Definition/General
Introduction:
Gastric carcinoid tumors are well-differentiated neuroendocrine tumors (NETs) arising from gastric mucosa
They represent 2-3% of all gastric neoplasms
Classified into three distinct types based on pathogenesis and clinical behavior
They have variable malignant potential depending on type and size.
Origin:
Arise from enterochromaffin-like (ECL) cells in gastric mucosa
These cells are located in the gastric fundus and body
ECL cells produce histamine and are regulated by gastrin
Chronic hypergastrinemia leads to ECL cell hyperplasia and eventual neoplasia.
Classification:
Type I (75-80%): Associated with chronic atrophic gastritis and hypergastrinemia
Type II (5-10%): Associated with Zollinger-Ellison syndrome and MEN-1
Type III (15-20%): Sporadic tumors without hypergastrinemia
Each type has distinct clinical behavior and prognosis.
Epidemiology:
Increasing incidence due to better recognition and endoscopic screening
Female predominance in Type I (3:1 ratio)
Mean age 50-60 years for Type I and II
Type III occurs in older patients (60-70 years)
Racial predilection varies by geographic location.
Clinical Features
Presentation:
Asymptomatic in majority of Type I cases (incidental finding)
Dyspepsia and epigastric pain (30-40%)
Nausea and vomiting (20-30%)
Carcinoid syndrome rare (<5% cases)
Gastrointestinal bleeding in larger lesions
Abdominal pain and weight loss in advanced cases.
Symptoms:
Type I: Usually asymptomatic, symptoms related to underlying gastritis
Type II: Peptic ulcer symptoms from gastrinoma
Type III: Abdominal pain, weight loss, bleeding
Carcinoid syndrome: Flushing, diarrhea, bronchospasm (rare)
Carcinoid heart disease in advanced metastatic cases.
Risk Factors:
Chronic atrophic gastritis (Type I)
Pernicious anemia and vitamin B12 deficiency
Helicobacter pylori infection
MEN-1 syndrome (Type II)
Zollinger-Ellison syndrome
Family history of neuroendocrine tumors
Advanced age for Type III.
Screening:
Upper endoscopy with biopsy for suspicious lesions
Serum gastrin levels (elevated in Type I and II)
Chromogranin A serum levels
24-hour urine 5-HIAA if carcinoid syndrome suspected
Octreotide scintigraphy for staging
CT/MRI for metastasis detection.
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Gross Description
Appearance:
Type I: Multiple small (<1 cm) polypoid lesions in fundus/body
Type II: Few small to moderate lesions (1-2 cm)
Type III: Usually solitary large lesions (>2 cm)
Surface may show ulceration in larger tumors.
Characteristics:
Well-circumscribed nodules or polyps with smooth surface
Yellow-tan cut surface with homogeneous appearance
Firm consistency
Submucosal location with mucosal elevation
Larger lesions may show central ulceration.
Size Location:
Type I: Multiple lesions 0.5-1 cm in fundus/body
Type II: 1-2 cm lesions, usually few in number
Type III: >2 cm, often >5 cm, usually solitary
Fundus and body most common locations
Antral involvement rare.
Multifocality:
Type I: Multifocal in >70% cases (2-50 lesions)
Type II: Usually few lesions (2-5)
Type III: Typically solitary (>80% cases)
ECL cell hyperplasia often present in background mucosa (Type I and II).
Microscopic Description
Histological Features:
Composed of uniform small cells with round nuclei and granular eosinophilic cytoplasm
Salt-and-pepper chromatin pattern characteristic
Organoid, trabecular, or solid growth patterns
Minimal nuclear pleomorphism
Low mitotic activity (<2/10 HPF).
Cellular Characteristics:
Uniform cells with round to oval nuclei
Fine granular chromatin (salt-and-pepper)
Inconspicuous nucleoli
Moderate eosinophilic cytoplasm with fine granules
Indistinct cell borders
Minimal pleomorphism and rare mitoses.
Architectural Patterns:
Organoid pattern (nests and ribbons)
Trabecular pattern (cords of cells)
Solid pattern less common
Pseudorosette formation may be seen
Rich vascular stroma
Amyloid deposition occasionally present.
Grading Criteria:
WHO Grade 1 (G1): <2 mitoses/10 HPF and <3% Ki-67
WHO Grade 2 (G2): 2-20 mitoses/10 HPF and/or 3-20% Ki-67
WHO Grade 3 (G3): >20 mitoses/10 HPF and/or >20% Ki-67
Most gastric carcinoids are Grade 1 or 2.
Immunohistochemistry
Positive Markers:
Chromogranin A (95-98% positive)
Synaptophysin (90-95% positive)
CD56 (NCAM) (85-90% positive)
Neuron-specific enolase (NSE) (80-85%)
INSM1 (nuclear, 95% positive)
Vesicular monoamine transporter 2 (VMAT2).
Negative Markers:
TTF-1 (negative, helps exclude lung primary)
CDX2 (negative to weak positive)
Cytokeratin 7 (usually negative)
Cytokeratin 20 (negative to focal positive)
p63 (negative)
Smooth muscle actin (negative).
Diagnostic Utility:
Neuroendocrine markers confirm diagnosis
INSM1 most sensitive and specific
Ki-67 proliferation index for grading
Serotonin positive in minority of gastric carcinoids
Gastrin occasionally positive
TTF-1 negativity helps exclude lung metastasis.
Molecular Subtypes:
No established molecular subtypes
Histamine production characteristic of gastric ECL cell origin
Serotonin production less common than in small bowel carcinoids
Multiple hormones may be co-expressed
Functional vs non-functional classification based on hormone secretion.
Molecular/Genetic
Genetic Mutations:
MEN1 gene mutations in Type II associated with MEN-1 syndrome
CDKN1B mutations (MEN4 syndrome)
Loss of chromosome 18q in some cases
TP53 mutations rare in low-grade tumors
RAS mutations uncommon
Microsatellite stability in most cases.
Molecular Markers:
BCL-2 overexpression in some cases
p53 overexpression rare in low-grade tumors
VEGF expression correlates with angiogenesis
SSTR expression (somatostatin receptors) for imaging and therapy
mTOR pathway activation in some cases.
Prognostic Significance:
Type I: Excellent prognosis (>95% 10-year survival)
Type II: Good prognosis if small (<2 cm)
Type III: Intermediate prognosis (70-80% 5-year survival)
Size >2 cm increases metastatic risk
Grade and stage most important prognostic factors.
Therapeutic Targets:
Somatostatin analogs (octreotide, lanreotide) for functional tumors
Everolimus (mTOR inhibitor) for progressive disease
Sunitinib (multi-kinase inhibitor)
PRRT (peptide receptor radionuclide therapy) for SSTR-positive tumors
Surgery remains primary treatment.
Differential Diagnosis
Similar Entities:
Small cell carcinoma (high-grade neuroendocrine carcinoma)
Poorly differentiated adenocarcinoma
Lymphoma (especially marginal zone)
Metastatic neuroendocrine tumor (lung, pancreas)
Inflammatory myofibroblastic tumor.
Distinguishing Features:
Carcinoid tumor: Well-differentiated morphology
Carcinoid tumor: Low Ki-67 <20%
Carcinoid tumor: Low mitotic rate
Small cell carcinoma: High-grade morphology
Small cell carcinoma: High Ki-67 >55%
Adenocarcinoma: Glandular differentiation
Adenocarcinoma: Mucin production.
Diagnostic Challenges:
Distinguishing well-differentiated NET from poorly differentiated NEC
Identifying primary vs metastatic origin
Determining grade accurately with Ki-67 and mitoses
Recognizing mixed neuroendocrine-non-neuroendocrine neoplasms.
Rare Variants:
Mixed adenoneuroendocrine carcinoma (MANEC)
Goblet cell carcinoid (rare in stomach)
Tubular carcinoid
Atypical carcinoid (intermediate grade)
Oncocytic variant with abundant eosinophilic cytoplasm.
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
Well-differentiated neuroendocrine tumor (carcinoid tumor)
WHO Classification & Grade
Neuroendocrine tumor, WHO Grade [G1/G2/G3], Type [I/II/III]
Histological Features
Well-differentiated neuroendocrine cells in [growth pattern], mitoses: [count]/10 HPF
Size and Extent
Size: [X] cm, depth: [mucosal/submucosal/muscularis propria]
Immunohistochemistry
Chromogranin A: [+/-], Synaptophysin: [+/-], Ki-67: [%]%, INSM1: [+/-]
Grade Assessment
Mitotic count: [X]/10 HPF, Ki-67 proliferation index: [X]%, WHO Grade: [G1/G2/G3]
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Lymph Node Status
Regional lymph nodes: [X] positive out of [X] examined
TNM Staging
TNM: T[X]N[X]M[X], Stage: [I/II/III/IV]
Final Diagnosis
Gastric neuroendocrine tumor (carcinoid), Type [I/II/III], WHO Grade [G1/G2/G3]