Definition/General
Introduction:
Fallopian tube large cell carcinoma is an extremely rare variant of tubal carcinoma with neuroendocrine differentiation
It represents less than 1% of all fallopian tube carcinomas
The tumor is characterized by large cells with abundant cytoplasm and neuroendocrine features
It demonstrates aggressive biological behavior with poor prognosis
The diagnosis requires demonstration of neuroendocrine markers by immunohistochemistry.
Origin:
Originates from the epithelial cells of the fallopian tube that undergo neuroendocrine differentiation
The neuroendocrine transformation may occur de novo or within pre-existing adenocarcinoma
Molecular mechanisms involving neuroendocrine transcription factors (ASCL1, NEUROD1) are implicated
The tumor may arise from stem cell populations with pluripotent differentiation capacity
Environmental factors and genetic predisposition may contribute to development.
Classification:
WHO classification includes it under neuroendocrine tumors of the female genital tract
Large cell neuroendocrine carcinoma (LCNEC) is the preferred terminology
Distinguished from small cell carcinoma by larger cell size and abundant cytoplasm
High-grade neuroendocrine carcinoma category includes both large cell and small cell types
Grading is uniformly high-grade (Grade 3)
Staging follows FIGO system for fallopian tube carcinomas.
Epidemiology:
Extremely rare with fewer than 50 cases reported in literature
Peak incidence in 6th-7th decades (similar to other tubal carcinomas)
No specific racial predilection identified
No association with BRCA mutations established
May be associated with smoking (similar to pulmonary large cell NEC)
No specific geographic clustering reported
Incidence may be underreported due to diagnostic challenges.
Clinical Features
Presentation:
Rapidly growing pelvic mass with aggressive clinical course
Severe pelvic pain due to mass effect and rapid growth
Abnormal vaginal bleeding (postmenopausal or irregular)
Abdominal distension and bloating
Constitutional symptoms (weight loss, fatigue, night sweats)
Paraneoplastic syndromes may occur (SIADH, ectopic ACTH)
Rapid clinical deterioration distinguishes from typical adenocarcinomas.
Symptoms:
Severe pelvic cramping and constant pain
Heavy vaginal bleeding or postmenopausal bleeding
Early satiety and abdominal fullness
Unexplained weight loss (>10% body weight)
Fatigue and weakness
Nausea and vomiting
Paraneoplastic symptoms (hyponatremia from SIADH, Cushing syndrome from ectopic ACTH)
Neurological symptoms from brain metastases.
Risk Factors:
Smoking history (potential association similar to pulmonary LCNEC)
Advanced age (>60 years)
No established association with BRCA mutations
No clear hereditary pattern identified
Possible environmental exposures (occupational carcinogens)
No association with reproductive factors
No protective effect of oral contraceptives established.
Screening:
No specific screening protocols due to extreme rarity
Standard gynecological examination and imaging for pelvic masses
High index of suspicion for rapidly growing adnexal masses
CA-125 levels may be elevated but non-specific
Neuroendocrine markers (chromogranin, synaptophysin) not used for screening
Genetic counseling may be considered despite no clear hereditary pattern.
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Gross Description
Appearance:
Large, bulky tumor replacing normal tubal architecture
Tan to gray-brown cut surface with areas of necrosis and hemorrhage
Soft to firm consistency depending on degree of necrosis
Friable surface with easy bleeding on manipulation
Well-circumscribed to infiltrative margins
Extensive necrosis (30-50% of tumor volume) is characteristic
Hemorrhagic areas throughout the tumor.
Characteristics:
Heterogeneous appearance with solid and necrotic areas
Tan-brown discoloration from extensive necrosis
Soft, fleshy consistency in viable areas
Geographic necrosis with sharp demarcation
Vascular proliferation visible as prominent vessels
Calcifications may be present but less common than in serous carcinomas
Extension into adjacent structures common.
Size Location:
Size ranges from 5-15 cm (typically larger than other tubal carcinomas)
May involve entire fallopian tube length
Preferential involvement of ampullary and fimbrial portions
Bilateral involvement in 20-30% of cases
Extension to ovaries common at presentation
Peritoneal implants frequently present
Retroperitoneal lymph node involvement common.
Multifocality:
Often unifocal but extensive at presentation
Satellite nodules may be present
Vascular invasion leads to distant metastases
Peritoneal seeding common at diagnosis
Hematogenous spread to liver, lung, and brain
Lymphatic spread to para-aortic and pelvic lymph nodes
Skip metastases may occur.
Microscopic Description
Histological Features:
Large epithelial cells with abundant eosinophilic to amphophilic cytoplasm
Pleomorphic nuclei with prominent nucleoli and coarse chromatin
Sheet-like growth pattern with areas of solid nesting
High mitotic activity (>20 mitoses per 10 HPF)
Geographic necrosis with abrupt transition
Vascular invasion commonly present
Crush artifact may be seen in small biopsies.
Cellular Characteristics:
Large cells (3-4 times normal epithelial cell size) with well-defined cell borders
Abundant cytoplasm (eosinophilic to amphophilic)
Large, vesicular nuclei with prominent, often multiple nucleoli
Coarse chromatin pattern with nuclear membrane irregularities
Multinucleated giant cells may be present
Mitotic figures including atypical forms
Apoptotic bodies scattered throughout.
Architectural Patterns:
Solid sheet-like pattern predominates (>70% of cases)
Nesting pattern with peripheral palisading
Trabecular arrangement in some areas
Rosette formation (true rosettes rare, pseudorosettes more common)
Organoid pattern with central necrosis
Diffuse infiltrative pattern into surrounding stroma
Vascular invasion with tumor emboli.
Grading Criteria:
High-grade neuroendocrine carcinoma by definition (Grade 3)
Mitotic count >20 per 10 HPF
Necrosis present in >50% of cases
Nuclear pleomorphism marked (Grade 3)
Ki-67 proliferation index >55%
No grading system specific for tubal LCNEC
WHO criteria for neuroendocrine carcinomas apply.
Immunohistochemistry
Positive Markers:
Synaptophysin (positive in 90-95% of cases, diffuse cytoplasmic staining)
Chromogranin A (positive in 70-80%, may be focal)
CD56 (NCAM) (positive in 85-90%, membranous pattern)
TTF-1 (may be positive in 30-40%, nuclear staining)
CK7 (positive, confirms epithelial origin)
PAX8 (positive, confirms müllerian origin)
p53 (often mutant pattern).
Negative Markers:
CK20 (negative, excludes gastrointestinal origin)
CDX2 (negative, excludes intestinal origin)
ER/PR (typically negative)
WT1 (usually negative, unlike serous carcinomas)
Inhibin (negative, excludes sex cord-stromal tumors)
Calretinin (negative, excludes mesothelioma)
Cytokeratins 5/6 (negative).
Diagnostic Utility:
Neuroendocrine markers (synaptophysin, chromogranin, CD56) essential for diagnosis
At least 2 of 3 markers should be positive for diagnosis
PAX8 positivity confirms müllerian/gynecological origin
TTF-1 positivity may suggest pulmonary metastasis (requires clinical correlation)
High Ki-67 (>55%) confirms high-grade nature
p53 aberrant pattern may be present.
Molecular Subtypes:
ASCL1-positive subtype (similar to pulmonary small cell carcinoma)
NEUROD1-positive subtype (alternative neuroendocrine program)
POU2F3-positive subtype (tuft cell-like features)
p53-mutant subtype (majority of cases)
RB1-deficient subtype (cell cycle dysregulation)
Mixed subtype (with adenocarcinoma components).
Molecular/Genetic
Genetic Mutations:
TP53 mutations (present in 80-90% of cases)
RB1 mutations (common in neuroendocrine carcinomas, 60-70%)
MYC amplification (associated with aggressive behavior)
MYCL amplification (specific for neuroendocrine carcinomas)
PIK3CA mutations (less common, 10-20%)
KRAS mutations (uncommon)
BRCA1/2 mutations (not typically associated).
Molecular Markers:
Neuroendocrine transcription factors (ASCL1, NEUROD1, POU2F3)
p53 protein accumulation (correlates with TP53 mutations)
RB protein loss (correlates with RB1 mutations)
High proliferation markers (Ki-67 >55%)
Chromatin remodeling genes (CREBBP, EP300 mutations)
DNA repair pathway genes (may be altered)
Chromosomal instability (complex karyotype).
Prognostic Significance:
Extremely poor prognosis (median survival 6-12 months)
Advanced stage at diagnosis (majority present as Stage III-IV)
Rapid disease progression despite treatment
High metastatic potential to brain, liver, and lung
Poor response to standard chemotherapy
Resistance to platinum-based therapy
p53 mutation status may influence treatment response.
Therapeutic Targets:
Platinum plus etoposide (similar to small cell lung cancer regimen)
Topoisomerase inhibitors (topotecan, irinotecan)
PD-1/PD-L1 inhibitors (immunotherapy for high TMB cases)
PARP inhibitors (if DNA repair defects present)
Aurora kinase inhibitors (targeting cell cycle)
BCL-2 inhibitors (targeting apoptosis resistance)
mTOR inhibitors (targeting growth signaling).
Differential Diagnosis
Similar Entities:
Small cell carcinoma of fallopian tube (smaller cells, less cytoplasm)
Poorly differentiated adenocarcinoma (lacks neuroendocrine markers)
Metastatic large cell neuroendocrine carcinoma from lung
Undifferentiated carcinoma (lacks specific lineage markers)
Sarcomatoid carcinoma (spindle cell morphology)
Lymphoma (lymphoid markers positive)
Melanoma (S-100, melanoma markers positive).
Distinguishing Features:
Large cell vs small cell: Cell size, amount of cytoplasm, nuclear features
LCNEC vs adenocarcinoma: Neuroendocrine markers, morphology, behavior
Primary vs metastatic: Clinical history, PAX8 positivity, imaging findings
LCNEC vs undifferentiated: Neuroendocrine marker expression
Carcinoma vs lymphoma: Epithelial markers (CK7, PAX8) vs lymphoid markers.
Diagnostic Challenges:
Distinguishing from metastatic LCNEC (especially pulmonary origin)
Crush artifact in small biopsies may obscure morphology
Focal neuroendocrine marker expression may be missed
Mixed tumors with adenocarcinoma components
Poor preservation due to extensive necrosis
Limited tissue for comprehensive immunohistochemical workup.
Rare Variants:
Mixed large cell neuroendocrine and adenocarcinoma
Large cell neuroendocrine with sarcomatoid features
LCNEC with clear cell changes
Composite tumor with other histological types
LCNEC with rhabdoid features
Pleomorphic variant with giant cells
LCNEC with squamous differentiation.
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
[Unilateral/Bilateral] salpingo-oophorectomy, fallopian tube measuring [size] cm with bulky tumor
Diagnosis
Large cell neuroendocrine carcinoma of fallopian tube
Classification
High-grade neuroendocrine carcinoma (Grade 3)
Histological Features
Shows large cells with abundant cytoplasm, pleomorphic nuclei, sheet-like growth pattern, and extensive necrosis
Neuroendocrine Features
High mitotic activity (>20/10 HPF), geographic necrosis, organoid growth pattern
Extent of Disease
Size: [X] cm, Extensive necrosis: [percentage], Vascular invasion: [present/absent]
Special Studies
Synaptophysin: positive, Chromogranin A: [positive/negative], CD56: positive
CK7: positive, PAX8: positive (confirming müllerian origin)
Ki-67 index: [>55%] - high-grade
Molecular Features
p53: [aberrant pattern], TTF-1: [positive/negative], Consider molecular profiling for targeted therapy
FIGO Staging
FIGO Stage: [IA/IB/IC/II/III/IV] - [staging details]
Prognostic Factors
Large cell neuroendocrine carcinoma (poor prognosis), High-grade (Grade 3), Extensive necrosis, High proliferation index
Final Diagnosis
Primary fallopian tube large cell neuroendocrine carcinoma, FIGO Stage [IA/IB/IC/II/III/IV]