Loss of protective pigmentation makes individuals vulnerable t
--- Disorders of Pigmentation & Melanocytes Pathology — Comprehensive Study Notes --- Overview Loss of protective pigmentation makes individuals vulnerable to UV damage (e.g., albinism) Changes in preexisting pigmentation may indicate: Primary skin disorders (e.g., malignant transformation of a mole) Underlying systemic disease (e.g., Addison disease) --- 1. Freckle (Ephelis) Definition: Most common pigmented lesion of childhood in lightly pigmented individuals Pathogenesis: Possibly due to focal abnormality in pigment production, enhanced melanin transfer to basal keratinocytes, or both Café au lait spots (seen in neurofibromatosis type 1) are histologically similar but differ: larger, arise independently of sun exposure, contain macromelanosomes Morphology: Small (1 mm to several mm), tan-red or light brown macules Appear after sun exposure Hyperpigmentation results from increased melanin within basal keratinocytes Melanocytes may be slightly enlarged but are normal in density Fade in winter, darken in summer — due to degree of pigmentation, NOT changes in melanocyte number --- 2. Lentigo Definition: Common benign localized hyperplasia of melanocytes Epidemiology: All ages, most common in infants and children No sex or racial predilection Cause and pathogenesis unknown Morphology: Small (5–10 mm), oval, tan-brown macules or patches May involve mucous membranes and skin Histology: linear (non-nested) melanocytic hyperplasia restricted to the layer immediately above the basement membrane → hyperpigmented basal cell layer Unlike freckles, lentigines do NOT darken with sun exposure --- 3. Melanocytic Nevus (Pigmented Nevus / Mole) Definition: Common benign neoplasms caused by acquired activating mutations in RAS signaling pathway components Key Points: Diverse and dynamic group of neoplasms Acquired melanocytic nevi are the most common type, found in virtually all individuals Must be distinguished from melanoma — some nevi carry risk of malignant transformation Pathogenesis: Acquired mutations → constitutive activation of RAS or BRAF (downstream of RAS) RAS/BRAF activation → limited proliferation → permanent growth arrest via accumulation of p16/INK4a (inhibitor of CDK4 and CDK6) — this is oncogene-induced senescence This protective mechanism is disrupted in melanoma Morphology & Progression: Stage Features --- --- Junctional nevus Nests of round cells along the dermoepidermal junction; earliest lesion Compound nevus Nests grow into underlying dermis; more elevated Intradermal nevus Epidermal nests lost entirely; purely dermal Deeper nevus cells: smaller, less pigment, appear as cords and single cells, may acquire fusiform contours (neurotization) — resembles neural tissue Progressive loss of tyrosinase activity and acquisition of cholinesterase activity in deeper cells These maturation changes help distinguish benign nevi from melanoma --- 4. Variant Forms of Melanocytic Nevi Variant Architecture Cytology Clinical Significance --- --- --- --- Congenital nevus Deep dermal/subcutaneous growth around adnexa, neurovascular bundles, vessel walls Identical to ordinary acquired nevi Present at birth; large variants have increased melanoma risk Blue nevus Non-nested dermal infiltration, often with fibrosis Highly dendritic, heavily pigmented cells Black-blue nodule; often confused with melanoma clinically Spitz nevus Fascicular growth Large, plump cells with pink-blue cytoplasm; fusiform cells Common in children; red-pink nodule; often confused with hemangioma Halo nevus Lymphocytic infiltration surrounding nevus cells Identical to ordinary acquired nevi Host immune response against nevus cells and surrounding melanocytes Dysplastic nevus Coalescent intraepidermal nests Cytologic atypia Potential marker or precursor of melanoma --- 5. Dysplastic Nevi Definition: Important lesions that can be direct precursors of melanoma and markers of increased melanoma risk Clinical Significance: Dysplastic nevus syndrome (familial atypical mole and melanoma syndrome) — autosomal dominant Probability of developing melanoma in dysplastic nevus syndrome: 50% by age 60 Apparent transformation of dysplastic nevi to melanoma documented histologically Vast majority of dysplastic nevi are clinically stable and never progress Isolated dysplastic nevi in otherwise normal individuals carry very low malignant transformation risk Pathogenesis: Frequent acquired activating mutations in NRAS and BRAF (like conventional nevi) Additional factor: loss-of-function mutations in CDKN2A (encodes p16 — negative regulator of CDK4/CDK6) Some families have CDK4 mutations making it resistant to p16 inhibition Result: RAS/BRAF activation + increased CDK4 activity → dysplastic nevi development Additional modifier genes suspected but not fully identified Morphology: Larger than common acquired nevi (often 5 mm); may number in the hundreds in syndrome patients Flat macules, slightly raised "pebbly" plaques, or target-like lesions (darker raised center, irregul