Cutanenous markers of internal malignancy

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CUTANEOUS MARKERS OF INTERNAL MALIGNANCY

INTRODUCTION

• Cutaneous changes due to internal malignancy vary in their reliability for predicting underlying neoplasia • Some changes are specific to the disease, occurring primarily due to the internal tumour, such as cutaneous metastasis • Other changes are non specific and include cutaneous infections and pigmentary lesions • Recognition of external clues is important to facilitate early diagnosis and prompt treatment

CLASSIFICATION

1. Multisystem and haematopoietic tumours that involve the skin 2. Direct tumour spread 3. Genodermatoses with malignant potential 4. Paraneoplastic disorders 5. Indirect cutaneous markers of internal malignancy (eg: dermatological features of carcinogen exposure)

MULTISYSTEM AND HAEMATOPOIETIC TUMOURS THAT INVOLVE THE SKIN

• The skin is involved as a part of a multisystem neoplasm • Seen in haematopoietic malignancies such as lymphoma, leukemia and Langerhan’s cell histiocytosis • The patient may present with skin lesions, or the skin may be an accessible site for biopsy • This category also includes non-specific skin changes due to malignancy, such as purpura due to thrombocytopenia

LEUKEMIA CUTIS

• Extramedullary manifestation of leukemia • Invasion of leukemic cells into epidermis/dermis/subcutis • Pink/red/brown-purple macules, papules, plaques, nodules • Firm and painless • Mucosal involvement- gum hypertrophy • Most commonly in acute myeloid leukemia- M4, M5

LYMPHOMA CUTIS

• Systemic lymphoma involving skin • Seen in both T cell and B cell lymphomas • More common in non-Hodgkin than Hodgkin’s lymphoma • Skin lesions similar to leukemia cutis

TUMOUR SPREAD FROM ADJACENT AND DISTANT TISSUES

CUTENOUS METASTASIS

• Of patients with metastatic cancer, 10% have cutaneous metastases • Most common sources in order of frequency:  Breast  Melanoma  Lung  Colon  Stomach  Upper aerodigestive tract, uterus, kidney

MECHANISM AND DITRIBUTION: • Occurs due to lymphatic or haematogenous dissemination of tumour • 75% of metastases are found on the head, neck and upper trunk • The pattern of distribution provides clues to the route of metastasis:  metastases to extremities suggest intra‐arterial embolic spread  widespread skin metastases suggest that tumour cells are present in the general circulation  metastases to the skin in the vicinity of the affected organdissemination by lymphatic vessels or veins

• ‘Tumour‐to‐tumour metastasis’- metastases froma malignancy localize to another (usually benign) tumour  postulated mechanism is the trapping effect of fibrin in the vessels of the recipient tumour  most such metastases occur within vascular neoplasms, such as thyroid or adrenal adenomas

CLINICAL FEATURES: • Painless, firm to hard nodules • May be skin‐coloured, blue‐brown or reddish purple • Most common pattern- solitary nodule • Ulceration • Other patterns: morphoea‐like sclerotic plaques, scar infiltration, erysipelas‐like diffuse skin infiltration, infiltrated areas of alopecia (alopecia neoplastica) and embolic metastasis to digits

• Sister Mary Joseph nodule- metastasis to umbilicus • Most commonly due to bowel tumours

HISTOPATHOLOGY: • Cells of metastasis usually resemble the cells of the primary tumour • Immunohistochemical markers aid in diagnosis • Some cases may have marked oedema or dilated lymphatic vessels that make diagnosis difficult • Lymphatic spread of tumour cells may lead to an ‘Indian filing’ appearance, sometimes with fibrosis

PROGNOSIS: • Cutaneous metastases are suggestive of disseminated disease and indicate poor prognosis • Survival is typically about 3 months in patients with disseminated lesions • Patients with solitary metastases may have a better survival rate • Infrequent cases of regression after primary tumour removal have been documented • Treatment options may include excision or other destructive therapy (e.g. laser destruc- tion, radiotherapy, photodynamic therapy) for limited numbers of lesions, and chemotherapy or other systemic treatment for disseminated lesions

CARCINOMA EN CUIRASSE

• Dermal infiltration causing sclerosis • Breast carcinoma • May occur with maligancy of lung, GIT, kidney • Early inflammatory stage; may be nodularity • Late stage- sclerodermoid appearance

CARCINOMA ERYSIPELOIDES

• Due to plugging of dermal lymphatics by tumour cell emboli • Most commonly associated with breast carcinoma • Resembles erysipelas- extensive, warm, oedematous, tender plaque • No pyrexia or toxaemia • HPE: plugging of the dermal lymphatics at all levels by aggregates of carcinoma cells

TELANGIECTATIC METASTATIC CARCINOMA • Typically associated with breast cancer • Lesional skin can resemble angiosarcoma • Erythematous plaques with telangiectasia, papulovesicles • HPE: tumor nests in dilated small blood vessels

A The skin biopsy sample shows numerous dilated vessels in the dermis with thrombi of neoplastic cells and erythrocytes B Neoplastic cells show positive results for HER2

PAGET DISEASE OF THE BREAST

• Direct epidermal extension of an underlying ductal adenocarcinoma • Underlying tumour is usually small and superficial, so early recognition is important • Presents as scaling, erythema, oozing and crusting on or around the nipple • Tumour spread may be due to a keratinocytederived chemoattractant called heregluin alpha

HPE: • Paget cells present in epidermis- large rounded cells, large nucleus, light-staining cytoplasm, no intercellular bridges • Lie singly or in groups • Flattened basal cells lying between Paget cells and dermis • Dermis- inflammatory reaction

• Histopathological markers: • EMA (epithelial membrane antigen) • CEA (carcinoembryonic antigen) • Cytokeratins CK7 and CK 8/18 • Mucin- MUC1 • CD23 (positive in both mammary and extramammary forms)

EXTRAMAMMARY PAGET DISEASE: • Majority of cases are primary with no other underlying malignancy- develops as in situ intraepidermal carcinoma • Secondary EMPD arises from underlying adnexal ca or internal malignancy (due to epidermotropic spread) • Occurs in apocrine gland bearing areas- anogenital and axillary sites • Presents as reddish-brown or hypopigmented plaque • Pruritus, burning sensation, oedema, bleeding • Histological and immunohistochemical features similar to mammary Paget disease; the antigen RCAS1 is particularly sensitive

• 60% cases vulval, 20% perianal, 15% penile/scrotal • Vulval Paget disease- may arise locally from apocrine sweat glands or Bartholin’s glands; the remainder arise from the vagina, cervix, bladder, ovary, colon or rectum, or occasionally from more distant sites such as the breast or gallbladder • Perianal Paget disease- associated with an adnexal tumour in about 10% and a distant tumour in about 25% (rectum, stomach, ureter, breast) • Male genital Paget disease- associated with carcinoma of the prostate, bladder, ureter, kidney or testes in10% of cases. In other cases, it arises locally in the epidermis

GENODERMATOSES ASSOCIATED WITH INTERNAL MALIGNANCIES

HOWEL EVANS SYNDROME

• Autosomal dominant • Focal palmoplantar keratoderma (tylosis) • Oesophageal carcinoma • Oral leukoplakia also frequently occurs

GORLIN SYNDROME

• Nevoid basal cell carcinoma syndrome • Basal cell carcinomas, mandibular odontogenic keratocysts, skeletal anomalies, abnormal calcification and dyskeratotic pits of palms and soles • Risk of developing medulloblastoma and ovarian tumours.

FAMILIAL MELANOMA SYNDROME

• Large multiple and irregular nevi • Early onset of melanoma • Family history of melanoma or multiple atypical nevi • CDKN2A germline mutation in the 9p21 gene region • Mutations that impair p16 functionincreased risk (22‐fold) in pancreatic cancer

VON-HIPPEL-LINDAU DISEASE

• Autosomal dominant- mutation of VHL gene on chromosome 3 • Benign and malignant tumours of various systems, particularly:  haemangioblastomas of the CNS  angiomatosis of the retinae,  phaeochromocytoma (which may be bilateral)  renal carcinoma  pancreatic adenoma, carcinoma and cysts • Non‐specific cutaneous manifestations- haemangiomas and café‐au‐ lait spots

NEUROFIBROMATOSIS • Autosomal dominant • Cutaneous and plexiform neurofibromas • Café‐au‐lait macules • Flexural freckling • Lisch nodules (pigmented iris hamartomas) • NF1- optic gliomas, neurofibrosarcomas, juvenile myelomonocytic leukemia • NF2- bilateral vestibular schwannomas, peripheral nerve schwannomas, meningiomas, spinal tumours

TUBEROUS SCLEROSIS • Autosomal dominant- TSC1, TSC2 • Cutaneous angiofibromas, ash leaf spots, shagreen patches • Koenen’s tumours • Oral mucosal fibromas, dental pits • Associated tumours: intracranial cortical/subcortical tubers, cardiac rhabdomyoma, renal angiomyolipoma, lung lymphangiomatosis • Malignant sarcomatous change can occur with angiomyolipomas and rhabdomyomas

MEN 1 SYNDROME (WERMER SYNDROME) • Familial cancer syndrome affecting parathyroid, pancreas and pituitary gland • Mutation in the MEN1 gene (chromosome 11q13) • Cutaneous findings:  multiple facial angiofibromas  collagenomas  lipomas  café‐au‐lait macules • 60–100% of cases have gastroenteropancreatic lesions- especially pancreatic neuroendocrine tumours (NETs) • Incidence of tumours is as follows: ZES 54%, insulinoma 21%, glucagonoma 3% and VIPoma (vasoactive intestinal peptide) 1%

MEN 2A SYNDROME

• MEN 2 – autosomal dominant- mutations of the RET proto-oncogene (chr 10q11) • Cutaneous features: scapular macular or lichen amyloidosis • Presents as bilateral symmetrical pruritic skin lesions over the scapular area, with hyperpigmentation and hyperkeratosis • Medullary thyroid carcinoma • Phaeochromocytoma • Hyperparathyroidism

MEN 2B SYNDROME • Mucosal neuromas- apparent at birth or in the first years of life • Asymptomatic soft, flesh‐coloured papules or nodules • Characteristic facial appearance- soft, lumpy ‘blubbery’ protuberant lips; everted, thickened, eyelids; and prominent eyebrows • Neuromas affect mucosal surfaces- anterior border of the tongue, buccal mucosa inside the commissures of the lips • Gingival, palatal and pharyngeal surfaces may be affected

• Cutaneous nodules or plaques occasionally reported • Patients may have a marfanoid appearance; muscle weakness and musculoskeletal anomalies (eg kyphoscoliosis) • MEN2B is associated with medullary thyroid carcinoma in 75% of cases, and phaeochro- mocytoma in almost 50% • MTC in type 2B presents earlier and more aggressively than in type 2A.

CARNEY COMPLEX (MYXOMA SYNDROME) • Group of disorders with cutaneous pigmented lesions associated with cutaneous, subcutaneous and internal myxomas, and associated endocrinopathy (mainly tumours) • Includes involvement of one or more of- adrenal cortex/thyroid/pituitary/gonads

NAME syndrome: • Naevi (congenital melanocytic) • Atrial myxomas • Myxoid neurofibromas • Ephelides LAMB syndrome: • Lentigines • Atrial myxomas • Mucocutaneous myxomas • Blue naevi.

AUTOSOMAL RECESSIVE GENETIC SYNDROMES

X-LINKED RECESSIVE GENETIC SYNDROMES

PARANEOPLASTIC PHENOMENA INVOLVING THE SKIN

• Paraneoplastic dermatoses are skin conditions that have an association with internal malignancy but are not themselves malignant. • At least one of the following should be present to consider a dermatosis as being related to an underlying malignancy (Curth’s postulates): 1. The malignancy and the cutaneous disorder should occur concurrently 2. The two disorders should follow a parallel course 3. There should be a specific tumour site/cell type associated with the cutaneous disease 4. There should be a statistical association between the two processes 5. There should be a genetic association between the two processes

ACANTHOSIS NIGRICANS

• Malignancy‐associated AN is less common than the benign type • Rapid onset of symmetrical, hyperpigmented, rugose, velvety plaques on axillae and other flexures, areolar area and nape of the neck • There may be acrochordon‐like papillomatosis arising from the plaques • Generalized pruritus, weight loss • Pathogenesis: Production of TGF-α or cytokines that activate insulin‐like growth factors or their cutaneous receptors by tumour cells

• Most common site of underlying neoplasm is GIT (70–90%); gastric adenocarcinoma is the most frequent • Other tumours include lung, breast, endometrium, kidney, bladder, prostate, testis, cervix, thyroid and adrenal

ACANTHOSIS PALMARIS

• Known as tripe palms, pachydermatoglyphy • Thickened skin of the palms and occasionally the soles, with exageratted dermatoglyphics • Velvety or less commonly a pitted, honeycombed pattern of the hand • Associated with neoplasia in 90% of cases; may occur along with malignant acanthosis nigricans or the sign of Leser Trélat • Most commonly the underlying tumour is bronchial or gastric

• Tripe plams alone in a male patient with clubbing – lung cancer • Tripe palms with acanthosis nigricans - suggestive of gastric carcinoma. • The appearance or exacerbation of tripe palms in a patient with history of cancer may be a sign of recurrence of the malignancy

SIGN OF LESER TRÉLAT

• Sudden development of numerous seborrhoeic keratoses, in an eruptive fashion, with or without pruritus • Predominantly on trunk and extremities • Lesions similar to normal SKs both clinically and histologically • Adenocarcinomas- majority of associated malignancies- most commonly GIT • Lymphoproliferative disorders- Sezary syndrome, mycosis fungoides, leukemia

FLORID CUTANEOUS PAPILLOMATOSIS • Wide- spread, often pruritic eruption of warty papules associated with an underlying malignancy, particularly gastric adenocarcinoma • Resembles disseminated HPV infection • May appear concomitantly with other paraneoplastic phenomena especially acanthosis nigricans

ACQUIRED ICHTHYOSIS

• Paraneoplastic ichthyosis- sudden onset, extensive, prominent fissuring, affects trunk • May occur with other paraneoplastic signs - erythema gyratum repens, Bazex syndrome and dermatomyositis • Strongest association is with Hodgkin disease (over 70% of cases) and other lymphoreticular tumours • Solid tumours- ovary, kidney, liver, breast, leiomyosarcoma

PITYRIASIS ROTUNDA

• Round/oval asymptomaic hypo or hyperpigpmented ichthyosiform scaly patches • Trunk, extremities • Type 1- associated with malignancy (GI and haematologic) • Type 2- familial pityriasis rotunda- no underlying disease

ACROKERATOSIS PARANEOPLASTICA (BAZEX SYNDROME) • SCC of upper respiratory tract/GIT • Initially- violaceous erythema and scaling on the peripheries- helices of the ears, tip of the nose, hands and feet • Lesions becomes hyperkeratotic, with a keratoderma on the hands and feet; followed by generalized eruption

• Changes on the face may appear eczematous or lupus erythematosus‐like, whereas acral changes are often psoriasiform • Nail dystrophy and paronychia often present • HPE non‐diagnostic-hyperkeratosis, parakeratosis, focal spongiosis and a mixed inflammatory cell infiltrate • Resolution may occur with successful tumour resection. Systemic retinoids may improve the cutaneous changes

MIGRATORY ERYTHEMA ERYTHEMA GYRATUM REPENS: • Mobile, concentric, often palpable, erythematous, wave‐ like bands • ‘Wood‐grain’ appearance of skin • Peripheral scale or collarette • Complete torso usually affected • Lesions migrate from day to day, usually changing position by about 1 cm daily • Internal malignancy in >80% of cases: particularly lung • Other tumour sites: oesophagus, breast, bowel, uterus, cervix, kidney, pancreas haematological

NECROLYTIC MIGRATORY ERYTHEMA: • Strongly associated with a glucagon-secreting α-cell tumour of the pancreas • Repeated eruptions of irregular polycyclic erythematous patches with expanding scaling margins • Lesions blister and break down with superficial epidermal necrolysis and crusting • Predilection for the anogenital region and trunk • NME is one of the components of the glucagonoma syndrome along with weight loss, diabetes, stomatitis and diarrhoea • If glucagon levels are restored to normal rash will usually rapidly remit

VASCULAR DISORDERS RAYNAUD PHENOMENON & DIGITAL ISCHEMIA: • Hyperviscosity syndrome- PCV, leukemia, myeloma‐ linked cryoglobulinaemia • Cancer‐associated coagulopathy can cause vascular occlusion ERYTHROMELALGIA: • Myeloproliferative disorders- PCV, essential thrombocythaemia

FLUSHING: • Carcinoid syndrome, mastocytosis, phaeochromocytoma, medullary carcinoma of thyroid, pancreatic tumours producing vasoactive intestinal peptide, renal cell carcinoma • Component of POEMS syndrome in myeloma CHILBLAIN LIKE LESIONS: • Leukemias and myeloproliferative disorders • Persistent rather than episodic, refractory to treatment with drugs (calcium channel blockers) • HPE: may show blast cells as well as vascular changes.

CANCER ASSOCIATED THROMBOSIS

DEEP VEIN THROMBOSIS: • Adenocarcinomas of the GIT, urogenital tract, breast or lung • Mucin secretion causes non‐enzymatic activation of factor X to factor Xa, initiating the thrombotic cascade

MIGRATORY THROMBOPHLEBITIS: • Thrombophlebitis associated with neoplasia is often recurrent and migratory (Trousseau sign) • Variety of sites- especially upper extremities and trunk • Intravascular, low‐grade hypercoagulation • Altered blood viscosity, vascular endothelial changes, small tumour emboli • Responds poorly to anticoagulant therapy; heparin more effective than warfarin • Ca pancreas, stomach, colon and lung; pancreatic carcinoma accounts for about half of all cases

MONDOR DISEASE: • Cord‐like lesion is palpable in the subcutaneous tissue of the anterior or lateral thorax, sometimes abdomen • Thrombophlebitis of thoracic or epigastric veins, usually unilateral but occasionally bilateral • May occur as a result of trauma, inflammation or post‐surgery.10–15% of patients have an associated breast carcinoma

PARANEOPLASTIC PRURITUS

• May be secondary to uremia or cholestasis; may be related to iron deficiency or xerosis/ichtyhosis • Generalized pruritus- Hodgkin disease (>25% patients), Sézary syndrome, mycosis fun- goides, leukaemia • Aquagenic pruritus- polycythaemia vera, lymphoproliferative diseases (T‐cell lymphoma, myelodysplasia) • Localized pruritus- nerve damage due to tumour • Rx- moisturizers, opioid antagonists, antidepressants, neuroleptics

PARANEOPLASTIC PIGMENTATION

• Occurs due to production of an ACTH‐like hormone from tumours • Most common cause- small cell bronchial carcinoma • Others: gastric, pancreatic, oesophageal and ovarian cancers; thymoma, phaeochromocytoma, carcinoid syndrome • Pigmentation is diffuse with photoaccentuation and greater prominence over pressure points and in flexures, genital skin, scars and oral mucosa

CLUBBING OF NAILS

• Increased transverse and longitudinal nail curvature with hypertrophy of the soft‐tissue components of the digit pulp • Most common malignancy- carcinoma of bronchus • Also associated with GIT tumours and metastasis to the lung • High incidence of hypertrophic osteoarthropathy with mesothelioma,

PARANEOPLASTICHYPERTRICHOSIS LANUGINOSA ACQUISITA • Development of fine, downy lanugo type hair • Affects the face initially, extending down the body with time • Possibly due to prolongation of the anagen growth phase • Resolution occurs after treatment of the underlying tumour, and regrowth can be related to recurrence of the neoplasm • 70% cases- women, usually aged 40–70 years, and most patients have metastatic tumours at presentation • Most common tumour sites in men are lung followed by colorectal, and in women are colorectal followed by lung and breast

REFERNCES

• Rook’s textbook of dermatology- 9th edition • Fitzpatrick’s dermatology- 9th edition • IADVL textbook of dermatology- 5th edition • Lever’s textbook of histopathology of skin- 11th edition

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