Definition/General
Introduction:
Malignant melanoma is an aggressive skin cancer arising from melanocytes
It constitutes 4-5% of all skin cancers but causes majority of skin cancer deaths
It demonstrates high metastatic potential
It can arise from pre-existing nevus or develop de novo
It shows strong correlation with UV radiation exposure.
Origin:
Originates from melanocytes in basal layer of epidermis
Can arise from melanocytes in hair follicles
May develop from pre-existing melanocytic nevi (30% of cases)
De novo development occurs in 70% of cases
Melanocytes derive from neural crest cells
Shows predilection for sun-exposed and sun-protected areas.
Classification:
WHO classification recognizes major histological subtypes
Superficial spreading melanoma (70% of cases)
Nodular melanoma (15-20%)
Lentigo maligna melanoma (5-10%)
Acral lentiginous melanoma (5-10%)
Amelanotic melanoma (2-8%)
Desmoplastic melanoma (1-4%)
Mucosal melanoma (1-2%).
Epidemiology:
Peak incidence in 5th-6th decades
Equal gender distribution with slight female predominance
Risk factors include fair skin
Family history
Multiple atypical nevi
CDKN2A mutations
History of melanoma
Indian population shows lower incidence but higher proportion of acral melanomas.
Clinical Features
Presentation:
ABCDE criteria for suspicious lesions
Asymmetry of the lesion
Border irregularity
Color variation (multiple colors)
Diameter >6mm
Evolving (changing appearance)
Ugly duckling sign (different from other nevi).
Symptoms:
Change in existing mole or nevus (most common)
New pigmented lesion
Itching or tenderness (30%)
Bleeding or ulceration (25%)
Pain (uncommon in early stages)
Satellite lesions (advanced cases)
Regional lymphadenopathy.
Risk Factors:
Age >50 years
Fair skin (Fitzpatrick types I-II)
Multiple atypical nevi (>50 nevi)
Family history of melanoma
Personal history of melanoma
CDKN2A/CDK4 mutations
Immunosuppression
Intense intermittent sun exposure
History of severe sunburns.
Screening:
Total body skin examination
Dermoscopy of suspicious lesions
Photography for comparison
Biopsy of suspicious lesions
Annual screening for high-risk patients
Self-examination education
Genetic counseling for familial cases.
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Gross Description
Appearance:
Irregularly shaped pigmented lesion
Variable pigmentation (black, brown, blue, red, white)
Asymmetric borders with irregular outline
May show areas of ulceration
Raised or flat surface
Cut surface shows variegated appearance.
Characteristics:
Variable size (usually >6mm)
Multiple colors within single lesion
Irregular surface with possible nodularity
May show regression areas (white/pink)
Satellite lesions may be present
Cut surface shows heterogeneous pigmentation.
Size Location:
Variable size (few mm to several cm)
Common sites include back in men
Lower extremities in women
Head and neck in elderly
Acral sites (palms, soles, nails) in dark-skinned individuals
Mucosal sites (rare but aggressive).
Multifocality:
Satellite metastases (within 2cm of primary)
In-transit metastases (2cm beyond primary)
Multiple primary melanomas (5-10% of patients)
Familial melanoma may show multiple lesions
Dysplastic nevus syndrome shows numerous atypical nevi.
Microscopic Description
Histological Features:
Atypical melanocytes with nuclear pleomorphism
Intraepidermal and dermal components
Single cell growth pattern in epidermis
Loss of maturation with depth
Mitotic activity including atypical forms
Melanin pigment variable.
Cellular Characteristics:
Large pleomorphic cells with prominent nucleoli
Abundant cytoplasm (epithelioid cells)
Spindled cells in some areas
High nuclear-cytoplasmic ratio
Melanin pigment in cytoplasm
Multinucleated giant cells may be present.
Architectural Patterns:
Radial growth phase (horizontal spread)
Vertical growth phase (dermal invasion)
Pagetoid spread (upward migration)
Lentiginous pattern (basal layer involvement)
Nodular pattern (dermal nodules)
Desmoplastic pattern (fibrous stroma).
Grading Criteria:
Clark levels (I-V based on anatomic depth)
Breslow thickness (measured in mm)
Mitotic rate (per mm²)
Ulceration (present/absent)
Regression (present/absent)
Tumor-infiltrating lymphocytes (brisk/non-brisk/absent).
Immunohistochemistry
Positive Markers:
S-100 protein (95-100% positive)
Melan-A (MART-1) (85-95%)
HMB-45 (80-90%)
Tyrosinase (85-95%)
MITF (85-95%)
SOX10 (90-95%)
Melanin bleach for heavily pigmented lesions.
Negative Markers:
Cytokeratins (usually negative)
EMA (negative)
CEA (negative)
CD45 (negative)
Desmin (negative)
Muscle-specific actin (negative in most cases)
Help distinguish from carcinomas and sarcomas.
Diagnostic Utility:
S-100 most sensitive marker
Melan-A more specific than S-100
HMB-45 useful for metastases
Essential for amelanotic melanoma
Useful in small biopsies
SOX10 useful for desmoplastic type.
Molecular Subtypes:
BRAF mutations (40-50% cutaneous)
NRAS mutations (15-25%)
KIT mutations (acral and mucosal)
GNAQ/GNA11 (uveal melanoma)
NF1 mutations (10-15%)
CDKN2A/CDK4 (familial cases).
Molecular/Genetic
Genetic Mutations:
BRAF mutations (40-50% cutaneous melanoma)
NRAS mutations (15-25%)
CDKN2A mutations (familial melanoma)
TP53 mutations (10-15%)
KIT mutations (acral/mucosal melanoma)
PTEN loss (30-40%)
TERT promoter mutations (70-80%).
Molecular Markers:
BRAF V600E most common mutation
NRAS Q61 mutations
KIT amplification in acral melanoma
CDKN2A/p16 loss
Cyclin D1 overexpression
p53 protein accumulation
PTEN loss of expression.
Prognostic Significance:
BRAF mutations associated with younger age
NRAS mutations correlate with thickness
KIT mutations predict targeted therapy response
CDKN2A loss indicates familial predisposition
TERT mutations associated with poor prognosis
Tumor mutation burden predicts immunotherapy response.
Therapeutic Targets:
BRAF inhibitors (vemurafenib, dabrafenib)
MEK inhibitors (trametinib, cobimetinib)
KIT inhibitors (imatinib, dasatinib)
PD-1 inhibitors (pembrolizumab, nivolumab)
CTLA-4 inhibitors (ipilimumab)
Combination targeted therapy.
Differential Diagnosis
Similar Entities:
Atypical nevus (dysplastic nevus)
Spitz nevus (spindled and epithelioid cells)
Pigmented basal cell carcinoma (peripheral palisading)
Seborrheic keratosis (benign keratinocytic lesion)
Metastatic carcinoma (poorly differentiated).
Distinguishing Features:
Melanoma: Asymmetry and pleomorphism
Melanoma: Loss of maturation
Melanoma: High mitotic rate
Atypical nevus: Symmetrical architecture
Spitz nevus: Maturation pattern
BCC: Peripheral palisading
SK: Horn pseudocysts.
Diagnostic Challenges:
Distinguishing atypical nevus from melanoma
Spitzoid lesions in children
Amelanotic melanoma diagnosis
Desmoplastic melanoma recognition
Regression artifacts
Sampling issues in large lesions
Immunohistochemistry essential.
Rare Variants:
Balloon cell melanoma (clear cell change)
Myxoid melanoma (myxoid stroma)
Rhabdoid melanoma (rhabdoid cells)
Signet ring melanoma (signet ring morphology)
Nevoid melanoma (nevus-like appearance)
Minimal deviation melanoma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Wide local excision from [site], measuring [X x Y x Z] cm
Diagnosis
Malignant Melanoma
Histological Subtype
Subtype: [superficial spreading/nodular/lentigo maligna/acral lentiginous/other]
Breslow Thickness
Breslow thickness: [X.X] mm
Clark Level
Clark level: [I/II/III/IV/V]
Mitotic Rate
Mitotic rate: [X] mitoses per mm²
Ulceration
Ulceration: [present/absent]
Margins
Margins: [involved/uninvolved], closest margin [X] mm
Additional Features
Regression: [present/absent]; TILs: [brisk/non-brisk/absent]; Satellites: [present/absent]
Special Studies
IHC: [S-100/Melan-A/HMB-45/other]: [result]
Molecular: [BRAF/NRAS/other]: [result if performed]
TNM Staging
pT[X]: [staging based on thickness, ulceration]
Final Diagnosis
Malignant Melanoma, [subtype], Breslow thickness [X.X] mm, pT[X]