Stomach

• The 5th edition of the WHO 2019 Digestive Tumors Classification definition of neuroendocrine tumor (NET): well differentiated, grade 1, 2 or 3 based on mitotic rate per 2 mm² (based on counting 10 mm² and taking the average) and Ki67 immunohistochemical index (counted in ≥ 500 cells in the area of highest staining); grade assigned by whichever value is higher (see Diagrams / tables)
• Must lack features of carcinoma, which includes poorly differentiated morphology, tumoral necrosis, high N/C ratio and prominent nucleoli

• Gastric NETs often occur in the setting of certain diseases (Surg Pathol Clin 2020;13:377):
  • Type I:
    • Derived from enterochromaffin-like (ECL) cells
    • Occurs in a setting of chronic atrophic gastritis (type A) and hypergastrinemia
    • More frequent in women
  • Type II:
    • Derived from ECL cells
    • Occurs in a setting of hypergastrinemia due to Zollinger-Ellison syndrome
    • Can be seen in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome
    • Affects men and women equally
  • Type III:
    • Sporadic
    • More frequent in men
  • Type IV:
    • Discussed in the literature but not currently recognized by the WHO
  • Serotonin producing EC cell NET:
    • Rare and usually nonfunctional
  • Gastrin producing G cell NET:
    • Usually nonfunctional but can cause Zollinger-Ellison syndrome and is then referred to as a gastric gastrinoma
• All types tend to occur in the age range of 50 - 60 years

• May arise in the setting of autoimmune gastritis (type I), Zollinger-Ellison syndrome (type II) or in the absence of a known precursor (type III) (Surg Pathol Clin 2020;13:377)

Gastric NET grade	Mitotic rate (per 2 mm2)	Ki67 rate
Grade 1	< 2	< 3%
Grade 2	2 - 20	3 - 20%
Grade 3	> 20	> 20%

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Contributed by Dana Razzano, M.D. and @RaulSGonzalezMD on Twitter

• Chromogranin, synaptophysin diffusely and strongly positive
• CD56, INSM1
• NSE, Leu7 / B3GAT1, protein gene product 9.5 (PGP9.5)
• Somatostatin receptors (SSTRs) (Exp Ther Med 2021;22:1179)

• Mutations in MEN1, DAXX and ATRX are entity defining for well differentiated NETs (Histopathology 2020;76:182)
• Small cohort studies show associations with germline mutation in the ATP4A gene, with other studies demonstrating loss of heterozygosity at chromosome 11p13 (MEN1 locus) and hypermethylation at the CDKN2A locus as possibly frequent events in gastric NETs (Endocr Rev 2019;40:506)
• Lack the common TP53 and Rb mutation found in most gastric neuroendocrine carcinomas (Histopathology 2020;76:182)

• Stomach, partial gastrectomy:
  • Well differentiated neuroendocrine tumor, WHO grade 1, 1.8 cm, excised (see comment and synoptic table)
  • Oxyntic mucosa with moderate chronic gastritis
  • Mild intestinal metaplasia, incomplete type
  • Severe atrophy
  • No Helicobacter organisms on immunohistochemistry
  • Comment: Histologic sections of the stomach demonstrate involvement by nests of tumor cells with round nuclei, variably prominent nucleoli and abundant clear to eosinophilic cytoplasm, consistent with a well differentiated neuroendocrine tumor. Immunostains show that the tumor cells are positive for synaptophysin, chromogranin and INSM1. In accordance with recommended criteria for grading neuroendocrine tumors, mitotic activity assessed within 50 high power fields (10 mm²) on the resection specimen is < 1 mitotic figure per 10 high power fields (2 mm²); Ki67 index, assessed in 2,000 cells in the area of highest proliferation, is < 1%. Based on these proliferation indices, the tumor is best considered WHO grade 1.
  • The background gastric mucosa shows moderate chronic gastritis with pseudopyloric and intestinal metaplasia. Linear and nodular endocrine cell hyperplasia are also present, confirmed by immunohistochemical stain for chromogranin. Gastrin immunostain is negative, indicating oxyntic mucosa with severe atrophy. The features are consistent with autoimmune gastritis in the appropriate clinical context. Correlation with clinical and laboratory findings is recommended.

A 51 year old symptomatic man was found to have multiple gastric polyps on screening esophagogastroduodenoscopy (EGD). One polyp showed an aggregate of nested bland tumor cells (seen in the figure above) that stained positive for synaptophysin and chromogranin. What is the appropriate way to grade this tumor?

1. Ki67 and mitotic figure count, whichever is higher
2. Ki67 and mitotic figure count, whichever is lower
3. Ki67 index alone
4. Mitotic figure count

A. Ki67 and mitotic figure count, whichever is higher

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Reference: Well differentiated neuroendocrine tumor

What is the most common type of gastric neuroendocrine neoplasm?

1. Gastric well differentiated NET type I
2. Gastric well differentiated NET type II
3. Gastric well differentiated NET type III
4. Gastrin producing G cell NET
5. Serotonin producing EC cell NET

A. Gastric well differentiated NET type I

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Reference: Well differentiated neuroendocrine tumor