Rectal Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA Garrett  Friedman, MD  Department of Surgery, Mike O’Callaghan Federal Medical Center, Las Vegas, NV, USA Department of Surgery, University of Las Vegas- Nevada School of Medicine, Las Vegas, NV, USA Thomas J. George Jr., MD  Division of Hematology and Oncology, Department of Medicine, University of Florida Health Cancer Center, Miami, FL, USA vii

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Francis  M.  Giardiello, MD  Department of Medicine, Department of Oncology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Robert  Gryfe, MD, PhD Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, ON, Canada Princess Margaret Hospital, University Health Network, Toronto, ON, Canada Jose G. Guillem, MD, MPH  Gastrointestinal Surgery, University of North Carolina, Chapel Hill, NC, USA Heather  Hampel, MS, LGC Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA Todd E. Heaton, MD, MPH  Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Rory Kennelly  St Vincent’s University Hospital, Dublin, Ireland University College Dublin, Dublin, Ireland Coen L. Klos, MD  Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA Jennifer K. Maratt, MD, MS  Department of Internal Medicine, Indiana University; Richard L. Roudebush VA Medical Center; Regenstrief Institute, Inc., Indianapolis, IN, USA Marcelli Marcante, MD  Department of Surgery, Hospital Israelita Albert Einstein, Sao Paulo, Brazil Gabriela Möslein, MD, PhD  University Witten/Herdecke, Witten, Germany Center for Hereditary Gastrointestinal Tumors, Helios University Hospital Wuppertal, Wuppertal, Germany Farhan Quader, MD  Division of Gastroenterology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA Elena  M.  Stoffel, MD, MPH  Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA

 Contributors

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Michael  F.  Walsh, MD Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA Department of Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA Aung K. Win  Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Carlton, VIC, Australia University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia Paul E. Wise, MD  Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA Y. Nancy You, MD, MHSc  Departments of Surgical Oncology and of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA

Introduction

During the past three decades, tremendous advances have been made in our understanding of hereditary colorectal cancer in terms of the genetic basis, the clinical presentation, and natural history of several distinct hereditary syndromes. During this time, advances in endoscopic and surgical techniques as well as chemopreventive approaches have also occurred that have allowed us to better manage these complex cases in a multidisciplinary manner. However, these numerous specialty-specific advances have often only been presented in specialty journals and therefore publications on how a multidisciplinary team integrates all these advancements are lacking. This book, comprised of chapters written by leading experts, addresses this deficit by focusing on six distinct groups, namely: patients with early age-of-onset colorectal cancer and adenomas, patients with hamartomatous colorectal polyps, patients afflicted with familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MYH associated polyposis (MAP), and Lynch syndrome (LS). Coauthors represent the disciplines that work together to manage these patients and families and include surgeons, gastroenterologists, geneticists, medical oncologists, genetic counselors, and epidemiologists. Since the focus of this book is state-of-the-art clinical management, authors describe how they utilize current technologies in genetic testing, pathological review, and endoscopic, surgical, and chemotherapeutic/immunotherapeutic approaches to manage these patients. Details on causation and molecular basis are not a

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focus. Rather, details on timing of genetic testing, endoscopic screening and surveillance, prophylactic surgical options, and chemopreventive interventions when available are discussed in terse, but precise detail. The overriding goal is to present an expert and timely protocol for clinical management of these complex entities. The target audience includes surgeons, gastroenterologists, genetic counselors, geneticists, medical oncologists, and any health-care provider involved with the management of patients and families afflicted with a hereditary form of colorectal cancer. We include early ageof-onset colorectal cancer because it is a common feature for all forms of known hereditary colorectal cancer syndromes and because of the recently noted worldwide rise in its incidence. Jose  G.  Guillem Garrett  Friedman

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Early-Age-of-Onset Colorectal Carcinoma: An Emerging Public Health Issue Aung K. Win, Garrett Friedman, and Jose G. Guillem

The etiology of colorectal cancer (CRC) is complex and appears to involve a combination of underlying genetic susceptibility, somatic alterations, and environmental exposures which people experience since conception [1]. Young age at diagnosis is a hallmark of hereditary cancer syndromes as discussed in the chapters that follow. Currently known genetic predispositions to CRC include Lynch syndrome (caused by germline mutations in DNA A. K. Win Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Carlton, VIC, Australia University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia G. Friedman Department of Surgery, Mike O’Callaghan Federal Medical Center, Las Vegas, NV, USA Department of Surgery, University of Las Vegas- Nevada School of Medicine, Las Vegas, NV, USA J. G. Guillem (*) Gastrointestinal Surgery, University of North Carolina, Chapel Hill, NC, USA e-mail: [email protected] © Springer Nature Switzerland AG 2020 J. G. Guillem, G. Friedman (eds.), Management of Hereditary Colorectal Cancer, https://doi.org/10.1007/978-3-030-26234-1_1

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mismatch repair genes), familial adenomatous polyposis (due to APC mutations), MUTYH-associated polyposis (due to mutations in both alleles of MUTYH gene), and germline mutations in other genes such as SMAD4, BRCA1, TP53, POLE, and POLD1. However, only 20–30% of CRC diagnosed under age 50 are attributable to these known hereditary syndromes [2–4]. The remaining majority of young adult CRC may be associated with other genetic predispositions which have yet to be identified [5], polygenic factors such as single-nucleotide polymorphisms (SNPs), and/or environmental and lifestyle factors of the person [6]. An analysis of 450 patients diagnosed with CRC under the age of 50 detected 75 gene mutations in 72 patients for a mutation rate of 16%. Of note, 33% of the patients that had a gene mutation did not meet current guidelines for genetic testing. The high frequency and wide spectrum of mutations noted in this study support the argument for more routine multigene testing [7]. In addition, these results are consistent with older studies demonstrating that the frequency of HNPCC (previous name for clinical diagnosis of Lynch syndrome) in CRC patients 40–45  years of age ranges between 15% and 20%, which is greater than a fourfold increase in the rate of HNPCC noted in non-age-stratified CRC [8].

I ncreasing Incidence of CRC in Young Adults Is a Global Health Issue In the USA, whereas overall CRC incidence and mortality have been steadily declining over the last 30 years, both incidence and mortality of CRC have been increasing in young adults under age 50 years. The increase occurs in both men and women of all race/ ethnicities combined, for white men and women and for black men, especially for distal colon and rectal cancers, during the last three decades [9, 10]. In Canada, CRC incidence has been increasing in young adults of all age groups of 15–29, 30–39, and 40–49 years between 1997 and 2010 [11]. In an analysis using the 1990–2010 population incidence data from the Australian Institute of Health and Welfare (AIHW), it was noted that CRC incidence

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has been increasing steadily in young adults under age 40 years over the last two decades, whereas the overall incidence of CRC has remained stable and mortality has declined in recent decades. Incidences have increased by 85–100% in the age group 20–29 years, and by 35% in those aged 30–39 between 1990 and 2010 [12]. An analysis of 25 population-based state registries in the USA also noted the incidence of CRC has risen significantly in young adults (age 25–49), with steeper increases that rise in successively younger generations [13]. This increasing trend also occurs in some European as well as Asian countries such as Japan, Korea, and Singapore [14, 15]. Interestingly, in some studies, it appears that these increases in early-onset CRC have been driven primarily by left-sided and rectal cancers. The incidence of rectal cancer in younger patients has increased from 3.0 per 100,000 in 1992 to 4.7 per 100,000  in 2015 [16], outpacing the increased incidence of more proximal colon cancers during this time period.

 easons for Increasing Incidence of CRC in Young R Adults Are Not Known Population-based screening for CRC is assumed to be the main factor influencing the stabilizing or decreasing trend of CRC cancer incidence and mortality overall or in people aged ≥50 years [9]. The fact that such routine screening is largely confined to those older people, therefore, might partially explain age-related disparities in colorectal cancer incidence and mortality trends [14]. But this does not explain the reasons for the increasing incidence of CRC cancer in young adults.

 urrently Known Risk Factors for CRC May Not C Be Relevant for Young Adults Epidemiological studies have identified several factors associated with the risk of CRC diagnosed at all ages or older age. Obesity [17], type 2 diabetes [18], cigarette smoking [19], low physical activities [20], and consumption of red meat and processed meat

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[21] are associated with an increased risk of CRC, while use of estrogen and progesterone [22], folate, calcium [23], and aspirin [24] are inversely associated with the disease risk. However, the majority of these studies are based on cohorts of people of all ages or older than age 50. Therefore, these known risk factors may not be relevant for CRC in young adults. Consequently, almost all existing CRC risk prediction tools are not applicable to young people [25, 26]. The recent analysis of 25 US cancer registries examining cancer trends for 30 common cancers, including 12 obesity-related cancers in young adults demonstrated an increase in 6 of 12 obesity-­related cancers in the younger cohort. CRC was one the six cancers that demonstrated an increase in incidence [13]. Although this study raises questions of why some and not all obesity-­related cancers increased in young adults, it nevertheless emphasizes the need for careful epidemiological and etiological studies of exposures (such as obesity and other risk factors) that may explain the trend noted in early-age-of-onset CRC.

 urrent Data on Risk Factors for CRC in Young C Adults Are Limited Given that 90% of CRCs are diagnosed in individuals over age 50  years, any associations with risk factors––and differences in associations––for those younger than 50  years are difficult to detect (8% of cases are diagnosed between ages 40 and 49 years and 2% before age 40). One main reason is the lack of relevant data because almost all cohorts or studies around the world recruited or studied only CRC diagnosed in later ages. Only three relatively small case-control studies investigated just a few lifestyle factors for CRC diagnosed at a young age and they all have been underpowered [27–29]. A case-control study from Italy (329 cases diagnosed at age 19–45 and 1361 controls) has reported that family history, meat consumption, and alcohol consumption are associated with an increased risk of CRC diagnosed at a young age and there is no evidence of associations with increased body mass, physical

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activity, and diabetes [27]. A case-control study from Los Angeles County (147 cases diagnosed at age 25–44 and 147 controls) has reported that organic dust was associated with an increased risk of rectal cancer and there is no evidence of associations with alcohol consumption and cigarette smoking [29]. A New Zealand study reported no evidence of school milk consumption associated with CRC in a subset of study participants of age 30–49 years [28].

 opulation-Based CRC Screening Programs Do P Not Cover Young Adults The incidence of CRC generally increases with age; particularly the incidence rises sharply and progressively from age 50 [10, 12]. Therefore, at the population level CRC screening is generally recommended for everyone aged 50 and above [30]. In Australia, the National Bowel Cancer Screening Program provides free screening to everyone aged between 50 and 74  years using the immunohistochemical fecal occult blood test (iFOBT) biennially. However, in Australia the sentiment is that screening for everyone under age 50 is currently not justified due to low yield, and procedure-­related complications that have the potential to exceed any benefit from screening [31]. Recently, however, the American Cancer Association has updated their colonoscopy screening guidelines, moving the initial screening age for average risk individuals from 50 to 45 [32], in acknowledgement of the increased incidence of early-onset CRC noted in the USA.

 urrent CRC Screening Guidelines Are Limited C in Use for Young Adults Most current CRC clinical practice guidelines do not recommend young adults under age 50 for screening unless they have moderate or strong family history of CRC or known hereditary colorectal cancer syndromes or predisposing conditions (e.g., inflammatory bowel disease) [33]. However, only 10–15% of the population have a family history of colorectal cancer in their first-­degree relatives.

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Most CRC in Young Adults Present in Late Stages Most CRC diagnosed under the age of 50 years are due to symptoms and usually present in late stages [12, 14] and have bad pathological features [34]. Unfortunately, there are delays in diagnosis and treatment of CRC in young adults. Missed symptoms and initial misdiagnosis occur in 15–50% of CRC cases diagnosed under age 50. This delay may be due to both patient (such as lack of awareness of potential serious symptoms, embarrassment about or denial of symptoms) and doctors (low suspicion of cancer in young adults may delay the thorough symptom evaluation needed to effectively establish or rule out CRC) [14]. Most CRCs in young adults present symptoms such as rectal bleeding (51%), change in bowel habits (18%), abdominal pain (32%), weight loss (13%), and nausea/vomiting (7%), and a majority (approx. 60%) are in their late stages (Stage III or IV) [35].

Burden of Young Adult CRC Is Huge Although less than 10% of all CRCs are diagnosed before age 50 [36], the cancer burden in terms of years of life lost, quality of life, and morbidity is greater for men and women diagnosed at a young age given their comparatively longer time living with the disease and potential years of life to lose due to mortality.

 isk-Based Screening Is a Way to Reduce the CRC R Burden in Young Adults Although it is not feasible to screen everyone under age 50, identification of those at high risk of developing CRC can facilitate targeted screening in a cost-effective, efficient manner. To enable such targeted screening, all potential risk factors for the disease (personalized risk assessment) have to be taken into consideration. Currently, very little is known about risk factors for CRC in young adults, which are essential for risk assessment of disease.

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References 1. Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, et al. Cancer incidence in five continents, vol. IX. Lyon: International Agency for Research on Cancer; 2007. 2. Chang DT, Pai RK, Rybicki LA, Dimaio MA, Limaye M, Jayachandran P, et al. Clinicopathologic and molecular features of sporadic early-onset colorectal adenocarcinoma: an adenocarcinoma with frequent signet ring cell differentiation, rectal and sigmoid involvement, and adverse morphologic features. Mod Pathol. 2012;25(8):1128–39. 3. Mork ME, You YN, Ying J, Bannon SA, Lynch PM, Rodriguez-Bigas MA, et al. High prevalence of hereditary cancer syndromes in adolescents and young adults with colorectal cancer. J Clin Oncol. 2015;33(31):3544–9. 4. Ballester V, Rashtak S, Boardman L.  Clinical and molecular features of young-onset colorectal cancer. World J Gastroenterol. 2016;22(5):1736–44. 5. Tanskanen T, Gylfe AE, Katainen R, Taipale M, Renkonen-Sinisalo L, Jarvinen H, et  al. Systematic search for rare variants in Finnish early-­ onset colorectal cancer patients. Cancer Genet. 2015;208(1–2):35–40. 6. Siegel RL, Jemal A, Ward EM. Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiol Biomark Prev. 2009;18(6):1695–8. 7. Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, Bacher J, Bigley C, Nelsen L, Goodfellow PJ, Goldberg RM. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 2017;3(4):464– 71. https://doi.org/10.1001/jamaoncol.2016.5194. 8. Guillem JG, et al. Clustering of CRC in families of probands under 40 years of age. Dis Colon Rectum. 1996;39:1004–7. 9. Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, et  al. Annual report to the nation on the status of cancer, 1975–2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116(3):544–73. 10. Siegel RL, Fedewa SA, Anderson WF, Miller KD, Ma J, Rosenberg PS, et  al. Colorectal cancer incidence patterns in the United States, 1974– 2013. J Natl Cancer Inst. 2017;109(8):1–6. 11. Patel P, De P. Trends in colorectal cancer incidence and related lifestyle risk factors in 15–49-year-olds in Canada, 1969–2010. Cancer Epidemiol. 2016;42:90–100. 12. Young JP, Win AK, Rosty C, Flight I, Roder D, Young GP, et al. Rising incidence of early-onset colorectal cancer in Australia over two decades: report and review. J Gastroenterol Hepatol. 2015;30(1):6–13.

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13. Sung H, Siegel RL, Rosenberg PS, Jemal A. Emerging cancer trends among young adults in the USA: analysis of a population-based cancer registry. Lancet Public Health. 2019;4(3):e137–47. pii: S2468-­ 2667(18)30267-6. https://doi.org/10.1016/S2468-2667(18)30267-6. 14. Ahnen DJ, Wade SW, Jones WF, Sifri R, Mendoza Silveiras J, Greenamyer J, et al. The increasing incidence of young-onset colorectal cancer: a call to action. Mayo Clin Proc. 2014;89(2):216–24. 15. Hubbard JM, Grothey A. Adolescent and young adult colorectal cancer. J Natl Compr Cancer Netw. 2013;11(10):1219–25. 16. Murphy CC, Singal AG. Establishing a research agenda for early-onset colorectal cancer. PLoS Med. 2018;15(6):e1002577. https://doi. org/10.1371/journal.pmed.1002577. 17. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M.  Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569–78. 18. Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst. 2005;97(22):1679–87. 19. Botteri E, Iodice S, Bagnardi V, Raimondi S, Lowenfels AB, Maisonneuve P.  Smoking and colorectal cancer: a meta-analysis. JAMA. 2008;300(23):2765–78. 20. Larsson SC, Rutegård J, Bergkvist L, Wolk A. Physical activity, obesity, and risk of colon and rectal cancer in a cohort of Swedish men. Eur J Cancer. 2006;42(15):2590–7. 21. Larsson SC, Wolk A. Meat consumption and risk of colorectal cancer: a meta-analysis of prospective studies. Int J Cancer. 2006;119(11):2657–64. 22. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD.  Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002;288(7):872–81. 23. Cho E, Smith-Warner SA, Spiegelman D, Beeson WL, van den Brandt PA, Colditz GA, et al. Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst. 2004;96(13):1015–22. 24. Dube C, Rostom A, Lewin G, Tsertsvadze A, Barrowman N, Code C, et  al. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146(5):365–75. 25. Win AK, Macinnis RJ, Hopper JL, Jenkins MA. Risk prediction models for colorectal cancer: a review. Cancer Epidemiol Biomark Prev. 2012;21(3):398–410. 26. Usher-Smith JA, Walter FM, Emery JD, Win AK, Griffin SJ. Risk prediction models for colorectal cancer: a systematic review. Cancer Prev Res (Phila). 2016;9(1):13–26. 27. Rosato V, Bosetti C, Levi F, Polesel J, Zucchetto A, Negri E, et al. Risk factors for young-onset colorectal cancer. Cancer Causes Control. 2013;24(2):335–41.

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28. Cox B, Sneyd MJ. School milk and risk of colorectal cancer: a national case-control study. Am J Epidemiol. 2011;173(4):394–403. 29. Peters RK, Garabrant DH, Yu MC, Mack TM.  A case-control study of occupational and dietary factors in colorectal cancer in young men by subsite. Cancer Res. 1989;49(19):5459–68. 30. Win AK, Ait Ouakrim D, Jenkins MA. Risk profiling: familial colorectal cancer. Cancer Forum. 2014;38(1):15–25. 31. Imperiale TF, Kahi CJ, Stuart JS, Qi R, Born LJ, Glowinski EA, et al. Risk factors for advanced sporadic colorectal neoplasia in persons younger than age 50. Cancer Detect Prev. 2008;32(1):33–8. 32. GF ref 11. https://www.cancer.org/latest-news/american-cancer-societyupdates-colorectal-cancer-screening-guideline.html. 33. Cancer Council Australia Colorectal Cancer Guidelines Working Party. Clinical practice guidelines for the prevention, early detection and management of colorectal cancer. Sydney: Cancer Council Australia; 2017. 34. Khan SA, Morris M, Idrees K, Gimbel MI, Rosenberg S, Zeng Z, Li F, Gan G, Shia J, LaQuaglia MP, Paty PB.  Colorectal cancer in the very young: a comparative study of tumor markers, pathology and survival in early onset and adult onset patients. J Pediatr Surg. 2016;51(11):1812–7. 35. Dozois EJ, Boardman LA, Suwanthanma W, Limburg PJ, Cima RR, Bakken JL, et al. Young-onset colorectal cancer in patients with no known genetic predisposition: can we increase early recognition and improve outcome? Medicine (Baltimore). 2008;87(5):259–63. 36. Australian Institute of Health and Welfare & Australian Government Department of Health and Ageing. National bowel cancer screening program annual monitoring report. Canberra: AIHW; 2009.

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Management of Hamartomatous Polyps Peter C. Ambe and Gabriela Möslein

Introduction Hamartomatous polyps (HPs) in the gastrointestinal (GI) tract are the most common type of polyps in children and are overall extremely rare compared to other histologies, especially adenomas. Index patients usually present with symptoms of rectal bleeding, anemia, abdominal pain, obstipation, and/or small bowel obstruction (specifically in Peutz-Jeghers syndrome). Based on their histopathological features, HPs are classified as juvenile polyps or Peutz-Jeghers polyps. Frequently, especially if occurring in childhood, a solitary polyp may be removed successfully endoscopically,

P. C. Ambe Department of Visceral, Minimally Invasive and Oncologic Surgery, Marien Hospital Düsseldorf, Düsseldorf, Germany University Witten/Herdecke, Witten, Germany G. Möslein (*) University Witten/Herdecke, Witten, Germany Center for Hereditary Gastrointestinal Tumors, Helios University Hospital Wuppertal, Wuppertal, Germany e-mail: [email protected]

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and if only one or a few juvenile polyps are identified, clinical follow-up is not usually recommended, since based on the underlying histology, the malignant potential is anticipated to be low. However, this first polyp may be indicative of an underlying HPS and as such presents a tremendous preventative potential for the affected individual, based on a substantially increased risk of cancer, recurrences of polyps, and extraintestinal complications, causing severe morbidity and mortality. Some of the affected may have an indicative family history; however sporadic mutations have been estimated to be the underlying genetic cause in up to 30% of syndromic patients. In an era of more broadly available genetic testing (gene panel testing, next generation sequencing) with ever-decreasing cost, genetic testing at the event of a solitary hamartomatous polyp should be warranted. The underlying genetic cause delivers important genotype phenotype information that increasingly should translate into defined surveillance and prophylactic strategies and if possible offered from childhood or early adolescence. Hamartomatous polyposis syndromes (HPS) constitute a heterogeneous group of syndromes with both gastrointestinal and additionally in most cases extraintestinal manifestations. Peutz-­ Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and PTEN hamartoma tumor syndrome (PHTS) constitute the most common hamartomatous polyposis syndromes. The PHTS group includes syndromes with germline pathogenic mutations in the PTEN gene like Cowden syndrome (CS) and Bannayan-Riley-­ Ruvalcaba syndrome (BRRS). The prevalence of HPS is not well documented. A close to 2% prevalence has been reported by Brosens et  al. in the pediatric population [1]. These syndromes have an autosomal dominant inheritance pattern, with a 50% risk of transmitting the pathogenic variants to the next generation. Although HPS initially present as benign lesions, malignant transformation with the development of both intestinal and extraintestinal tumors is part of the natural course of these syndromes. Currently, a hamartoma to carcinoma sequence analogue to the adenoma carcinoma sequence has been propagated as a possible pathway to malignancy in hamartomatous syndromes [2].

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The clinical manifestation varies widely amongst the different syndromes. This is also true with regard to the frequency and distribution of polyps. Bleeding, bowel obstruction, and intussusception can be associated with serious morbidity or mortality and represent the most common clinical symptoms. The risk of cancer is syndrome specific and may be related to the frequency and distribution of polyps. The diagnosis of HPS is suspected based on histological and clinical features and family history. Genetic counseling and testing enable a specific diagnosis which is paramount for patient’s guidance and surveillance as well as counseling of at-risk family members. Clearly from the patient’s perspective, the less invasive the polyp management approach, the better. This implies endoscopic polyp removal – number and size allowing. Surgery is sometimes indicated to manage symptoms of bleeding and bowel obstruction, which can be encountered at initial presentation or following an unsuccessful intervention like endoscopy. Both resecting and non-resecting procedures are available for such cases. Similarly, the presence of either high-grade dysplasia or cancer mandates oncologic resection. Prophylactic GI surgery certainly has its place in the management of specific HPS in individualized cases, mainly for the colon and stomach; however this management implies multidisciplinary commitment in dedicated and experienced centers.

Peutz-Jeghers Syndrome Peutz-Jeghers syndrome (PJS) is characterized by melanotic mucocutaneous pigmentation, gastrointestinal polyposis, and an increased cancer risk. PJS was first reported by Connor as a familial syndrome of intestinal polyps with pigmentation of the mouth and other body parts in a pair of identical twins [3]. One of the twins later died of bowel intussusception at the age of 20 while the other died from breast cancer at the age of 51. In 1921 Johannes Peutz reported intestinal polyposis and mucocutaneous melanotic pigmentation in two members of the same family [4]. In 1949 Harold Jeghers and colleagues reported additional cases with

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similar clinical picture from many different families [5]. This clinical combination was coined in 1957 as Peutz-Jeghers syndrome [6]. PJS is an autosomal dominantly inherited condition caused by germline mutations of the STK11 gene (also known as LKB1 gene), a tumor suppressor gene located on chromosome 19p13.3. The product of the STK11 gene is a serine–threonine kinase that controls cell proliferation and polarity. Germline mutations of STK11 gene have been identified in over 75% of PJS patients, while 25% of the mutations are thought to have a sporadic basis [7, 8]. Mucocutaneous pigmentation is the most prominent clinical feature of PJS.  The pigmentation is readily seen on the skin around the lips, face, genitalia, and palmar surfaces of the hands as well as on the mucosa of the oral cavity and perioral tissues (Fig.  2.1). These pigmented lesions are present in over 95% of PJS patients and begin in infancy. While skin pigmentation may fade after puberty, mucosal pigmentation of the oral cavity tends to persist [9]. In fact, melanotic mucocutaneous pigmentation might be the first clue to individuals with PJS.

Fig. 2.1  Mucocutaneous melanotic pigmentation (lentiginosis) in Peutz-­ Jeghers syndrome

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The prevalence of PJS is estimated at 1 in about 200,000 [10, 11]. The mean age at the time of diagnosis is 22 years [12], and the median time to initial presentation with gastrointestinal polyps is about 11 years [13]. Intestinal polyps in PJS are comprised of disorganized normal tissues, thus the term hamartoma. PJS polyps can be hardly ­differentiated from other intestinal polyps based on endoscopy alone. PJS polyps can develop long stalks which render them relative mobile, thereby predisposing to intussusception, especially when occurring in the small bowel (Fig. 2.2). PJS polyps are typically multilobulated with a papillary surface. Under the microscope, PJS polyps harbor an extensive smooth muscle proliferation with branching bands of muscles with a hyperplastic glandular mucosa (Fig.  2.3). These unique histologic features are used to differentiate between PJS and sporadic hamartomatous polyps. Nonetheless, adenomatous and hyperplastic polyps have also been described in PJS patients [14].

Fig. 2.2  Small bowel intussusception in a PJS patient caused by a large pedunculated polyp

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Fig. 2.3  Microscopic appearing of PJS polys at histopathology. Note the extensive smooth muscle proliferation with branching bands of muscles and a hyperplastic glandular mucosa. (Courtesy of Dr. Daniel Goedde, Department of Pathology, Helios University Hospital Wuppertal, Witten/Herdecke University)

Intestinal polyposis in PJS is believed to clinically manifest and initiate growth during the first decade of life. PJS polyps are most frequently (60–90%) found in the jejunal segment of the small bowel. Colonic polyposis in PJS is present in about 50–60% of patients [15]. Gastric polyposis and extraintestinal polyps have been described in the gallbladder and the urinary bladder [16]. PJS patients usually develop approximately about 20 s­ ynchronous polyps with a wide variation in size from a few millimeters to more than 5 cm in diameters [17]. Polyp-associated gastrointestinal symptoms are frequent in early childhood with over 30% of PJS patients reporting intermittent abdominal symptoms by the age of 10  years. The prevalence of gastrointestinal symptoms increases with rising age leading to more than half of PJS patients reporting abdominal episodes by the age of 20 [18]. Gastrointestinal symptoms might include recurrent abdominal pain, rectal

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bleeding, prolapse, and bowel obstruction. These symptoms may be caused by large polyps while chronic anemia and failure to thrive might be indicative of an occult gastrointestinal bleed. The diagnosis of PJS is based on typical clinical and histopathologic features, a positive family history and the finding from genetic testing. PJS should be suspected if one of the following criteria is fulfilled [19]: • Two or more PJS characteristic hamartomatous polyps • PJS typical polyps in an individual with a family history of PJS • The presence of characteristic mucocutaneous melanotic pigmentation in an individual with a family history of PJS • PJS typical polyps in an individual with characteristic mucocutaneous melanotic pigmentations All suspected individuals should undergo genetic counseling and genetic testing. It is important to note that familial association might be absent in some patients with clinical PJS symptoms due to sporadic mutations. In a study by Aretz et al., pathogenic STK 11 mutations were found in over 94% of patients meeting clinical diagnostic criteria of PJS [20]. This finding indicates the diagnostic accuracy of the clinically established criteria for PJS. PJS is associated with a marked increased lifetime risk of malignancy. Hearle and colleagues investigated the risk of cancer in 419 PJS patients and found a sequentially increasing risk of cancer development from 2% by the age of 20 up to 85% by the age of 70. Compared to the risk of cancer by the age of 70 in the general population, PJS patients have a close to fourfold increase in the risk of cancer [21]. The risk for gastrointestinal cancers in this study rose from 1% by the age of 30 to 57% by the age of 70. A hamartoma carcinoma sequence, analogue to the adenoma carcinoma sequence has been postulated as a pathway from benign hamartomatous polyps to malignant cancers in HPS patients [22]. Within the gastrointestinal tract, the risk of cancer is highest for the large bowel reaching 40–60% by the age of 70. This finding is in accordance with the results of a systematic review by Giardiello et al. [23]. The cumulative risk for small bowel and gastric cancer in PJS patients in this meta-analysis was 13% and 29%, respectively.

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Radiologic Imaging in PJS Despite the presence of unique clinical diagnostic criteria, imaging plays a huge role in the diagnosis, surveillance, and management of PJS.  Traditionally, contrast-enhanced radiologic techniques like barium follow through, enteroclysis, and double-­ contrast enema have been employed in PJS patients. However, there is a considerable risk of false-negative findings following enteroclysis and double-contrast enema studies. Both techniques therefore are hardly in use today. Nowadays, high-resolution ultrasound, multidetector computed tomography, and high-­ resolution magnet resonance imaging have revolutionized diagnostic imaging in PJS. Abdominal ultrasound sonography is a readily available and good initial imaging tool in PJS patients. Large polyps in the small bowel as well as small bowel intussusceptions may be easily and unequivocally diagnosed on abdominal ultrasound. Bowel intussusception usually appears as a “dough-nut” or “pseudokidney” on abdominal ultrasound sonography, with the hypoechoic outer region representing the edematous bowel wall while the hyperechoic center represents the trapped mesenteric fat [24]. Unfortunately, abdominal ultrasound sonography has limited role in diagnosing colonic pathologies [25]. Also, findings from abdominal ultrasound sonography may be limited by patient- and examiner-specific factors such as obesity and the expertise of the examiner. These factors greatly limit the use of abdominal ultrasound sonography in the workup and management of PJS patients, especially in the fairly frequent emergency setting. Multidetector computed tomography (CT) has emerged to be the imaging modality of choice in the emergency situation. Bowel intussusception is readily diagnosed on contrast-enhanced CT and a localization of the involved bowel region is usually possible [21]. CT may be combined with angiography in an emergency situation to localize the source of gastrointestinal bleeding [26]. Although significant bleeding (1  ml/min) must be present to enable visualization of contrast agent extravasation, the identification of the source of hemorrhage on CT opens up an option for radiologic angiographic intervention as a possible alternative to endoscopic or surgical management.

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Another diagnostic option to investigate chronic anemia due to recurrent gastrointestinal bleeding is “bleeding scintigraphy” using 99mTc-labeled red blood cells (RBC) [27]. Because gastrointestinal bleeding in intestinal polyposis is typically intermittent and episodic, imaging over a prolonged period might be necessary to identify the source of bleeding. According to Bunker et  al., 83% of positive findings on RBC scintigraphy are detected after about 90  minutes from the time of application [28]. Another advantage of this technique is its ability to detect minimal bleeding with rates of hemorrhage as low as 0.1 ml/min to 0.04 ml/min [29, 30]. An additional radiologic diagnostic tool in PJS is magnetic resonance imaging (MRI). The value of MRI in evaluating intestinal polyposis in patients with PJS is debatable. In a comparative analysis on the diagnostic accuracy of MRI vs. capsule endoscopy in patients with intestinal polyposis, Caspari et al. reported that polyps less than 5 mm could be missed on MRI. However, there was no difference in the detection rate of larger (≥15 mm) polyps amongst both diagnostic tools [31]. A more recent study attested a good diagnostic yield for MRI in PJS patients [32]. Two MRI protocols have been proposed for imaging in PJS. The first consists of using an enteral contrast agent given per os, while the second involves administering the enteral contrast media via a nasogastric tube directly into the small bowel [32, 33]. In both cases an MR–enteroclysis using a biphasic contrast media is achieved and a high contrast between the bowel lesions and intraluminal contrast agent is obtained. MR and enteroclysis using images obtained in both the supine and the prone positions have been shown by Maccioni et al. to be very effective in detecting even small polyps of about 3  mm. The overall concordance between MR–enteroclysis and endoscopy in that study was 75% for small polyps and 93% for polyps ≥15 mm [32]. Besides its role in screening for intestinal polyps, MRI facilitates a more precise anatomical location of the polyps and may guide both endoscopic and minimally invasive surgical interventions [34]. Also, MRI may enable the diagnosis of extraintestinal disease manifestations. Therefore, because it is radiation-free and noninvasive, MRI is an attractive option for screening PJS patients who are usually young and may not be candidates for regular

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endoscopic surveillance. In addition, MRI has value following surgical resections where bowel narrowing may occur.

Endoscopy in PJS Although data guiding the initiation of endoscopy in PJS patients is inconsistent, endoscopy plays a key role in the diagnosis, surveillance, and management of PJS.  Peutz-Jeghers polyps are best removed endoscopically before they cause intussusception and obstruction, develop dysplasia, or become too big for endoscopic removal. The endoscopic armamentarium in PJS includes the standard upper GI endoscopy, colonoscopy, double-balloon endoscopy (DBE), and video capsule endoscopy (VCE). Double-balloon endoscopy is a modification of the push enteroscopy. DBE can be performed in an anterograde technique via the upper GI tract or in a retrograde fashion in association with colonoscopy to address pathologies in the distal portion of the small bowel [35]. The feasibility, diagnostic, and therapeutic yield of DBE was investigated by Ell et al. in a European Multicenter Study including 100 patients with small bowel pathologies from three European centers. Recurrent and chronic small bowel bleeding was the leading symptom in 64 patients followed by small bowel polyposis in eight cases. The mean insertion depth was 220 ± 90 cm from the oral route and 130 ± 80 cm from the anal route. The small bowel was completely visualized in 72% of cases. Endoscopic intervention was performed in 42% of cases. Procedural complications were not recorded [36]. A more recent study by May et al. reported a diagnostic yield of 78% from 353 patients undergoing DBE. Using the oral route, a median of 270 cm small bowel was visualized compared to 150  cm through the anal route. In this study 60% of the DBE was performed due to small bowel bleeding with a high diagnostic and therapeutic yield. The findings from these studies are very encouraging considering the fact that many PJS patients present with small bowel bleeding [37]. Video capsule endoscopy (VCE) allows visualization of the small bowel enabling the detection of small bowel pathologies [38–40]. In a retrospective study, Burke et al. investigated the

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value of VCE in the surveillance of small bowel polyposis [41]. The study population included 19 patients: 15 with familial adenomatous polyposis (FAP) and 4 with PJS. VCE was complete in 75% of PJS patients. In one case recording was stopped prematurely after 7  hours. Findings from VCE led to further intervention including surgical resection in 50% of PJS patients. Gupta and colleagues found no significant difference in a prospective study comparing the diagnostic yield of MR–enteroclysis and VCE in 19 patients with 41 large polyps (diameters >10  mm) [42]. Although three polyps (>15  mm) were missed, more smaller polyps were seen using VCE compared to MR– enteroclysis. In another comparative investigation by Schulmann et al., VCE missed a large polyp in one of four cases [43]. This shortcoming of VCE has been largely attributed to luminal debris, limitation of field of view, slow frame capture, and a rapid transit time in the upper GI tract [44, 45]. These aspects of VCE constitute relevant limitations of VCE in the diagnosis and surveillance of intestinal polyposis. More so, we have observed some cases of bowel obstruction during VCE with the need of urgent surgery. Therefore, VCE should be used with caution in patients with relevant small bowel polyposis.

Surveillance PJS patients and at-risk individuals should undergo syndrome-­ specific gastrointestinal and extracolonic surveillance. We will not address the extracolonic manifestations here, since it is beyond the scope of the chapter. The goal of surveillance is to monitor the development of intestinal polyps and treating them prophylactically (size depending) in order to prevent mechanical and bleeding complications that cause significant morbidity, mainly due to emergency surgeries and small bowel removal. Another rationale for bowel surveillance in PJS is to prevent transformation from benign polyps to cancer by disrupting the hamartoma carcinoma sequence via primary endoscopic polypectomy. According to the European guidelines, baseline endoscopic surveillance with upper GI endoscopy and colonoscopy should be

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initiated at the age of 8 years in order to enable the identification of individuals at risk of polyp-associated complications in childhood or early adolescence. At this point a revision of these European guidelines is taking place, especially in the light of a substantial number of PJS patients reported and in our own experience presenting with intussusception < 8 years of age requiring emergency surgical intervention. Perhaps surveillance initiation even without any abdominal symptoms will be required at an earlier time. In any case, in known families with PJS and children presenting with abdominal pain, consequent diagnostic procedures excluding polyps in the small bowel is mandatory. Also, anemia is a valid surrogate marker for relevant polyp formation. Surveillance should then be performed every 2–3  years in all cases in order to assess the individual polyp growth. Because of the increased risk of progression to cancer with increasing age, endoscopy is recommended every 1–2  years thereafter [18]. A similar surveillance program has been proposed by Giardiello and colleagues [17]. Dunlop et  al. [46] and Hemminki [47] recommended endoscopic screening being at the age of 18, which our group considers to be too late. A screening frequency of 3 years is recommended by Dunlop et al. while Hemminki suggests screening every 2–5 years. The conflicting recommendations reflect the poor level of evidence on which these recommendations and guidelines are based. Nonetheless, surveillance is best performed in a center with expertise in the management of patients with intestinal polyposis syndromes and the above recommendations should be adjusted based on individual disease burden. The next dynamic guidance based on more collaborative data under evaluation by the EHTG (European Hereditary Tumor Group, www. ehtg.org) is expected in early 2020 with a complete review of all literature available and will be a thorough revision of the above outlined recommendations.

Management of PJS PJS patients can be managed using both surgical and non-surgical methods. A combination of both surgical and non-surgical strategies increases the rate of success and may reduce the risk of morbidity.

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Thus, PJS patients are best managed in an interdisciplinary setting with gastroenterologists and gastrointestinal surgeons. Non-surgical management generally involves endoscopic intervention via polypectomy or management of bleeding. The argument that endoscopic polypectomy might prevent cancer in PJS is derived from the data of patients with sporadic adenomatous polyps. Sporadic adenomatous bowel cancer has been shown to develop in a stepwise transformation known as the adenoma carcinoma sequence. Endoscopic polypectomy in this group has been associated with a reduction of cancer [48, 49]. In analogy to sporadic cancer, bowel cancer in PJS is believed to follow a similar sequence, i.e., the hamartoma-carcinoma sequence. Therefore, endoscopic polypectomy might equally reduce the risk of bowel cancer in PJS. This argument is supported by the findings from a retrospective study by Latchford et al. [50]. Therefore, standard upper GI endoscopy and colonoscopy with polypectomy is recommended to reduce the risk of cancer and very importantly also the risk of polyp-associated complications in PJS patients. Too many PJS patients to date suffer from short bowel syndrome, due to emergency surgeries at the event of small bowel obstruction due to intussusception of polyps. Small bowel polyps in PJS are challenging, since the methods of detection are uncomfortable at least or very invasive in the event of removal. DBE and intraoperative enteroscopy (IOE) represent two management options that should be prioritized as organ-preserving, less-invasive approaches, compared with classical bowel resection. DBE has advanced to become a good option in experienced centers even after previous abdominal surgery. Gao et al. reported a 100% success rate for DBE in 13 PJS patients including 11 (85%) with a history of abdominal surgery [51]. In another study by Sakamoto et al. from Japan, 88 DBE were performed on 15 PJS patients with resection of small bowel polyps in 80.7% of cases [52]. Interestingly, five of six cases with intussusception (three with and three without symptoms) in this study were successfully managed with DBE. The rate of morbidity in this study was 6.8%: pancreatitis (2.7%), delayed bleeding (2.7%), and bowel perforation (1.4%).

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Small bowel pathologies not amendable by DBE are best managed via intraoperative enteroscopy (IOE). IOE can be performed during laparoscopy or laparotomy. Intraoperative endoscopy via an enterotomy enables the identification and removal of small bowel polyps without the need for multiple enterotomies with a corresponding increased risk of postoperative bowel leakage. Also, the removal of all detected polyps during IOE (“clean sweep”) might reduce the need for repeated bowel resection with the risk of short bowel syndrome [53]. More so, IOE has a higher sensitivity in detecting polyps compared to palpation and transillumination. In a paper by Spigelman et al., about 38% more polyps were detected on IOE compared to other methods [54]. IOE can be performed in an interdisciplinary setting including interventional endoscopy and gastrointestinal surgery. This hybrid procedure does not only facilitate the visualization of the entire small bowel but also enables the identification and management of small bowel pathologies [55]. Despite the reported lower yield with palpation and transillumination, the need for any kind of small bowel examination during surgery in PJS patients cannot be overemphasized. Due to advances in endoscopy, traditional surgery either via minimally invasive or open access is reserved for the management of cases not amenable to endoscopy, complications of endoscopy, and malignancies. For non-malignant indications, bowel-­ preserving techniques should be favored. If needed, bowel resection should be as limited as possible to reduce the risk of short bowel syndrome. Severe dysplasia and cancer are to be managed in accordance with oncologic principles. Prophylactic surgery of the colon and rectum does not play a major role in PJS. However, prophylactic gastric surgery and pancreatic surgery have lately been in the focus due to an as yet underestimated rate of cancers. Hopefully, the updated recommendations of the EHTG (European Hereditary Tumour Group), may be awaited with great special interest in the evaluation of the value of prophylactic measures in these organs. Until then, all decisions regarding prophylactic surgery must be based on polyp burden, dysplasia or frank cancer, family history, and individual

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choice of risk reduction. Currently, prophylactic surgery has no designated role in the management of PJS.

Juvenile Polyposis Syndrome Juvenile polyposis syndrome (JPS) is probably the most common hamartomatous polyposis syndrome with an incidence of 1  in 100.000 to 160,000 individuals [56, 57]. JPS is characterized by multiple juvenile polyps of the GIT and is associated with an increased lifetime risk of cancers [19]. Polyposis in JPS involves the large bowel (colon and rectum) in over 98% of cases, the stomach in about 14%, and the duodenum in 2–7%, while the remaining small bowel is involved in 7% [58, 59]. Besides increased risk for colorectal cancer, JPS is associated with high risk for other gastrointestinal (gastric, duodenum, small bowel) and pancreatic cancer. JPS is an autosomal dominantly inherited condition caused by germline mutations in the SMAD 4 (Smad family of signal transduction proteins) or BMPR1A (bone morphogenic protein receptor 1 A) gene, both tumor suppressor genes belonging to the transforming growth factor-ß (TGF-ß)/bone morphogenetic protein (BMP) family of molecules and serving as mediators of TGF-ß and BMP signalling, which affect cell growth, inhibition, and apoptosis. Pathogenic variants of both SMAD 4 and BMPR1A genes have been identified in up to 60% of JPS patients [60, 61]. SMAD4 pathogenic mutations, in addition to their role in tumorigenesis have been associated with a juvenile polyposishereditary hemorrhagic telangiectasia overlap syndrome. Interestingly, microdeletions occurring in both the BMPR1A and the PTEN gene loci on chromosome 10q22-q23 have been attributed to patients presenting with early-onset JPS and features of PTEN hamartoma-tumor syndrome, with an invariably severe ­phenotype. To date scarce data does not allow for clinically actionable genotype-phenotype correlations for SMAD4- and BMPR1A-­associated juvenile polyposis. However, the hemorrhagic telangiectasia appears to be associated exclusively with

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SMAD4 mutations. The putative roles of these genes as tumor suppressors and the spectrum of respective somatic alterations (second hit) involved in polyp formation remain yet to be investigated. Affected individuals usually present with numerous intestinal polyps. Sporadic solitary juvenile polyps of the large bowel have been described in about 2% of the pediatric population [62]. Unlike juvenile polyps in JPS, solitary juvenile polyps are not associated with increased risk of colorectal cancer [62]. SMAD 4 pathogenic variants are associated with a more aggressive gastrointestinal phenotype with higher incidence of adenoma, dysplasia, and cancer besides a more frequent gastric and small bowel polyposis compared to pathogenic BMPR1A variants (Fig. 2.4) [63]. The clinical criteria for the diagnosis of JPS include [19]:

Fig. 2.4 Severe small bowel polyposis in a 10-month-old child with BMPRA1 and PTEN mutation

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• At least five synchronous and/or metachronous JP in the large bowel • Multiple JP throughout the GI tract • Any number of juvenile polyps in a person with a family history of JPS JPS has been classified by Sachatello et al. in three categories based on the clinical phenotype [64]. This first category is termed juvenile polyposis of infancy. This form of JPS presents early in the childhood with generalized polyps in the stomach and small and large bowel. Affected infants usually suffer from chronic diarrhea, malnutrition, bleeding, and intussusception and the outcome is usually fatal. In addition, several other congenital abnormalities like hypotonia and macrocephaly may also be present [65]. In the second category known as juvenile polyposis coli, polyps are restricted to the large bowel, while the third group is characterized by a generalized polyposis. Both the colonic and the generalized JPS usually present in later childhood or in adult life [66]. The colonic phenotype was shown by Coburn et al. to present between 5 and 15  years, while the generalized phenotype presents at a much younger age [67]. Gastrointestinal bleeding was the most common symptom in over 70% of cases reported from a Tel Aviv collective by Rozen et al. [68]. Abdominal pain, diarrhea, bowel obstruction, and prolapsed rectal polyps represent other common presenting symptoms [69]. As with many hereditary polyposis syndromes, extraintestinal manifestations have been described in patients with JPS [70]. JPS is associated with a marked increase in the risk of cancer. Kinzler and Vogelstein postulated that carcinogenesis in JPS develops through the so-called landscaper mechanism. This hypothesis is based on the observation that genetic alterations at the BMPR1A gene locus on chromosome 10q22 occurred predominantly in the stroma of juvenile polyps. Transformation to cancer according to the landscaper mechanism is secondary to an abnormal stromal environment [71]. Secretory products from the proliferating stroma in PJS create an abnormal stromal microenvironment which influences the adjacent epithelium. The

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resulting regeneration of damaged epithelium predisposes to dysplasia and neoplasia. In a study by Howe et  al., 16 of 29 JPS patients developed cancer including 11 with colorectal cancer, four with gastric cancer and one with cancer of the duodenum and pancreas, respectively [66]. In a Jewish cohort studied by Rozen et al., the reported incidence cancer was 22.9% [68]. This finding is in accordance with findings from a literature review by Agnifili et al. indicating a cancer incidence of over 17% in JPS patients [72]. The risk of cancer begins early at the age of 20 and increases in the 30s. The lifetime risk for CRC in JPS patients based on The Johns Hopkins Polyposis Registry was estimated by Brosens et al. at 38.7% [65]. However, there is no correlation between time of onset of JPS and risk of cancer. The diagnosis of JPS, as is the case with other hereditary polyposis syndromes, is based on clinical suspicion in the presence of typical features and family history. The diagnosis is reached following genetic counseling and testing. Genetic testing aims at confirming the diagnosis in the index person and identifying at-­ risk individuals to determine future surveillance strategies. Besides, genetic testing may be the only means of discriminating JPS patients from other conditions like Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS), which may also present with juvenile polyps [73]. A correlation with hemorrhagic telangiectasia (HHT) occurs in approximately 20–30% of patients and seems to be exclusively attributable to SMAD4 mutations. HHT is much more frequent than JPS, and the most common clinical signs of HHT include recurrent epistaxis (nosebleeds), frequently from childhood, and cutaneous or mucosal telangiectasias generally presenting later, and increasing with age, where anemia may become an important part of the disease. Visceral arteriovenous malformations (AVMs) are usually asymptomatic but can lead to complications that produce highly variable ­manifestations. This genetic disorder is due to pathogenic variants primarily in ENG (9q34.11) or ACVRL1 (12q13.13), encoding proteins involved in vascular development and angiogenic homeostasis of capillaries. Mutations in SMAD4 occur in 1–3%) of cases and result in HHT associated with juvenile polyposis. In

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these cases of JPS, the diagnosis may be made earlier due to the overlap of symptoms such as bleeding and severe anemia.

Surveillance and Management Surveillance recommendations for JPS are based mainly on expert opinions due to the paucity of data from high-quality investigations. Although different recommendations vary with regard to the timing of the baseline surveillance, there is good consensus regarding surveillance methods. Howe et  al. recommends baseline endoscopic screening of the small and large bowel at age 15 or at the time of first symptoms [74]. Dunlop et al. on the other hand recommend baseline screening with colonoscopy at 15–18 yrs. and then every 1–2 years thereafter. According to this protocol, upper GI endoscopy should start at the age of 25 and should be repeated every 1–2 years [46]. We advocate beginning endoscopic surveillance with upper GI endoscopy and colonoscopy at the age of 15 for asymptomatic cases or with the beginning of symptoms as recommended by Howe et al. If uneventful, surveillance should be repeated every 2–3 years or annually following polypectomy until the patient is polyp-free, then every 2–3  years. Our surveillance protocol includes abdominal MRI in the form of MR–enteroclysis to survey the post-duodenal segments of the small bowel every 2–3 yrs. (Fig. 2.5). Management options and priority depend on the presentation of symptoms (bleeding, chronic diarrhea with protein loss, or bowel obstruction) and severe dysplasia or cancer. Both surgical and non-surgical options are available for the management of JPS patients. Endoscopic intervention includes polypectomy and management of hemorrhage. The indications for surgical intervention of JPS includes symptomatic cases not manageable by endoscopy (rapie progression, high burden of polyps) including recurrent hemorrhage with severe anemia, bowel obstruction, and chronic diarrhea. Also, surgery may be indicated to manage the complications of endoscopic intervention. Severe polyposis with or without severe dysplasia

P. C. Ambe and G. Möslein

30 > 15 years < 15 years + symptoms

No polyps

Polyp + Polypectomy

Surveillance every 3 years

Annual Surveillance

Polyps

Fig. 2.5  Surveillance protocol for hamartomatous polyposis syndromes with intestinal polyposis (PJS and JPS)

and cancer may warrant surgical management, including prophylactic surgery. Gastric polyposis may be predominant in some cases and should be endoscopically managed in cases with few polyps. Interestingly, most cases of severe gastric involvement are attributed to patients with SMAD4 mutations. Endoscopic management of significant gastric polyposis may be technically challenging, but also an unreasonable option with recurrent bleeding and severe anemia and/or dysplasia. These cases are best managed via total prophylactic gastrectomy, taking the overall relevant risk for gastric cancer into account. Gastric surgery for severe cases should be considered early to minimize the risk of morbidity and mortality associated with recurrent bleeding and chronic anemia. In the light of achieving the best possible long-term quality of life (QoL), construction of a jejunal reservoir at the time of gastrectomy should be the procedure of choice for these JPS patients [75]. Surgical options for colorectal polyposis might include subtotal colectomy with an ileosigmoidal or ileorectal anastomosis in

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cases with limited distal polyposis, which appears to be the rule rather than the exception. The advantage of this less-invasive procedure when compared to the standard surgical procedure of a proctocolectomy and ileoanal pouch as the standard recommendation for patients with FAP (familial adenomatous polyposis) is the better quality of life associated with reduced stool frequency secondary to the retained rectosigmoid or rectum. This option must be complemented by frequent postoperative endoscopic surveillance of the retained rectum with subsequent polypectomies. However, it is important to counsel the patient about the remaining long-term risk of a later indicated proctocolectomy due to recurrent rectal polyposis [76, 77]. In light of this possible development, an extended resection in the form of proctocolectomy in some cases may be a reasonable option and should be discussed based on the individual polyposis and also family history. Segmental colectomy may be indicated in those cases, where a segmental, mainly right-sided polyp burden is exclusive. Again, on an individualized basis, this option can be a good alternative to subtotal colectomy and should be guided by polyp burden and distribution. The need of prophylactic surgery in JPS both for the stomach and for the colorectum is a very individual decision-making process and must involve an informed patient. Hamartomatous polyposis syndromes, unlike familial adenomatous polyposis (FAP), have a less-predominant cancer risk and do not exhibit full penetrance. Nevertheless, prophylactic surgery may reasonably considered in JPS patients with significant polyposis unmanageable via endoscopy. Similarly, severe diarrhea, dysplasia, or lower GI bleeding and a positive family history of colorectal cancer might guide decision-making with regard to the need of prophylactic surgery [65]. Although close rectal dissection of the mesocolon and mesorectum is definitely an option in JPS patients undergoing ­prophylactic proctocolectomy, we advocate an oncologic dissection for the management of hereditary polyposis syndromes [78, 79]. JPS patients might harbor some risk of undiscovered dysplasia or cancer which may only become evident on surgical histopathology. Performing oncologic dissection with complete

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mesocolic excision (CME) of the colon, partial mesorectal excision (PME) or total mesorectal excision for rectal dissection during the initial surgery eliminates the need of a redo procedure for lymph nodal clearance in cases with incidental cancer. Proctocolectomy in JPS patients should be with restorative intent using an ileoanal pouch. Thus, restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) should be considered in those patients exhibiting severe rectal polyp involvement, dysplasia, or frank cancer. This procedure will remain the exception for JPS patients. For all prophylactic surgeries discussed here, a minimally invasive approach should be preferred, also as a secondary procedure. Besides the many known short-term advantages of minimally invasive surgery, long-term advantages for a lastingly improved quality of life (QoL) including less hernia development, possibly less adhesions, and better pregnancy rates that have been demonstrated in female patients following laparoscopic restorative proctocolectomy compared to those undergoing open surgery [80]. Since PJS patients are usually young, focusing on all aspects of maintaining an excellent QoL should be the main focus when dealing with patients and mandates the experienced, multidisciplinary approach.

PTEN Hamartoma Tumor Syndrome PTEN hamartoma tumor syndrome (PHTS) includes four clinically distinct syndromes: Cowden syndrome (CS), Bannayan-­ Riley-­Ruvalcaba syndrome (BRRS), Proteus syndrome (PS) and Proteus-like syndrome. These syndromes are associated with germline mutations of the tumor suppressor gene PTEN. Germline mutations lead to unregulated cellular proliferation with the formation of hamartomas. Similar to the abovementioned hamartomatous syndromes, PTEN syndromes are autosomal ­ dominantly transmitted [7]. Cowden syndrome was first described by Lloyd and Dennis in 1963 in a 20-year-old woman after which the disease was named [81]. CS is usually identified in late childhood and is characterized by multiple hamartomas. Mucocutaneous manifestations

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including trichilemmomas, papillomatous papules, and acral and plantar keratoses are common in over 99% of cases by the age of 30  years. Other findings commonly encountered in CS include megacephaly, macrocephaly, dolichocephaly, and Lhermitte-­ Duclos disease. Gastrointestinal polyps are less common and usually asymptomatic. CS is associated with an increased risk of developing both benign and malignant tumors of the thyroid, endometrium, and breast [82]. Bannayan-Riley-Ruvalcaba syndrome (BRRS) unlike CS is a congenital condition and is usually diagnosed very early in life. Common clinical findings include macrocephaly, hemangiomas, pigmented macules of the penis, high birth weight, scoliosis, intestinal polyposis, and developmental delay, amongst others [82]. BRRS is diagnosed following the presence of clinical features and genetic testing for PTEN mutations [83]. Proteus syndrome and Proteus-like syndrome represent rare complex syndromes characterized by a rapid progressing overgrowth of different tissues. Similar to BRRS, the Proteus and Proteus-like syndromes are frequently congenital. Various kinds of nevi and hyperkeratosis are the most common clinical features [84]. Generally, the intestinal disease burden in PHTS is low and the risk of bowel cancer is not higher than in the normal population.

Summary Hamartomatous polyposis syndromes constitute autosomal dominantly inherited familial syndromes including Peutz-Jeghers syndrome, juvenile polyposis syndrome, and the PTEN hamartoma tumor syndromes. PJS and JPS are rare causes of intestinal polyposis. The distribution of polyps along the gastrointestinal tract varies extensively amongst both syndromes. Although both syndromes may have overlapping clinical features including abdominal pain, anemia due to gastrointestinal bleeding, intussusception, and bowel obstruction, mucocutaneous pigmentation is a leading feature of PJS. Conversely, chronic diarrhea with malnutrition is commonly encountered in JPS.  Both syndromes are associated

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with an increased risk of gastrointestinal cancer. The diagnostic workup is similar for both syndromes. Genetic counseling and testing should be initiated at an early state to enable a syndrome-­ specific surveillance of patients and at-risk relatives. While prophylactic surgery may be indicated due to extensive polyposis in JPS, there is no role for prophylactic surgery in PJS. Patients with both syndromes are best managed in an interdisciplinary setting including surgeons, gastroenterologists, radiologists, and pediatricians. All patients with confirmed diagnosis should be managed in centers with expertise in these syndromes.

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Familial Adenomatous Polyposis: Prophylactic Management of the Colon and Rectum Chady Atallah, Francis M. Giardiello, and Jonathan Efron Introduction Familial adenomatous polyposis (FAP) is an autosomal dominant disease and is the most common adenomatous polyposis syndrome. It was first described by Virchow in 1863 [1]. It is caused by a mutation of the adenomatous polyposis coli (APC) gene, a tumor suppressor gene located on chromosome 5q21. Its most characteristic clinical feature is the early onset of hundreds to thousands of colonic adenomas. Extracolonic manifestations include gastric and duodenal polyposis with increased risk of malignancies in these organs. FAP is also associated with papillary thyroid cancer, desmoid tumors, and osteomas. C. Atallah (*) · J. Efron Department of Surgery, Ravitch Division of Colon and Rectal Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA e-mail: [email protected] F. M. Giardiello Department of Medicine, Department of Oncology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

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The incidence of FAP is between 1:10,000 and 1:15,000 live births. Both genders and all races are affected equally. The penetrance of the disease is very high, and if left untreated, 95% of patients with FAP will develop colorectal cancer at an average age of 39. About 1% of all colorectal cancers are caused by FAP. Diagnosing FAP is crucial not only for appropriate patient management but also to evaluate and survey all at-risk family members. Once the diagnosis is made, close endoscopic surveillance and prophylactic surgery are the mainstay of management of FAP. The aim is to prevent colorectal cancer, but also to decrease the morbidity and mortality associated with other cancers associated with FAP, including duodenal and thyroid malignancies. In this chapter, we briefly review the clinical presentation and the molecular and genetic basis of FAP and discuss the most recent recommendations and important trials that guide our prophylactic (chemopreventive and surgical) management of this disease with a focus primarily on the colon and rectum.

Clinical Presentation Most patients with FAP are completely asymptomatic for years, until the adenomas become larger and more numerous. Some patients present with nonspecific symptoms, including rectal bleeding, diarrhea, mucous discharge, or vague abdominal pain. When the adenomas become larger, or a cancer develops, patients can present with anemia, weight loss, and in rare cases large bowel obstruction [2]. Patient phenotype can be variable, even within the same family. FAP is classified as severe when there are thousands of polyps in the colon and rectum, mild when the number is between 100 and 1000 polyps. In severe FAP often no normal mucosa is seen between the adenomas [2]. Attenuated FAP (AFAP) is another phenotypic variant of FAP, defined as the presence of less than 100 adenomatous polyps. It is estimated to represent about 6% of adenomatous polyposis syndromes. The adenomas are predominantly found in the right

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colon, and the rectum is often spared. This milder phenotype is also less likely to be associated with extracolonic manifestations. Patients usually present at a later age, typically in the fourth and fifth decade of life. Similarly to FAP, it is caused by a mutation of the APC gene, but at the 5′ and 3′ ends of the gene, and it has an autosomal dominant inheritance. This should not be confused with MUTYH-associated polyposis that can have a similar clinical presentation, but instead has an autosomal recessive inheritance, which is caused by a mutation in the MUTYH gene. The risk of developing colorectal cancer is less than the risk with FAP and is estimated to be around 80% [3]. Extracolonic manifestations are very common with FAP and require specific evaluation and screening. Approximately 90% of patients with FAP develop duodenal polyps, but only 5% will progress to duodenal cancer [4, 5]. On the other hand, 50% of patients have gastric polyps, but it is rare for these patients to develop gastric adenocarcinoma [6]. Desmoid tumors occur in about 15% of patients. They are locally invasive non-­metastasizing tumors with potential to become very large, causing significant morbidity and mortality. They are the third leading cause of death in patients with FAP after colon cancer and duodenal cancer. They typically develop 3–5 years after surgery, mostly in the intestinal mesentery or abdominal wall, presumably due to a significant inflammatory response [7]. Papillary thyroid cancer (PTC) is another rare manifestation of FAP, occurring in 2–4% of patients [8, 9]. Women are more likely to develop PTC than men. Other rare malignant tumors can develop in patients with FAP, including pancreatic adenocarcinoma, hepatoblastoma, and medulloblastoma. Benign lesions can also occur, specifically congenital hypertrophy of the retinal pigment epithelium, which is present in 60–85% of patients [10]. It manifests in childhood and is easy to detect on indirect ophthalmoscopy. The presence of 4 or more areas of large, patchy, fundic discoloration is highly specific for FAP, with a positive predictive value of 93%. Other benign lesions include osteomas, epidermoid cysts, lipomas, and fibromas, which rarely require intervention. One specific FAP subtype is Turcot syndrome. It is defined as FAP associated with central nervous system neoplasms [11, 12].

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Diagnosis and Screening The diagnosis of FAP starts with a thorough history, as the majority of patients will have an extensive family history of polyposis and colorectal cancer. The identification of high-risk patients allows implementation of screening strategies and genetic testing [13]. The absence of family history of polyposis should not exclude the diagnosis of FAP, since 15% of mutations in the APC gene are de novo [14]. The diagnosis is usually confirmed endoscopically. The presence of 100 or more adenomatous colorectal polyps is pathognomonic. Genetic testing is recommended for these patients to identify specific mutations and allow genetic screening in family members. The diagnosis should also be suspected in patients with less than 100 polyps, but more than 20 cumulative adenomas, or with the presence of extracolonic manifestations [15]. In fact, only 17% of patients with 20–99 polyps will have specific mutations found on genetic testing. This makes the diagnosis more challenging and requires a combination of clinical findings, family history, genetic testing, and a high index of suspicion. There are more than 850 different APC gene mutations that cause FAP.  Several methods for APC gene testing have been developed. The American College of Medical Genetics and Genomics currently recommends full sequencing of the APC gene to detect mutations [16], which includes direct sequencing of all 15 coding exons, through a simple blood test. Eighty-seven percent of these patients will have mutations detected using this technique, while the remaining patients will require additional testing, such as MLPA, Southern blot, or real-time quantitative PCR analysis. Importantly, affected individuals should receive genetic counseling before undergoing any testing [17]. The pros and cons of genetic testing should be thoroughly discussed with the patients, and it should be determined whether they are emotionally able to receive such information. Other implications such as confidentiality, and screening of other family members, should

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also be considered. Once genetic counseling is complete and a family mutation is identified, at-risk family members should be offered genetic testing. Testing at-risk members is then cheaper since the mutation is known and site-specific testing can be done. Genetic testing is offered to first-degree relatives starting at puberty, since it is very rare for a colorectal cancer to develop before the age of 15 [18]. If no mutation is identified in the affected individual, or if no genetic testing is performed (usually because of patient refusal), flexible colonoscopy should be done in first-degree relatives starting at age 10–12 and repeated every 1–2 years, then every 2 years after the age of 25, and every 3 years after the age of 35. If polyps are found at any point in time, surgical management should be offered, usually once adulthood is reached [19].

Genetics FAP is an autosomal dominant disease, and affected patients have a 50% chance of transmitting the mutated allele to descendants. However, de novo germline mutations can occur in about 15–20% of cases. These patients will have no family history of FAP [20]. The disease results from a mutation in the APC gene, a tumor suppressor gene located in chromosome 5q21–22, which has 15 coding exons. The gene encodes a protein that plays a role in the WNT signal transduction pathway. Patients with FAP are born with 1 mutated allele. Sporadic mutations will then lead to loss of the second allele, resulting in the rapid development of hundreds to thousands of adenomas. Different germline mutations are associated with different phenotypes of the disease (severe/profuse, intermediate, and attenuated). Other mutations are associated with extracolonic manifestations. Despite these associations, significant variability exists even among members of the same family. This suggests potential environmental influence on the phenotype [21].

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Chemoprevention Chemoprevention has, in some clinical trials, decreased the size and numbers of adenomas in patients with FAP. The most important RCTs are summarized in Table 3.1. The agents most tested are aspirin and Sulindac (COX-1 inhibitors) and celecoxib (COX-2 inhibitors). These drugs are thought to act by decreasing prostaglandin synthesis in the epithelial cells of the colon and rectum, thus decreasing the development and growth of adenomas. They are thought to have the same effects on gastric and duodenal mucosa. Some reports have also speculated an effect on the development and progression of desmoid disease. The first randomized controlled trial that showed a positive effect of Sulindac in FAP was published in 1993 by Giardello et al. [22]. It showed a 56% reduction in number and 65% in size of colorectal adenomas in patients with diagnosed FAP. Sulindac Table 3.1  Randomized controlled trials for chemoprevention of colorectal adenomas RCT Giardiello et al. [22]

Chemopreventive agent N Sulindac 150 mg bid vs 22 placebo

Results 56% reduction in number and 65% in size of colorectal adenomas 41 No prevention in the initiation of colorectal adenomas 133 No effect on the number of polyps A trend for aspirin in reducing the size of polyps in patients treated more than 1 year 77 28% reduction in the number of polyps (P = 0.003) and 30.7% in size of polyps (P = 0.001) 21 6.8% reduction in polyp number (P = 0.004), significant reduction in the polyp size as well (P 5–6 mm, a significant increase in adenoma number, the presence

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of adenomas with high-grade dysplasia, or an inability to adequately survey the colon because of multiple diminutive polyps. For most individuals with FAP, total proctocolectomy (TPC) with IPAA remains the recommended surgical intervention and, in the case of classic polyposis, usually takes place at 15–25  years of age [4–6]. IPAA was first described as a technique to regain bowel continuity following TPC for ulcerative colitis (UC) [7]. Several techniques for ileal pouch construction have been described [8]; however, the stapled J-pouch has become the dominant technique due to the combination of short learning curve, ease of technique, and relatively good function. The use of IPAA in FAP has obvious benefits. Given that most FAP patients are young, restoration of bowel continuity is attractive. It has also become apparent that pouchitis, a major problem in UC patients, is far less of an issue for patients undergoing IPAA for FAP [9]. Therefore, an FAP patient with a well-constructed IPAA can reliably expect good function. However functional outcome must be balanced against reduction of cancer risk. Given that postoperative surveillance for individuals with polyposis is inherently tied to primary surgical decision-making, we must start by reviewing the results of this surgery. When creating an IPAA for FAP, the surgeon decides to perform either a mucosectomy and handsewn (HS) anastomosis or a double-stapled (DS) anastomosis [10]. For mucosectomy and HS IPAA, a standard abdominal proctectomy to the pelvic floor is performed and the most distal dissection is then completed through a transanal approach, excising the low rectal mucosa off the bowel from immediately above the dentate line until the plane of dissection from the abdominal resection is reached. Following TPC and mucosectomy, an S-, W- or J-ileal pouch reservoir is constructed and HS to the cut edge of the anorectum (ATZ) under direct vision from the perineum. The technically easier, but theoretically less oncologically radical DS anastomosis involves dissection of the rectum to the pelvic floor, stapled division of the rectum just above the dentate line (generally, 1–2 cm), and formation of an end-to-end anastomosis by introduction of a circular stapler through the anus.

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The plane of dissection for patients undergoing prophylactic proctectomy for polyposis can be controversial. Close-rectal (intra-mesorectal) dissection is thought to provide superior protection for the pelvic nerves, resulting in less sexual or urinary dysfunction [11]. Additionally, there is also a school of thought, largely extrapolated from the UC literature, that close-rectal dissection may minimize the chances of long-term IPAA dysfunction by reducing the likelihood of ileal pouch elongation and torsion by reducing the space within the pelvis [12]. That said, total mesorectal excision (TME) conforms to surgical norms of oncological surgery and follows a more bloodless anatomical plane compared to intra-mesorectal dissection. Due to the fact that early T-stage cancer is not uncommon and often cannot be reliably ruled out preoperatively, it is the authors’ preference to generally perform TME surgery with appropriate lymph node harvest for patients undergoing proctectomy for polyposis. The concept behind proctectomy with mucosectomy and HS IPAA is that theoretically (near) all rectal mucosa is removed and, as such, cancer risk should be optimally reduced. While hypothetically attractive, this technique can be challenging and it is not clear if the presumed oncologic benefit is realized. While early postoperative complications rates appear similar, expert centers have observed that FAP pouch failure requiring subsequent salvage surgery is 6–11% following mucosectomy and HS IPAA versus 2–4% for DS pouches [13, 14]. Additionally, while global quality of life scores appeared similar for both approaches, rates of bowel incontinence have been observed to be higher following mucosectomy and HS anastomosis compared to DS IPAA [14]. Given that mucosectomy with HS anastomosis is subject to greater technical and functional challenges, it is important to understand whether the prophylactic oncologic benefits of this approach warrant its utility compared to DS IPAA. There are no randomized controlled trials (RCTs) to establish the oncologic risk-benefit of proctectomy with mucosectomy over standard proctectomy, and as such, we must rely on data from relatively large, retrospective cohort studies. Ozdemir et al. have published the experience of the Cleveland Clinic following 240 patients with FAP post-TPC and IPAA (HS = 76 and DS = 164) between

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1983 and 2010 [14]. Annual pouchoscopy was recommended for all patients. Follow-up was significantly longer for those undergoing HS (12.9  ±  8.2  years) compared to DS (7.9  ±  5.8  years, p  10 mm), are obstructing, or feature significant dysplasia.

 anagement of Gastric and Duodenal M Neoplasms Screening and Surveillance Screening esophagogastroduodenoscopy (EGD) is recommended for individuals with FAP, with surveillance intervals dictated largely by the duodenal polyp burden (e.g., Spigelman stage). Currently, the recommended technique for screening and surveillance of gastric and duodenal adenomas requires using both a high-definition, forward-viewing gastroscope and a side-viewing duodenoscope for full visualization of the ampulla and periampullary area.

Gastric Polyps Endoscopists should pay particular attention to the gastric polyposis phenotype of FAP patients, closely examining the appearance of FGPs with random sampling of polyps to screen for dysplasia. Gastric polyps that are large (>10  mm in size) and located in the gastric antrum (an atypical location for benign FGPs) and/or those that have an atypical appearance should be biopsied and/or resected [28]. While the severity of duodenal polyposis has traditionally been used to determine upper GI tract surveillance intervals, experts suggest that surveillance intervals should be guided by the area of the upper GI tract (i.e., stomach or duodenum) with the most severe polyposis [10]. Patients with high-grade gastric dysplasia should undergo close surveillance every 6  months or more often. Mass lesions should be further

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evaluated with endoscopic ultrasound (EUS) and/or cross-sectional imaging. Patients whose biopsies exhibit high-grade dysplasia should undergo ­ further gastric mapping. Those with multifocal high-grade dysplastic lesions or adenocarcinoma(s) that are not endoscopically resectable should be referred for surgical resection [10]. Given recent reports of FAP patients with bulky gastric polyposis developing metastatic gastric cancer while under surveillance, the risks and benefits of gastrectomy should be discussed with such patients [10].

Duodenal Adenomas Screening for duodenal polyps in FAP patients should begin at the age of 20–25 or prior to colectomy (whichever is earlier) [5]. As with colon adenomas in FAP, not all duodenal adenomas require immediate resection. As long as the polyps are small in size and do not have concerning features, they can be surveyed as recommended based on the Spigelman stage; however, duodenal adenomas that are larger and/or have advanced histology (tubulovillous or villous features) should be resected endoscopically if possible. In their study of the natural history of duodenal adenomas in FAP patients, Burke et  al. studied 114 FAP patients who underwent surveillance without any intervention for a mean of 51  months (range 10–151 months) [22]. They found that during the surveillance period, 26% of duodenal polyps progressed in size, 32% in number, and 11% in histology. This study highlighted that the majority of duodenal adenomas do not exhibit rapid progression of endoscopic features or histology; therefore, surveillance based on Spigelman stage is an appropriate management strategy. As adjuncts to standard white light endoscopy, imaging techniques such as narrow band imaging (NBI) and chromoendoscopy have also been investigated for duodenal adenoma surveillance, with variable results. Lopez-Ceron et al. compared high-­definition, white light to NBI in classification of duodenal polyps in a prospective study. They found that NBI allowed for detection of a greater number of duodenal adenomas, but did not impact the clinically relevant classification of duodenal polyps based on Spigelman stage [26]. Similarly, Dekker et al. compared the outcomes between white light endoscopy to chromoendoscopy at

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two academic endoscopy centers in the Netherlands. They found that chromoendoscopy increased the number of duodenal ­adenomas that were detected as compared to standard white light endoscopy, but led to a higher Spigelman stage in only 5/43 patients [29]. Meanwhile, in a more recent study, Hurley et  al. examined a cohort of FAP patients at two academic centers in the UK and found that chromoendoscopy increased duodenal adenoma detection by threefold compared to standard white light endoscopy, leading to a significant increase in Spigelman stage with the addition of chromoendoscopy [30]. At present neither NBI nor chromoendoscopy has been incorporated into routine screening or surveillance of duodenal adenomas in FAP patients.

Ampullary Adenomas Screening for ampullary adenomas is recommended to begin at the same time as for duodenal adenomas and can be best accomplished using a side-viewing duodenoscope. If the ampulla appears enlarged or abnormal, biopsies should be obtained, paying careful attention to avoid trauma to the orifice as this can precipitate pancreatitis. In certain cases, EUS can be useful for further characterizing the extent of ampullary adenomas. For example, EUS can delineate whether ampullary adenomas have an intraductal component, which will aid in the decision of whether to proceed with endoscopic or surgical resection. Gluck et al. reported outcomes of 10 years of duodenal surveillance in a cohort of 80 FAP patients at Tel Aviv Medical Center [31]. Biopsies of the ampullary region, even if normal-appearing, were obtained during surveillance for all patients. A total of 38/80 (47.5%) patients had ampullary adenomas and underwent EUS. Using EUS, nine ampullary adenomas, which were previously classified as nonadvanced by endoscopy, were reclassified as advanced by EUS, leading to a change in management from surveillance to ampullectomy. A total of 15 patients underwent ampullectomy with adverse events in 3/15 (20%) of patients due to pancreatitis and minor bleeding. Ten of the 15 patients had recurrence of ampullary adenoma after an average of 28 months from initial ampullectomy. Overall, out of this cohort, only 2% of patients required prophylactic surgery, and none developed duo-

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denal or ampullary adenocarcinoma during the study period [31]. Because of the high rate of recurrence, ampullary adenomas should not be resected unless they are large (>10 mm), have dysplasia, or cause biliary obstruction.

 ndoscopic Resection of Gastric and Duodenal E Neoplasms Endoscopic resection of gastric and duodenal polyps can be accomplished using endoscopic mucosal resection (EMR) and/or endoscopic submucosal dissection (ESD). EMR, a technique pioneered by Soetikno et al., is a commonly used polypectomy technique in which a submucosal injection of a viscous solution is performed to lift a polyp prior to resection. The lift creates a cushion between the mucosal layer and the muscularis propria, allowing for resection to occur in the intervening submucosal layer [32]. While EMR was initially developed in Japan to resect gastric cancers, it was later found that some lesions were incompletely resected or unable to be resected by EMR due to deeper submucosal invasion. Therefore, ESD was developed in the late 1990s [33]. In ESD, after submucosal injection, an incision is made in the mucosal layer that allows for dissection of the gastric lesion using a special knife. ESD allows for en bloc resection of large lesions that have deeper invasion than just the superficial mucosal layer [33, 34]. Neither EMR nor ESD allows for resection of lesions that invade layers beyond the submucosal layer, such as into the muscularis layers. These lesions should be managed surgically. With such advancements in endoscopic techniques, gastrectomy, due to its high morbidity, is now reserved for patients with invasive cancers and/or endoscopically unresectable advanced neoplasms. Roos et  al. reported two FAP patients in the Netherlands with large (20–60 mm in size) gastric adenomas that presented as white-in-appearance plaques in areas of the gastric mucosa that were carpeted with FGPs. Biopsies of each of the plaques demonstrated tubulovillous adenoma with low-grade dysplasia, and both lesions were successfully resected by EMR. The

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white mucosal patch has also been reported by others [35, 36] and is, in fact, considered to be a high-risk feature for gastric cancer. In another recent case report, Yaguchi et  al. described an FAP patient who underwent ESD for nine synchronous gastric polyps that had a gross appearance suspicious for adenocarcinoma [37]. With three successive endoscopy sessions, they were able to completely resect the adenocarcinoma-containing polyps. If endoscopic resection is unable to be performed, especially for adenomas with high-grade dysplasia and gastric adenocarcinoma, gastrectomy should be considered. Similar to gastric polyps, not all duodenal adenomas require resection; however, those that are large (>10 mm in size) or have other concerning features such as dysplasia should be resected. As long as it is feasible, endoscopic polypectomy is the preferred approach for resection of duodenal adenomas rather than surgery. Jagonmohan et al. reviewed 15 years of data from a cohort of 71 FAP patients at MD Anderson Cancer Center and found that that 98.5% of their patients had multiple, flat, duodenal lesions. Those who were treated endoscopically underwent either cautery of the lesion(s) with argon plasma coagulation or EMR. Follow-up after endoscopic resection showed that although a majority of these patients had recurrence of adenomas, none progressed to adenocarcinoma during their surveillance period [38]. It should be noted that EMR is the standard approach for management of large duodenal adenomas. Argon plasma coagulation can be used as an adjunct to obliterate resection margins to prevent recurrence after large polyps are removed by EMR, but is not used as a primary management tool.

Endoscopic Resection of Ampullary Adenomas As with most gastric polyps and adenomas in other portions of the duodenum in FAP patients, most ampullary adenomas will not require resection, but rather can be surveilled closely. As discussed earlier, once ampullary adenomas are identified, EUS is a valuable modality to better characterize the lesions. Features of ampullary adenomas on EUS for which endoscopic ampullec-

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tomy may be considered include size 10  mm and positive margins were associated with recurrence, which in many cases can be managed endoscopically; however, scarring can significantly complicate subsequent endoscopic resection attempts [42]. Given the risk of recurrence, ampullary adenomas should not be routinely resected unless they have concerning features.

 urgical Resection of Duodenal and Ampullary S Neoplasms Some duodenal and ampullary adenomas that are deemed to be endoscopically unresectable, such as those that are nearly circumferential lesions and/or those with high-grade dysplasia or carcinoma, should be surgically resected [38]. Historically, it had been recommended that patients that meet criteria for Spigelman stage IV duodenal adenomas (i.e., large (or >20) adenomas, high-grade dysplasia, and villous features) be referred for surgery. However, recent data demonstrate that certain patients who meet Spigelman stage IV duodenal polyposis criteria can be considered candidates for endoscopic management. In a study in France by Moussata

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et  al., 35 patients with Spigelman stage IV duodenal polyposis underwent endoscopic treatment. After a mean of 1.5 (range 1–4) therapeutic endoscopy procedures, 9 patients had downstaging of Spigelman stage by 6  ±  2.2 points after a mean follow-up of 9 ± 4.5 years from index procedure to end of study. The adverse event rate was 6% and included delayed bleeding, pancreatitis, and perforation [43]. There are several surgical approaches for management of duodenal adenomas. These include pancreaticoduodenectomy (Whipple procedure), pylorus-sparing duodenectomy, pancreas-sparing duodenectomy, or segmental duodenectomy. Pancreaticoduodenectomy, pylorus-sparing duodenectomy, and pancreas-sparing duodenectomy are considered the most definitive interventions for prevention of duodenal cancer in patients with FAP with high duodenal polyp burden. Augustin et  al. reviewed 767 FAP patients in the Cleveland Clinic registry and found that over a 22-year period from 1994 to 2016, 63 (8.2%) underwent surgery for duodenal adenomas [44]. The management protocol at Cleveland Clinic included offering patients with Spigelman stage III or IV pancreas-sparing duodenectomy for diffuse duodenal polyposis or pancreaticoduodenectomy if there was high suspicion for cancer (based on EUS or symptoms such as jaundice). Patients with focal or dominant disease were offered segmental duodenectomy or ampullectomy, according to location of duodenal adenoma(s). The majority of patients had endoscopic surveillance for 10 years, on average, prior to surgery and were asymptomatic at time of surgery. A total of 42 patients (67%) had pancreas-sparing duodenectomy, 15 (24%) had pancreaticoduodenectomy, and 6 (9.6%) had segmental duodenal resection for Spigelman stage III–IV disease. Of the 57 patients that underwent pancreas-sparing duodenectomy or pancreaticoduodenectomy, 10% were found to have adenocarcinoma on surgical pathology. There were no significant differences in postoperative complications (i.e., biliary fistula, pancreatic fistula, infection, pancreatitis, delayed gastric emptying) across the three surgical procedure groups. The median recurrence-free survival was 15.6  years [44]. The results from this large case series highlight the need for close

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surveillance for patients with duodenal polyps and timely referral to centers with expertise in endoscopic and surgical resection of such polyps.

Chemoprevention Given the associated morbidity and cancer-related mortality in FAP, efforts to identify medications that are effective for chemoprevention for FAP-associated neoplasia are ongoing. Initially studied for their effects on the prevention of colon polyp formation, several mechanisms of chemoprevention have also been studied for upper GI tract polyps in FAP.

Sulindac Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) that was first shown to reduce colorectal polyp burden in FAP patients in 1983 [45, 46]. The mechanism of action of sulindac is based on the loss of tumor suppressor activity with the APC mutation in FAP that has been shown to be associated with an increase in cyclooxygenase-2 (COX-2) expression [47]. Sulindac inhibits COX-2 expression, reducing colorectal adenoma formation, and has been approved by the Food and Drug Administration (FDA) for FAP patients. However, despite its effects in the colon, sulindac used as a single agent has been shown to have limited efficacy in reducing duodenal adenoma formation [48, 49]. Sulindac has also been studied in combination with other agents. Seow-Choen et  al. combined sulindac with calcium and calciferol; however, they found no significant change in duodenal polyposis after 6 months of treatment [45, 50].

Celecoxib Celecoxib, which is also an NSAID and selective COX-2 inhibitor, has also been studied for treatment of FAP-associated

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duodenal polyposis. Celecoxib briefly had FDA approval for this indication based on a randomized controlled trial that demonstrated that celecoxib at a dose of 400  mg twice daily was associated with a 31% reduction in duodenal polyposis as compared to placebo [51]. However, the emergence of data demonstrating increased cardiovascular risks led the FDA to withdraw its approval for use in polyp chemoprevention for FAP patients.

Agents Under Investigation Erlotinib, a tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR), has shown promising results recently. Samadder et al. randomized FAP patients to receive the combination of sulindac plus erlotinib versus placebo for 6  months. Though the trial was stopped early due to adverse events (acne-­ like rash) in a large proportion of patients, they found a significant decrease in the duodenal polyp burden (number and median size of polyps) among patients in the sulindac plus erlotinib arm compared to placebo [52]. Another clinical trial investigating the effectiveness of lower-dose erlotinib as a single agent is currently ongoing. Eflornithine, which irreversibly binds to ornithine decarboxylase (ODC), is also being studied currently. APC suppresses oncogenes (i.e., MYC) that regulate expression of the enzyme ODC.  This enzyme mediates polyamine production [53, 54]. ODC and polyamine levels are increased in FAP patients’ colonic mucosa; therefore, polyamine reduction has been proposed as a mechanism to reduce progression of colorectal adenomas in FAP.  Eflornithine has been shown to reduce the incidence of colorectal polyps in mouse models [55, 56], and a randomized trial found the combination of eflornithine with sulindac reduced recurrence of adenomas in humans with sporadic polyps. Results of a phase III trial comparing the efficacy of eflornithine with and without sulindac on colorectal and duodenal polyposis in FAP patients are expected soon [57].

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Summary With improved management of colorectal adenomas, we have seen a reduction in CRC incidence and mortality in FAP patients. As survival for FAP patients improves, effective management of upper GI tract polyps is increasingly important. To ensure continued effective surveillance, FAP patients should be under the care of gastroenterologists and/or surgeons with specific expertise in management of gastric, duodenal, and ampullary neoplasia. Given increased risks for gastric and duodenal cancers, and the potential morbidity associated with surgery for severe upper GI tract polyposis, endoscopic surveillance, early recognition and resection of advanced lesions, and chemoprevention offer opportunities to manage upper GI tract polyp burden for FAP patients.

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37. Yaguchi K, Makazu M, Hirasawa K, Sugimori M, Kobayashi R, Sato C, et al. Familial adenomatous polyposis with multiple helicobacter-­negative early gastric cancers treated by endoscopic submucosal dissection. Intern Med. 2017;56:3283–6. 38. Jaganmohan S, Lynch PM, Raju RP, Ross WA, Lee JE, Raju GS, et al. Endoscopic management of duodenal adenomas in familial adenomatous polyposis—a single-center experience. Dig Dis Sci. 2011;57:732–7. 39. Rejeski JJ, Kundu S, Hauser M, Conway JD, Evans J, Pawa R, et  al. Characteristic endoscopic ultrasound findings of ampullary lesions that predict the need for surgical excision or endoscopic ampullectomy. Endosc Ultrasound. 2016;5:184–5. 40. Palma GDD.  Endoscopic papillectomy: indications, techniques, and results. World J Gastoenterol. 2014;20:1537–43. 41. Patel R, Varadarajulu S, Wilcox CM.  Endoscopic ampullectomy: techniques and outcomes. J Clin Gastroenterol. 2012;46:8–15. 42. Ma T, Jang EJ, Zukerberg LR, Odze R, Gala MK, Kelsey PB, et  al. Recurrences are common after endoscopic ampullectomy for adenoma in the familial adenomatous polyposis (FAP) syndrome. Surg Endosc. 2014;28:2349–56. 43. Moussata D, Napoleon B, Lepilliez V, Klich A, Ecochard R, Lapalus M-G, et  al. Endoscopic treatment of severe duodenal polyposis as an alternative to surgery for patients with familial adenomatous polyposis. Gastrointest Endosc. 2014;80:817–25. 44. Augustin T, Moslim MA, Tang A, Walsh RM. Tailored surgical treatment of duodenal polyposis in familial adenomatous polyposis syndrome. Surgery. 2018;163:594–9. 45. Lynch PM.  Chemoprevention of familial adenomatous polyposis. Familial Cancer. 2016;15:467–75. 46. Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. NEJM. 1993;328:1313–6. 47. Eisinger AL, Prescott SM, Jones DA, Stafforini DM. The role of cyclooxygenase-­2 and prostaglandins in colon cancer. Prostaglandins Other Lipid Mediat. 2007;82:147–54. 48. Nugent KP, Farmer KC, Spigelman AD, Williams CB, Phillips RK.  Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg. 2019;801:1618–9. 49. Debinski HS, Trojan J, Nugent KP, Spigelman AD, Phillips RKS. Effect of sulindac on small polyps in familial adenomatous polyposis. Lancet. 1995;345:855–6. 50. Seow-Choen F, Vijayan V, Keng V.  Prospective randomized study of sulindac versus calcium and calciferol for upper gastrointestinal polyps in familial adenomatous polyposis. Br J Surg. 1996;83:1763–6.

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51. Phillips R, Wallace MH, Lynch PM, Hawk E, Gordon GB, Saunders BP, et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut. 2002;50:857–60. 52. Samadder NJ, Neklason DW, Boucher KM, Byrne KR, Kanth P, Samowitz W, et al. Effect of sulindac and erlotinib vs placebo on duodenal neoplasia in familial adenomatous polyposis. JAMA. 2016;315:1266–21. 53. Paz EA, Garcia-Huidobro J, Ignatenko NA. Polyamines in cancer. 1st ed. Adv Clin Chem. 2011;54:45–70. 54. Babbar N, Gerner EW. Targeting polyamines and inflammation for cancer prevention. Recent Results Cancer Res. Berlin, Heidelberg: Springer Berlin Heidelberg. 2011;188:49–64. 55. Ignatenko NA, Besselsen DG, Stringer DE, Blohm-Mangone KA, Cui H, Gerner EW. Combination chemoprevention of intestinal carcinogenesis in a murine model of familial adenomatous polyposis. Nutr Cancer. 2008;60:30–5. 56. Meyskens FL Jr, McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res. 2008;1:32–8. 57. Burke CA, Dekker E, Samadder NJ, Stoffel E, Cohen A.  Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a randomized, double-blind, Phase III trial. BMC Gastroenterol. 2016;16:1–9.

6

Desmoids in Familial Adenomatous Polyposis Susan K. Clark

What Are Desmoids? Desmoids are thought to arise from myofibroblasts and have been described as fibroblastic tumours and also as a type of fibromatosis (similar to Dupuytren’s contracture) [1]. They appear to be truly neoplastic and in FAP have been found to contain clones of cells with somatic mutation of wild-type APC. In this respect they seem to arise by a process similar to carcinogenesis, with inherited loss of function of one copy of the APC tumour suppressor gene (the germline mutation present in every cell of the patient’s body resulting in FAP) and subsequent somatic mutation or loss of the single normal (wild-type) APC allele in a cell triggering neoplasia. Although the underlying mechanism of desmoid formation seems to involve tumour suppressor gene inactivation, desmoids do not metastasise [1]. They do, however, have infiltrative and indistinct margins, appearing to invade locally. Complete excision can be difficult to identify and achieve, although it is unclear how S. K. Clark (*) The Polyposis Registry, St Mark’s Hospital, Harrow, UK e-mail: [email protected]

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important that is. It is likely that many ‘recurrences’ are actually new desmoid occurring as a result of the trauma of excision, and many undoubtedly incompletely excised desmoids do not regrow.

Epidemiology Overall, desmoids are very rare, accounting for only about 2% of soft tissue tumours and arising with an annual incidence of two to four per million of the population [2]. About 10% occur in individuals with FAP, and 90% are sporadic.

Desmoids in FAP The proportion of patients with FAP who develop overt desmoid is 10–20%, although clinically unsuspected disease is more often encountered on cross-sectional imaging or at surgery. Patients with FAP are at 1000-fold higher risk of developing desmoid than the general population [2]. The commonest presentation is in young adults within a few months or a few years after prophylactic surgery, the trauma of which is probably the initiating factor in the formation of the majority of FAP-associated desmoids. Desmoid disease can, however, arise apparently spontaneously prior to surgery or any other clear traumatic insult [3]. Desmoid can occur in very young children with FAP and has been reported as the first manifestation of the condition in an individual or family [4]. One of the major difficulties in interpreting the literature on desmoids arising in patients with FAP is that many series and reports contain cases of both sporadic and FAP-associated desmoids and desmoids at various anatomical sites. This causes confusion because, although there are many similarities between FAP-associated and sporadic desmoids, there are also important differences in underlying biology, anatomical distribution, and behaviour following treatment. This chapter will focus in desmoids arising in the context of FAP.

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Desmoid Formation Desmoid is thought to arise due to disturbance of the Wnt signalling pathway. Activation of Wnt signalling results in elevated levels of beta-catenin in the cytoplasm, which then enters the nucleus and activates processes resulting in cell division [1]. Sporadic desmoids are characterised by somatic mutation of the CTNNB1 gene, which codes for beta-catenin. Patients with FAP have inherited a germline mutation in one copy of the APC gene, which codes for a key component of Wnt signalling; desmoids arising in FAP have been found to have lost the remaining normal copy of the gene. Thus both sporadic and FAP-­associated desmoids arise from disturbance of the same signalling pathway but by different mechanisms. About 70% of FAP-associated (in contrast to sporadic) desmoids occur within the abdomen, and most of these are within the small bowel mesentery. The next commonest site is the abdominal wall. Desmoids have also been reported at virtually every other anatomical location, but the paraspinous muscles and thoracic wall seem to be particularly frequent sites [2]. Intra-abdominal desmoids are thought to begin as small plaque-like areas of peritoneal thickening [5]. Some, but by no means all, of these plaques progress to fibromatosis of the small bowel mesentery (mesenteric fibromatosis). This is localised or generalised thickening and puckering of the small bowel mesentery which draws in loops of small bowel, reducing mobility and sometimes causing bowel perforation and obstruction, and encases blood vessels. Some of these areas of mesenteric fibromatosis progress further to form a frank mass (Fig. 6.1).

Growth and Progression One of the challenges when managing patients with desmoid is that they exhibit very variable and unpredictable behaviour. About 50% remain stable once they have become apparent; 30% undergo cycles of growth and resolution; 10% have been reported to

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Fig. 6.1  A typical small bowel mesenteric desmoid

regress spontaneously. About 10% grow relentlessly and cause really very major clinical problems, sometimes even death [6]. The effects that a desmoid has depend very much on location, and the preponderance of intra-abdominal desmoid in FAP contributes to the particularly severe problems associated with them.

Risk Factors for Desmoid Formation There have been a number of studies examining risk factors for desmoid formation in patients with FAP, and a recent meta-­ analysis of these [7] summarises them.

Genetic There is a distinct genotype-phenotype correlation with respect to the APC gene, in that people who have FAP as a result of an APC mutation 3′ of codon 1400 (or thereabouts) appear to be at an increased risk of desmoid compared with those who have a

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g­ ermline mutation elsewhere in the gene [2]. Having a germline mutation in the 3′ of the APC gene gives an odds ratio of 4.37 (95% CI 2.14–8.91) of desmoid formation compared with mutation elsewhere [3]. Over 40% of patients with germline mutation beyond codon 1444 have multiple desmoids compared with less than 10% of patients with a more 5′ mutation. The strongest risk factor of all is having a family history of desmoid independent of the site of the germline APC mutation in the family. This results in an odds ratio of 7.02 (95% CI 4.15– 11.9) [3] and is likely to be due to the action of a modifier gene in some families; to date attempts to identify such a gene have not been successful.

Gender Sporadic desmoid appears more common in women than in men, though this difference is less marked in FAP. Sinha et al. [3] found an odds ratio of 1.57 (95% CI 1.13–2.18) in females compared to males. This difference is thought to be due to the influence of oestrogens, supported by the observation that sporadic desmoids often appear during pregnancy and anecdotal reports of effective treatment with anti-oestrogens. Trauma There have been reports of desmoids occurring apparently spontaneously, but most are found at sites of trauma. Of course, virtually every patient with FAP will undergo the trauma of prophylactic surgery in adolescence or early adulthood. This probably influences the presentation of desmoid in the months and, few years following this surgery, may also explain why a much greater proportion FAP-associated desmoids are found within the abdomen than is the case for those arising sporadically. The risk of desmoid in those who have had previous abdominal surgery compared with those who have not has an odds ratio of 3.35 (95% CI 1.33–8.41) [3]. Desmoid formation has also been reported after accidental trauma or at the site of other surgery, including caesarean section, nephrostomy insertion, sinus surgery, and mandibular osteoma excision.

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I nterrelationship Between Desmoids and Surgery There is a complex interrelationship between desmoids and surgery in individuals with FAP: surgery, which virtually all of these patients require to prevent colorectal cancer, seems to be the commonest trigger of desmoid formation; in some high-risk individuals, desmoid can occur before any surgery is undertaken and can make prophylactic surgery extremely difficult; a more frequent scenario is a patient who has had prophylactic surgery, following which desmoid has occurred, rendering further surgery (such as duodenectomy or completion proctectomy) challenging or even impossible. Most patients with FAP undergo prophylactic colectomy with ileorectal anastomosis (IRA) or restorative proctocolectomy (RPC). There is some controversy regarding the choice between these procedures, but many major centres adopt a selective approach, recommending IRA for those with a relatively light colorectal polyp burden, and RPC for those with endoscopically unmanageable rectal disease, a heavier polyp burden (over 500 colonic adenomas or 20 rectal adenomas), or a genotype predicting more severe disease (mutation between codon 1250 and 1350 of the APC gene) [7–9]. The aim is to prevent colorectal cancer while sparing otherwise healthy adolescents the risks of pelvis surgery or the need for a stoma and obtaining the best functional outcome. There is good evidence that performing IRA laparoscopically rather than open, as well as the other associated advantages, reduces the risk of subsequent desmoid formation [9–11]. This is not surprising, as a laparoscopic procedure results in less extensive abdominal wounds and subjects the peritoneal content to less handling, cooling and drying than an open operation. There is also some evidence that RPC results in more desmoid formation than IRA [9, 12]. This may be due to the longer incision, additional dissection required to remove the rectum and mobilise the small bowel into the pelvis, and creation of a defunctioning ileostomy. What is rather more surprising is that it seems

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RPC performed laparoscopically is associated with a higher rate of subsequent desmoid formation than any other procedure [9]. While this seems counterintuitive, there is building evidence of this from the Cleveland Clinic [12], the largest volume FAP centre worldwide, which is sufficiently compelling that at the author’s institution RPC is avoided if at all possible in individuals with high risk of desmoid (personal or strong family history of desmoid or germline APC mutation beyond codon 1400); if there is a rectal polyp burden mandating it, the operation is performed open rather than laparoscopically in this group. One study has shown reduced risk of subsequent desmoid formation if prophylactic surgery is delayed [13]. Prophylactic surgery is usually undertaken in late teenage years, to ensure that it is done before cancer can develop, and so that it can be planned at a time when it is least socially and educationally disruptive [7]. Patients who have elevated risk of desmoid because of a germline APC mutation beyond codon 1400 of the APC gene usually also have an attenuated colorectal phenotype which may make it safe to defer surgery for some years and minimise the risk of desmoid formation in response. It is probably advisable to attempt to delay surgery in others with a high risk of desmoid (due to a strong family history or pre-existing desmoid in the patient), although the colorectal adenoma burden may preclude it. It is also sensible to obtain cross-sectional imaging prior to surgery in individuals in these high-risk groups, to aid decision-­ making and planning; the presence of unexpected small bowel mesenteric desmoid can make ileoanal pouch formation impossible, for example. If further abdominal surgery of any kind is being contemplated in someone who has already undergone initial operation for FAP, it is important that cross-sectional imaging is performed, even if there is no overt clinical evidence of desmoid. Mesenteric fibromatosis or even a small desmoid mass may prevent Roux loop reconstruction following duodenectomy or prevent an ileoanal pouch reaching the pelvic floor following completion ­proctectomy.

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Diagnosis Apparently Sporadic Desmoid The likelihood of someone without FAP developing a sporadic desmoid is a great deal lower than that of a patient with FAP developing desmoid, even though the vast majority of desmoids are sporadic. The two key issues in someone not thought to have FAP who develops a mass compatible with desmoid are to confirm the diagnosis and ensure that this is not actually a presentation of FAP. In most cases patients present with a mass which is biopsied to exclude alternative diagnoses such as sarcoma. Some malignancies are surrounded by desmoplastic reaction, indistinguishable histologically from desmoid, so biopsies should be interpreted with caution. The finding of CTNNB1 mutation within a desmoid is essentially diagnostic of sporadic desmoid; it is not present in low-grade sarcomas and not present in FAP-associated desmoids. In this scenario no further action is needed with regard to excluding FAP, and the patient is usually best managed by a sarcoma unit. In the situation where a lesion is thought to be a desmoid, but there is no CTNNB1 mutation identified within it, careful thought should be given as to whether or not the patient has FAP. A family history should be taken, focusing on cases of colorectal cancer or desmoid; the patient should be questioned about gastrointestinal symptoms and other extra-intestinal manifestations of FAP (such as osteomas and epidermoid cysts) and carefully examined for such features. A colonoscopy should be performed – but it is important to bear in mind that mutation in the far 3′ end of the APC gene result in high risk of desmoid accompanied by an often markedly attenuated colorectal phenotype, with very late onset of scanty adenomas. Thus colonoscopy should be done carefully, with high-quality preparation and chromoendoscopy, and biopsies taken to identify microadenomas; this should not be done before the age of 12–15  years unless there are gastrointestinal symptoms. If such a colonoscopy is normal, it is probably prudent to repeat it at five yearly intervals

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until the patient is well into middle age. Genetic testing in an attempt to identify an inherited APC mutation is only helpful if an undoubtedly pathogenic mutation is found; mutation detection is unsuccessful in a small proportion of patients with undoubted FAP, so absence of a mutation cannot exclude the condition, and the finding of variants of unknown significance can simply add to the confusion.

Desmoid in Patients with FAP The situation is very different in a patient with FAP, in whom a mass that has typical clinical behaviour and imaging appearances of a desmoid is highly likely to be one, and biopsy is usually not required. The presentation, treatment options, and outcome related to a desmoid depend in large part upon its anatomical site. Most patients present with a lump, but symptoms of bowel obstruction, or even peritonitis, can be the first manifestation.

Imaging Imaging has several purposes in the management of desmoid. The first is to make a diagnosis and examine the anatomy of the desmoid with respect to its size and neighbouring structures. In addition, there has been some suggestion that imaging can be used to predict growth. CT has been the mainstay, but in terms of detail and image quality, MRI is now marginally better [14]. MRI has a possible additional benefits. There is some evidence that high image intensity on T2-weighted sequences (reflecting high water content due to high cellularity) is associated with subsequent growth [15]. Patients with desmoid often undergo repeated imaging and can accumulate quite high radiation doses, which can be limited by using MRI. It should be borne in mind that it can be quite difficult to assess the growth of a desmoid when sequential scans are been done using different imaging modalities.

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FDG-PET scanning has been explored as a means of predicting growth. Undoubtedly some desmoids are FDG avid and there have been reports of this causing confusion during cancer follow­up in patients with FAP, with FDG avid desmoid being incorrectly interpreted as recurrent cancer. There is some preliminary evidence that desmoids which are actively growing are more likely to be FDG avid than those that are quiescent, offering a potential tool for growth prediction, although considerable further work needs to be done [16]. A common effect of intra-abdominal desmoid is ureteric obstruction, and regular monitoring of the renal tract using ultrasound scanning is useful to avoid missing silent obstruction and also to minimise radiation dose [17].

Treatment Drug Treatment A vast range of drugs has been used in the treatment of desmoids. There are numerous case reports and very small series in the published literature [2], but no randomised controlled trial has been undertaken in the treatment of desmoid. Most publications mix FAP-related and sporadic desmoids, as well as including desmoids at a variety of anatomical sites, and few used any objective measure of disease volume. Given the variable natural history, these are obviously very major flaws, and most of the largest series published have outcomes that are very similar to what would be expected if the desmoids were not treated at all; cessation of growth, slight decrease in size, and complete resolution have all been interpreted as treatment success, even though all of these occur spontaneously in a significant proportion of untreated desmoids [6]. The drugs in most widespread use are non-steroidal anti-­ inflammatories (in particular sulindac) and anti-oestrogens [2]. In this latter category, high-dose tamoxifen was originally used, but toremifene can be given at higher doses with fewer adverse effects, particularly nausea. Raloxifene [18] has an even better

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side effect profile, with a lower risk of endometrial cancer and cataracts, and is the preferred agent at the author’s institution. There is anecdotal evidence of commencement of anti-oestrogen therapy being fairly rapidly followed by desmoid necrosis, suggesting that it may well have an effect in some cases. Although there is no level I, and very limited level II, evidence to support drug treatment, the adverse effects of these agents are usually mild, and given the limited options available, it is difficult to avoid starting some form of drug therapy if a patient has a troublesome desmoid [2].

Cytotoxic Chemotherapy There is some evidence that cytotoxic chemotherapy can cause desmoids to regress, at least in the short to medium term, although the adverse effects can be significant. In some cases of relentlessly growing desmoid which cannot be safely removed surgically or is multifocal, but has not caused sepsis or fistulation, such treatment is reasonable. A number of different drugs and drug combinations have been used, but methotrexate with vincristine or vinblastine [19] and doxorubicin with dacarbazine [20] are the best documented.

Other Treatments There has been some recent interest in imatinib and similar agents, but in reported series mix FAP-associated and sporadic desmoids are uncontrolled, so once again there is no good evidence of efficacy.

Surgery Once again, there are a number of small series of the literature, usually mixing sporadic and FAP-associated desmoids and desmoids at various sites. There are really two difficulties with surgery. The first is that depending on the anatomical location,

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surgery can involve considerable damage to neighbouring structures resulting in significant morbidity. The other major issue is that a desmoid can recur, or new desmoid occurs, as a result of the trauma of surgery. Abdominal wall desmoids can often be excised relatively safely [2], although careful assessment is needed to ensure that bowel is not adherent to the deep aspect. The use of mesh to repair the abdominal wall does not seem to be associated with an increased risk of recurrence or excess complications. Recurrence rates have been reported in the region of 40–60% [2]; further excision can be a successful. Generally excision of abdominal wall desmoid is relatively safe, and although there is a high recurrence rate, it is probably the best way to treat these lesions if they are causing symptoms. Excision of intra-abdominal desmoid is a very different situation, as the majority occur in the small bowel mesentery and encase the superior mesenteric artery to a variable extent. This means that excision usually involves removal of a significant part, if not all, of the small bowel, and major haemorrhage can be difficult to prevent and control [2]. Early reports documented very high perioperative mortality of up to 35%, mostly due to bleeding. In addition, a high proportion of patients required subsequent long-term parenteral nutritional support. Later reports from specialist centres have shown better results, probably due to a combination of careful case selection and preparation, surgeons with experience of operating for desmoid, and better long-term nutritional support. In view of the risk of significant small bowel loss, surgery is usually avoided as a first-line treatment in FAP-­associated desmoid involving the small bowel mesentery and is reserved for patients with desmoids which are rapidly growing or causing sepsis or other complications. Careful preoperative imaging with particular reference to the origin of the superior mesenteric artery can be very useful in establishing the extent of small bowel resection that is likely to result. Over the last few years small bowel, small bowel and abdominal wall or multivisceral transplant has been undertaken with success in patients with FAP.

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Other Therapies Gene therapy has been investigated with little success. Various substances, including ethanol and interferons have been injected into desmoids, but given the tiny numbers reported and the natural history of the disease, it is impossible to tell if there is any effect. There have been some reports of success using radiofrequency ablation for abdominal wall and extra-abdominal desmoids. These are hard to interpret, but provided structures such as bowel are not in close proximity this is a minimally invasive and safe treatment that may have a role. Radiotherapy is used, often in combination with surgery, in the treatment of sporadic desmoids, to reduce recurrence rates. Its use in patients with FAP is very limited, however, because most desmoids are within the abdomen or in the abdominal wall, where the proximity of the small bowel precludes its use [2].

Treatment Strategy Guidelines for the management of FAP have been produced by a number of national and international bodies, but most make little mention of desmoid, and all are based on the same extremely limited literature. The main challenge is to identify the minority of life-threatening, relentlessly growing desmoids from the majority which will be nothing more than an inconvenience, and avoid harming the patients with the latter. More active monitoring and aggressive treatment is justified for the former group, which ideally should be commenced before the desmoid has reached a size where the patient is too sick or the tumour is too large for effective treatment to be possible. A staging system for desmoids, based on size, symptoms, and growth rate, has been proposed [21]. This can be useful to aid distinguishing harmless desmoids from those that require active treatment, best provided in a specialised centre with experience of dealing with this challenging clinical problem. The management protocol for desmoids used in the author’s institution is outlined below and in Fig. 6.2.

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116 Clinically relevant solitary1 desmoid tumour

Abdominal wall or extraabdominal tumour: have a low threshold for surgery Assess - can tumour be safely resected? Yes

No

Surgery

Intra-abdominal tumour: usually high threshold for surgery

Assess - CT and biopsy to determine anatomy, MRI to determine potential behaviour If ureteric involvement refer to urology for stenting Even if negative, reassess ureters six monthly with ultrasound

Start sulindac2 200mg bd for 6 months then reassess

No tumour progression

Tumour progression Add Raloxifene 120mg per day for 6 months then reassess Tumour progression

No tumour progression

Reassess for surgery. For mesenteric tumour, surgical consideration is relationship to SMA and likelihood of massive small bowel resection Clearly inoperable Operable Refer for cytotoxic chemotherapy. doxorubicinbased or ‘low-dose’ with vinblastine and methotrexate

Maintain on sulindac

Surgery

Maintain on sulindac and antioestrogen Equivocal / only with massive small bowel resection Refer for cytotoxic chemotherapy but be prepared to reconsider surgery

Fig. 6.2  St. Mark’s Hospital Polyposis Registry management algorithm for desmoid. (1) In the case of multiple tumours, the balance of treatment is adjusted towards pharmacological management and away from surgery, particularly in individuals at known high risk of developing further or recurrent tumours (3′ germline APC mutation, strong family history). (2) If unable to tolerate sulindac consider switching to raloxifene

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 bdominal Wall and Extra-Abdominal Desmoid A If a patient presents with a symptomatic abdominal wall or extra-­ abdominal desmoid, the threshold for surgery is low and surgery is usually considered the first-line therapy. If a troublesome desmoid can safely be resected, surgery should be recommended. If it is felt that surgical excision would be difficult because of the anatomical location or the resulting defect, then we recommend starting sulindac 200 mg twice a day. The patient is reassessed after 3–6 months both clinically and using cross-sectional imaging. If the desmoid continues to grow, careful thought needs to be given to whether resection should be undertaken after all, because if the desmoid continues to grow, the difficulties associated with surgery may simply increase. If it is still considered that surgery is not appropriate or can be further deferred, raloxifene 120 mg daily is added and then further reassessment undertaken at 3–6 months. If the desmoid continues to grow further, consideration should be given again to surgery, and if this really still does not seem to be a reasonable option, then cytotoxic chemotherapy or alternative treatments such as radiofrequency ablation can be considered. Intra-abdominal Desmoid If a desmoid is predominantly intra-abdominal, surgery is usually avoided if at all possible. If there is ureteric obstruction, the patient needs to be referred to a urologist for stenting. The urinary tract needs to be evaluated for obstruction initially every 6 months and then annually once the desmoid is stable. The first-line treatment is sulindac 200 mg twice daily with further assessment after 3–6 months. If the desmoid has stopped growing, the medication is continued, although there is absolutely no evidence on which to base a judgement on how long this should go on. It does seem reasonable to try stopping therapy if the desmoid has remained stable for a year or two. If the desmoid continues to grow, raloxifene 120 mg daily is added and the patient reassessed. Once again, if the situation is stable, the medication is continued with consideration given to

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reduction or withdrawal after 1–2  years. If an abdominal desmoid is clearly continuing to grow, it is important to refer to an oncologist for consideration of cytotoxic chemotherapy, which has shown good evidence of effect at least in the short to medium term. This needs to be given before the desmoid results in bowel fistulation or necroses and causes sepsis, which of course is a contraindication to chemotherapy. If there is sepsis present, or chemotherapy is for some other reason contraindicated, but the desmoid is clearly growing, then surgery may be the only option, even though it may well result in extensive small bowel loss and the need for either long-term parenteral nutrition or small bowel transplantation.

Multiple Sites Desmoids are often multiple, being present in several sites. In these cases the balance of treatment is adjusted towards pharmacological management, but each individual desmoid needs to be treated on its own merits, and there is no reason why a patient with multiple desmoids should not undergo excision of one isolated to the abdominal wall while undergoing drug treatment or even chemotherapy for an intra-abdominal desmoid.  cute Presentation of Intra-abdominal Desmoid A A relatively common presentation of intra-abdominal desmoid is with central necrosis resulting in sepsis [22]. It is not clear how this situation arises but it is probably due to central necrosis and liquefaction of a rapidly growing desmoid which outstrips its blood supply. Because bowel is frequently drawn into the desmoid, there can be associated communication with the bowel lumen, or the necrotic centre can become infected by bacterial translocation. An algorithm for managing this scenario is shown in Fig. 6.3 [22]. The first important step is to control sepsis. In a few cases this can simply be done with antibiotics. More often, percutaneous drainage is required. This can usually be achieved with radiological guidance (Fig. 6.4), but sometimes the drain that is inserted is too fine to provide adequate drainage. Sometimes the extremely

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Symptomatic IAD with AFL

Generalized peritonitis

Yes

No

IV antibiotics

Surgery (excision or drainage ± defunctioning) No

Yes

Is IAD multiloculated or solid rim > 2 cm or difficult location/access

Resolution of symptoms

Yes No

Outpatient follow-up

USS or CT-guided percutaneous drainage

No

Resolution of symptoms

Yes

Fig. 6.3  Management algorithm for intra-abdominal desmoids with air-fluid levels. IAD intra-abdominal desmoid, AFL air-fluid level, USS ultrasound scan, IV intravenous. (Reproduced from [22] with permission)

fibrous desmoid tissue surrounding the central necrosis is simply too tough to allow a radiological drain to be placed. Under these circumstances it can be helpful to use cross-sectional imaging to plan an access route and then to insert a drain in the operating theatre under general anaesthetic, sometimes using a small abdominal incision directly over an access point to the desmoid or occasionally requiring a laparotomy. If drainage alone will not control the situation, or the desmoid is clearly communicating with the lumen of the bowel or there is a complete bowel obstruction, then a laparotomy to raise a stoma proximal to the desmoid is the next step. This can be an extremely technically difficult operation as there is often very limited mobil-

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Fig. 6.4  CT scan showing small bowel mesenteric desmoid with central necrosis and air-fluid level (arrow) and percutaneous drain

ity of the small bowel, and particularly in the obese patient it can even be impossible to create a stoma upstream of the desmoid. When it can be achieved, it often results in a proximal stoma with high output and the need for intravenous fluid and nutritional support.

Challenges We can to an extent identify groups at high risk and make efforts to ensure that surgery in them is delayed and minimises the risk of desmoid. Prevention, perhaps using drugs, is an attractive prospect, but currently unsupported by any evidence. Likewise there is no evidence that screening all patients with FAP for desmoid is helpful; many will have subclinical desmoid, and this will result in increased anxiety for no gain, given that many desmoids do not require treatment and there is so little evidence on which to base treatment when it is required. Better techniques to distinguish stable or only very slowly growing desmoids from those that are fast growing and rapidly

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life-threatening, to allow timely and appropriately aggressive treatment when required, would be enormously helpful. High-­ quality trials of treatment need to be carefully designed and done over many centres in order to include sufficient numbers. This is only likely to occur through national and international groups such as the Collaborative Group of the Americas on Inherited Colorectal Cancer (CGA) or the International Society for Gastrointestinal Hereditary Tumours (InSiGHT).

References 1. Zippel DB, Temple WJ. When is a neoplasm not a neoplasm? When it is a desmoid. J Surg Oncol. 2007;95:190–1. 2. Sturt NJH, Clark SK. Current ideas in desmoid tumours. Familial Cancer. 2006;5:275–85. 3. Sinha A, Tekkis PP, Gibbons DC, Phillips RK, Clark SK.  Risk factors predicting desmoid occurrence in patients with familial adenomatous polyposis: a meta-analysis. Color Dis. 2011;13:1222–9. 4. Clark SK, Pack K, Pritchard J, Hodgson SV. Familial adenomatous polyposis presenting with childhood desmoids. Lancet. 1997;349:471–2. 5. Clark SK, Smith TG, Katz DE, Reznek RH, Phillips RK. Identification and progression of a desmoid precursor lesion in patients with familial adenomatous polyposis. Br J Surg. 1998;85:970–3. 6. Church JM. Desmoid tumours in patients with familial adenomatous polyposis. Semin Colon Rectal Surg. 1995;6:29–32. 7. Tudyka VN, Clark SK. Surgical treatment in familial adenomatous polyposis. Ann Gastroenterol. 2012;25:201–6. 8. Sinha A, Tekkis PP, Rashid S, Phillips RKS, Clark SK. Risk factors for secondary proctectomy in patients with familial adenomatous polyposis. Br J Surg. 2010;97:1710–5. 9. Chittleborough TJ, Warrier SK, Heriot AG, Kalady M, Church J. Dispelling misconceptions in the management of familial adenomatous polyposis. ANZ J Surg. 2017 7;253:661–5. 10. Vitellaro M, Bonfanti G, Sala P, et al. Laparoscopic colectomy and restorative proctocolectomy for familial adenomatous polyposis. Surg Endosc. 2010;25:1866–75. 11. Sinha A, Burns EM, Latchford A, Clark SK. Risk of desmoid formation after laparoscopic versus open colectomy and ileorectal anastomosis for familial adenomatous polyposis. BJS Open. 2018;3:121–4. 12. Vogel JD, Church JM, LaGuardia L. Minimally invasive pouch surgery predisposes to desmoid tumor formation in patients with familial adenomatous polyposis. Dis Colon Rectum. 2005;48:662–3.

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13. Durno C, Monga N, Bapat B, Berk T, Cohen Z, Gallinger S. Does early colectomy increase desmoid risk in familial adenomatous polyposis? Clin Gastroenterol Hepatol. 2007;5:1190–4. 14. Sinha A, Hansmann A, Bhandari S, Gupta A, Burling D, Rana S, et al. Imaging assessment of desmoid tumours in familial adenomatous polyposis: is state-of-the-art 1.5 T MRI better than 64-MDCT? Br J Radiol. 2012;85:e254–61. 15. Healy JC, Reznek RH, Clark SK, Phillips RK, Armstrong P. MR appearances of desmoid tumors in familial adenomatous polyposis. AJR Am J Roentgenol. 1997;169:465–72. 16. Bhandari S, Taylor NJ, Sinha A, Sonoda L, Sanghera B, Wong WL, et al. Can combined 18F-FDG-PET and dynamic contrast-enhanced MRI predict behavior of desmoid tumors in patients with familial adenomatous polyposis? Dis Colon Rectum. 2012;55:1032–7. 17. Walton SJ, Malietzis G, Clark SK, Havranek E. Urological sequelae of desmoids associated with familial adenomatous polyposis. Familial Cancer. 2018;77:665. 18. Tonelli F, Ficari F, Valanzano R, et al. Treatment of desmoids and mesenteric fibromatosis in familial adenomatous polyposis with raloxifene. Tumori. 2003;89:391–6. 19. Azzarelli A, Gronchi A, Bertulli R, Tesoro JD, Baratti D, Pennacchioli E, et  al. Low-dose chemotherapy with methotrexate and vinblastine for patients with advanced aggressive fibromatosis. Cancer. 2001;92:1259–64. 20. Schnitzler M, Cohen Z, Blackstein M, Berk T, Gallinger S, Madlensky L, et al. Chemotherapy for desmoid tumors in association with familial adenomatous polyposis. Dis Colon Rectum. 1997;40:798–801. 21. Church J, Berk T, Boman BM, Guillem J, Lynch C, Lynch P, et al. Staging intra-abdominal desmoid tumors in familial adenomatous polyposis: a search for a uniform approach to a troubling disease. Dis Colon Rectum. 2005;48:1528–34. 22. Bhandari S, Ranchod P, Sinha A, Gupta A, Clark SK, Phillips RKS. Familial adenomatous polyposis-related desmoids presenting with air-fluid level: a clinical review and management algorithm. Dis Colon Rectum. 2012;55:810–4.

7

Hepatoblastoma in Infants Born to Parents with Familial Adenomatous Polyposis Todd E. Heaton and Michael F. Walsh

Introduction Familial adenomatous polyposis (FAP), which is caused by an autosomal dominant alteration in the adenomatous polyposis coli (APC) gene, can be associated with a variety of extraintestinal benign and malignant lesions, including thyroid papillary carcinoma, adrenal carcinoma, periampullary carcinoma, and desmoid tumors. FAP has also been associated with an increased risk of hepatoblastoma (HB), a malignant tumor of the liver in children. HB in FAP patients represents a unique challenge, because it presents almost exclusively in patients younger than 5  years, well before intestinal manifestations of FAP occur. This chapter T. E. Heaton (*) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA e-mail: [email protected] M. F. Walsh Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA Department of Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

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describes the history, genetic basis, and treatment of HB in general and in patients with FAP and discusses the potential benefits of early genetic testing for FAP and image-based screening for HB in infants born to parents with APC gene mutations.

I ncidence of FAP in Hepatoblastoma Patients and of Hepatoblastoma in FAP Patients The incidence of HB was recently reported as 1.2–1.5 cases per million per year, a slight increase from earlier estimates of 1 case per million per year [1], and FAP occurs in 1 in every 9000–18,000 live births [2]. The first documented intersection of these disorders was reported by physicians from London in 1952 [3]: an infant with a family history of FAP diagnosed with HB.  Four more cases were reported in 1983 by Kingston et al., who went on to conclude that this association was too frequent to be explained by chance alone [4]. The bidirectional conundrum of this association became immediately apparent: if infants with HB are much more likely to have FAP than other infants, then HB survivors and their family members are at a higher risk of FAP-associated cancers, and conversely, infants of FAP families are at a much higher risk of HB than other infants. While the risk of FAP in HB survivors is a delayed phenomenon and the majority of cases can be identified before the risks of FAP manifest, HB presents much earlier than any overt signs of FAP and is immediately life-­ threatening. Understanding the association and incidence of each disorder in the patient population at risk is essential for appropriate clinical management. In order to ascertain the incidence of FAP in survivors of HB, Garber et al. identified 11 new cases of HB in patients with a family history of FAP and reviewed 14 similar cases from the literature. Of 11 survivors, 5 had congenital hypertrophy of the retinal pigmented epithelium (CHRPE), and 6 of 7 survivors evaluated for polyposis developed polyps between 7 and 25 years of age [5]. In another series, 3 of 3 HB survivors born to families with a history of FAP developed polyposis between 9 and 18 years of age [6]. A more recent literature review of HB patients with FAP

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found that 27 (96%) of 28 patients evaluated for CHRPE or polyps had abnormal findings and that all 64 patients tested had identifiable APC mutations [7]. Understandably, the vast majority of HB survivors with family histories of FAP will go on to develop FAP, which became the basis for the recommendation to screen all HB patients for a family history of polyposis and colon cancer [8]. However, these studies did not examine the incidence of FAP in an unselected group of HB patients. In 2005, the Children’s Oncology Group reported that 8 (8.6%) of 93 patients in their HB registry had family histories suggestive of FAP [9]; however, this analysis would miss patients with de novo APC mutations who lack a family history (12–40% of FAP patients). A similar German registry study performed APC germline testing on all patients and found 5 (10%) of 50 HB patients had APC mutations that would lead to FAP; 2 of the 5 patients had parents without APC mutations and proven paternity, i.e., these were de novo APC mutations [10]. In another recent study, 4 (14%) of 29 patients with apparently sporadic cases of HB were found to have FAP-­ pathogenic mutations on germline APC testing [11]. A recent comprehensive literature review identified a total of 109 cases of HB in patients with a prior or posttreatment diagnosis of FAP [7]. An early analysis by the Mayo Clinic found a 0.75% incidence of HB in children of FAP patients [12], far outstripping the incidence in the general population (1 per 100,000 live births or 1.5 per million individuals) [1]. A similar registry study from Johns Hopkins calculated the relative risk of HB in infants born to one parent with FAP to be 847 (95% confidence interval, 230–2200) times that in the general population; this study was the first to suggest the possibility of lab or image-based screening for HB in FAP kindreds [13]. More recent studies have shown a higher incidence. In fact, the most recent Mayo Clinic registry study found an overall HB incidence of 2.5% in infants born to FAP parents [14]. Another registry study found an incidence of 2.65% in infants born to FAP parents [15]. All of these reports are based on the number of infants at risk by relation to a parent with FAP, so with correction for the fact that only 50% of these infants would inherit the gene, the incidence of HB in infants with proven APC mutations would be twice as high.

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In summary, the best available data estimate the risk of a HB patient with a family history of FAP going on to develop FAP at over 90% and the overall likelihood of a survivor of sporadic HB having FAP at 9–14%, with 12–40% of those patients who develop FAP having de novo APC mutations. On the opposite side of the association, an infant born to a parent with the diagnosis of FAP would have a 0.75–2.65% risk of developing HB in the first decade of life.

 enetic Overlap Between Hepatoblastoma G and Familial Adenomatous Polyposis Childhood solid tumors in general, and HB in particular, are known to have a low number of specific genetic and chromosomal alterations in comparison to adult cancers. Like many childhood tumors, HB is driven by an imbalance of the same cellular signaling that governs the development of the organ of origin. The Wnt pathway is a major regulator of growth and development in the fetal liver, and abnormalities in Wnt signaling have been implicated in HB pathogenesis [16]. Two genes that modulate the activity of Wnt signaling in HB and mature hepatocytes are the oncogene β-catenin and the tumor suppressor APC [17]. Even without genetic sequencing, the abnormal Wnt signaling in HB is evident by immunohistochemistry showing abnormal accumulation of β-catenin in HB cells [18]. The most common cause of this imbalance is activating mutations of β-catenin, which have been found in 50–75% of HB patients [19–22]. These activating mutations result in abnormal β-catenin accumulation and Wnt activation driving cell growth. The immunolocalization of β-catenin has even been shown to vary between HB subtypes and is postulated to control the growth, invasion, and metastasis of the different HB subtypes [17]. While less commonly identified in HB, loss of the tumor suppressor activity of the APC gene has the same end effect on Wnt signaling as an activating mutation of β-catenin. The APC gene product is required for degradation of the Wnt signaling complex, and mutation or allelic loss of APC leads to similar β-catenin accumulation [23]. Although the loss of APC is a less

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common perturbation of the Wnt pathway leading to HB, it predisposes patients to abnormalities in Wnt signaling and is the likely cause of the increased risk of HB in FAP patients. While FAP can be clinically diagnosed without an APC mutation, 85–90% of patients with clinical FAP have an identifiable APC mutation on genetic testing, 12–40% of these mutations are de novo, and to date, all patients with FAP-associated HB who have undergone genetic sequencing have had an identifiable APC mutation [7, 14]. The vast majority of these mutations result in truncation of the APC protein, causing loss of APC function in the degradation of β-catenin [24, 25]. This loss of growth regulation manifests in multiple organs, leading to the FAP phenotype, with the associated increased risk of colorectal, duodenal, adrenal, and thyroid cancers and increased risk of HB. Certain manifestations of APC mutation—such as desmoid tumor, attenuated forms of FAP, and more severe forms of FAP—have been traced to specific regions on the gene [26–28]. Some early reports of APC mutations in patients with FAP-associated HB postulated that this extraintestinal manifestation of FAP may also cluster to a particular region of the gene [29], but larger analyses have shown that the risk of HB in infants of FAP kindreds cannot be predicted by the location of the APC mutation [6, 7, 9, 10]. Given these findings, any child of an FAP kindred is at risk for HB, whether the particular history is of attenuated or aggressive polyposis with or without other extracolonic manifestations. However, the risk of HB may be lower in families without an identifiable APC mutation, and HB has not been reported to be associated with other polyposis syndromes, such as juvenile polyposis, Peutz-Jeghers syndrome, and MYH-associated polyposis.

 resentation, Prognosis, and Treatment P of Hepatoblastoma HB is a disease of infancy, with a median patient age at presentation of 13–18 months and >90% of patients presenting in the first 4 years of life. The ratio of male predominance is between 1.2 to 1 and 1.9 to 1 [30–32]. HB associated with other genetic

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p­ redispositions presents significantly earlier than sporadic cases [33]; however, the epidemiology of FAP-associated HB is very similar to that of sporadic HB. The largest study to date reported a median age of onset of 20 months, with 95% 76% 57% 65–75%

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Recently, an international collaboration between the major HB cooperative treatment groups has developed. The Children’s Hepatic tumors International Collaboration (CHIC) has become a model for international data sharing and cooperation. CHIC has revised, refined, and combined the risk stratification systems previously used around the world into one universal system based primarily on the pretreatment extent (PRETEXT) of disease [36, 37]. PRETEXT staging is based on tumor imaging at diagnosis and how many of the four anatomic sections of the liver, separated by the three hepatic veins, are involved by the tumor. In PRETEXT I, only one section is involved, without crossing any veins; in PRETEXT II two sections are involved, and so on. PRETEXT also incorporates significant image-based risk factors such as vascular involvement, multifocality, extrahepatic invasion, and metastases. The benefit of this system is that the risk information is available at diagnosis and can be used to decide between levels of neoadjuvant, adjuvant, and surgical therapy. As in the previous staging system, the majority of patients present with PRETEXT III or IV tumors and survival decreases with each higher PRETEXT stage (Table 7.2) [37]. A recent European study reported that 59% of patients presented with PRETEXT III or IV tumors, overall survival for PRETEXT I–II patients was 90%, and the hazard ratios for death in patients with PRETEXT III disease and patients with PRETEXT IV disease were 1.5 and 2.2, respectively [38]. The treatment of HB has evolved remarkably over the last 30 years. Based on its universally agreed-upon risk stratification Table 7.2  Hepatoblastoma survival by PRETEXT group in patients without additional imaging, lab, or demographic risk factors

5-yr overall survival

PRETEXT I/II 92%

PRETEXT III 87%

Adapted from Czauderna et al. [36]

PRETEXT IV 77%

Any PRETEXT with metastasis 18–48%

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for HB [37], CHIC has designed the Pediatric Hepatic International Tumour Trial (PHITT; NCI 03017326), which is currently enrolling patients. The trial’s stratification is complex, but much care was taken to streamline treatment for patients with very-low-­risk disease (patients with PRETEXT I or II disease and no other risk factors who undergo upfront tumor resection), maintain high survival levels for patients with low- or intermediate-risk disease, and continue attempts to improve survival in patients with high-­risk disease (PRETEXT III and IV patients with additional risk factors and patients with metastatic disease) [37]. The recommended treatments for the different risk groups are listed in Table 7.3. The advances detailed above have greatly improved the prognosis for all patients diagnosed with HB.  However, the majority of patients still present with advanced disease and must face the long-term effects of highly aggressive treatment. Table 7.3  A simplified description of medical and surgical therapy for hepatoblastoma risk groups in the PHITT trial (NCI# 03017326) Risk group Very low

Neoadjuvant chemotherapy None

Low

2–4 cisplatin cyclesa Delayed

Intermediate 2–4 cisplatin or C5VD cyclesb High 3 cisplatin/ doxorubicin cycles with potential for morec

Surgical resection Upfront

Delayed/transplant Delayed/transplant +/− metastasectomy

Adjuvant chemotherapy 0–2 cisplatin cycles 2–4 cisplatin cycles 2–4 cisplatin or C5VD cyclesb Dependent on disease status

Response assessment after 2 cycles and resection if possible or 2 more cycles if not b Randomized to cisplatin monotherapy or C5VD (cisplatin, 5-FU, vincristine, doxorubicin) c SIOPEL 4 induction followed by response assessment and further neoadjuvant treatment according to disease status and resectability a

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 enefits of Screening for FAP in Hepatoblastoma B Patients and for Hepatoblastoma in FAP Patients Screening can help improve outcomes by early detection when the disease is more responsive to treatment. The case for screening HB patients for FAP is strong for several reasons: the low incidence of HB keeps the population in need of screening small; current genetic screening consists of a single, relatively inexpensive test; and identification of an APC mutation can benefit multiple relatives. These attributes have led to multiple recommendations over the last three decades for universal screening of HB patients for FAP [4, 6–10, 12]. The screening begins with a thorough family history to identify relatives with early-­ onset colon cancer or other FAP-associated cancers. Among HB patients with a family history of FAP (8.6% of HB patients), nearly all will develop FAP, and their family members will also require screening to identify their risk for FAP-associated cancers. Screening should be extended to all first-degree relatives of APC mutation-carrying HB patients and be performed in a timely manner, as some of the older family members are at high risk for or may already have undiagnosed cancer. However, screening only those HB patients who have a family history of FAP will miss HB patients with de novo APC mutations (12–40% of all FAP patients), whereas genetic screening of all HB survivors will definitively identify all individuals with APC mutations (10–14% of HB patients) and may prevent deaths associated with late diagnosis of FAP-associated cancer in HB survivors [7, 9–11, 14]. The costs and benefits of screening infants of FAP parents for HB are more difficult to estimate. Because of the higher incidence of FAP, a larger population would need to be screened. The testing must be repeated multiple times over the years the child remains at risk, and the benefits extend only to a small percentage of the patients screened. The risk of false positives, leading to further testing and potential overtreatment, is higher. The recent improvement in overall survival in HB patients to 70% must also be taken into account. However, the possibility of early diagnosis leading to better outcomes and decreased exposure to toxic chemotherapy

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has led multiple researchers to advocate for HB screening in infants born to FAP parents [4–7, 9, 10, 12, 14]. The 0.75–2.65% incidence of HB in infants born to a parent with FAP is similar to the incidence of HB in children with Beckwith-Wiedemann syndrome, for whom HB screening is recommended [39–41]. Clericuzio et al. reported five infants with Beckwith-Wiedemann syndrome who were screened for HB had tumors found, and all five had stage I HB, in contrast to the 55–60% rate of stage III or IV diagnosis in cases of sporadic HB [42]. Despite the availability of that model, protocols proposed for HB screening in infants born to a parent with FAP vary significantly [2, 43]. Support for HB screening in this population has increased greatly in recent years, but a uniform screening protocol and supportive evidence of early diagnosis are lacking. Currently, our institution recommends that all HB survivors undergo testing for germline APC mutations and that any first-­ degree relative of a patient with an APC mutation also be tested. Given the repercussions of late diagnosis of HB, we also recommend hepatic ultrasound screening of any infant born to a parent with FAP, beginning at birth and continuing every 3 months until the age of 5 years. Alpha-fetoprotein measurement is not included in the screening due to the difficulty of interpreting the levels in infants under 1  year of age, the potential for elevation prior to actionable imaging findings, the 20% chance of normal serum levels in HB patients, and the invasiveness of the test. This protocol has identified one case of HB, which was stage I and pure fetal histology, and the patient was cured with upfront surgical resection and no chemotherapy.

Conclusion The association between FAP and HB is well documented and requires clinical investigation on both sides. The risk of late-stage diagnosis of other FAP-associated cancers in HB survivors and the risk of HB in infants born to an FAP parent can be lowered with appropriate screening. Further studies are needed to define the most cost-effective screening protocol and demonstrate its benefit.

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Funding All authors are supported by the MSK Cancer Center Support Grant/Core Grant P30 CA008748.

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28. van der Luijt RB, Meera Khan P, Vasen HF, Breukel C, Tops CM, Scott RJ, et al. Germline mutations in the 3′ part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli. Hum Genet. 1996;98(6):727–34. 29. Cetta F, Mazzarella L, Bon G, Zuckermann M, Casorelli A, Nounga H.  Genetic alterations in hepatoblastoma and hepatocellular carcinoma associated with familial adenomatous polyposis. Med Pediatr Oncol. 2003;41(5):496–7. 30. Jung SE, Kim KH, Kim MY, Kim DY, Lee SC, Park KW, et al. Clinical characteristics and prognosis of patients with hepatoblastoma. World J Surg. 2001;25(2):126–30. 31. Fuchs J, Rydzynski J, Von Schweinitz D, Bode U, Hecker H, Weinel P, et  al. Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94. Cancer. 2002;95(1):172–82. 32. Malogolowkin MH, Katzenstein H, Krailo MD, Chen Z, Bowman L, Reynolds M, et al. Intensified platinum therapy is an ineffective strategy for improving outcome in pediatric patients with advanced hepatoblastoma. J Clin Oncol. 2006;24(18):2879–84. 33. Maas SM, Vansenne F, Kadouch DJ, Ibrahim A, Bliek J, Hopman S, et al. Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups. Am J Med Genet A. 2016;170(9):2248–60. 34. Sasaki F, Matsunaga T, Iwafuchi M, Hayashi Y, Ohkawa H, Ohira M, et  al. Outcome of hepatoblastoma treated with the JPLT-1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: a report from the Japanese Study Group for Pediatric Liver Tumor. J Pediatr Surg. 2002;37(6):851–6. 35. Pham TA, Gallo AM, Concepcion W, Esquivel CO, Bonham CA. Effect of liver transplant on long-term disease-free survival in children with hepatoblastoma and hepatocellular cancer. JAMA Surg. 2015;150(12):1150–8. 36. Czauderna P, Haeberle B, Hiyama E, Rangaswami A, Krailo M, Maibach R, et  al. The Children’s Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer. 2016;52:92–101. 37. Meyers RL, Maibach R, Hiyama E, Haberle B, Krailo M, Rangaswami A, et al. Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children’s Hepatic tumors International Collaboration. Lancet Oncol. 2017;18(1):122–31. 38. Maibach R, Roebuck D, Brugieres L, Capra M, Brock P, Dall’Igna P, et  al. Prognostic stratification for children with hepatoblastoma: the SIOPEL experience. Eur J Cancer. 2012;48(10):1543–9.

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39. DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr. 1998;132(3. Pt 1):398–400. 40. Teplick A, Kowalski M, Biegel JA, Nichols KE.  Educational paper: screening in cancer predisposition syndromes: guidelines for the general pediatrician. Eur J Pediatr. 2011;170(3):285–94. 41. Kalish JM, Doros L, Helman LJ, Hennekam RC, Kuiper RP, Maas SM, et  al. Surveillance recommendations for children with overgrowth syndromes and predisposition to Wilms tumors and hepatoblastoma. Clin Cancer Res. 2017;23(13):e115–e22. 42. Clericuzio CL, Chen E, McNeil DE, O’Connor T, Zackai EH, Medne L, et al. Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr. 2003;143(2):270–2. 43. Septer S, Lawson CE, Anant S, Attard T. Familial adenomatous polyposis in pediatrics: natural history, emerging surveillance and management protocols, chemopreventive strategies, and areas of ongoing debate. Familial Cancer. 2016;15(3):477–85.

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MYH-Associated Polyposis: Manifestations, Management, and Surveillance of the Colorectum Coen L. Klos, Farhan Quader, Dayna Early, and Paul E. Wise Clinical Presentation The phenotype of patients with MYH-associated polyposis (MAP) covers a wide spectrum. Most commonly MAP presents in a similar fashion to the attenuated form of familial adenomatous polyposis (AFAP) with 100 colorectal adenomas more similar to classic familial adenomatous polyposis (FAP) [1]. A minority of patients will

C. L. Klos ∙ P. E. Wise (*) Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA e-mail: [email protected] F. Quader ∙ D. Early Division of Gastroenterology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

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present with early-onset colon cancer (age 2 cm were resected at the time of baseline colonoscopy with hot snare polypectomy or endoscopic mucosal resection (EMR) while smaller polyps were removed at subsequent colonoscopy. These findings suggest that endoscopic management of colon polyps can be considered in MAP patients if the polyp burden can be managed endoscopically. There is no general consensus on polypectomy techniques and these can vary depending on polyp size and appearance. We recommend cold jumbo biopsy forceps polypectomy for removal of polyps less than 6 mm in size while a cold or hot snare can be used for polyps 6–10 mm in size (see Fig.  8.1). Hot snare polypectomy is the preferred method for polyps 1  cm or greater in size, while endoscopic mucosal resection (EMR) can be performed for polyps greater

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a

b

Fig. 8.1 (a) Sessile serrated adenoma in the right colon, with snare tip present. (b) Cold snare (9 mm, blue arrows) around sessile serrated adenoma in the right colon

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than or equal to 2 cm [10]. We recommend resection of all polyps that are 1 cm or greater, or that have a surface appearance suggestive of an adenoma or a sessile serrated polyp, whether with white light or narrow band imaging (NBI) (see below). Diminutive polyps in the rectosigmoid with a surface pattern suggestive of hyperplastic polyps should be sampled, but it may not be necessary to resect all polyps in this situation. Large polyps (>2 cm) that are sessile or removed in a piecemeal fashion should be monitored with follow up colonoscopy 3–6 months after resection to identify and remove any residual polyp tissue if present. Argon plasma coagulation and hot biopsy avulsion at the time of index polypectomy is associated with a lower rate of residual polyp tissue on follow up colonoscopy. Close surveillance of patients with MAP who have undergone polypectomy should be performed. If a large sessile polyp or polyp with high-grade dysplasia is removed, and complete resection has been confirmed, surveillance can occur at 1 year. Surveillance can occur at 1–2 years in those patients with lower-risk polyps (less than 1 cm in size, no high-grade dysplasia, low polyp burden) or no polyps. The goal of endoscopic management of MAP is resection of all premalignant lesions and close surveillance, especially in patients with high-risk lesions. This can be achieved with close attention to adequate bowel cleansing prior to colonoscopy, close examination of the colonic mucosa, particularly in the right colon, and complete resection of all premalignant polyps. Although standard high definition white light endoscopy is most often used for polyp detection, one study has suggested the use of chromoendoscopy using 0.2 percent indigo carmine solution to maximize adenoma detection [11]. In this study, there was some evidence that NBI is superior to standard white light endoscopy in identifying higher risk lesions, although other studies have not shown an advantage of NBI over high definition white light colonoscopy for adenoma detection [12]. Another study using chromoendoscopy for surveillance of duodenal polyps in those with MYH mutations found a three-fold higher adenoma detection rate [13]. Although this study examined duodenal tumors, this data suggests some benefit in utilizing chromoendoscopy for surveillance colonoscopy. We recommend consideration of NBI during colonoscopy in patients with MAP and multiple (>20) polyps.

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Surgical Management of the Colon and Rectum The optimal surgical management of MAP is a topic of ongoing discussion in the literature. This is mainly due to the broad spectrum of phenotypes with which the disease presents. Although the presence of an MYH mutation would alter surgical treatment in the opinion of most surgeons, MAP is challenging to recognize [14, 15]. Once a biallelic MYH mutation has been confirmed, those patients who present with multiple polyps should be managed endoscopically with frequent screening and polypectomies until the polyp burden becomes unamenable to endoscopic treatment or high-grade dysplasia (in some cases) or CRC develops [16]. If the rectal polyp burden is low, and surgical intervention is indicated, these patients should be offered a total abdominal colectomy with ileorectal anastomosis (TAC/IRA). Postoperatively these patients will still require frequent surveillance by proctoscopy. We recommend annual surveillance initially, and consider transitioning to biannually if the patients do not show any rectal polyps over the course of 3–5  years. Those with colon cancer upon presentation should be offered a TAC/IRA if the disease stage allows for treatment with curative intent, especially if there are multiple concomitant colon polyps. However, we will consider segmental colectomy for MAP patients if their polyp phenotype is limited, bowel function/continence or comorbidities increase the impact of a more extended resection, and/or if their age precludes the likelihood of metachronous cancer. Segmental colectomy for colon cancer in the setting of MAP may also be considered if they have clearly demonstrated through the informed consent process their understanding of subsequent risk and need for continued surveillance. For those patients with a rectal cancer in the setting of MAP, assuming it is high enough above the anorectal ring to allow for resection and anastomosis, or when the phenotype mimics classic FAP, a restorative proctocolectomy (RPC, total proctocolectomy with ileal pouch anal anastomosis) should be considered [17], although total proctocolectomy and end ileostomy may be required for those with incontinence, obesity, and/or significant comorbidities. In those latter circumstances, especially if the colon phenotype

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is milder, the rectal cancer may require a segmental resection (low anterior resection with end colostomy or abdominoperineal resection). Similar to the setting of MAP and colon cancer, if a rectal cancer is present with a mild colon polyp phenotype, some patients may be a candidate for segmental resection in the form of a low anterior resection with anastomosis. Of course, the need for neoadjuvant chemoradiation therapy after preoperative staging for any MAP patient with rectal cancer needs to be determined prior to any operative intervention. If neoadjuvant therapy is required and the patient is a candidate for anastomosis, ileal pouch function is often very poor postoperatively after radiation and subsequent RPC, such that we do not favor RPC except under extreme circumstances with very motivated patients who have gone through a detailed informed consent process. For those rectal cancers involving the sphincter, especially those without a significant colon phenotype, abdominoperineal resection and end colostomy is reasonable. In the setting of MAP without CRC, prophylactic colectomy is not indicated solely based upon the presence of a biallelic mutation found by genetic screening. Patients with this genotype and without polyposis should start endoscopic surveillance as described above and should only require surgical intervention if CRC or other polyp disease not amenable to endoscopic treatment develops. Those with a monoallelic mutation are at a slightly higher lifetime risk of developing CRC and require more frequent endoscopic screening (every 3–5  years). When CRC does occur in this population, the optimal surgical management should be decided on a case-by-case basis. In the absence of polyposis, a segmental colectomy or proctectomy is often sufficient.

Summary MYH-associated polyposis is an uncommon autosomal recessive condition that is often diagnosed later in life and with an attenuated phenotype that is usually endoscopically manageable.

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Table 8.1 summarizes the risks and treatment recommendations for both monoallelic and biallelic MYH mutation patients. Endoscopic surveillance of the upper and lower GI tracts is based on the phenotype but usually starts in the early to mid-20s. Operative management for MAP is dependent on the phenotype and can include segmental resection for cancer to more extended resection for CRC or polyposis phenotype that cannot be managed endoscopically. Prophylactic colectomy for MAP is rarely, if ever, needed.

Table 8.1  Characteristics regarding MYH mutation: Monoallelic versus biallelic Number of polyps Lifetime risk of colorectal cancer Risk for offspring   Partner without mutation   Partner with monoallelic mutation Endoscopic screening

Surgical management

Monoallelic No polyposis Slightly elevated

Biallelic 15–100+ ~80%

50% of children are carriers 25% of children are biallelica

100% of children are carriers

10 years before youngest family member with colorectal cancer and 5-year intervals

Start screening at age 25 (or 10 years before youngest family member with colon cancer) 1–2 year intervals depending on polyp burden TAC/IRAb or restorative proctocolectomy or segmental resection, depending on polyp burden and polyp/cancer location(s)

Limited/segmental resection if cancer occurs

50% of children are biallelic

Alternatively, this is the risk for siblings of those with a biallelic mutation, and unaffected parents, to have a biallelic mutation b Total abdominal colectomy and ileorectal anastomosis a

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References 1. Bouguen G, Manfredi S, Blayau M, et al. Colorectal adenomatous polyposis associated with MYH mutations: genotype and phenotype characteristics. Dis Colon Rectum. 2007;50(10):1612–7. 2. Sereno M, Merino M, Lo’pez-Go’mez M, et  al. MYH polyposis syndrome: clinical findings, genetics issues and management. Clin Transl Oncol. 2014;16:675–9. 3. Lefevre JH, Parc Y, Svrcek M, et  al. APC, MYH, and the correlation genotype-­ phenotype in colorectal polyposis. Ann Surg Oncol. 2009;16:871–7. 4. Grover S, Kastrinos F, Steyerber E, et al. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA. 2012;308(5):485–92. 5. Goodenberger M, Lindor N.  Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol. 2011;45:488–500. 6. Syngal S, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110(2):223–62. https://doi.org/10.1038/ajg.2014.435. 7. Kantor M, Sobrado J, Patel S, Eiseler S, Ochner C. Hereditary colorectal tumors: a literature review on MUTYH-associated polyposis. Gastroenterol Res Pract. 2017;2017:8693182, 1–4. 8. Boparai KS, Dekker E, Van Eeden S, et al. Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology. 2008;135(6):2014–8. 9. Ishikawa H, et al. Endoscopic management of familial adenomatous polyposis in patients refusing colectomy. Endoscopy. 2015;48(01):51–5. https://doi.org/10.1055/s-0034-1392774. 10. Fyock CJ, Draganov PV. Colonoscopic polypectomy and associated techniques. World J Gastroenterol. 2010;16(29):3630–7. https://doi. org/10.3748/wjg.v16.i29.3630. 11. Matsumoto T, et al. Chromoendoscopy, narrow-band imaging colonoscopy, and autofluorescence colonoscopy for detection of diminutive colorectal neoplasia in familial adenomatous polyposis. Dis Colon Rectum. 2009;52(6):1160–5. https://doi.org/10.1007/dcr.0b013e31819ef6fe. 12. Rastogi A, Early DS, Gupta N, Bansal A, Singh V, Ansstas M, Jonnalagadda SS, Hovis CE, Gaddam S, Wani SB, Edmundowicz SA, Sharma P.  Randomized, controlled trial of standard-definition whitelight, high-­definition white-light, and narrow-band imaging colonoscopy for the detection of colon polyps and prediction of polyp histology. Gastrointest Endosc. 2011;74(3):593–602. https://doi.org/10.1016/j. gie.2011.04.050. Epub 2011 Jul 29.

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13. Hurley JJ, et al. The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis. Gastrointest Endosc. 2018;24. https://doi. org/10.1016/j.gie.2018.04.2347. 14. Warrier SK, Kalady MF, Kiran RP, Church JM. Results from an American Society of Colon and Rectal Surgeons survey on the management of young-onset colorectal cancer. Tech Coloproctol. 2014;18:265–72. 15. Warrier SK, Yeung JM, Lynch AC, et al. Managing young colorectal cancer: a UK and Irish perspective. World J Surg. 2014;38:1827–33. 16. Kastrinos F, Syngal S. Inherited colorectal cancer syndromes. Cancer J. 2011;17:405–15. 17. Leite JS, Isidro G, Martins M, et al. Is prophylactic colectomy indicated in patients with MYH-associated polyposis? Color Dis. 2005;7:327–31.

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Lynch Syndrome: Management of the Colon, What Operation? William C. Cirocco and Heather Hampel

Introduction Approximately 5–10% of all colorectal cancer (CRC) cases are hereditary CRC (both nonpolyposis and polyposis syndromes), originating from pathogenic variants in any one of a number of genes that can lead to Lynch syndrome or multiple polyposis syndromes. High-risk hereditary predisposition syndromes have been associated with high lifetime risk for CRC, young age at diagnosis of CRC, and synchronous or metachronous cancers, and many syndromes carry an increased risk for extra-intestinal manifestations. Lynch syndrome (LS; formerly known as hereditary nonpolyposis colorectal cancer or HNPCC) is the most common of these conditions and is caused and defined by a pathogenic variant in one or more mismatch repair (MMR) genes. LS accounts for approxi-

W. C. Cirocco (*) Colon & Rectal Surgery Section, Banner MD Anderson Cancer Center, Phoenix, AZ, USA H. Hampel Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

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mately 3–6% of the total CRC burden and 10–19% of CRCs diagnosed before the age of 50. LS is an autosomal dominant condition with 70–80% penetrance and 80% lifetime risk for CRC.  When CRC develops, it is characterized by onset at an early age, right colon predominance (60% proximal to the splenic flexure), and excess of synchronous and metachronous CRC along with extracolonic tumors of the endometrium, ovary, stomach, renal pelvis, ureter, and other organs. The identification of LS has several treatment implications for the patient and the surgeon. For instance, screening for CRC is intense and lifelong, beginning at age 20–25 and repeated every 1–2  years. Furthermore, LS patients are at increased risk of metachronous cancer which may potentially be reduced by more extensive colorectal resection at the time of the initial CRC diagnosis. In addition, prophylactic colectomy may even be considered. Risk-reducing prophylactic resection of reproductive organs may be recommended for women with LS who have completed childbearing or do not wish to preserve fertility. Surveillance for gastric, urothelial, pancreatic, skin, or brain tumors is considered on a case-by-case basis depending on factors such as family history, ancestry, and the specific gene(s) involved.

Risk CRC Risk The precursor lesion for LS appears to be a discrete colon adenoma, which may occasionally appear flat, rather than raised or polypoid [1]. LS patients develop fewer colorectal adenomas by 50  years of age compared with attenuated polyposis syndromes such as FAP; however, LS adenomas typically demonstrate features of an increased risk of cancer, including villous histology and high-grade dysplasia [2, 3]. The adenoma-to-carcinoma sequence is more rapid in LS [4, 5] with polyp to cancer dwell times estimated at 35 months versus 10–15 years in sporadic CRC [2]. This abbreviated time to CRC is likely related to dysfunction of the MMR genes, leaving frequent DNA mismatches in multiple genes leading to malfunction. The

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Table 9.1  Lynch syndrome cancer risks up to 70 years of age Cancer type Colorectal Endometrial Stomach Ovarian

MLH1 and MSH2 40–80% 25–60% 1–13% 4–24%

MSH6 10–22% 16–26% ≤3% 1–11%

PMS2 15–20% 15%