Definition/General
Introduction:
Cervical neuroendocrine carcinoma is a rare and aggressive type of cervical cancer with neuroendocrine differentiation
It represents <5% of all cervical cancers and includes small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, and carcinoid tumors.
Origin:
Arises from cervical epithelium with neuroendocrine differentiation
May develop from pluripotent stem cells or through neuroendocrine transdifferentiation
Strong association with high-risk HPV infection.
Classification:
WHO 2020 Classification recognizes: Small cell neuroendocrine carcinoma, Large cell neuroendocrine carcinoma, and Carcinoid tumor (well-differentiated neuroendocrine tumor).
Epidemiology:
Peak incidence 40-60 years
Represents 1-6% of cervical cancers
Strong HPV association (especially HPV 18)
Extremely aggressive behavior with poor prognosis
Higher metastatic potential.
Clinical Features
Presentation:
Abnormal vaginal bleeding
Rapidly growing cervical mass
Early systemic symptoms
Often advanced stage at presentation
May have paraneoplastic syndromes.
Symptoms:
Vaginal bleeding (irregular, heavy)
Pelvic pain
Constitutional symptoms (weight loss, fatigue)
Paraneoplastic syndromes possible (SIADH, Cushing's)
Symptoms of metastatic disease.
Risk Factors:
High-risk HPV infection (especially HPV 18)
Smoking (strong association)
Immunosuppression
Previous cervical dysplasia
DES exposure.
Screening:
Standard cervical screening (Pap smear)
HPV testing important
Often requires tissue diagnosis
High index of suspicion for rapid symptom onset.
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Gross Description
Appearance:
Polypoid, ulcerative, or infiltrative mass
Often larger than other cervical cancers
Soft, fleshy consistency
May show necrosis and hemorrhage.
Characteristics:
Size typically >3 cm at presentation
Soft to firm consistency
Friable surface
Gray-white to tan coloration
Hemorrhage and necrosis common.
Size Location:
Usually involves entire cervix
Early parametrial extension
May extend to vagina and uterus
Lymph node involvement common at presentation.
Multifocality:
Often unifocal but may be extensive
Associated with other cervical lesions possible
Skip metastases in lymph nodes.
Microscopic Description
Histological Features:
Small cell type: Small cells with scant cytoplasm, hyperchromatic nuclei, high mitotic rate
Large cell type: Larger cells with more cytoplasm, vesicular nuclei, prominent nucleoli.
Cellular Characteristics:
Small cell: High nuclear-cytoplasmic ratio, molding, crush artifact
Large cell: Larger nuclei, vesicular chromatin, prominent nucleoli
Both show high mitotic activity.
Architectural Patterns:
Nests, sheets, and ribbons
Rosette formation possible
Extensive necrosis common
Lymphovascular invasion frequent
Salt-and-pepper chromatin pattern.
Grading Criteria:
High-grade by definition
Small cell: >10 mitoses per 10 HPF
Large cell: >10 mitoses per 10 HPF
Extensive necrosis
High Ki-67 index.
Immunohistochemistry
Positive Markers:
Synaptophysin positive
Chromogranin A positive
CD56 positive
TTF-1 may be positive (especially small cell)
p16 positive (HPV-associated).
Negative Markers:
CK7 variable
CK20 negative
CDX2 negative
WT1 negative
Estrogen receptor negative.
Diagnostic Utility:
Neuroendocrine markers confirm diagnosis
p16 indicates HPV association
TTF-1 helps distinguish from pulmonary origin
Ki-67 typically >70%.
Molecular Subtypes:
HPV-associated neuroendocrine carcinoma
Small cell vs large cell subtypes
Mixed carcinomas possible.
Molecular/Genetic
Genetic Mutations:
HPV integration (especially HPV 18)
TP53 mutations
RB1 alterations
PIK3CA mutations
STK11 mutations possible.
Molecular Markers:
High-risk HPV DNA detection
p16 overexpression
High Ki-67 proliferation index
Neuroendocrine gene expression profile.
Prognostic Significance:
Extremely poor prognosis
Early metastasis common
Resistant to standard therapy
Small cell worse than large cell type.
Therapeutic Targets:
Platinum-based chemotherapy (similar to lung small cell)
Etoposide
Immune checkpoint inhibitors
Anti-angiogenic therapy.
Differential Diagnosis
Similar Entities:
Metastatic neuroendocrine carcinoma (lung, GI)
Carcinoid tumor
Poorly differentiated squamous or adenocarcinoma
Lymphoma
Melanoma.
Distinguishing Features:
Cervical NEC: p16+, HPV+
Lung origin: TTF-1+, napsin A+
GI origin: CDX2+
Carcinoid: Well-differentiated, low mitotic rate.
Diagnostic Challenges:
Distinction from metastatic disease
Small biopsy diagnosis
Mixed histology assessment
Primary site determination.
Rare Variants:
Mixed neuroendocrine-non-neuroendocrine carcinoma
Carcinoid tumor
Large cell neuroendocrine carcinoma with rhabdoid 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]