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Carcinoid / Well Differentiated Neuroendocrine Neoplasm / Tumor of the Ileum, Distal Jejunum and Cecum

Definition

  • Low grade neoplasm of the the ileum, distal jejunum or cecum demonstrating neuroendocrine differentiation

Note

Alternate/historical Names

  • Argentaffin carcinoma
  • Midgut carcinoid
  • Well differentiated (neuro-)endocrine tumor/carcinoma

Diagnostic Criteria

  • Site of origin in the ileum, distal jejunum or cecum
    • Most common in distal ileum
    • Cecal carcinoids generally arise near the ileocecal valve and share histopathologic and clinical features with ileal carcinoids
    • May be multiple in 25-30% of cases (as many as 100 tumors)
  • Most cells show evidence of neuroendocrine differentiation
    • Synaptophysin stain positive in nearly all cases
      • Chromogranin positive in most
    • Argyrophil stain positive in nearly all cases
      • Argentaffin positive in most
    • Neuron specific enolase, PGP9.5 and CD56 are sensitive but not specific
  • Most well differentiated neoplasms exhibit characteristic cytologic and architectural features
    • Round regular nuclei
      • Stippled (salt and pepper) chromatin
    • Moderate to abundant cytoplasm
    • Various growth patterns
      • Insular growth pattern
        • Round nests of cells
        • May palisade
      • Trabecular
        • Rows and strands of cells
        • Cells are “stacked” with their long axis perpendicular to the long axis of the row
      • Tubular
        • Lined by single layer of uniform cells
        • True glands with intracytoplasmic mucin not seen
      • May form rosette-like pseudo-glandular structures
        • True glands with intracytoplasmic mucin not seen
    • Usually involves only base of crypts, leaving mucosa largely intact
  • Carcinoids can be subdivided by pattern and secretory products
    • Enterochromaffin (EC) cell serotonin producing carcinoid is the most common type in the small intestine (93-98%)
      • Predominantly insular
        • May have rosette-like pseudo-glandular structures
        • May have single file pattern in desmoplastic areas
        • No S100 positive sustentacular cells around nests
          • (Differs from appendiceal carcinoids LINK)
      • Produce serotonin and substance P
        • Prostatic acid phosphatase positive in 28% of cases
      • Synaptophysin and chromogranin A positive
      • Argentaffin and argyrophil positive
      • Frequent invasion
        • Muscularis propria and serosa
        • May elicit desmoplastic response
    • L cell glucagon-like peptide and pancreatic polypeptide (PP/PYY) producing carcinoid is very rare in small intestine
      • Predominantly tubular and/or trabecular
      • Produce GLP-1, GLP-2, glycentin, oxyntomodulin, PP/PYY
      • Synaptophysin positive, may be chromogranin A negative
        • Chromogranin B positive (not detected by most common anti-chromogranin antibodies)
      • Argyrophil positive, may be argentaffin negative
  • Elastic adventitial sclerosis may occlude vessels
    • Involves mesenteric arteries and veins
      • May cause ischemic lesions
    • Present in cases with adjacent invasive carcinoid
    • Small vessels in and around primary tumor not involved
  • Carcinoids arising in Meckel diverticula appear similar histopathologically and clinically to other ileal carcinoids

    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

  • Conventional GI adenocarcinoma
  • Site of origin of metastatic well differentiated endocrine carcinoma
Ileal Carcinoid / Well Differentiated Neuroendocrine Cell Neoplasm Ileal or Other GI Adenocarcinoma
Bland cytologic features Atypical cytology
Chromogranin or synaptophysin positive Chromogranin and synaptophysin negative
No desmoplastic response Desmoplastic response frequent
Rare mitotic figures Mitotic figures frequently numerous
Cohesive nests and cords Frequent single cell infiltration
No surface adenoma or in situ lesion May have surface adenoma or in situ component
No intracytoplasmic mucin May have intracytoplasmic mucin and/or signet ring cells

 

Determination of common sites of origin for metastatic well differentiated endocrine neoplasms
  TTF1 CDX2 PDX1 ISL1 PAX8
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

Clinical

  • Five year survival
    • No liver metastases at presentation 70%
    • Liver metastases at presentation 35%
    • Deaths due to disease continue to occur beyond 5 years
  • Carcinoid syndrome is usually present only if the liver is involved by metastases
  • 15% of patients also have a non-endocrine neoplasm, usually gastrointestinal adenocarcinoma
  • Less frequently associated with MEN-1 than are gastric and duodenal endocrine neoplasms
  • Patients with multiple jejuno-ileal carcinoids have a decreased survival
  • Histopathologic features are predictive of behavior
    • Benign
      • Non-functioning
      • Well differentiated
      • ≤1 cm in greatest dimension
      • Confined to mucosa and submucosa
        • No involvement of muscularis propria
      • No vascular invasion
    • Uncertain malignant behavior
      • As for benign, but with:
        • >1 but ≤2 cm in greatest dimension and/or
        • Vascular invasion
    • Low grade malignant
      • Non-functioning and well differentiated, with
        • Invasion of muscularis propria or beyond and/or
        • Metastasis and/or
        • >2 cm in greatest dimension (not uniformly accepted)
      • OR, functioning and well differentiated
        • Any size and extent

Grading and Staging

  • WHO 2010 recommends the following grading scheme

      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.
    • Other features described above should also be reported
  • High grade / poorly differentiated neuroendocrine carcinoma is covered separately
  • AJCC TNM 7th edition now includes carcinoids of the ileum
    • Key cutoffs in size are 0.5 mm, 1 cm and 2 cm

Classification/Lists

Gastrointestinal Endocrine Cell Proliferations and Neoplasms

Bibliography

  • Riddell RH, Petras RE, Williams GT, Sobin LH. Tumors of the Intestines, Atlas of Tumor Pathology, AFIP Third Series, Fascicle 32, 2003.
  • Bosman FT, Carneiro F, Hruban RH, Thiese ND (Eds). WHO Classifiication of Tumors of the Digestive System, IARC, Lyon 2010.
  • 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.
  • Burke AP, Thomas RM, Elsayed AM, Sobin LH. Carcinoids of the jejunum and ileum: an immunohistochemical and clinicopathologic study of 167 cases. Cancer. 1997 Mar 15;79(6):1086-93.
  • Nies C, Zielke A, Hasse C, Rüschoff J, Rothmund M. Carcinoid tumors of Meckel's diverticula. Report of two cases and review of the literature. Dis Colon Rectum. 1992 Jun;35(6):589-96. Review.
  • Yantiss RK, Odze RD, Farraye FA, Rosenberg AE. Solitary versus multiple carcinoid tumors of the ileum: a clinical and pathologic review of 68 cases. Am J Surg Pathol. 2003 Jun;27(6):811-7.
  • Anthony PP, Drury RA. Elastic vascular sclerosis of mesenteric blood vessels in argentaffin carcinoma. J Clin Pathol. 1970 Mar;23(2):110-8.
  • Lin X, Saad RS, Luckasevic TM, Silverman JF, Liu Y. Diagnostic value of CDX-2 and TTF-1 expressions in separating metastatic neuroendocrine neoplasms of unknown origin. Appl Immunohistochem Mol Morphol. 2007 Dec;15(4):407-14.
  • Schmitt AM, Riniker F, Anlauf M, Schmid S, Soltermann A, Moch H, Heitz PU, Klöppel G, Komminoth P, Perren A. Islet 1 (Isl1) expression is a reliable marker for pancreatic endocrine tumors and their metastases. Am J Surg Pathol. 2008 Mar;32(3):420-5.
  • Moskaluk CA, Zhang H, Powell SM, Cerilli LA, Hampton GM, Frierson HF Jr.  Cdx2 protein expression in normal and malignant human tissues: an immunohistochemical survey using tissue microarrays. Mod Pathol. 2003 Sep;16(9):913-9.
  • 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.
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