Definition/General
Introduction:
Cervical small cell carcinoma is a rare, highly aggressive neuroendocrine carcinoma characterized by small cells with scant cytoplasm, hyperchromatic nuclei, and high mitotic activity
It represents 1-3% of all cervical cancers and has the worst prognosis among cervical malignancies.
Origin:
Arises from cervical epithelium with neuroendocrine differentiation
Develops from pluripotent stem cells or through neuroendocrine transdifferentiation
Strong association with high-risk HPV, especially HPV 18.
Classification:
WHO 2020 Classification categorizes as small cell neuroendocrine carcinoma
Part of neuroendocrine tumor spectrum
High-grade by definition.
Epidemiology:
Peak incidence 35-55 years (younger than other cervical cancers)
Represents 1-3% of cervical cancers
Strong HPV 18 association (>90%)
Extremely aggressive with 5-year survival <50%.
Clinical Features
Presentation:
Rapidly growing cervical mass
Abnormal vaginal bleeding
Early systemic symptoms
Often advanced stage at presentation
Paraneoplastic syndromes possible.
Symptoms:
Abnormal vaginal bleeding (heavy, irregular)
Pelvic pain
Constitutional symptoms (weight loss, fatigue)
Symptoms of hypercalcemia or SIADH
Early metastatic symptoms.
Risk Factors:
High-risk HPV infection (especially HPV 18)
Smoking (strong association)
Immunosuppression
Young age
No oral contraceptive association.
Screening:
Standard cervical screening less effective
Rapidly progressive between screens
High index of suspicion for young women with symptoms
HPV testing important.
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Gross Description
Appearance:
Polypoid, ulcerative, or infiltrative mass
Often larger than other cervical cancers at presentation
Soft, fleshy consistency
Hemorrhage and necrosis common.
Characteristics:
Size typically >4 cm at presentation
Soft consistency
Friable surface
Gray-white to tan coloration
Extensive necrosis typical.
Size Location:
Usually involves entire cervix
Early parametrial and vaginal extension
Lymph node metastases common at presentation
Distant metastases early.
Multifocality:
Often extensive local involvement
May be associated with CIN or AIS
Skip metastases characteristic.
Microscopic Description
Histological Features:
Small cells with scant cytoplasm arranged in sheets, nests, and ribbons
Hyperchromatic nuclei with salt-and-pepper chromatin
High mitotic rate with extensive necrosis.
Cellular Characteristics:
Small cell size (2-3 lymphocyte diameters)
High nuclear-cytoplasmic ratio
Nuclear molding common
Crush artifact frequent
Apoptotic bodies numerous.
Architectural Patterns:
Sheets and nests of small cells
Rosette formation rare
Extensive necrosis (>50% common)
Lymphovascular invasion extensive
Infiltrative borders.
Grading Criteria:
High-grade by definition
Mitotic rate >20 per 10 HPF
Ki-67 index >70%
Extensive necrosis
Salt-and-pepper chromatin pattern.
Immunohistochemistry
Positive Markers:
Synaptophysin positive (>90%)
Chromogranin A positive (70-80%)
CD56 positive
TTF-1 positive (80-90%)
p16 diffuse positive (HPV).
Negative Markers:
CK7 variable
CK20 negative
Estrogen receptor negative
Progesterone receptor negative
HER2 negative.
Diagnostic Utility:
TTF-1 positivity helps distinguish from GI origin
p16 confirms HPV association
Neuroendocrine markers mandatory for diagnosis
High Ki-67 confirms high grade.
Molecular Subtypes:
HPV-associated small cell carcinoma
Usually HPV 18 positive
Pure vs mixed with other histologies.
Molecular/Genetic
Genetic Mutations:
HPV 18 integration (>90% cases)
TP53 mutations (>80%)
RB1 alterations (>90%)
MYC amplification
PTEN loss.
Molecular Markers:
High-risk HPV DNA (predominantly HPV 18)
p16 overexpression
High Ki-67 (>70%)
Loss of p53 and Rb function.
Prognostic Significance:
Extremely poor prognosis
Early metastasis (75% have distant disease at diagnosis)
Chemotherapy resistance common
Median survival <2 years.
Therapeutic Targets:
Platinum-based chemotherapy (similar to lung SCLC)
Etoposide
Topotecan
Immune checkpoint inhibitors
Novel targeted therapies under investigation.
Differential Diagnosis
Similar Entities:
Metastatic small cell carcinoma (lung)
Large cell neuroendocrine carcinoma
Carcinoid tumor
Poorly differentiated squamous or adenocarcinoma
Lymphoma.
Distinguishing Features:
Cervical SCLC: p16+, HPV+
Lung SCLC: No p16, no HPV
LCNEC: Larger cells
Carcinoid: Low mitotic rate
Lymphoma: LCA+.
Diagnostic Challenges:
Distinction from metastatic disease
Mixed histology tumors
Small biopsy diagnosis
Crush artifact affecting morphology.
Rare Variants:
Combined small cell and squamous carcinoma
Combined small cell and adenocarcinoma
Small cell 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]