Stanford School of Medicine

Surgical Pathology Criteria

 use browser back button to return

High Grade / Poorly Differentiated Neuroendocrine Carcinoma of the Gastrointestinal Tract


  • High grade neoplasm of the GI tract demonstrating neuroendocrine differentiation

Alternate/Historical Names

  • Adenocarcinoma with endocrine differentiation/features
  • Atypical carcinoid
  • High grade / poorly differentiated endocrine carcinoma
  • Large cell neuroendocrine carcinoma
  • Oat cell carcinoma
  • Small cell carcinoma

Diagnostic Criteria

  • Two basic patterns
    • Small cell (undifferentiated) carcinoma
      • Scant cytoplasm, very high nucleus/cytoplasm ratio
      • Finely granular, stippled chromatin
      • Nucleoli small to absent
      • Nuclear molding
      • Immunohistochemical demonstration of neuroendocrine differentiation not required
        • Many are positive:
          • CD56  90%
          • Synaptophysin 72-100%
          • Chromogranin 64-78%
    • Large cell neuroendocrine carcinoma requires both morphologic and immunohistologic (or ultrastructural) evidence of neuroendocrine differentiation
      • Morphologic features suggestive of neuroendocrine differentiation (not all are seen in each case)
        • Generally uniform polygonal/cuboidal cells with slightly granular eosinophilic cytoplasm
        • Densely cellular with solid growth pattern
        • Nesting and/or broad trabeculae with nuclear palisading
        • Rosettes and rosette like structures but limited true gland formation
          • Focal gland formation or intracytoplasmic mucin is permitted
        • Fine to coarsely granular (stippled) chromatin pattern with thin nuclear membranes
          • Usually have vesicular nuclei with prominent nucleoli
        • Necrosis
      • Demonstration of neuroendocrine differentiation is required
        • Percent of cells required to stain ranges from 20 to 50% in various studies
        • Synaptophysin, chromogranin and CD56 are the most specific
        • Reported reactivity:
          • CD56  54%
          • Synaptophysin 94-100%
          • Chromogranin 71-78%
        • Neuron specific enolase and PGP9.5 are less specific but accepted by many studies
        • Specific endocrine secretory products less frequently seen
  • Frequently associated with adenoma and/or adenocarcinoma
    • Not associated with low grade, well differentiated neuroendocrine neoplasm (carcinoid)
  • Most frequent in esophagus, stomach, ampulla of Vater, colon, rectum and anus
    • Very rare in small intestine, appendix
    • (Rare throughout the GI tract compared to conventional adenocarcinomas)

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

Original posting/last update: 7/27/10, 1/25/15

Differential Diagnosis

  • Small Cell Endocrine Carcinoma
    • Metastatic carcinoma must always be ruled out, especially from the lung
      • TTF1 is positive in 16% of GI small cell carcinomas
      • Clinical correlation is usually required
  • Large Cell Endocrine Carcinoma vs Carcinoma NOS

    • Ddiagnosis of large cell endocrine carcinoma requires both morphologic and immunohistologic features as described above
    • It is not clear that large cell endocrine carcinoma presently behaves differently from small cell carcinoma and high grade adenocarcinoma
      • The distinction may be worthwhile for advances in therapy

Colorectal Undifferentiated Carcinoma NOS Colorectal Small Cell Neuroendocrine (Undifferentiated) Carcinoma
Chromogranin and synaptophysin at most focal or scattered Chromogranin or synaptophysin may be negative or positive
Vesicular nuclei Chromatin finely granular, stippled
Prominent nucleoli Inconspicuous nucleoli
Pleomorphic large cells Uniform small to medium size cells

Colorectal Undifferentiated Carcinoma NOS Colorectal Large Cell Neuroendocrine Carcinoma
Chromogranin and synaptophysin at most focal or scattered Chromogranin or synaptophysin must be positive in at least 20-50% of cells
Vesicular nuclei Chromatin finely granular, stippled
Prominent nucleoli Inconspicuous nucleoli
Does not form rosettes May form rosettes


  • Most cases present with nodal or distant metastases
  • Poor prognosis
  • Carcinoid syndrome is rare even if the liver is involved by metastases
  • It is not clear that large cell endocrine carcinoma presently behaves differently from small cell carcinoma and high grade adenocarcinoma with current therapy


Gastrointestinal Endocrine Cell Proliferations and Neoplasms


  • Riddell RH, Petras RE, Williams GT, Sobin LH. Tumors of the Intestines, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 32, 2003.
  • Hamilton SR, Aaltonen LA eds. Pathology and genetics of tumours of the digestive system. World Health Organization classification of tumours, Vol. 2. Lyon: IARC Press 2000.
  • Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer. 1997 Feb 15;79(4):813-29.
  • Williams GT. Endocrine tumours of the gastrointestinal tract-selected topics. Histopathology. 2007 Jan;50(1):30-41.
  • Klöppel G, Anlauf M. Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2005 Aug;19(4):507-17.
  • Fiocca R, Rindi G, Capella C, Grimelius L, Polak JM, Schwartz TW, Yanaihara N, Solcia E. Glucagon, glicentin, proglucagon, PYY, PP and proPP-icosapeptide immunoreactivities of rectal carcinoid tumors and related non-tumor cells. Regul Pept. 1987 Jan;17(1):9-29.
  • Federspiel BH, Burke AP, Sobin LH, Shekitka KM. Rectal and colonic carcinoids. A clinicopathologic study of 84 cases. Cancer. 1990 Jan 1;65(1):135-40.
  • Bernick PE, Klimstra DS, Shia J, Minsky B, Saltz L, Shi W, Thaler H, Guillem J, Paty P, Cohen AM, Wong WD. Neuroendocrine carcinomas of the colon and rectum. Dis Colon Rectum. 2004 Feb;47(2):163-9.
  • Rindi G, Klöppel G. Endocrine tumors of the gut and pancreas tumor biology and classification. Neuroendocrinology. 2004;80 Suppl 1:12-5.
  • Gaffey MJ, Mills SE, Lack EE. Neuroendocrine carcinoma of the colon and rectum. A clinicopathologic, ultrastructural, and immunohistochemical study of 24 cases. Am J Surg Pathol. 1990 Nov;14(11):1010-23.
  • Nassar H, Albores-Saavedra J, Klimstra DS. High-grade neuroendocrine carcinoma of the ampulla of vater: a clinicopathologic and immunohistochemical analysis of 14 cases. Am J Surg Pathol. 2005 May;29(5):588-94.
  • Xiao GQ, Strauchen JA. Pathologic quiz case: a 72-year-old woman presenting with intestinal obstruction and perforation. Small cell neuroendocrine carcinoma of small intestine. Arch Pathol Lab Med. 2003 Aug;127(8):e357-8.
  • Pantvaidya GH, Pramesh CS, Deshpande MS, Jambhekar NA, Sharma S, Deshpande RK. Small cell carcinoma of the esophagus: the Tata Memorial Hospital experience. Ann Thorac Surg. 2002 Dec;74(6):1924-7.
  • Nilsson O, Van Cutsem E, Delle Fave G, Yao JC, Pavel ME, McNicol AM, Sevilla Garcia MI, Knapp WH, Keleştimur F, Sauvanet A, Pauwels S, Kwekkeboom DJ, Caplin M; Frascati Consensus Conference; European Neuroendocrine Tumor Society. Poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic). Neuroendocrinology. 2006;84(3):212-5.
  • Jiang SX, Mikami T, Umezawa A, Saegusa M, Kameya T, Okayasu I. Gastric large cell neuroendocrine carcinomas: a distinct clinicopathologic entity. Am J Surg Pathol. 2006 Aug;30(8):945-53.
  • Ordóñez NG. Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol. 2000 Sep;24(9):1217-23.
  • Brenner B, Shah MA, Gonen M, Klimstra DS, Shia J, Kelsen DP. Small-cell carcinoma of the gastrointestinal tract: a retrospective study of 64 cases. Br J Cancer. 2004 May 4;90(9):1720-6.
  • Shia J, Tang LH, Weiser MR, Brenner B, Adsay NV, Stelow EB, SaltzLB, Qin J, Landmann R, Leonard GD, Dhall D, Temple L, Guillem JG, Paty PB, Kelsen D, Wong WD, Klimstra DS. Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? Am J Surg Pathol. 2008 May;32(5):719-31.
  • Maru DM, Khurana H, Rashid A, Correa AM, Anandasabapathy S, Krishnan S, Komaki R, Ajani JA, Swisher SG, Hofstetter WL. Retrospective Study of Clinicopathologic Features and Prognosis of High-grade Neuroendocrine Carcinoma of the Esophagus. Am J Surg Pathol. 2008 Sept;32(9):1404-1411.
Printed from Surgical Pathology Criteria:
© 2005  Stanford University School of Medicine