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Appendiceal Carcinoid / Well Differentiated Neuroendocrine Neoplasm / Tumor

Definition

  • Low grade neoplasm of the appendix demonstrating neuroendocrine differentiation

Note

Diagnostic Criteria

  • 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
      • Rarely may contain lipid vacuoles
    • 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 (see below)
        • Lined by single layer of uniform cells
        • True glands with intracytoplasmic mucin not seen
      • May form rosettes
    • Usually involves only base of crypts and below, 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 appendix
      • Predominantly insular
        • S100 positive sustentacular cells around nests
      • Produce serotonin and substance P
      • Synaptophysin and chromogranin A positive
      • Argentaffin and argyrophil positive
      • Frequent invasion
        • Muscularis propria and serosa
        • Usually permeates muscle without desmoplastic response
        • Lymphatics and perineural space involvement frequent
    • L cell glucagon-like peptide and pancreatic polypeptide (PP/PYY) producing carcinoid is uncommon in the appendix
      • Predominantly tubular and/or trabecular
      • Produce GLP-1, GLP-2, glycentin, oxyntomodulin, PP/PYY
      • Synaptophysin positive, usually chromogranin A negative,
        • Chromogranin B positive (not detected by most common anti-chromogranin antibodies)
      • Argyrophil positive, usually argentaffin negative,
      • Usually <3 mm and non-invasive
    • Tubular carcinoid is uncommon in the appendix
      • Predominantly tubular pattern
        • May contain inspissated mucin
        • Short trabeculae may be present
        • No other above described pattern present
          • Solid nests not seen
        • No sustentacular cells
      • True glands with intracytoplasmic mucin not seen
      • No desmoplastic response
      • May produce chromogranin, glucagon, serotonin
      • May stain for IgA
      • Argentaffin positive in scattered cells in 75% of cases
      • Benign
  • One report of lipid-rich clear cell carcinoids
    • Mixture of cells with microvesicular and clear cytoplasm
    • All reported cases were incidental with benign behavior
  • One small series of combined GCC and classical carcinoid reported (Chetty 2010)
    • This may represent a collision tumor as incidental classical carcinoids are not rare
  • Robert V Rouse MD
    Teri A Longacre MD
    Department of Pathology
    Stanford University School of Medicine
    Stanford CA 94305-5342

    Original posting / updates: 7/27/10, 8/21/10, 12/28/11

Differential Diagnosis

  • Conventional GI adenocarcinoma
  • Goblet cell carcinoid vs. appendiceal carcinoid
  • Site of origin of metastatic well differentiated endocrine carcinoma
Appendiceal Carcinoid / Well Differentiated Neuroendocrine Cell Neoplasm Appendiceal 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

 

Appendiceal Carcinoid / Well Differentiated Neuroendocrine Cell Neoplasm Goblet Cell Carcinoid and/or Carcinoma ex-GCC
Chromogranin or synaptophysin positive Chromogranin and synaptophysin stain rare to scattered cells only
No intracytoplasmic mucin (lumenal mucin may be present in tubular carcinoid) Intracytoplasmic mucin in goblets
CK7 negative, CK20 variable CK7 variable, CK20 100%
Rare mitotic figures at most Mitotic figures may be numerous in carcinoma ex-GCC
Cohesive nests and cords Single cell infiltration or sheet like growth in carcinoma ex-GCC
No desmoplasia Desmoplasia may be present in carcinoma ex-GCC

 

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
    • Confined to appendix 90%
    • Local invasion or metastases to lymph nodes 80%
    • Organ metastases 30%
  • Carcinoid syndrome is usually present only if the liver is involved by metastases
  • 4% of patients also have a small intestinal carcinoid
  • Indications for hemicolectomy for carcinoid (if noted at time of appendectomy)
    • >2 cm in greatest dimension
    • Involvement of mesoappendix
    • Transection
    • Lymph node involvement
  • Recommendations for re-opening the patient for right colectomy if tumor noted after closure
    • If <1 cm and margins clear, no further surgery
    • If 1-2 cm consider right colectomy if:
      • Deep mesoappendiceal invasion (>3 mm)
      • Margins not clearly negative
      • Vascular invasion
    • If >2 cm, recommend right colectomy
    • Metastatic workup should be performed before above decisions made.

Grading and Staging

  • Histopathologic features are predictive of behavior (based on WHO,  Odze and AFIP, each are a bit different)
    • Benign
      • Non-functioning
      • Well differentiated
      • ≤2 cm in greatest dimension
      • Confined to appendiceal wall
        • No involvement of mesoappendix
      • No vascular invasion
    • Uncertain malignant behavior
      • As for benign, but with:
        • >2 cm in greatest dimension and/or
        • Vascular invasion
    • Low grade malignant
      • Non-functioning and well differentiated, with:
        • Invasion of mesoappendix and/or
        • Metastasis
      • OR, functioning and well differentiated
        • Any size and extent
  • WHO 2010 also 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

 

  • Staging
    • AJCC TNM 7th edition now includes carcinoids of the appendix
      • Key elements in staging are size (1, 2, 4 cm) and extension to cecum or ileum

 

Classification/Lists

Gastrointestinal Endocrine Cell Proliferations and Neoplasms

Appendiceal Epithelial Neoplasms and Proliferations

Clinical / Descriptive Terms

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.
  • Moertel CG, Dockerty MB, Judd ES. Carcinoid tumors of the vermiform appendix. Cancer. 1968 Feb;21(2):270-8.
  • Williams GT. Endocrine tumours of the gastrointestinal tract-selected topics. Histopathology. 2007 Jan;50(1):30-41.
  • Carr NJ, Sobin LH. Neuroendocrine tumors of the appendix. Semin Diagn Pathol. 2004 May;21(2):108-19.
  • Iwafuchi M, Watanabe H, Ajioka Y, Shimoda T, Iwashita A, Ito S. Immunohistochemical and ultrastructural studies of twelve Argentaffin and six argyrophil carcinoids of the appendix vermiformis. Hum Pathol. 1990 Jul;21(7):773-80.
  • Warkel RL, Cooper PH, Helwig EB. Adenocarcinoid, a mucin-producing carcinoid tumor of the appendix: a study of 39 cases. Cancer. 1978 Dec;42(6):2781-93.
  • Burke A, Sobin L. The histogenesis of appendiceal carcinoid tumours. Histopathology. 1992 Dec;21(6):600-1.
  • Burke AP, Sobin LH, Federspiel BH, Shekitka KM, Helwig EB. Goblet cell carcinoids and related tumors of the vermiform appendix. Am J Clin Pathol. 1990 Jul;94(1):27-35.
  • 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.
  • La Rosa S, Finzi G, Puppa G, Capella C. Lipid-rich variant of appendiceal well-differentiated endocrine tumor (carcinoid). Am J Clin Pathol. 2010 May;133(5):809-14.
  • Chetty R, Serra S. Lipid-rich and clear cell neuroendocrine tumors ("carcinoids") of the appendix: potential confusion with goblet cell carcinoid. Am J Surg Pathol. 2010 Mar;34(3):401-4.
  • Plöckinger U, Couvelard A, Falconi M, Sundin A, Salazar R, Christ E, de Herder WW, Gross D, Knapp WH, Knigge UP, Kulke MH, Pape UF; Frascati Consensus Conference participants. Consensus guidelines for the management of patients with digestive neuroendocrine tumours: well-differentiated tumour/carcinoma of the appendix and goblet cell carcinoma. Neuroendocrinology. 2008;87(1):20-30.
  • Deschamps L, Couvelard A. Endocrine tumors of the appendix: a pathologic review. Arch Pathol Lab Med. 2010 Jun;134(6):871-5.
  • Long KB, Srivastava A, Hirsch MS, Hornick JL. PAX8 Expression in well-differentiated pancreatic endocrine tumors: correlation with clinicopathologic features and comparison with gastrointestinal and pulmonary carcinoid tumors. Am J Surg Pathol. 2010 May;34(5):723-9.
  • Chetty R, Klimstra DS, Henson DE, Albores-Saavedra J. Combined classical carcinoid and goblet cell carcinoid tumor: a new morphologic variant of carcinoid tumor of the appendix. Am J Surg Pathol. 2010 Aug;34(8):1163-7
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