Definition/General
Introduction:
Endometrial melanoma is an extremely rare malignant tumor arising from melanocytes in the uterus
It represents less than 0.1% of all uterine malignancies
It can be primary or metastatic
Primary endometrial melanoma is exceedingly uncommon.
Origin:
May arise from ectopic melanocytes in endometrium
Possible origin from neural crest cells
Can develop from melanocytic nevi in uterus
Most cases are metastatic from cutaneous or other sites
Primary uterine melanoma extremely rare.
Classification:
Classified as melanocytic tumor
Primary vs metastatic distinction crucial
Epithelioid, spindle cell, or mixed morphology
Amelanotic variants possible
High-grade malignant neoplasm.
Epidemiology:
Extremely rare tumor
Peak incidence in 5th-6th decades
Postmenopausal women predominantly affected
Most cases are metastatic melanoma
Primary uterine melanoma case reports only
No clear racial predilection.
Clinical Features
Presentation:
Abnormal uterine bleeding (most common)
Postmenopausal bleeding
Pelvic mass
Dark-colored discharge
Rapidly progressive symptoms
History of melanoma elsewhere.
Symptoms:
Heavy uterine bleeding
Dark, bloody discharge
Pelvic pain
Abdominal distension
Constitutional symptoms
Weight loss
Systemic metastases symptoms.
Risk Factors:
Previous cutaneous melanoma
History of melanoma at other sites
Fair skin
UV exposure (for primary cutaneous)
Familial melanoma syndrome
Immunosuppression.
Screening:
No specific screening
Thorough history of previous melanoma essential
Complete skin examination
Imaging for staging workup
Ophthalmologic examination.
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Gross Description
Appearance:
Black or dark brown polypoid mass
May be amelanotic (tan-gray)
Soft, friable consistency
Areas of hemorrhage and necrosis
Pigmented cut surface.
Characteristics:
Size ranges from 2-10 cm
Polypoid or sessile configuration
Melanin pigmentation variable
Hemorrhagic areas
Ulcerated surface common.
Size Location:
Variable size at presentation
Involves endometrial cavity
May extend to myometrium
Cervical involvement possible
Extrauterine spread common if metastatic.
Multifocality:
Usually unifocal in uterus
Multiple organ involvement if metastatic
Lymph node metastases common
Hematogenous spread typical pattern.
Microscopic Description
Histological Features:
Malignant melanocytes with marked atypia
Epithelioid or spindle cell morphology
Melanin pigment in cytoplasm
Prominent nucleoli
High mitotic activity
Necrosis common.
Cellular Characteristics:
Large, pleomorphic cells
Abundant eosinophilic cytoplasm
Vesicular nuclei
Prominent red nucleoli
Melanin granules (variable)
Multinucleated cells.
Architectural Patterns:
Solid sheets of cells
Alveolar pattern
Single file infiltration
Organoid pattern
Spindle cell fascicles
Extensive necrosis.
Grading Criteria:
All cases considered high-grade
High mitotic rate (>5/mm²)
Marked nuclear atypia
Ulceration (if applicable)
Breslow thickness (for primary cutaneous).
Immunohistochemistry
Positive Markers:
S-100 (diffuse, strong positivity)
Melan-A (MART-1)
HMB-45
Tyrosinase
SOX10 (nuclear)
Microphthalmia transcription factor (MITF)
Vimentin.
Negative Markers:
Cytokeratins (negative)
Desmin (negative)
CD45 (negative)
CD117 (negative)
Chromogranin (negative)
Synaptophysin (negative).
Diagnostic Utility:
S-100 positivity highly sensitive for melanoma
Melan-A and HMB-45 specific for melanocytes
SOX10 highly sensitive and specific
MITF transcription factor
Panel approach recommended.
Molecular Subtypes:
BRAF mutations (V600E most common)
NRAS mutations
KIT mutations (acral/mucosal)
GNAQ/GNA11 (uveal)
BAP1 loss (uveal).
Molecular/Genetic
Genetic Mutations:
BRAF V600E mutation (40-50%)
NRAS mutations (20-25%)
KIT mutations (mucosal melanomas)
TP53 mutations
CDKN2A deletions
PTEN loss.
Molecular Markers:
BRAF V600E protein expression
p16 loss
High Ki-67 index
PTEN loss
p53 overexpression
Chromosomal instability.
Prognostic Significance:
BRAF mutations may predict therapy response
Breslow thickness most important prognostic factor
Ulceration indicates poor prognosis
Mitotic rate correlates with outcome
Stage most important factor.
Therapeutic Targets:
BRAF inhibitors (vemurafenib, dabrafenib)
MEK inhibitors (trametinib)
Immunotherapy (pembrolizumab, nivolumab)
KIT inhibitors (imatinib for KIT-mutant)
Anti-PD-1/PD-L1 agents.
Differential Diagnosis
Similar Entities:
Undifferentiated carcinoma
Poorly differentiated sarcoma
Epithelioid smooth muscle tumor
Pigmented epithelioid melanocytoma
Clear cell carcinoma.
Distinguishing Features:
Carcinoma: Cytokeratin positive
Sarcoma: Specific markers positive
Melanoma: S-100, Melan-A positive
Melanoma: Melanin pigment
PEComa: HMB-45 and smooth muscle actin positive.
Diagnostic Challenges:
Distinguishing primary from metastatic
Recognizing amelanotic melanoma
Excluding other malignancies
Confirming melanocytic origin
Immunohistochemistry essential.
Rare Variants:
Epithelioid melanoma
Spindle cell melanoma
Amelanotic melanoma
Desmoplastic melanoma
Balloon cell 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], measuring [size] cm, [pigmented/amelanotic] appearance
Diagnosis
Malignant melanoma of the endometrium
Classification
[Primary/Metastatic] melanoma, [epithelioid/spindle cell/mixed] type
Histological Features
Malignant melanocytic tumor, melanin pigment [present/absent], mitoses: [count]/mm²
Melanin Pigmentation
Melanin pigment: [abundant/moderate/minimal/absent]
Immunohistochemistry
Melanocytic markers: S-100 [+/-], Melan-A [+/-], HMB-45 [+/-]
SOX10: [+/-], MITF: [+/-]
Negative: Cytokeratins, Desmin, CD45
Molecular Studies
BRAF V600E: [mutated/wild-type/not performed]
Clinical Correlation
History of melanoma: [yes/no/unknown], sites: [specify if known]
Final Diagnosis
[Primary/Metastatic] melanoma of endometrium, [subtype]