Definition/General
Introduction:
Gastric small cell carcinoma is a rare and aggressive neuroendocrine malignancy of the stomach
It comprises less than 1% of all gastric malignancies
It belongs to the family of poorly differentiated neuroendocrine carcinomas
It demonstrates high-grade morphology with rapid growth and early metastasis.
Origin:
Arises from neuroendocrine cells scattered throughout gastric mucosa
These cells are part of the diffuse neuroendocrine system
The cells may arise from enterochromaffin-like (ECL) cells
They can also originate from pluripotent stem cells with neuroendocrine differentiation.
Classification:
Classified under WHO 2019 as neuroendocrine carcinoma
High-grade neuroendocrine neoplasm (G3)
Distinguished from well-differentiated NETs by morphology and behavior
Similar to pulmonary small cell carcinoma in morphology and behavior.
Epidemiology:
Extremely rare tumor with male predominance (2:1 ratio)
Peak incidence in 6th-7th decade of life
More common in Western populations
Associated with smoking and alcohol consumption
Often presents with advanced stage at diagnosis.
Clinical Features
Presentation:
Rapid onset of abdominal pain (80-90% cases)
Weight loss and anorexia (70-80%)
Nausea and vomiting (60-70%)
Gastrointestinal bleeding (hematemesis or melena)
Early satiety and dyspepsia
Paraneoplastic syndromes (rare in gastric location).
Symptoms:
Severe epigastric pain often the first symptom
Rapid weight loss (>10% body weight)
Constitutional symptoms (fatigue, weakness)
Dysphagia if located in cardia
Bowel obstruction symptoms in advanced cases
Ectopic hormone syndromes (ACTH, ADH secretion).
Risk Factors:
Smoking history (most important risk factor)
Chronic alcohol consumption
Chronic atrophic gastritis
Helicobacter pylori infection
Family history of neuroendocrine tumors
Previous gastric surgery or radiation.
Screening:
No specific screening protocols available
Upper GI endoscopy for symptomatic patients
CT scanning for staging evaluation
Octreotide scintigraphy may be helpful
Serum chromogranin A and neuron-specific enolase levels.
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Gross Description
Appearance:
Ulcerated or polypoid mass with irregular borders
Gray-white to tan cut surface with areas of necrosis
Soft to firm consistency depending on stromal content
Surface shows ulceration and hemorrhage in most cases.
Characteristics:
Size ranges from 2-10 cm at presentation
Infiltrative growth pattern with poorly defined margins
Areas of necrosis and hemorrhage are common
May show submucosal extension beyond visible mucosal lesion.
Size Location:
Can occur anywhere in stomach but antrum most common (40-50%)
Body and fundus involvement in 30-40% cases
Cardia involvement in 10-20% cases
Size at presentation typically >5 cm indicating advanced disease.
Multifocality:
Usually solitary lesions at presentation
Multifocal disease uncommon (<10% cases)
Lymph node metastases present in 60-80% at diagnosis
Distant metastases (liver, lung, bone) in 40-60% cases.
Microscopic Description
Histological Features:
Composed of sheets and nests of small cells with high nuclear-cytoplasmic ratio
Scanty cytoplasm with indistinct cell borders
Salt-and-pepper chromatin pattern characteristic
High mitotic rate (>20/10 HPF)
Extensive necrosis and apoptosis.
Cellular Characteristics:
Small cells approximately 2-3 times lymphocyte size
Round to oval nuclei with fine chromatin
Inconspicuous nucleoli
Scant eosinophilic cytoplasm
Nuclear molding and crush artifact common
High proliferation index.
Architectural Patterns:
Solid sheets and nests separated by thin fibrovascular septa
Trabecular pattern may be seen focally
Rosette formation is uncommon
Invasive growth through gastric wall layers
Lymphovascular invasion frequently present.
Grading Criteria:
All gastric small cell carcinomas are high-grade (G3) by definition
Mitotic count >20/10 HPF
Ki-67 proliferation index >55%
Extensive necrosis (>50% of tumor)
Poor differentiation with primitive morphology.
Immunohistochemistry
Positive Markers:
Chromogranin A (80-90% positive)
Synaptophysin (90-95% positive)
CD56 (NCAM) (90-95% positive)
Neuron-specific enolase (NSE) (80-90%)
TTF-1 (30-40% positive)
INSM1 (95-98% positive).
Negative Markers:
CK7 (usually negative)
CK20 (usually negative)
CDX2 (negative)
p63 (negative)
Smooth muscle actin (negative)
S-100 (negative in tumor cells).
Diagnostic Utility:
Neuroendocrine markers essential for diagnosis
INSM1 most sensitive and specific
TTF-1 positivity suggests pulmonary origin but can be positive in gastric primary
CDX2 negativity helps distinguish from gastric adenocarcinoma
Ki-67 >55% confirms high-grade nature.
Molecular Subtypes:
No established molecular subtypes for gastric small cell carcinoma
TP53 mutations common (>90% cases)
RB1 mutations frequent (70-80%)
MYC amplification may be present
Microsatellite stability in most cases.
Molecular/Genetic
Genetic Mutations:
TP53 mutations (>90% cases)
RB1 mutations (70-80% cases)
PTEN loss (40-50%)
PIK3CA mutations (20-30%)
KRAS mutations (10-20%)
SMAD4 loss (30-40%).
Molecular Markers:
p53 overexpression (70-80% cases)
Rb loss (60-70% cases)
MYC overexpression (40-50%)
BCL-2 expression (30-40%)
High Ki-67 proliferation index (>55%)
Loss of heterozygosity at multiple loci.
Prognostic Significance:
TP53 mutations associated with poor prognosis
RB1 loss correlates with aggressive behavior
High Ki-67 indicates rapid proliferation
MYC amplification suggests treatment resistance
PTEN loss associated with poor survival.
Therapeutic Targets:
Platinum-based chemotherapy (carboplatin, cisplatin)
Etoposide combination therapy
Topotecan for relapsed disease
Immunotherapy (PD-1/PD-L1 inhibitors)
PARP inhibitors in selected cases
Targeted therapy limited options.
Differential Diagnosis
Similar Entities:
Poorly differentiated adenocarcinoma (signet ring variant)
Lymphoma (especially diffuse large B-cell)
Metastatic small cell carcinoma (especially lung)
Other neuroendocrine carcinomas (large cell type)
Undifferentiated carcinoma.
Distinguishing Features:
Small cell carcinoma: Neuroendocrine markers positive
Small cell carcinoma: Small cell morphology
Small cell carcinoma: High Ki-67 >55%
Adenocarcinoma: Mucin production
Adenocarcinoma: Glandular differentiation
Lymphoma: CD45 positive
Lymphoma: B-cell or T-cell markers.
Diagnostic Challenges:
Distinguishing from metastatic lung small cell carcinoma (TTF-1 may be positive in both)
Separating from poorly differentiated adenocarcinoma (mixed tumors possible)
Identifying neuroendocrine differentiation in poorly preserved specimens
Distinguishing from high-grade lymphoma.
Rare Variants:
Mixed adenoneuroendocrine carcinoma (MANEC) with adenocarcinoma component
Large cell neuroendocrine carcinoma (larger cells, more cytoplasm)
Combined small cell and squamous carcinoma
Small cell carcinoma 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
Small cell neuroendocrine carcinoma (high-grade)
WHO Classification
Neuroendocrine carcinoma, small cell type (WHO Grade 3)
Histological Features
Small cells with high nuclear-cytoplasmic ratio, salt-and-pepper chromatin, high mitotic activity, extensive necrosis
Size and Extent
Size: [X] cm, depth of invasion: [specify layer], T stage: [T1-T4]
Margins
Margins: [involved/uninvolved], closest margin: [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Lymph Node Status
Lymph nodes: [X] positive out of [X] examined, N stage: [N0-N3]
Immunohistochemistry
Chromogranin A: [positive/negative], Synaptophysin: [positive/negative], INSM1: [positive/negative]
Ki-67 proliferation index: [percentage]%
TTF-1: [positive/negative], CDX2: [positive/negative]
TNM Staging
TNM Stage: T[X]N[X]M[X], Overall Stage: [I-IV]
Final Diagnosis
Gastric small cell neuroendocrine carcinoma (high-grade), WHO Grade 3, TNM Stage [specify]