8. Melanocytic Lesions.pdf

Melanocytic Lesions Vitiligo Partial or complete loss of skin pigmentation Associated with: o Pernicious anemia o Autoimmune thyroid disorders o Diabetes Melanoma Clinical features: Hypopigmentation In situ, or invasive Malignancy of melanocytes Majority lead to skin cancer death Strong association...

Melanocytic Lesions Vitiligo Partial or complete loss of skin pigmentation Associated with: o Pernicious anemia o Autoimmune thyroid disorders o Diabetes Melanoma Clinical features: Hypopigmentation In situ, or invasive Malignancy of melanocytes Majority lead to skin cancer death Strong association with UV exposure High risk pts: o Excessive UV exposure o Whites (fair skin) o Red hair o Burns or freckles from sun exposure o Melanocytic nevi in large numbers o Xeroderma pigmentosum o Familial dysplastic nevi, melanosis, vitiligo o Neurofibromatosis type I assc pts Pathogenesis o Pro-growth signaling pathway: NRAS/BRAF, PI3KATK/PTEN (Gain of function) o Cell cycle control: CDKN2A (loss of function), cKIT (over-expression) o Telomerase activity: TERT promoter (gain of function) o Atypical melanocytes in epidermis with (invasive) or without dermal invasion (in situ) o Large atypical cells with: § Finely granular cytoplasm § Pleomorphic nuclei with large eosinophilic nucleoli § Nuclear pseudoinclusions § Folds or Grooves o Markers: § S-100 § HMB-45 § MelanA (Mart-1) § Tyrosinase § NOT cytokeratins o 2 Nevus stages § Benign Nevus § Dysplastic Nevus o 2 growth stages § Radial Growth Phase § Vertical Growth Phase metastatic Melanoma Radial: Horizontal spread in epidermis and superficial dermis o Superficial spreading o Lentigo malignant melanomas o Acral lentiginous melanomas o Mucosal lentiginous melanomas Vertical: Downward invasion into deeper dermal layers as an expansile mass o Nodular melanoma (NO radial growth, only vertical) FYI SLIDES NRAS (Neuroblastoma RAS Viral Oncogene Homolog) o Small GTPases o Control cell signaling pathways responsible for: § Growth § Migration § Adhesion § Cytoskeletal integrity § Survival and differentiation o In melanoma, RAS mutation occurs by the switch signaling from BRAF to CRAF and disrupted cyclic AMP signaling BRAF o A member of raf/mil family of serine/threonine protein kinase o Affects cell division, differentiation, and secretion o Germline mutations assc w cardiofaciocutaneous syndrome (heart defects, mental retardation, distinctive facial appearance o Mutations associated with various cancers § Non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung TERT (Telomerase reverse transcriptase) o Rapidly divides cells o Mutations of TERT promoters assc w ↑ telomerase activity, ↑ risk in various cancers (melanoma, acute myeloid leukemia) o Carcinogenesis due to impaired telomere maintenance, subsequent DNA damage CLINICAL FEATURES Change in color, size, symptoms of pigmented lesion Development of new pigmented lesion in adult life Irregular borders Asymmetry Color variation Hutchinson's sign: brown-black pigmentation from longitudinal melanonychia on cuticle, proximal and lateral nail folds o Hutchinson’s also assc with: § Benign melanocytic nevi § Subungual hematomas § Bowen’s disease Clinical Presentation Of Melanomas Asymmetry, Irregular borders, color variation Melanoma of Oral Cavity Melanoma of Uvea Amelanotic melanoma Reddish, elevated plaque Types of Melanomas Amelanotic Melanoma Reddish slightly elevated plaque Melanoma in Situ Malignant melanocytes in epidermis, NO dermal invasion (Radial growth only) Pagetoid spread o Paler cytoplasm spread in epidermis o Melanoma: S100/HMB45 positive, cytokeratin negative o Adenocarcinoma: S100/HMB45 negative, cytokeratin positive Pagetoid spread Hutchinson’s sign Invasive Melanoma Melanoma in situ + dermal involvement NO MATURATION Fast growing Large cells with abundant eosinophils Finely granular cytoplasm Nuclear pseudoinclusions Folds or Grooves Pleomorphic nuclei with large eosinophilic nucleoli Four major subtypes Nodular Melanomas (VERTICAL) Aggressive subtype with early vertical growth phase Rapid growth Sharp circumscription of tumor NO maturation Superficial Spreading Melanomas (RADIAL) Malignant cells stay within basal and upper epidermis Flat or slightly raised Non-invasive areas: o Nests and pagetoid spread -In basal and upper epidermis o Irregular acanthosis -Tendency to form nests Epithelioid subtype = Invasive Acral Lentiginous Melanomas (RADIAL) Affects: o Skin of soles o Palms, Digits o Nail apparatus Extensive Pagetoid Dermal has spindle-shaped melanocytes -Pagetoid spread -Spindle dermal component NOT epidermis Lentingo Maligna Melanoma (RADIAL) Any invasive melanoma associated w lentigo maligna (in situ) Atypical melanocytes in basal layer Multinucleated melanoma cells (including ‘starburst’ forms) Pagetoid is UNCOMMON Dermal is spindle or epithelioid Dermal is hyperchromatic melanocytes that lack pigment production Solar elastosis in underlying dermis Histo: o Nests or single cells at basal layer, with marked elastosis o Multinucleated melanoma cells Types o Elastosis Lentigo maligna o In situ Lentigo maligna o Invasive Lentigo maligna -Nests or single cells at basal layer -Solar elastosis -Multinucleated melanoma cells Invasive Melanomas Nodular Superficial Spreading Acral Lentiginous Lentigo Maligna Radial Growth None (b/c Vertical) Nests and pagetoid spread Pagetoid spread Basal layer, Pagetoid spread uncommon Invasive Components Most commonly Epithelioid/Vertical Epithelioid Spindled Spindled or epithelioid, solar elastosis Differential Diagnoses Paget’s disease: Negative to HMB45 melanA S100 Positive for CK7 and CAM5.2 Non melanocytic: Negative to HMB45 melanA S100 Pyogenic granuloma: Neg to HMB45 S100 Nevi: No Pagetoid spread Remember: o HMB45 melanA S100 are melanocytic markers o These are POSITIVE in both benign nevus and melanoma Clark’s Level of Invasion Level I: In Situ- No penetration in Basement membrane Level II: Papillary dermis Level III: Papillary dermis expansion (stops at interphase of papillary and reticular) Level IV: Reticular dermis Level V: Subcutaneous tissue Breslow’s System Thickness Measure tumor thickness with ocular micrometer at right angles to surface of adjacent normal skin from: o Top of granular layer OR from ulcer base to o Deepest invasive tumor cells AJCC Staging System thresholds for thickness (2009): o T1: ≤ 1 mm thickness o T2: 1.01 - 2.00 mm thick o T3: 2.01 - 4.00 mm thick o T4: > 4 mm