Definition/General
Introduction:
Gastric neuroendocrine carcinoma (NEC) is a high-grade malignant neuroendocrine neoplasm
It shows neuroendocrine morphology with high proliferation rate
Distinguished from neuroendocrine tumors (NET) by grade
It constitutes 0.1-0.2% of all gastric malignancies
Also termed poorly differentiated neuroendocrine carcinoma.
Origin:
Arises from gastric neuroendocrine cells
Originates from enterochromaffin-like (ECL) cells
May develop from gastric NET transformation
Can arise de novo from gastric mucosa
Results from neuroendocrine stem cell proliferation.
Classification:
Classified as Grade 3 (G3) neuroendocrine neoplasm
WHO classification based on mitotic rate and Ki-67 index
Distinguished from NET G1 and G2
Subcategorized into well-differentiated and poorly differentiated
High-grade malignancy by definition.
Epidemiology:
Peak incidence in 6th-7th decades
Male predominance (M:F ratio 2:1)
More common in Japanese population
Associated with atrophic gastritis
Risk factors include chronic gastritis
Rare in Indian population.
Clinical Features
Presentation:
Aggressive clinical course
Epigastric pain and discomfort
Rapid tumor growth
Weight loss and anorexia
Carcinoid syndrome rare due to gastric location
Palpable mass in advanced cases
Metastatic disease at presentation common.
Symptoms:
Abdominal pain (85%)
Weight loss and anorexia
Nausea and vomiting
Gastrointestinal bleeding
Early satiety
Carcinoid syndrome (<5% cases)
Systemic symptoms of malignancy.
Risk Factors:
Chronic atrophic gastritis
Helicobacter pylori infection
Pernicious anemia
Zollinger-Ellison syndrome
Previous gastric NET
Genetic syndromes (MEN1, NF1)
Smoking and alcohol.
Screening:
Upper endoscopy with biopsy
Chromogranin A levels
24-hour urine 5-HIAA
Octreotide scintigraphy
Cross-sectional imaging
Genetic counseling if syndromic.
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Gross Description
Appearance:
Large, firm tumor with irregular borders
Gray-tan to yellow cut surface
Areas of necrosis and hemorrhage
Infiltrative growth pattern
May show cystic degeneration.
Characteristics:
Firm to hard consistency
Lobulated appearance
Cut surface shows solid areas
Hemorrhagic regions common
May contain calcifications
Necrotic areas frequently present.
Size Location:
Size typically 3-15 cm
Most common in gastric antrum
May involve body and fundus
Submucosal origin common
Can be multifocal
Transmural invasion frequent.
Multifocality:
May be multifocal
High metastatic potential
Early lymph node involvement
Liver metastases common
Bone and lung metastases
Peritoneal spread possible.
Microscopic Description
Histological Features:
Solid sheets or trabecular pattern of cells
High nuclear grade with pleomorphism
High mitotic activity (>20 per 10 HPF)
Extensive necrosis common
Small to medium-sized cells
Vascular invasion frequent.
Cellular Characteristics:
Uniform small to medium cells
High nuclear-to-cytoplasmic ratio
Hyperchromatic nuclei
Prominent nucleoli
Scant cytoplasm
Salt-and-pepper chromatin
Crush artifact common.
Architectural Patterns:
Solid growth pattern predominant
Trabecular arrangement
Ribbon-like patterns
Organoid structures
Rosette formation rare
Invasive growth through gastric wall.
Grading Criteria:
WHO Grade 3 by definition
Mitotic count >20 per 10 HPF
Ki-67 index >20%
High nuclear grade
Extensive necrosis
Poor differentiation.
Immunohistochemistry
Positive Markers:
Chromogranin A (70-80%)
Synaptophysin (90-95%)
CD56/NCAM (85-90%)
Neuron-specific enolase (NSE)
Insulinoma-associated protein 1 (INSM1)
High Ki-67 index (>20%).
Negative Markers:
CK7 (usually negative)
CK20 (variable)
CDX2 (usually negative)
TTF1 (negative)
Specific hormones (insulin, gastrin) usually negative
S-100 (negative).
Diagnostic Utility:
Neuroendocrine markers confirm diagnosis
High Ki-67 distinguishes from NET
Chromogranin A may be focal in poorly differentiated tumors
Synaptophysin more reliable marker
INSM1 newer, sensitive marker.
Molecular Subtypes:
Poorly differentiated NEC subtype
p53 pathway alterations
RB pathway inactivation
Different from pancreatic NEC
Distinct molecular profile from gastric adenocarcinoma.
Molecular/Genetic
Genetic Mutations:
RB1 mutations/deletions (60-70%)
TP53 mutations (50-60%)
ARID1A mutations (30-40%)
KMT2D mutations (20-25%)
PIK3CA mutations (15-20%)
KRAS mutations (10-15%).
Molecular Markers:
Loss of Rb expression
p53 overexpression
High Ki-67 index (>20%)
Loss of p16
Cyclin E overexpression
DAXX/ATRX alterations rare.
Prognostic Significance:
RB1 loss associated with poor prognosis
High Ki-67 indicates aggressive behavior
p53 mutations correlate with metastasis
ARID1A loss affects chromatin remodeling
Overall poor prognosis.
Therapeutic Targets:
Somatostatin analogs (octreotide, lanreotide)
mTOR inhibitors (everolimus)
Tyrosine kinase inhibitors (sunitinib)
PARP inhibitors under investigation
Immunotherapy potential
Peptide receptor radionuclide therapy (PRRT).
Differential Diagnosis
Similar Entities:
Gastric neuroendocrine tumor (NET G1/G2)
Poorly differentiated adenocarcinoma
Small cell carcinoma
Lymphoma
Metastatic neuroendocrine carcinoma.
Distinguishing Features:
NEC G3: High Ki-67 (>20%)
NEC: Poor differentiation
NET G1/G2: Low Ki-67 (<20%)
NET: Well-differentiated morphology
Adenocarcinoma: Negative neuroendocrine markers
Lymphoma: CD45 positive
Small cell: Smaller cells, TTF1 positive if pulmonary.
Diagnostic Challenges:
Distinguishing NEC from NET
Excluding metastatic disease
Crush artifact interpretation
Adequate immunohistochemical panel
Ki-67 assessment crucial
Clinical correlation required.
Rare Variants:
Large cell neuroendocrine carcinoma
Small cell neuroendocrine carcinoma
Mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN)
Amphicrine carcinoma
Composite tumors.
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
Gastric Neuroendocrine Carcinoma (WHO Grade 3)
WHO Grading
Grade 3: Ki-67 index [X]%, Mitotic count [X] per 10 HPF
Histological Features
Poorly differentiated neuroendocrine carcinoma with solid growth pattern
Differentiation
[poorly] differentiated with neuroendocrine morphology
Extent
Invasion depth: [mucosa/submucosa/muscularis propria/serosa]
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: Chromogranin A: [positive/negative], Synaptophysin: [positive/negative], Ki-67: [X]%
Molecular: RB1: [lost/retained], p53: [overexpressed/normal]
CD56: [positive/negative], INSM1: [positive/negative]
TNM Staging
pT[X] pN[X] pM[X] - Stage [stage]
Final Diagnosis
Gastric Neuroendocrine Carcinoma, WHO Grade 3, Stage [stage]