Pathogenesis And Pathology

The genetic mechanisms involved in tumorigenesis of carcinoid tumors remain to be elucidated.7 The vast majority of cases are sporadic, although familial cancer syndromes associated with an increased risk of carcinoid tumors occur in multiple endocrine neoplasia (MEN) types I and II and in von Recklin-gausen's disease (duodenum).13-15 Interestingly, most of the carcinoids associated with MEN type I have been reported to be of foregut origin (thymus, bronchus, and stomach).15 MEN type I syndrome is attributable to mutations in a 10-exon gene located on chromosome 11q13 that encodes a nuclear protein (Menin) that represses Jun D transcriptional activity.16 Tumor development in MEN type I is thought to follow Knudson's two-hit hypothesis, that is, individuals affected by familial MEN type I inherit one inactive MEN type I allele; tumorigenesis in specific tissues then occurs after inactivation of the remaining wild-type allele, which can begin in just one cell.16 MEN type I gene involvement was confirmed in MEN type I pancreatic tumors but has not been confirmed for thymic carcinoid tumors.1718 Moreover, recent studies in sporadic carcinoid tumors showed a loss of heterozygosity at the MEN1 locus in 26 to 78% of these tumors. Mutations were identified at this locus using other techniques in 18% of cases.19,20 These alterations of the MEN1 gene have been found in only a subset of foregut sporadic tumors.21 This shows that MEN1 gene alterations are also an event in sporadic carcinoid tumor carcinogenesis.19 Links

Appendix 10%

Colon 6%

Rectum 13%

Figure 18-2. The distribution of gastrointestinal neuroendocrine tumor (NET) (percentage of NET of all locations).


Benign: Nonfunctioning, well-differentiated small tumor ( < 1 cm) within the mucosa-submucosa but without angioinvasion. Usually serotonin-producing tumors in the terminal ileum.

Benign or low grade malignant: Nonfunctioning, well-differentiated tumor of intermediate size (> 1 up to 2 cm) but without angioinvasion or extension beyond the submucosa. Usually serotonin-producing tumors of the terminal ileum.

Low grade malignant: (1) Nonfunctioning, well-differentiated large tumor (> 2 cm) or extending beyond the submucosa or angioinvasive (or both). Usually serotonin-producing tumors of the terminal ileum. (2) Functioning, well-differentiated tumor of any size and extension.

High grade malignant: Functioning or nonfunctioning poorly differentiated intermediate or small cell carcinoma.

between carcinogenesis (familial or sporadic tumors) and the MEN1 gene could be explained by growth factor-related angiogenesis (vascular endothelial growth factor, fibroblastic growth factor, and transforming growth factor), but this relation is difficult to confirm experimentally.22

Gains of chromosomes 4, 5, and 19 and losses of chromosome 18 by comparative genomic hybridization have recently been associated with sporadic NETs.14'23'24 Some of these genetic alterations were shared by foregut and midgut tumors, whereas others discriminated between the two groups.23 Nuclear oncogenes NMYC, BCL2, and CJUN, as well as HER2/neu, have been reported to be overexpressed in cell lines derived from carcinoid tumors.3 However, in contrast to a number of nonendocrine tumors, neither common oncogenes (RAS, SRC) nor common tumor suppressor genes (P53) are generally important in the molecular pathogenesis of carcinoid tumors except for the more atypical forms.19

Although the histogenesis of NETs is incomplete and varies from organ to organ, it appears that carci-noid tumors and naive endocrine cells arise from the same progenitor cell.310 Although controversial, it appears that NETs and low-grade neuroendocrine carcinomas arise from orthotopic neuroendocrine cells of the epithelium of the respective organs, whereas high-grade neuroendocrine carcinomas derive from a putative stem cell rather than from a neuroendocrine cell.25 Carcinoid tumor cells have been termed enterochromaffin cells because they stain with potassium chromate. They also take up and reduce silver and are thus termed argentaffin cells. Some tumor cells take up silver but are unable to reduce it and are termed argyrophilic (Figure 18-3).1 Because all neuroendocrine cells possess small synaptic vesicles regardless of their state of differentiation, it is essential to use both conventional his-tologic diagnosis and immunohistochemistry for cytosolic markers such as neuron-specific enolase (NSE) and for granular markers such as chromo-granin or synaptophysin.26 The immunohistologic detection of at least two or three markers is required for an accurate final diagnosis.27 The exact function of enterochromaffin cells is unknown, but carcinoid tumor cells are able to produce amines and peptides by amine precursor uptake and decarboxylation.28 Furthermore, carcinoid tumor cells are typically found to contain numerous membrane-bound neuro-secretory granules containing hormones and bio-genic amines including serotonin, corticotropin, his-tamine, dopamine, substance P, neurotensin, prostaglandin, kallikrein, and ghrelin.12,29 Foregut NETs generally have a low serotonin content and occasionally secrete 5-hydroxytryptophan or adrenocorticotrophic hormone (ACTH). Midgut NETs have a high serotonin content and infrequently secrete hydroxytryptophan or ACTH. Hindgut NETs usually contain somatostatin or peptide YY but rarely contain serotonin, hydroxytryptophan, or ACTH.26 Tumor cells not only make various pep-tides but also express many cell-surface peptide

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