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Gastrointestinal Carcinoid Tumors Treatment (PDQ®)

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Last Modified: 07/31/2014

Cellular and Pathologic Classification of Gastrointestinal Carcinoid Tumors

A variety of neuroendocrine cells normally populate the gastrointestinal (GI) mucosa and submucosa. The type, location, and secretory products of GI neuroendocrine cells are well defined and are summarized in Table 1 below. As previously noted, individual carcinoid tumors have specific histologic and immunohistochemical features based on their anatomic location and neuroendocrine cell type. However, all carcinoids share common pathologic features that characterize them as well-differentiated neuroendocrine tumors (NETs).[1]

Table 1. Gastrointestinal Neuroendocrine Cellsa
Cell Type Location Secretory Product
G cellGastric antrum and duodenumGastrin
ECL cellGastric fundus and bodyHistamine
D cellStomach, duodenum, jejunum, colon, and rectumSomatostatin
EC cellStomach, duodenum, jejunum, ileum, colon, and rectumSerotonin, motilin, and substance P
CCK cellDuodenum and jejunumCholecystokinin
GIP cellDuodenum and jejunumGastric inhibitory polypeptide
M cellDuodenum and jejunumMotilin
S cellDuodenum and jejunumSecretin
PP cellDuodenumPancreatic polypeptide
L cellJejunum, ileum, colon, and rectumPolypeptide YY
N cellJejunum and ileumNeurotensin

CCK = cholecystokinin; D = somatostatin-producing; EC = enterochromaffin; ECL = enterochromaffin-like; G = Gastrin cell; GIP = gastric inhibitory polypeptide; L = enteroendocrine; M = motilin; N = neurotensin; PP = pancreatic polypeptide; S = secretin.
a Adapted from [1-3]

Updated in 2000, the World Health Organization (WHO) classification of GI NETs is clinically and prognostically useful for patients with newly diagnosed NETs of the GI tract because it accounts for specific biological behavior according to location and tumor differentiation.[4,5]

This classification distinguishes between the following:

  • Well-differentiated, mostly benign tumors with an excellent prognosis.
  • Well-differentiated carcinomas with a low malignant potential and a favorable prognosis.
  • Poorly differentiated carcinomas (small cell and fewer large cell), which are highly malignant and carry a poor prognosis.

In this classification, the term carcinoid (or typical carcinoid) is used only for well-differentiated NETs of the GI tract, excluding the pancreas; the term malignant carcinoid (or atypical carcinoid) is used for the corresponding well-differentiated NETs at the same GI tract locations.[6,7] Despite some uncertainty surrounding the role of cell proliferation indices in the prognosis of NETs, it is clear that poorly differentiated carcinomas are highly aggressive and require a special therapeutic approach.[7-9] In a second step, the WHO classification subdivides GI NETs on the basis of localization and biology to achieve a prognostically relevant classification of the tumors.[5-7,9] In this subclassification, GI anatomical locations included the following:

  • Stomach (four different types).
  • Duodenum (and proximal jejunum) (five different types).
  • Ileum (including the distal jejunum).
  • Appendix.
  • Colon-rectum.

(Refer to the Site-Specific Clinical Features section in the General Information About Gastrointestinal Carcinoid Tumors section of this summary for more information about a clinicopathologic correlation of cell types and anatomical location.)

In addition, in the WHO classification scheme, GI NETs have been grouped with pancreatic NETS (islet cell tumors) and labeled as gastroenteropancreatic NETs (GEP-NETs). However, because of differences in chromosomal alteration patterns and molecular genetics between GI NETs and pancreatic NETs, some investigators have suggested that this GEP-NET grouping requires reassessment.[7,9,10]

Because there were no proven molecular and genetic alterations with clinical and prognostic relevance, only traditional morphologic and histopathologic criteria were used in the classification. In addition to the level of differentiation, these criteria include the following:

  • Size of the tumor.
  • Presence or absence of angioinvasion.
  • Proliferative activity (as measured by a Ki-67 index).[5,6]

Traditional cytologic and histopathologic assessment of growth patterns and cellular features of well-differentiated NETs are often of little help in predicting their functional behavior and degree of malignancy. In general, typical carcinoids occurring in the stomach, the appendix, or the rectum have an excellent prognosis.[6] In contrast, poorly differentiated NETs that are composed of cells displaying severe nuclear atypia, a high mitotic index, and few secretory granules are invariably high-grade malignancies.[7]

Diagnostic markers that help to identify GI NETs include the following:

  • Cytosolic and cell-membrane markers such as neuron-specific enolase, protein gene product 9.5, histidine carboxylase, vesicular monamine transporter 2 (VMAT2), and neural-cell adhesion molecule CD56 (high sensitivity and low specificity).

  • Small vesicle-associated markers such as synaptophysin and synaptic vesicle protein 2 (high sensitivity and high specificity).

  • Large secretory granule-associated markers such as chromogranins A, B, and C and CD57 (low sensitivity and high specificity).

  • Somatostatin receptors.

  • Specific peptide hormone markers such as serotonin, somatostatin, and gastrin.[7,8]

Hormones that are highly specific for certain GI NETs are serotonin and substance P for ileal and appendiceal NETs, and VMAT2 for ECLomas.[7]

References
  1. Levy AD, Sobin LH: From the archives of the AFIP: Gastrointestinal carcinoids: imaging features with clinicopathologic comparison. Radiographics 27 (1): 237-57, 2007 Jan-Feb.  [PUBMED Abstract]

  2. Hemminki K, Li X: Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. Cancer 92 (8): 2204-10, 2001.  [PUBMED Abstract]

  3. Burke AP, Thomas RM, Elsayed AM, et al.: Carcinoids of the jejunum and ileum: an immunohistochemical and clinicopathologic study of 167 cases. Cancer 79 (6): 1086-93, 1997.  [PUBMED Abstract]

  4. Capella C, Heitz PU, Höfler H, et al.: Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 425 (6): 547-60, 1995.  [PUBMED Abstract]

  5. Solcia E, Kloppel G, Sobin LH, et al.: Histological Typing of Endocrine Tumours. 2nd ed. New York, NY: Springer, 2000 . 

  6. Arnold R: Endocrine tumours of the gastrointestinal tract. Introduction: definition, historical aspects, classification, staging, prognosis and therapeutic options. Best Pract Res Clin Gastroenterol 19 (4): 491-505, 2005.  [PUBMED Abstract]

  7. Klöppel G: Tumour biology and histopathology of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 21 (1): 15-31, 2007.  [PUBMED Abstract]

  8. Williams GT: Endocrine tumours of the gastrointestinal tract-selected topics. Histopathology 50 (1): 30-41, 2007.  [PUBMED Abstract]

  9. Klöppel G, Perren A, Heitz PU: The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci 1014: 13-27, 2004.  [PUBMED Abstract]

  10. Zikusoka MN, Kidd M, Eick G, et al.: The molecular genetics of gastroenteropancreatic neuroendocrine tumors. Cancer 104 (11): 2292-309, 2005.  [PUBMED Abstract]