Efi.

Gelerstein 2011

Topic 14. Malignant melanoma Melanoma is a malignant tumor arise from melanocytes of skin, muscles, eyes (few cases: CNS, atopic localized) Accounts for only 4% of all skin cancers Very aggressive tumor Biological behavior is heterogeneous!!! Predictive value of prognostic factors are very poor for selected patients Early detection of thin cutaneous melanoma is the best means of mortality.

Epidemiology The risk of CMM is inversely related to distance from equator Melanoma incidence worldwide (highest incidence in Australia and New Zealand) 5 % of all cancers in male 4% of all cancers in female - leading cause of death in young females (USA) Less frequent in blacks and Asians (lesions occur on palms, soles and subungual area) Pathophysiology Melanomagenesis - normal melanocytes transform into melanoma cells Alter cell proliferation, differentiation, and death Impact susceptibility to the carcinogenic effects of ultraviolet radiation Risk factors: 1. Race Most frequent in fair skinned Caucasian Less frequent in Afro-American and Asian than in other populations In these racial groups lesions occur on palms, soles and subungual areas Ocular and mucosal melanomas occur with greater relative frequency 2. Phenotypical markers Freckling White skin Red / blond hair Blue eyes 3. Genetic Personal history of melanoma or other skin cancer Family history of melanoma 4. Precursor lesions 2/3 de novo 1/3 of all melanomas arise from precursor lesions Giant congenital nevi Dysplastic nevi syndrome /atypical multiple mole syndrome Cellular blue nevi

Efi. Gelerstein 2011

5. Sunlight Sun exposure Sun burning in childhood Sun sensitivity 6. Immunosuppression (iatrogenous, acquired) 7. Hormonal factors ?? - oral contraceptives and pregnancy Dysplastic nevus / atypical mole syndrome (Clark & Lynch) Numerous nevi (10 < ) Various part of the body Irregular (fried egg) Familial / sporadic CDKN2A andCDK4 mutation risk of melanoma (50-350x)

Familiar melanoma 10% of melanomas mutation is found in the tumor suppressor gene family (chromosome 9p) - CDKN2A mutation (30-50%) - CDK4 mutation (in few CMM families) FAMMM syndrome : Familiar Atypical Multiple Mole and Melanoma syndrome

ABCDE criteria for a changing mole A. Asymmetry lesion does not match the other half. B. Border irregularity The edges are ragged, notched, or blurred. C. Color irregular Pigmentation is not uniform D. Diameter > 0.5 mm is characteristic. Growth in nevus warrants an evaluation. E. Elevation + Evolving Changes in the lesion over time

Clinical subtypes of melanoma: 1. Lentigo Maligna Melanoma (LMM) 2. Superfical Spreading Melanoma (SSM) 3. Nodular Melanoma (NM) 4. Acral Lentiginous Melanoma (ALM) 5. Amelanotic melanoma (AMM) 6. Mucosal melanoma (MM)

Efi. Gelerstein 2011

1. Lentigo Maligna Melanoma (LMM): Macular, freckle-like lesion with irregular shape and color Seen on sun-exposed surfaces Mostly in elderly patients with atrophic skin Slow growing (5-20 years) 2. Superficial spreading melanoma (SSM) 60-70% Most common: trunk in men and women, legs in women Individuals aged 30-50 years. Manifests as a flat / slightly elevated brown lesion with pigmentation Irregular asymmetric borders are characteristic. - Deep pigmented macule / raised plaque horizontal growing phase - Nodular part vertical growing phase 3. Nodular melanoma (NM): 15-30% Most commonly seen on the legs and trunk Rapid growth occurs over weeks to months Dark brown-to-black papule or dome-shaped nodule, may ulcerate and bleed with minor trauma It tends to lack the typical ABCDE melanoma warning signs Exhibits elevation, ulceration with bleeding, or both at presentation 4. Acral lentiginous melanoma (ALM): The least common subtype 2-8% of melanoma cases in white persons 29-72% of melanoma cases in dark-skinned individuals Mostly on the palms, soles, or beneath the nail plate (subungual variant). Brown to black flat lesion with variegation in color and irregular borders 5. Amelanotic melanoma (AMM) 6. Mucosal melanoma (MM) Melanomas can also described by their colour, site and degree of spread. Totally amelanotic melanomas rare, and occur especially on the soles of the feet. Flecks of pigment can usually be seen with a lens. Subungual melanomas painless areas of pigmentation expanding under the nail and onto the nail fold. Metastatic melanoma has spread to surrounding skin, regional lymph nodes or to other organs. At this stage it can rarely be cured

Efi. Gelerstein 2011

7-point checklist Major criteria / score = 2 Atypical pigment network Grey/blue veil Atypical vascular pattern Minor criteria / score = 1 Atypical radial streaks/ pseudopods Atypical diffuse pigmentation Atypical dots/ globules Signs of regression Histology Asymmetry Intraepidermal melanocytes without cohesion Pagetoid (upward spread) invasion involvement of adnexal epidermis Melanocyte nests: shape and size variability Irregular clefts Confluent nests Lack of the maturation of dermal melanocytes Cytological characteristics of MM Atypia (large nucleus) Prominent nucleus Mitoses (on the basal site) Necrosis of the single cells Differential diagnosis 1. Melanocytic nevus 2. Seborrheic keratosis 3. Pigmented actinic keratosis, pigmented BCC and sclerosing hemangioma 4. Subungual or periungual hematoma Prognosis Tumor thickness (mm ) Breslow Ulceration Invasion rate Clark Nodal involvement Dissemination rate Regression (?) Gender and Age Localization

Efi. Gelerstein 2011

Staging: TNM stage I II III IV TNM A: non ulcerated B: ulcerated T1 < 1 mm T2 1-2 mm T3 2-4 mm T4 > 4 mm AJCC stage Ia Ib IIa IIb III IV Breslow thickness (mm) Up to 0.75 0.75-1.5 1.51-4.0 >4.0 Nodal disease Metastatic disease 5-year survival (%) 95 85 65 45 40 <10

N1-3 number of the involved nodes A: microscopic B: macroscopic C: in transit metastasis

M category M1A: distant skin, subcut. and distant LN M1B: lung M1C: any other and / or elevated LDH

Regression Vascularized scar-like tissue Inflammatory cells Melanophages Treatment Melanoma susp. Lesions - Intraop. Histology - 0,5 cm excision Low risk MM 1cm excision border High risk MM 2 cm excision + sentinel node biopsy Tumor screening: cranial CT, abdominal and lymph node US chest x-ray, bone scan Regional lymph node management Palpable Radical lymphadenectomy Non palpable Sentinel NB (1 mm < ulcerated, regressive, Clark IV) SNB + radical lymphadenectomy Adjuvant therapy 1. Primary tumor thickness > 1.5 mm, ulcerated, regressive, tumor invasion of the vessels: - Interferon- (3x3M.I.U. sc. weekly) - Stage IIA, IIB 2. Node metastasis (stage III): - Interferon- (3x5-10 M.I.U. sc weekly) - DTIC (4 hetente 5x400mg iv. 1x800mg/m2)

Efi. Gelerstein 2011

Surgical therapy of distant metastasis Single lung metastasis Single liver, spleen or any other site of abdominal metastasis (e.g. suprarenal gland) Solitary brain metastasis Management of multiple distant metastases BOLD Bleomycin - Oncovin - Lomustine - Dacarbazin DTIC - Interferon- IL-2- IFN -DTIC Fotemustine - DTIC Cisplatin-DTIC Temodal Vaccines Palliative therapy Irradiation - Cutaneous metastases - Bone metastases - Brain metastases CO2 LASER- multiple skin metastases in transit metastases: selective limb perfusion, electro chemotherapy Intra-arterial chemotherapy hepatic metastases