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Surgical Pathology Criteria

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Gastric Neuroendocrine Hyperplasia, Dysplasia and Neoplasia (Carcinoid Tumors)


  • Neuroendocrine cell proliferations of the stomach arise in various settings and show features ranging from hyperplasia to neoplasia

Alternate/Historical Names

  • WHO 2010 has changed back to neuroendocrine cell from endocrine cell for these lesions
    • Endocrine cell hyperplasia and neoplasia are equivalent terms to those used below

Diagnostic Criteria

  • Gastric carcinoids and neuroendocrine cell proliferations arise in three settings
    • Type A – autoimmune gastritis
      • Hyperplasia, dysplasia and neoplasia are not uncommon
      • Most carcinoids are <1 cm and are not aggressive
        • Local metastases in 8%
        • Distant metastases in 2%
        • May not progress even if not resected
      • Role of following is unclear
        • Helicobacter infection
        • Protein pump inhibitor therapy
    • Type B – Zollinger Ellison syndrome with and without MEN1
      • Without MEN1, generally only neuroendocrine cell hyperplasia is seen
      • With MEN1, may have neuroendocrine cell dysplasia and neoplasia
        • Such carcinoids may behave aggressively
    • Type C – sporadic
      • Frequently large and aggressive
        • Over half may invade deeply and metastasize
  • Types of neuroendocrine cell proliferations
    • Chromogranin and/or synaptophysin stains are necessary for evaluation of neuroendocrine cells
    • Normal endocrine cells
      • Scattered individually, primarily in the basal crypt epithelium
    • Hyperplasia
      • Linear or micronodular clusters of at least 5 cells
        • Micronodular clusters ≤150 microns in greatest dimension
        • At least 2 linear chains / mm or 1 micronodule / mm
    • Dysplasia (any of the below criteria)
      • Enlargement and fusion of five or more micronodules
      • >150 microns in greatest dimension
      • Microinfiltration of lamina propria
      • Nodule with formation of new stroma
    • Neoplasia (carcinoid tumor or well differentiated neuroendocrine tumor/neoplasm)
  • Gastric endocrine cell proliferations typically show features seen in other GI tract well differentiated endocrine proliferations
    • Generally uniform, bland nuclei
      • Occasional reports of scattered larger atypical nuclei
        • Uncertain significance
    • Trabecular, acinar, pseudo glandular architecture
    • Variable positivity for neuroendocrine markers
      • Most often serotonin

    Robert V Rouse MD
    Department of Pathology
    Stanford University School of Medicine
    Stanford CA 94305-5342

    Original posting/updates: 7/27/10, 12/28/11


Differential Diagnosis

Determination of common sites of origin for metastatic well differentiated endocrine neoplasms
Lung 40-50% Negative Negative Negative Negative
Pancreas Negative 0-18% 28% 68% 50-67%
Stomach Negative 0-17% 60% Negative 20%
Duodenum Negative 0-17% 60% Negative 100%
Ileum Negative >90% Negative Negative Negative
Appendix Negative >90% 55% Negative 21%
Rectum Negative 0-55% 17% Negative 85%
Detection of specific islet hormones may be useful; PAX8 data has been questioned (see Pancreas).


Determination of common sites of origin for metastatic well differentiated endocrine neoplasms-keratins
  CK7 CK20
Lung Variable Negative
Pancreas Variable Variable
Stomach Variable Negative
Duodenum Negative Variable
Ileum Negative Variable
Appendix Negative Variable
Rectum Variable Variable
CK7/20 staining is only helpful in instances of positivity where a negative result is expected


  • It has been proposed that type A and B hyperplasia and dysplasia may progress to carcinoid (Berna 2008, Annibale 2001)
    • This is not universally accepted for hyperplastic lesions (Solicia 1995)
    • It would appear that both merit followup
  • The behavior of carcinoids is dependent upon size, proliferation rate and the setting in which it arises (see Diagnostic Criteria) as well as proliferation grade


Proposed grading scale based on proliferation

Grade Mitotic count per 10 hpf % of cells Ki67+
G1 <2 ≤2
G2 2-20 3-20
G3 >20 >20
  • Mitotic counts based on 50 hpf
  • Ki67 % based on 500-2000 cells
  • If discrepant, use higher grade
  • Scale proposed by European Neuroendocrine Society (ENETS)
    • Carcinoids / neuroendocrine tumors may be G1 or G2
    • G3 is definitional for high grade neuroendocrine carcinoma
  • Progression from G1/2 to G3 is quite rare
    • G3 appears to be a separate process

Grading/Staging References

  • Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007 Oct;451(4):757-62.
  • Rindi G, Klöppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B; and all other Frascati Consensus Conference participants; European Neuroendocrine Tumor Society (ENETS). TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006 Oct;449(4):395-401.


Correlation of grade with stage
Grade Approx incidence of node mets Approx incidence of distant mets
G1 5% 2.5%
G2 30% 10%
G3 70% 70%


  • GI neuroendocrine tumors should be staged according to AJCC TNM 7th edition



Gastrointestinal Endocrine Cell Proliferations and Neoplasms


  • Bosman FT, Carneiro F, Hruban RH, Thiese ND (Eds). WHO Classifiication of Tumors of the Digestive System, IARC, Lyon 2010
  • Bordi C, Annibale B, Azzoni C, Marignani M, Ferraro G, Antonelli G, D'Adda T, D'Ambra G, Delle Fave G. Endocrine cell growths in atrophic body gastritis. Critical evaluation of a histological classification. J Pathol. 1997 Jul;182(3):339-46.
  • Solcia E, Fiocca R, Villani L, Luinetti O, Capella C. Hyperplastic, dysplastic, and neoplastic enterochromaffin-like-cell proliferations of the gastric mucosa. Classification and histogenesis. Am J Surg Pathol. 1995;19 Suppl 1:S1-7.
  • Reinecke P, Borchard F. Pattern of gastric endocrine cells in microcarcinoidosis--an immunohistochemical study of 14 gastric biopsies. Virchows Arch. 1996 Jul;428(4-5):237-41.
  • Solcia E, Villani L, Luinetti O, Fiocca R. Proton pump inhibitors, enterochromaffin-like cell growth and Helicobacter pylori gastritis. Aliment Pharmacol Ther. 1993;7 Suppl 1:25-8, discussion 29-31.
  • Solcia E, Capella C, Fiocca R, Rindi G, Rosai J. Gastric argyrophil carcinoidosis in patients with Zollinger-Ellison syndrome due to type 1 multiple endocrine neoplasia. A newly recognized association. Am J Surg Pathol. 1990 Jun;14(6):503-13.
  • Itsuno M, Watanabe H, Iwafuchi M, Ito S, Yanaihara N, Sato K, Kikuchi M, Akiyama N. Multiple carcinoids and endocrine cell micronests in type A gastritis. Their morphology, histogenesis, and natural history. Cancer. 1989 Mar 1;63(5):881-90.
  • Alsaad KO, Serra S, Schmitt A, Perren A, Chetty R. Cytokeratins 7 and 20 immunoexpression profile in goblet cell and classical carcinoids of appendix. Endocr Pathol. 2007 Spring;18(1):16-22.
  • Cai YC, Banner B, Glickman J, Odze RD. Cytokeratin 7 and 20 and thyroid transcription factor 1 can help distinguish pulmonary from gastrointestinal carcinoid and pancreatic endocrine tumors. Hum Pathol. 2001 Oct;32(10):1087-93.
  • Srivastava A, Hornick JL. Immunohistochemical staining for CDX-2, PDX-1, NESP-55, and TTF-1 can help distinguish gastrointestinal carcinoid tumors from pancreatic endocrine and pulmonary carcinoid tumors. Am J Surg Pathol. 2009 Apr;33(4):626-32.
  • Rindi G, Solcia E. Endocrine hyperplasia and dysplasia in the pathogenesis of gastrointestinal and pancreatic endocrine tumors. Gastroenterol Clin North Am. 2007 Dec;36(4):851-65.
  • Klöppel G, Anlauf M, Perren A. Endocrine precursor lesions of gastroenteropancreatic neuroendocrine tumors. Endocr Pathol. 2007 Fall;18(3):150-5.
  • Berna MJ, Annibale B, Marignani M, Luong TV, Corleto V, Pace A, Ito T, Liewehr D, Venzon DJ, Delle Fave G, Bordi C, Jensen RT. A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors. J Clin Endocrinol Metab. 2008 May;93(5):1582-91.
  • Annibale B, Azzoni C, Corleto VD, di Giulio E, Caruana P, D'Ambra G, Bordi C, Delle Fave G. Atrophic body gastritis patients with enterochromaffin-like cell dysplasia are at increased risk for the development of type I gastric carcinoid. Eur J Gastroenterol Hepatol. 2001 Dec;13(12):1449-56.
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