Definition/General

Introduction:
-Vulvar small cell carcinoma is an extremely rare, highly aggressive malignant tumor with neuroendocrine differentiation
-Represents the most aggressive subtype of vulvar neuroendocrine carcinoma
-Morphologically identical to pulmonary small cell carcinoma
-Characterized by small cells with scant cytoplasm and high mitotic activity
-Has extremely poor prognosis with early metastasis.
Origin:
-Arises from neuroendocrine cells in vulvar skin or deeper structures
-Merkel cells as potential cell of origin
-Pluripotent stem cells with neuroendocrine commitment
-Transformation from other vulvar tumors possible
-Neural crest derivation
-May be associated with HPV infection
-De novo development from primitive neuroendocrine cells.
Classification:
-Classified as small cell neuroendocrine carcinoma (WHO classification)
-Subtype of poorly differentiated neuroendocrine carcinoma
-Pure small cell carcinoma or mixed with other elements
-Combined small cell carcinoma (with squamous or adenocarcinoma)
-Primary vulvar vs metastatic from lung or other sites.
Epidemiology:
-Peak incidence in 6th-8th decades
-Extremely rare with <30 reported cases worldwide
-Worst prognosis among vulvar malignancies
-Median survival <2 years
-High propensity for metastasis
-Treatment resistance common
-Indian population - no reported cases due to extreme rarity.

Clinical Features

Presentation:
-Rapidly growing vulvar mass
-Ulceration and necrosis
-Bleeding and pain
-Early inguinal lymphadenopathy
-Systemic symptoms at presentation
-Paraneoplastic syndromes
-SIADH (syndrome of inappropriate ADH secretion)
-Distant metastases at diagnosis.
Symptoms:
-Vulvar mass (95-100% cases)
-Rapid growth over weeks to months
-Bleeding (80-90%)
-Pain (70-80%)
-Constitutional symptoms (weight loss, fatigue)
-Paraneoplastic symptoms
-Neurological symptoms (if brain metastases)
-Respiratory symptoms (if lung metastases).
Risk Factors:
-Advanced age (>60 years)
-Smoking history
-Immunosuppression
-Previous malignancy
-Radiation exposure
-Genetic predisposition (extremely rare)
-Environmental carcinogens
-Chronic inflammation.
Screening:
-No specific screening available
-High clinical suspicion for rapidly growing vulvar masses
-Urgent biopsy and diagnosis
-Immediate staging workup
-Serum neuroendocrine markers
-Multidisciplinary team involvement
-Palliative care consideration early.

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Gross Description

Appearance:
-Soft, fleshy, gray-white mass
-Friable consistency
-Extensive necrosis and hemorrhage
-Poorly defined borders
-Infiltrative growth
-Size typically 3-10 cm at presentation
-Ulcerated surface common.
Characteristics:
-Fish-flesh appearance
-Homogeneous gray cut surface
-Soft to firm consistency
-Areas of necrosis and cystic change
-Hemorrhagic areas
-Well-vascularized
-Infiltrative margins
-Satellite nodules.
Size Location:
-Size ranges from 2-15 cm (mean 5-7 cm)
-Can arise anywhere in vulva
-Labia majora most common
-Bartholin gland area
-Clitoral region
-Vestibule
-May be multifocal
-Rapid local spread.
Multifocality:
-Often multifocal at presentation
-Rapid local invasion
-Early lymphatic spread
-Hematogenous metastasis very common
-Liver metastases (most common)
-Lung metastases
-Brain metastases
-Bone involvement.

Microscopic Description

Histological Features:
-Small cells arranged in sheets, nests, or trabecular pattern
-High nuclear-cytoplasmic ratio
-Salt-and-pepper chromatin
-Inconspicuous nucleoli
-Numerous mitoses (>20/10 HPF)
-Extensive necrosis
-Crush artifact common
-Lymphovascular invasion invariable.
Cellular Characteristics:
-Small cells (2-3 times lymphocyte size)
-Scant cytoplasm
-Round to oval nuclei
-Finely granular chromatin
-Nuclear molding
-Fragile cells with crush artifact
-High mitotic rate
-Apoptotic bodies numerous.
Architectural Patterns:
-Solid sheets (most common pattern)
-Nested arrangement
-Trabecular pattern
-Single cell infiltration
-Rosette formation (rare)
-Infiltrative growth
-Perineural invasion
-Vascular invasion common.
Grading Criteria:
-Always considered high-grade (Grade 3)
-Mitotic rate >20/10 HPF
-Extensive necrosis (>50%)
-Ki-67 index >80%
-p53 aberrant expression
-Loss of Rb expression
-High proliferation markers
-Aggressive behavior regardless of size.

Immunohistochemistry

Positive Markers:
-Chromogranin A (60-80% positive)
-Synaptophysin (80-95%)
-CD56/NCAM (90-100%)
-INSM1 (95-100%, most specific)
-TTF-1 (70-90%, distinguishes from extrapulmonary)
-Neuron-specific enolase (80-90%)
-Ki-67 (>80%).
Negative Markers:
-CK5/6 (negative)
-p63 (negative)
-CK7 (usually negative)
-CK20 (negative)
-CDX2 (negative)
-PSA (negative)
-Thyroglobulin (negative)
-Melanoma markers (negative)
-Lymphoid markers (negative).
Diagnostic Utility:
-Essential for confirming neuroendocrine differentiation
-INSM1 most specific marker
-TTF-1 positivity suggests pulmonary origin
-Combination of markers increases diagnostic confidence
-Ki-67 confirms high-grade nature
-Rb loss characteristic
-p53 aberrant pattern common.
Molecular Subtypes:
-TTF-1 positive type: likely metastatic from lung
-TTF-1 negative type: primary vulvar or extrapulmonary origin
-p53-mutated type: aberrant p53 staining
-Rb-deficient type: loss of Rb expression
-High Ki-67 type: >80% proliferation index.

Molecular/Genetic

Genetic Mutations:
-TP53 mutations (80-100%)
-RB1 mutations/deletions (70-90%)
-NOTCH family mutations
-PIK3CA mutations
-MYC amplification
-SOX2 amplification
-FGFR1 amplification
-DNA repair gene mutations.
Molecular Markers:
-Chromosomal instability (high)
-Copy number alterations extensive
-Microsatellite stable (usually)
-High tumor mutational burden
-Aneuploidy
-Telomerase activation
-Oncogene amplifications.
Prognostic Significance:
-Stage most important (often advanced at diagnosis)
-Performance status at presentation
-Response to initial therapy
-Presence of paraneoplastic syndromes
-Extent of metastatic disease
-Median survival 6-24 months
-5-year survival <10%.
Therapeutic Targets:
-Platinum-etoposide chemotherapy (standard)
-Carboplatin-etoposide
-Topotecan (second-line)
-Immunotherapy: PD-1/PD-L1 inhibitors
-Lurbinectedin
-DLL3-targeted therapy
-PARP inhibitors
-Radiation therapy (palliative).

Differential Diagnosis

Similar Entities:
-Metastatic small cell carcinoma (lung, other sites)
-Merkel cell carcinoma
-Poorly differentiated neuroendocrine carcinoma
-Lymphoma
-Melanoma
-Ewing sarcoma/PNET
-Rhabdomyosarcoma
-Poorly differentiated carcinoma NOS.
Distinguishing Features:
-Primary vulvar: no lung primary, TTF-1 may be negative
-Metastatic lung: TTF-1 positive, lung primary on imaging
-Merkel cell: CK20+, specific morphology
-Lymphoma: CD45+, lymphoid markers
-Melanoma: melanoma markers positive
-Clinical correlation essential.
Diagnostic Challenges:
-Distinguishing primary from metastatic
-TTF-1 interpretation (can be positive in primary)
-Crush artifact affecting morphology
-Small biopsy samples
-Urgent diagnosis required
-Immunohistochemistry panel essential
-Clinical staging crucial.
Rare Variants:
-Combined small cell carcinoma (with squamous/adenocarcinoma)
-Small cell carcinoma with rhabdoid features
-Small cell carcinoma with sarcomatoid features
-Large cell neuroendocrine carcinoma
-Composite small cell-squamous carcinoma.

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 with extensive necrosis

Diagnosis

Small cell neuroendocrine carcinoma

Classification

Type: Small cell carcinoma, Grade: High-grade (Grade 3), Primary vs Metastatic: [assessment]

Histological Features

Shows [small cell morphology] with [high mitotic activity] and [extensive necrosis]

Small Cell Features

Cell size: [2-3x lymphocyte], chromatin: [salt-and-pepper], cytoplasm: [scant], mitoses: [>20/10 HPF]

Necrosis and Invasion

Necrosis: [extensive, >50%], lymphovascular invasion: [present], perineural invasion: [present/absent]

Tumor Size

Tumor size: [X] cm, viable tumor: [X] cm (after excluding necrosis)

Margins

Margins: [involved/close/clear], closest margin [X] mm

Special Studies

Neuroendocrine markers: Chromogranin: [result], Synaptophysin: [result], INSM1: [result]

TTF-1: [positive/negative] (primary vs metastatic assessment)

Ki-67 proliferation index: [X]% (high-grade)

Primary vs Metastatic Assessment

Assessment: [primary vulvar/metastatic from lung/indeterminate], TTF-1: [result], clinical correlation recommended

Prognostic Factors

Poor prognostic factors: small cell histology, high grade, extensive necrosis, early metastasis

Final Diagnosis

Vulvar small cell neuroendocrine carcinoma, high-grade, [primary/metastatic assessment]

Clinical Note

Note: Extremely aggressive tumor requiring urgent multidisciplinary management and staging