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High Grade / Poorly Differentiated Neuroendocrine Carcinoma of the Gastrointestinal Tract

Definition

  • 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
  • Mixed patterns with areas of conventional carcinoma may be seen
    • May also show focal glandular or squamous differentiation within endocrine areas
  • 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/updates: 7/27/10, 12/28/11

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

Clinical

  • 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

Lists

Gastrointestinal Endocrine Cell Proliferations and Neoplasms

Bibliography

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