Surgical Pathology Criteria

Mixed Adenoneuroendocrine Carcinoma (MANEC) of the GI Tract

  • Gastrointestinal tract carcinoma with both high grade neuroendocrine and adenocarcinoma features


Alternate/Historical Names
  • High grade neuroendocrine carcinoma
Diagnostic Criteria
  • High grade, poorly differentiated neuroendocrine carcinoma makes up 30-70% of the tumor
    • Morphologic features may suggest large cell 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
      • Proliferative rate >90%
    • Small cell high grade neuroendocrine features are same as those of other sites
      • Scant cytoplasm, very high nucleus/cytoplasm ratio
      • Finely granular, stippled chromatin
      • Nucleoli small to absent
      • Nuclear molding
    • Demonstration of neuroendocrine differentiation is required for large cell but not for a characteristic small cell component
      • Synaptophysin, chromogranin and CD56 are the most specific
      • Synaptophysin is most sensitive, CD56 the least sensitive
  • Differentiated adenocarcinoma makes up 30-70% of the tumor
    • If less, use the term High Grade Poorly Differentiated Neuroendocrine Carcinoma with Glandular Differentiation
    • If more, use the term Adenocarcinoma with Neuroendocrine Features


  • The distinction between poorly differentiated large cell neuroendocrine, small cell neuroendocrine and mixed adenoneuroendocrine carcinomas may not critical
    • All three show similar aggressive behavior
      • It has been suggested that (at least in the esophagus) the prognosis for MANEC is better than the other two but still quite poor (Maru 2008)
    • All three are generally treated simiilarly

Differential Diagnosis



  • Bosman FT, Carneiro F, Hruban RH, Thiese ND (Eds). WHO Classifiication of Tumors of the Digestive System, IARC, Lyon 2010
  • Shia J, Tang LH, Weiser MR, Brenner B, Adsay NV, Stelow EB, Saltz LB, 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. doi: 10.1097/PAS.0b013e318159371c. PubMed PMID: 18360283.
  • 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 Sep;32(9):1404-11. doi: 10.1097/PAS.0b013e31816bf41f. PubMed PMID: 18670347.
  • Sorbye H, Strosberg J, Baudin E, Klimstra DS, Yao JC. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer. 2014 Sep 15;120(18):2814-23. doi: 10.1002/cncr.28721. Epub 2014 Apr 25. Review. PubMed PMID: 24771552.
  • Hirabayashi K, Zamboni G, Nishi T, Tanaka A, Kajiwara H, Nakamura N. Histopathology of gastrointestinal neuroendocrine neoplasms. Front Oncol. 2013 Jan 22;3:2. doi: 10.3389/fonc.2013.00002. eCollection 2013. PubMed PMID: 23346552; PubMed Central PMCID: PMC3551285.

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

Original posting/last update: 1/25/15


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