Definition/General
Introduction:
Cervical large cell carcinoma is a rare, aggressive neuroendocrine carcinoma characterized by large cells with vesicular nuclei, prominent nucleoli, and neuroendocrine differentiation
It has intermediate behavior between small cell carcinoma and conventional carcinomas.
Origin:
Arises from cervical epithelium with neuroendocrine differentiation
Develops through similar pathways as small cell carcinoma but with larger cell morphology
Associated with high-risk HPV infection.
Classification:
WHO 2020 Classification categorizes as large cell neuroendocrine carcinoma
Part of neuroendocrine tumor spectrum
High-grade by definition.
Epidemiology:
Peak incidence 40-60 years
Represents <1% of cervical cancers
HPV association (especially HPV 16, 18)
Better prognosis than small cell but worse than conventional carcinomas.
Clinical Features
Presentation:
Rapidly growing cervical mass
Abnormal vaginal bleeding
Advanced stage at presentation common
Less aggressive than small cell carcinoma.
Symptoms:
Abnormal vaginal bleeding (irregular, heavy)
Pelvic pain
Constitutional symptoms possible
Paraneoplastic syndromes rare compared to small cell.
Risk Factors:
High-risk HPV infection (HPV 16, 18)
Smoking
Immunosuppression
Age (middle-aged women)
No specific environmental factors.
Screening:
Standard cervical screening may detect
Rapidly progressive
High index of suspicion for unusual cytology
Tissue diagnosis essential.
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Gross Description
Appearance:
Large, polypoid or ulcerative mass
Firmer than small cell carcinoma
Variable hemorrhage and necrosis
May be well-circumscribed.
Characteristics:
Size typically 3-8 cm at presentation
Firm to soft consistency
Variable circumscription
Gray-white to tan coloration
Necrosis less extensive than small cell.
Size Location:
Usually involves cervix with possible extension
Parametrial involvement less common than small cell
Lymph node metastases possible.
Multifocality:
Usually unifocal
Less extensive than small cell carcinoma
May be associated with conventional cervical lesions.
Microscopic Description
Histological Features:
Large cells arranged in nests, sheets, and ribbons
Vesicular nuclei with prominent nucleoli
Moderate to abundant cytoplasm
Neuroendocrine features present.
Cellular Characteristics:
Large cell size (>3 lymphocyte diameters)
Vesicular nuclei with prominent nucleoli
Moderate pleomorphism
Eosinophilic to amphophilic cytoplasm.
Architectural Patterns:
Sheets and large nests
Rosette formation possible
Organoid pattern may be seen
Moderate stromal desmoplasia
Necrosis variable.
Grading Criteria:
High-grade by definition
Mitotic rate >10 per 10 HPF
Moderate to high Ki-67 index (40-80%)
Neuroendocrine differentiation required.
Immunohistochemistry
Positive Markers:
Synaptophysin positive (>70%)
Chromogranin A positive (50-70%)
CD56 positive
TTF-1 variable
p16 positive (HPV)
Cytokeratins positive.
Negative Markers:
Estrogen receptor negative
Progesterone receptor negative
HER2 negative
CK20 negative
CDX2 negative.
Diagnostic Utility:
Neuroendocrine markers confirm diagnosis
p16 indicates HPV association
TTF-1 may help distinguish from GI origin
Ki-67 confirms high grade.
Molecular Subtypes:
HPV-associated large cell neuroendocrine carcinoma
Pure vs mixed with other histologies.
Molecular/Genetic
Genetic Mutations:
HPV integration (HPV 16, 18)
TP53 mutations (60-80%)
RB1 alterations
PIK3CA mutations
MYC amplification possible.
Molecular Markers:
High-risk HPV DNA detection
p16 overexpression
Moderate to high Ki-67
Neuroendocrine gene expression profile.
Prognostic Significance:
Intermediate prognosis between small cell and conventional carcinomas
Better than small cell but still aggressive
Stage most important factor.
Therapeutic Targets:
Platinum-based chemotherapy
Etoposide
Taxanes
Immune checkpoint inhibitors
Targeted therapy based on molecular profile.
Differential Diagnosis
Similar Entities:
Small cell neuroendocrine carcinoma
Poorly differentiated squamous carcinoma
Poorly differentiated adenocarcinoma
Metastatic large cell carcinoma.
Distinguishing Features:
Large cell NEC: Larger cells, vesicular nuclei
Small cell: Smaller cells, salt-and-pepper chromatin
Conventional carcinomas: No neuroendocrine markers.
Diagnostic Challenges:
Distinction from small cell carcinoma
Recognition of neuroendocrine features
Mixed histology assessment
Metastatic disease exclusion.
Rare Variants:
Large cell with rhabdoid features
Mixed large cell and squamous
Large cell with sarcomatoid features.
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 in greatest dimension
Diagnosis
[diagnosis name]
Classification
Classification: [classification system] [grade/type]
Histological Features
Shows [architectural pattern] with [nuclear features] and [mitotic activity]
Size and Extent
Size: [X] cm, extent: [local/regional/metastatic]
Margins
Margins are [involved/uninvolved] with closest margin [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Lymph Node Status
Lymph nodes: [X] positive out of [X] examined
Special Studies
IHC: [marker]: [result]
Molecular: [test]: [result]
[other study]: [result]
Prognostic Factors
Prognostic factors: [list factors]
Final Diagnosis
Final diagnosis: [complete diagnosis]