Definition/General
Introduction:
Melanoma is a malignant neoplasm derived from melanocytes
It represents the most aggressive skin cancer
It has high propensity for metastasis
It constitutes 4% of skin cancers but causes 80% of skin cancer deaths.
Origin:
Arises from melanocytes in skin, mucosa, or eye
Most commonly develops in pre-existing nevi
Can arise de novo in normal skin
Associated with UV radiation exposure
Genetic predisposition important.
Classification:
WHO Classification includes superficial spreading (70%)
Nodular melanoma (15-20%)
Lentigo maligna melanoma (5-10%)
Acral lentiginous melanoma (5%)
Desmoplastic melanoma
Amelanotic melanoma.
Epidemiology:
Incidence increasing worldwide
Peak incidence 5th-6th decades
Fair-skinned populations more susceptible
Male predominance for nodular type
Indian population: Lower incidence but acral lentiginous more common.
Clinical Features
Presentation:
ABCDE criteria: Asymmetry, Border irregularity, Color variation, Diameter >6mm, Evolving
New pigmented lesion
Change in existing mole
Ulceration
Bleeding
Itching.
Symptoms:
Change in size, shape, or color of mole
Irregular borders
Multiple colors
Diameter >6mm
Ulceration or bleeding
Itching or pain
Satellite lesions
Regional lymphadenopathy.
Risk Factors:
Fair skin
UV radiation exposure
History of sunburns
Multiple nevi (>50)
Atypical nevi
Family history
CDKN2A mutations
Immunosuppression
Previous melanoma.
Screening:
Full body skin examination
Dermoscopy
Photography for monitoring
Biopsy of suspicious lesions
Genetic counseling for familial cases
Regular self-examination.
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Gross Description
Appearance:
Irregular, asymmetric lesion
Variable pigmentation from tan to black
May be amelanotic (flesh-colored)
Ulceration in advanced cases
Satellite nodules around primary.
Characteristics:
Irregular borders with notching
Variegated coloration
Surface may be smooth or nodular
Ulceration in thick melanomas
Bleeding and crusting possible.
Size Location:
Size varies from few millimeters to several centimeters
Back and legs most common in fair-skinned
Palms, soles, nails in darker skin
Head and neck in elderly
Mucosal sites possible.
Multifocality:
Usually solitary
Multiple primary melanomas in 5% cases
Satellite metastases within 2cm of primary
In-transit metastases between primary and regional nodes
Distant metastases to any organ.
Microscopic Description
Histological Features:
Atypical melanocytes with nuclear pleomorphism
Pagetoid spread in epidermis
Loss of maturation in dermal component
Mitotic activity including atypical forms
Melanin pigment variable.
Cellular Characteristics:
Large cells with enlarged, hyperchromatic nuclei
Prominent nucleoli
Abundant cytoplasm
Melanin granules (variable)
Epithelioid or spindle cell morphology
Multinucleated giant cells.
Architectural Patterns:
Radial growth phase: Intraepidermal spread
Vertical growth phase: Dermal invasion
Pagetoid pattern: Single cells ascending epidermis
Nested pattern: Cell clusters
Desmoplastic pattern: Spindle cells in fibrous stroma.
Grading Criteria:
No standard grading system
Breslow thickness most important
Ulceration upstages tumor
Mitotic rate >1/mm² significant
Clark level anatomic depth
Growth phase assessment.
Immunohistochemistry
Positive Markers:
S-100 (positive)
Melan-A (positive)
MITF (positive)
SOX10 (positive)
Tyrosinase (positive)
HMB-45 (positive, may be lost in metastases)
MART-1 (positive).
Negative Markers:
Cytokeratins (negative)
EMA (negative)
CD45 (negative)
CD68 (negative, but positive in melanophages)
Desmin (negative)
Smooth muscle actin (negative in most cases).
Diagnostic Utility:
Essential for diagnosis confirmation
S-100 most sensitive but least specific
Melan-A and MITF more specific
SOX10 retained in desmoplastic melanoma
HMB-45 may be lost in spindle cell areas.
Molecular Subtypes:
BRAF-mutated (40-50%)
NRAS-mutated (15-20%)
KIT-mutated (acral, mucosal)
NF1-mutated (desmoplastic)
Triple wild-type
UV signature mutations.
Molecular/Genetic
Genetic Mutations:
BRAF V600E mutations (40-50%)
NRAS mutations (15-20%)
KIT mutations (acral, mucosal subtypes)
NF1 mutations (desmoplastic)
CDKN2A/p16 mutations (familial)
TP53 mutations.
Molecular Markers:
BRAF mutations most common driver
NRAS mutations in sun-exposed skin
KIT amplification in acral/mucosal
TERT promoter mutations
UV mutational signature
Chromosomal instability.
Prognostic Significance:
Breslow thickness most important prognostic factor
Ulceration worsens prognosis
Mitotic rate predicts outcome
Lymph node status crucial
BRAF mutation may predict response to targeted therapy.
Therapeutic Targets:
BRAF inhibitors: vemurafenib, dabrafenib
MEK inhibitors: trametinib, cobimetinib
Immunotherapy: pembrolizumab, nivolumab, ipilimumab
KIT inhibitors: imatinib (KIT-mutated)
Anti-VEGF therapy.
Differential Diagnosis
Similar Entities:
Atypical nevus (dysplastic nevus)
Spitz nevus
Pigmented basal cell carcinoma
Seborrheic keratosis
Pigmented squamous cell carcinoma
Metastatic melanoma.
Distinguishing Features:
Melanoma: Asymmetry and irregular borders
Melanoma: Nuclear atypia and mitoses
Melanoma: Pagetoid spread
Atypical nevus: Symmetry and maturation
Spitz nevus: Spindled and epithelioid cells
BCC: Basaloid cells and palisading.
Diagnostic Challenges:
Atypical nevus vs thin melanoma
Breslow thickness measurement critical
Spitz nevus vs spitzoid melanoma
Immunohistochemistry helpful
Desmoplastic melanoma vs scar
S-100 and SOX10 positive in desmoplastic.
Rare Variants:
Amelanotic melanoma (lacks pigment)
Desmoplastic melanoma (spindle cells, neural differentiation)
Balloon cell melanoma
Clear cell melanoma
Nevoid melanoma
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
[specimen type] from [anatomic site], measuring [size] cm
Diagnosis
Melanoma, [subtype]
Histologic 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]
Ulceration
Ulceration: [present/absent]
Mitotic Rate
Mitotic rate: [X] per mm²
Margins
Margins: [negative/positive], closest margin [X] mm
Lymph Node Status
Lymph nodes: [X] positive out of [X] examined
Special Studies
IHC: [S-100, Melan-A, MITF]: [results]
Molecular: [BRAF, NRAS]: [results]
[other studies]: [results]
TNM Staging
pT[X]N[X]M[X], Stage [I-IV]
Final Diagnosis
Final diagnosis: Melanoma, [subtype], Breslow [X.X] mm, pT[X]N[X]M[X]