Definition/General
Introduction:
Vulvar neuroendocrine carcinoma is an extremely rare malignant tumor with neuroendocrine differentiation arising from the vulva
Represents <1% of all vulvar malignancies
Can be pure neuroendocrine or mixed with squamous/adenocarcinomatous elements
Shows aggressive behavior with high metastatic potential
Diagnosis requires immunohistochemical confirmation of neuroendocrine markers.
Origin:
May arise from neuroendocrine cells normally present in vulvar skin
Merkel cells as potential source
Pluripotent stem cells with neuroendocrine differentiation
Malignant transformation of benign neuroendocrine proliferation
Neural crest origin
May arise in association with HPV infection
De novo development most common.
Classification:
WHO classification: Well-differentiated neuroendocrine tumor (carcinoid)
Moderately differentiated neuroendocrine carcinoma
Poorly differentiated neuroendocrine carcinoma (small cell type)
Mixed neuroendocrine-non-neuroendocrine neoplasm
Large cell neuroendocrine carcinoma
Small cell neuroendocrine carcinoma.
Epidemiology:
Peak incidence in 6th-7th decades
Extremely rare with <50 cases reported worldwide
Poor prognosis overall
High propensity for metastasis
Frequent recurrence after treatment
Paraneoplastic syndromes possible
Indian population - no specific data due to extreme rarity.
Clinical Features
Presentation:
Vulvar mass or nodule
Rapid growth
Ulceration and bleeding
Pain and discomfort
Inguinal lymphadenopathy
Systemic symptoms (paraneoplastic syndromes)
Flushing and diarrhea (carcinoid syndrome)
Early metastasis.
Symptoms:
Vulvar mass (90-95% cases)
Bleeding (60-80%)
Pain (50-70%)
Pruritus (30-40%)
Carcinoid syndrome (flushing, diarrhea) if functional
Weight loss
Fatigue
Paraneoplastic symptoms
Rapid symptom progression.
Risk Factors:
Advanced age (>60 years)
Immunosuppression
HPV infection (controversial)
Chronic vulvar inflammation
Previous malignancy
Genetic predisposition (rare)
Environmental carcinogens
Radiation exposure.
Screening:
No specific screening guidelines
High index of suspicion for unusual vulvar tumors
Immunohistochemistry essential for diagnosis
Serum neuroendocrine markers (chromogranin A, neuron-specific enolase)
Imaging for staging and metastasis detection
Multidisciplinary approach.
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Gross Description
Appearance:
Firm, gray-white nodule or mass
Well-circumscribed or infiltrative borders
Fleshy, solid consistency
Areas of necrosis and hemorrhage
Tan to gray coloration
Size varies from 1-10 cm
Ulcerated surface possible.
Characteristics:
Solid, firm tumor
Homogeneous cut surface
Fish-flesh appearance
Well-vascularized
Areas of cystic change possible
Calcifications rare
Infiltrative growth pattern
Satellite lesions possible.
Size Location:
Size ranges from 1-15 cm (mean 3-5 cm)
Can occur anywhere in vulva
Labia majora most common site
Clitoral area
Vestibule
Bartholin gland area
Unilateral involvement typical.
Multifocality:
Usually unifocal
Early lymphatic spread
Hematogenous metastasis common
Liver metastases frequent
Bone metastases
Lung involvement
Skip metastases to distant lymph nodes.
Microscopic Description
Histological Features:
Sheets, nests, or trabecular pattern
Monotonous cell population
High nuclear-cytoplasmic ratio
Salt-and-pepper chromatin
Inconspicuous nucleoli
Abundant mitoses
Necrosis common
Lymphovascular invasion frequent.
Cellular Characteristics:
Small to medium-sized cells
Round to oval nuclei
Finely granular chromatin
Scant cytoplasm
Nuclear molding
Crush artifact common
Mitotic activity high
Apoptotic bodies frequent.
Architectural Patterns:
Solid sheets (most common)
Nested pattern
Trabecular arrangement
Rosette formation (rare)
Ribbon-like pattern
Insular pattern
Infiltrative growth
Perineural invasion common.
Grading Criteria:
Well-differentiated: <2 mitoses/10 HPF, no necrosis
Moderately differentiated: 2-20 mitoses/10 HPF, focal necrosis
Poorly differentiated: >20 mitoses/10 HPF, extensive necrosis
Ki-67 index: <3% (low), 3-20% (intermediate), >20% (high)
Small cell type: always high-grade.
Immunohistochemistry
Positive Markers:
Chromogranin A (70-90% positive)
Synaptophysin (80-95%)
CD56/NCAM (90-95%)
Neuron-specific enolase (80-90%)
INSM1 (95-100%, most specific)
CD117/c-kit (variable)
TTF-1 (small cell type)
Ki-67 (high proliferation).
Negative Markers:
CK5/6 (negative, excludes squamous)
p63 (negative)
CK7 (usually negative)
CK20 (negative)
TTF-1 (negative except small cell)
CDX2 (negative)
PSA (negative)
Melanoma markers (negative).
Diagnostic Utility:
Essential for confirming neuroendocrine differentiation
INSM1 most specific and sensitive
Chromogranin and synaptophysin classic markers
CD56 supportive but not specific
Ki-67 for grading
TTF-1 suggests pulmonary primary if positive
Exclude metastatic disease.
Molecular Subtypes:
Small cell type: TTF-1+, aggressive behavior
Large cell type: TTF-1 variable
Well-differentiated type: lower Ki-67
Carcinoid type: classic neuroendocrine markers
Mixed type: neuroendocrine + epithelial markers
SCLC-like: similar to lung small cell carcinoma.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (60-80%)
RB1 mutations (small cell type)
NOTCH mutations
MEN1 gene alterations
DAXX/ATRX mutations (well-differentiated)
Chromatin remodeling genes
DNA repair gene mutations
Oncogene amplifications.
Molecular Markers:
Chromosomal instability
High tumor mutational burden
Microsatellite instability (rare)
Neuroendocrine transcription factors
Chromatin modifications
Angiogenesis markers
Apoptosis resistance.
Prognostic Significance:
Grade most important prognostic factor
Stage at presentation
Ki-67 index correlates with outcome
Small cell type worst prognosis
Metastatic disease at diagnosis common
Treatment resistance frequent
Overall 5-year survival <30%.
Therapeutic Targets:
Platinum-based chemotherapy
Etoposide (small cell type)
Somatostatin analogs (functional tumors)
Targeted therapy: mTOR inhibitors
Immunotherapy: checkpoint inhibitors
Peptide receptor radionuclide therapy
Surgery for localized disease.
Differential Diagnosis
Similar Entities:
Metastatic neuroendocrine carcinoma
Merkel cell carcinoma
Small cell carcinoma
Poorly differentiated carcinoma
Malignant melanoma
Lymphoma
Ewing sarcoma/PNET
Rhabdomyosarcoma.
Distinguishing Features:
Primary NET: appropriate immunoprofile, no primary elsewhere
Metastatic: clinical history, imaging findings
Merkel cell: CK20+, TTF-1-, specific location
Melanoma: S-100+, melanoma markers+
Lymphoma: CD45+, B/T-cell markers
Clinical correlation essential.
Diagnostic Challenges:
Distinguishing primary from metastatic
Small biopsy material limitations
Crush artifact affecting morphology
Mixed tumors with focal neuroendocrine differentiation
Poorly differentiated carcinomas with neuroendocrine features
Extensive sampling needed.
Rare Variants:
Composite neuroendocrine-squamous carcinoma
Adenoneuroendocrine carcinoma
Paraganglioma-like tumor
Carcinoid with squamous differentiation
Large cell neuroendocrine carcinoma
Mixed neuroendocrine-epithelial tumor.
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
Vulvar excision from [site], measuring [size] cm
Diagnosis
Neuroendocrine carcinoma, [subtype]
Classification and Grade
Type: [small cell/large cell/carcinoid], Grade: [well/moderate/poorly differentiated]
Histological Features
Shows [growth pattern] with [neuroendocrine morphology] and [mitotic activity]
Neuroendocrine Features
Cell morphology: [small/large cells], chromatin: [salt-and-pepper/vesicular], nucleoli: [inconspicuous/prominent]
Tumor Size
Tumor size: [X] cm in greatest dimension
Margins
Margins: [clear/involved], closest margin [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Special Studies
IHC: Chromogranin: [result], Synaptophysin: [result], INSM1: [result]
Ki-67 proliferation index: [X]%
[other study]: [result]
Grading
Mitotic rate: [X]/10 HPF, Necrosis: [present/absent], Ki-67: [X]%
Prognostic Factors
Risk factors: grade, size, stage, Ki-67 index, subtype
Final Diagnosis
Vulvar neuroendocrine carcinoma, [subtype], [grade]