Definition/General
Introduction:
Endometrial small cell carcinoma is an extremely rare and highly aggressive neuroendocrine carcinoma
It represents less than 1% of all endometrial malignancies
It is morphologically similar to pulmonary small cell carcinoma
It has an extremely poor prognosis with rapid dissemination.
Origin:
Arises from endometrial epithelial cells with neuroendocrine differentiation
May develop through transdifferentiation of conventional adenocarcinoma
Shows neuroendocrine phenotype with hormone production
Molecular mechanisms poorly understood due to rarity.
Classification:
WHO classification includes under neuroendocrine tumors of endometrium
Classified as high-grade neuroendocrine carcinoma
May be pure small cell carcinoma or mixed with adenocarcinoma
All cases considered high-grade by definition.
Epidemiology:
Extremely rare with less than 100 cases reported in literature
Peak incidence in 6th-7th decades
Mean age 60-70 years
No specific risk factors identified
May be associated with smoking history
Prognosis uniformly poor regardless of stage.
Clinical Features
Presentation:
Postmenopausal bleeding (most common)
Rapidly progressive symptoms
Pelvic mass
Abdominal distension
Paraneoplastic syndromes (SIADH, Cushing syndrome)
Constitutional symptoms (weight loss, fatigue)
Metastatic disease at presentation common.
Symptoms:
Abnormal uterine bleeding (80-90%)
Rapid symptom onset
Pelvic pain
Abdominal bloating
Hormonal symptoms (paraneoplastic)
Respiratory symptoms (pulmonary metastases)
Neurological symptoms (brain metastases)
Bone pain (skeletal metastases).
Risk Factors:
No specific risk factors identified
Smoking history (possible association)
Advanced age
Previous radiation exposure (rare)
Family history of neuroendocrine tumors (rare)
Lynch syndrome (uncertain association).
Screening:
No specific screening guidelines
Endometrial sampling for abnormal bleeding
Neuroendocrine markers in serum (chromogranin A, NSE)
Imaging studies (CT, MRI, PET scan)
Octreotide scan may be positive
Comprehensive staging workup required.
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Gross Description
Appearance:
Soft, fleshy, gray-tan mass with extensive necrosis and hemorrhage
Polypoid or infiltrative growth pattern
Cut surface shows homogeneous, soft consistency
Size variable but often large at presentation.
Characteristics:
Soft, friable texture with areas of necrosis
Hemorrhagic areas common
Gray to tan coloration
May show cystic degeneration
Surface often ulcerated
Consistency similar to lymphoma.
Size Location:
Usually involves entire endometrial cavity
Size ranges from 3-15 cm
Deep myometrial invasion common at presentation
Cervical extension frequent
Extrauterine spread common at diagnosis.
Multifocality:
Usually unifocal but extensive
Lymphovascular invasion grossly evident
Lymph node metastases common
Peritoneal implants frequent
Distant metastases (lung, liver, bone) at presentation.
Microscopic Description
Histological Features:
Sheets and nests of small, round cells with scant cytoplasm
High nuclear-to-cytoplasmic ratio
Salt-and-pepper chromatin pattern
Absent or inconspicuous nucleoli
Crushing artifact and apoptosis common
Rosette formation may be seen.
Cellular Characteristics:
Small, uniform cells with round to oval nuclei
Finely granular chromatin (salt-and-pepper pattern)
Inconspicuous nucleoli
Scant cytoplasm
High mitotic activity (>20 mitoses/10 HPF)
Nuclear molding
Apoptotic bodies numerous.
Architectural Patterns:
Solid sheets and nests of cells
Ribbons and trabeculae
Rosette-like structures
Crushing artifact common
Extensive necrosis
Lymphovascular invasion prominent
Perineural invasion may be present.
Grading Criteria:
All small cell carcinomas are high-grade by definition
Mitotic count typically >20/10 HPF
Ki-67 proliferation index usually >70%
Extensive necrosis present
No formal grading system applicable.
Immunohistochemistry
Positive Markers:
Neuroendocrine markers: Chromogranin A (70-80%)
Synaptophysin (80-90%)
CD56 (90-100%)
Cytokeratins (CK7, CAM5.2)
TTF-1 (may be positive)
p16 (usually diffuse)
p53 (often mutant pattern).
Negative Markers:
Hormone receptors (ER, PR) - typically negative
CK20 - usually negative
CDX2 - negative (helps exclude GI primary)
PAX8 - may be negative
Thyroglobulin - negative
Calcitonin - negative.
Diagnostic Utility:
Neuroendocrine markers confirm neuroendocrine differentiation
Cytokeratins confirm epithelial origin
TTF-1 does not distinguish from pulmonary primary
PAX8 may support gynecologic origin
Combination panel essential for diagnosis.
Molecular Subtypes:
p53-aberrant pattern common
Rb protein loss frequent
High Ki-67 proliferation index
Microsatellite status variable
Most cases show chromosomal instability
Neuroendocrine differentiation markers positive.
Molecular/Genetic
Genetic Mutations:
RB1 mutations common (similar to pulmonary small cell carcinoma)
p53 mutations frequent
TP53 pathway alterations
PIK3CA mutations possible
PTEN mutations reported
Chromosomal instability pattern.
Molecular Markers:
p53 overexpression (mutant pattern)
Rb protein loss
High Ki-67 proliferation index (>70%)
Chromosomal instability
Neuroendocrine marker expression
High tumor mutational burden possible.
Prognostic Significance:
Uniformly poor prognosis regardless of molecular features
p53 mutations associated with aggressive behavior
Rb loss correlates with neuroendocrine phenotype
High proliferation indicates rapid growth
Molecular markers do not predict response.
Therapeutic Targets:
Platinum-based chemotherapy (similar to lung small cell carcinoma)
Etoposide combinations
Immunotherapy under investigation
PARP inhibitors for DNA repair defects
Topoisomerase inhibitors
Anti-angiogenic therapy.
Differential Diagnosis
Similar Entities:
Metastatic small cell carcinoma (lung, GI tract)
Endometrial carcinoid tumor
Lymphoma
Undifferentiated carcinoma
Poorly differentiated endometrioid carcinoma
Neuroendocrine carcinoma (large cell type).
Distinguishing Features:
Primary endometrial: No extrauterine primary
Primary endometrial: May have associated adenocarcinoma
Metastatic: Clinical history of primary tumor
Metastatic: Imaging shows primary site
Carcinoid: Lower grade
Carcinoid: Less mitotic activity
Lymphoma: LCA positive
Lymphoma: Cytokeratin negative.
Diagnostic Challenges:
Distinguishing primary from metastatic small cell carcinoma
Excluding pulmonary primary
Separating from lymphoma
Recognition of mixed patterns
Confirming neuroendocrine differentiation
Determining site of origin.
Rare Variants:
Mixed small cell and adenocarcinoma
Combined small cell and squamous carcinoma
Small cell carcinoma with sarcomatous elements
Amphicrine carcinoma (dual endocrine and exocrine differentiation)
Pure small cell pattern (most common).
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
Hysterectomy specimen measuring [X x Y x Z] cm, weighing [X] grams
Diagnosis
Endometrial small cell carcinoma (neuroendocrine carcinoma)
Classification
WHO Classification: Neuroendocrine carcinoma, small cell type, FIGO Grade: High-grade
Histological Features
Small cell carcinoma with neuroendocrine morphology and high mitotic activity
Neuroendocrine Differentiation
Confirmed by immunohistochemistry: [markers positive]
Associated Carcinoma
[Present/Absent]: [type if present] ([percentage]%)
Size and Extent
Tumor size: [X] cm, myometrial invasion: [depth/total thickness], [percent]%
Margins
Margins: [involved/uninvolved], closest margin: [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Cervical Involvement
Cervical involvement: [present/absent]
Special Studies
IHC: Chromogranin A: [result], Synaptophysin: [result], CD56: [result], Cytokeratins: [result]
TTF-1: [result], p53: [pattern], Ki-67: [percentage]%
Molecular studies: [if performed]
Metastatic Workup
Clinical and imaging evaluation: [negative/positive for extrauterine primary]
FIGO Staging
FIGO Stage: [stage] ([staging criteria])
Prognostic Factors
High-grade neuroendocrine carcinoma, Stage: [X], poor prognosis
Final Diagnosis
Endometrial small cell carcinoma (neuroendocrine carcinoma), FIGO Stage [X]