Definition/General
Introduction:
Primary esophageal melanoma is an extremely rare malignancy representing 0.1-0.2% of all esophageal tumors and 0.5% of all melanomas
Arises from melanocytes present in normal esophageal mucosa
Shows extremely poor prognosis with median survival 10-15 months
Most cases are metastatic disease rather than primary tumors.
Origin:
Arises from melanocytes normally present in esophageal basal epithelium
Melanocytes comprise 4-8% of basal layer cells in normal esophagus
Undergoes malignant transformation similar to cutaneous melanoma
Associated with junctional melanocytic proliferation
May arise from pre-existing melanosis or melanocytic hyperplasia.
Classification:
WHO classification as primary melanoma of esophagus
Requires absence of cutaneous or ocular primary
Staging follows AJCC melanoma staging system
Clark levels not applicable
Breslow thickness not standard measure
Ulceration and mitotic rate important prognostic factors.
Epidemiology:
Peak incidence in 5th-6th decades
No significant gender predilection
Higher prevalence in Japanese population
No association with sun exposure
No racial predisposition unlike cutaneous melanoma
Most cases occur in distal esophagus.
Clinical Features
Presentation:
Progressive dysphagia (70-80% cases)
Weight loss and anorexia
Retrosternal chest pain
Upper GI bleeding (hematemesis, melena)
Heartburn and reflux symptoms
Regurgitation
Iron deficiency anemia
Advanced cases may present with metastatic symptoms.
Symptoms:
Dysphagia initially to solids
Progressive dysphagia to liquids
Significant weight loss (>20% body weight)
Constitutional symptoms prominent
Bone pain from skeletal metastases
Neurological symptoms (brain metastases)
Abdominal pain from liver metastases.
Risk Factors:
Pre-existing melanosis (most important)
Barrett's esophagus (possible association)
Gastroesophageal reflux disease
Genetic factors (BRAF, NRAS mutations)
Previous radiation exposure
Immunosuppression
Age >50 years
No association with UV exposure.
Screening:
Upper endoscopy for high-risk patients
Chromoendoscopy to identify melanotic lesions
Full-body skin examination to exclude cutaneous primary
Ophthalmologic examination to exclude ocular primary
PET-CT scan for staging
Brain MRI for CNS metastases.
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Gross Description
Appearance:
Polypoid or ulcerated mass with irregular surface
Black or dark brown pigmentation typical but not always present
Amelanotic variants appear gray-white
Friable consistency with easy bleeding
Necrotic areas common
Surface may show satellite nodules.
Characteristics:
Size ranges from 2-15 cm at presentation
Circumferential growth pattern common
Deep infiltration through esophageal wall
Variable pigmentation - may be heavily pigmented or amelanotic
Soft to firm consistency
Hemorrhage and necrosis frequent.
Size Location:
Most common in distal third of esophagus (60-70%)
Middle third involvement (20-25%)
Proximal third involvement (10-15%)
Average size at presentation 6-10 cm
Multifocal disease in 15-20% cases
Skip lesions may be present.
Multifocality:
Satellite lesions around main tumor
In-transit metastases in esophageal wall
Associated melanosis in adjacent mucosa
Junctional melanocytic activity at tumor periphery
Regional lymph node involvement common
Submucosal spread extensive.
Microscopic Description
Histological Features:
Epithelioid cells most common pattern
Spindle cell pattern in 20-30% cases
Mixed epithelioid and spindle pattern
Variable melanin pigmentation
Prominent nucleoli
High mitotic activity
Junctional activity at interface with normal epithelium.
Cellular Characteristics:
Large epithelioid cells with abundant eosinophilic cytoplasm
Vesicular nuclei with prominent nucleoli
Melanin pigment in cytoplasm (variable)
Spindle cells in some areas
Nuclear pleomorphism prominent
Mitotic figures numerous (>6 per mm²)
Atypical mitoses present.
Architectural Patterns:
Sheet-like growth pattern most common
Nested pattern with alveolar arrangement
Fascicular pattern in spindle cell areas
Pagetoid spread in overlying epithelium
Desmoplastic response variable
Lymphovascular invasion common
Perineural invasion may be seen.
Grading Criteria:
No standard grading system for esophageal melanoma
Mitotic rate important (>6 per mm² indicates poor prognosis)
Ulceration indicates aggressive behavior
Breslow thickness not applicable
Clark levels not used
Tumor thickness and depth of invasion prognostically important.
Immunohistochemistry
Positive Markers:
S-100 protein positive (95-100%)
Melan-A positive (85-90%)
HMB-45 positive (70-80%)
MITF positive (90-95%)
SOX10 positive (90-95%)
Tyrosinase positive (70%)
PNL2 positive (newer marker)
PRAME positive (70-80%).
Negative Markers:
Cytokeratins negative (AE1/AE3, CK7, CK20)
p63 negative
TTF-1 negative
CDX2 negative
Desmin negative
CD68 negative (differentiates from melanophages)
EMA negative
Chromogranin A negative.
Diagnostic Utility:
S-100 and SOX10 most sensitive markers
Melan-A and HMB-45 more specific
Combination of markers increases diagnostic accuracy
Negative cytokeratins exclude carcinoma
MITF shows nuclear positivity
BRAF V600E mutation testing important.
Molecular Subtypes:
BRAF-mutated subtype (40-50%) potentially targetable
NRAS-mutated subtype (20-30%)
KIT-mutated subtype (10-15%) rare
Triple wild-type subtype (20-30%)
c-KIT expression variable
PD-L1 expression variable (20-40%).
Molecular/Genetic
Genetic Mutations:
BRAF mutations (40-50%), mainly V600E
NRAS mutations (20-30%), mainly Q61
KIT mutations (10-15%) in exons 9, 11, 13, 17
GNAQ/GNA11 mutations rare
BAP1 mutations occasional
TERT promoter mutations (30-40%).
Molecular Markers:
BRAF V600E mutation in 40-50% cases
KIT overexpression in subset of cases
p16 loss frequent
p53 mutations common
PTEN loss in some cases
Cyclin D1 amplification
MDM2 amplification occasionally.
Prognostic Significance:
BRAF mutations may predict response to targeted therapy
KIT mutations predict imatinib response
High tumor mutational burden may predict immunotherapy response
TERT mutations associated with worse prognosis
Chromosome 3 monosomy rare (unlike uveal melanoma).
Therapeutic Targets:
BRAF inhibitors (dabrafenib, vemurafenib) for BRAF-mutated tumors
MEK inhibitors (trametinib) in combination
KIT inhibitors (imatinib) for KIT-mutated tumors
Immunotherapy (anti-PD-1, anti-CTLA-4)
Adoptive cell therapy under investigation.
Differential Diagnosis
Similar Entities:
Metastatic melanoma from cutaneous or ocular primary
Poorly differentiated carcinoma
Sarcoma (especially leiomyosarcoma)
Melanophages or melanosis
Gastrointestinal stromal tumor (GIST)
Lymphoma
Carcinoid tumor with melanin-like pigment.
Distinguishing Features:
Primary melanoma: junctional activity present
Primary melanoma: associated melanosis
Metastatic melanoma: no junctional activity
Metastatic melanoma: clinical history of primary elsewhere
Carcinoma: cytokeratin positive
Sarcoma: specific sarcoma markers positive
GIST: CD117, DOG1 positive.
Diagnostic Challenges:
Distinguishing primary from metastatic melanoma
Amelanotic variants difficult to recognize
Small biopsy specimens may be inadequate
Excluding occult cutaneous or ocular primary
Differentiating from pigmented carcinoma.
Rare Variants:
Amelanotic melanoma (20-30% cases)
Desmoplastic melanoma with fibrous stroma
Balloon cell melanoma
Clear cell melanoma
Rhabdoid melanoma
Small cell melanoma
Melanoma with myxoid stroma.
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
Esophagectomy specimen with [pigmented/non-pigmented] tumor in [location], measuring [size] cm
Diagnosis
Melanoma, [primary/metastatic if known]
Histological Features
Shows [epithelioid/spindle/mixed] cell melanoma with [melanin pigmentation status]
Junctional Activity
Junctional melanocytic activity: [present/absent] (indicates [primary/metastatic])
Mitotic Activity
Mitotic rate: [X] per mm². Ulceration: [present/absent]
Size and Extent
Tumor thickness: [X] mm. Greatest dimension: [X] cm. Depth of invasion: [level]
Invasion Status
Lymphovascular invasion: [present/absent]. Perineural invasion: [present/absent]
Margins
Margins: [status and distances]
Lymph Node Status
Lymph nodes: [X] positive out of [X] examined
Special Studies
IHC: S-100 [+/-], Melan-A [+/-], HMB-45 [+/-], SOX10 [+/-]
Molecular: BRAF [status], NRAS [status], KIT [status] if performed
Final Diagnosis
Melanoma, [cell type], [primary/metastatic], with [mitotic activity] and [ulceration status]