Pathogenesis and Pathophysiology

Although the histogenesis of neuroendocrine tumors is incomplete and varies from organ to organ, it appears that neuroendocrine tumors and naive endocrine cells arise from the same progenitor cell.319 Although controversial, it appears that neuroendocrine tumors 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 neuroendocrine cells.20 Microenvironmental or functional differentiation or dedifferentiation may lead the enterochromaffin cells to produce and secrete neuroendocrine peptides. They also express many cell surface peptide receptors that enable them to respond to several growth factors.1 The exact function of Kulchitsky cells is not known, although they are presumed to have endocrine and enzymatic functions.11 The cells have a characteristically uniform pattern and neurosecretory granules. Neuroendocrine tumors are able to metabolize biogenic amines and thus are called APUDomas.1415

Phylogenically, neuroendocrine tumors are divided into those from the foregut, midgut, and hindgut. The foregut includes the bronchus, thymus, stomach, duodenum, and pancreas. The midgut includes the small bowel, appendix, and right hemicolon. The hindgut includes the left colon, rectum, and ovaries.13 Each group of neuroendocrine tumors has a typical clinical presentation and prognosis. Foregut neuroendocrine tumors may stain for multiple hormones with preferential production and secretion of 5-hydroxytryp-tophan. Hindgut tumors may also stain for multiple hormones, but they usually do not secrete any hormone (Fig. 86-1).

The exact cause of neuroendocrine tumors is not known. The vast majority of cases are sporadic, although familial cancer syndromes associated with an increased risk of

FIGURE 86-1. Carcinoid tumors of the primitive gut. (From Simon D, Goretzki PE, Branscheid D, et al. Chirurgische Therapie von intestinalen Karzinoidtumoren. Aktuel Chir 1992;27:8.)

neuroendocrine tumors occur in multiple endocrine neoplasia type 1 (MEN 1), in MEN 2, and in von Recklinghausen's disease (duodenum).21 Moreover, studies of sporadic neuroendocrine tumors showed that a loss of heterozygosity at the MEN 1 locus was present in 26% to 78% of these tumors. Mutations were identified at this locus using other techniques in 18% of cases.22,23 Foregut tumors very often show involvement of the MEN 1 gene.24 Links between carcinogenesis (familial or sporadic tumors) and MEN 1 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.25

Gastric neuroendocrine tumors are frequently found in patients with chronic atrophic gastritis (with or without pernicious anemia) and Zollinger-Ellison syndrome, leading to the assumption that hypergastrinemia is one pathogenic factor. Experimental studies and clinicopathologic results give strong evidence that omeprazole through achlorhydria leads to hypergastrinemia and enterochromaf-fin-like (ECL) cell hyperplasia. Thus, ECL cell hyperplasia may be the first step in the development of carcinoid tumors. Loss of function of one allele of the MEN 1 gene is probably required for progression to true neoplasia, and this gene may function as a tumor suppressor gene for fundic tumors in Zollinger-Ellison syndrome.26 However, the problem may be more complex than was initially appreciated because gastric neuroendocrine tumors can occur in MEN 1 patients without hypergastrinemia and the MEN 1 gene is not lost in some patients with gastric type II lesions.27

Gains of chromosomes 4, 5, and 19 and losses of chromosome 18 by comparative genomic hybridization have been associated with sporadic midgut carcinoids.28 30 Hindgut tumors in general show rather low proliferation capacity, and transforming growth factor-a or epidermal growth factor receptor autocrine mechanism may play a role in the tumor development.24 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 neuroendocrine tumors except for the more atypical forms.22

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