[Frontiers in Bioscience 2, d271-282, June 1, 1997]
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THE ROLE OF LANGERHANS ISLETS IN PANCREATIC DUCTAL ADENOCARCINOMA
Parviz M. Pour

The UNMC/Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE

Received 5/6/97 Accepted 6/2/97

9. ASSOCIATION BETWEEN PANCREATIC CANCER AND ALTERED GLUCOSE METABOLISM

These data suggest that some exocrine pancreatic cancers may be derived from islets and may explain the abnormal glucose metabolism in tumor-bearing hamsters. According to a study by Ahrén and Andrén­Sandberg, in pancreatic carcinogen­treated hamsters, the oral glucose test remained normal until the 20th­30th week, during which no tumors were produced. However, after the 30th week, the impaired glucose tolerance test occurred concomitantly with the appearance of pancreatic cancer (69). These results were confirmed by another group of investigators (70).

Similar findings are seen in patients with pancreatic cancer. The presence of malignant ductules within the human islets was first described by Warren in 1938 (71). Endocrine cells within normal exocrine pancreas and ductular structures within islets have been demonstrated by immunohistochemistry (28,29,45,47,72). The ultimate association of exocrine and endocrine cells was exaggerated in pancreatic tumors. Islet cell tumors admixed with ductular structures (73) and malignant ducts with interspersed endocrine cells are commonly found (44,53). Many ductal adenocarcinomas contain a few or a conspicuous number of different types of islet cells (Fig. 12), sometimes in a pattern consistent with the term "duct­islet­carcinoma" (44,72). The argument that the presence of islet cells within the malignant glandular structures merely represents entrapped islets was refuted by studies showing that these endocrine cells were abnormal in terms of their location, appearance, and immunoreactivity with islet hormone antibodies (44,72). Moreover, their presence in the invasive part of cancers (44) and in their metastasis (72) indicate that these endocrine cells are an integral part of the malignant exocrine tissue. Some investigators suggest that the presence of malignant ductules in islets is the result of cancer invasion. However, a thorough histological study on serially sectioned tissues did not confirm this assumption (29). Moreover, islets containing malignant glandular structures in the tail of the pancreas (Fig. 13) far from the cancers in the body of the pancreas can be found. The patterns of a mixture of islet cells and malignant epithelial cells in atrophic areas of the pancreas suggest differentiation of islet (stem) cells to cancer cells (Fig. 14), as does the presence of neuroendocrine granules in the cells of well-differentiated ductal adenocarcinomas (Fig. 15; 29,53).

Fig. 12. A mixture of malignant glands with cells immunoreactive for chromogranin A are seen in a well-differentiated ductal adenocarcinoma. X 65.


Fig. 13. Malignant mucin-producing cells are seen within islets of a patient with pancreatic cancer. H&E, X 80. (From reference 53, with permission).

Fig. 14. A few malignant, mucin-producing cells are seen within the atrophic islets in the tal of the pancreas of a patient with pancreatic cancer in the head of the pancreas (arrow) H&E, X 120.

Fig. 15. A few neuroendocrine granules (arrows) are seen within cells of a well-differentiated pancreatic ductal adenocarcinoma. X 3000. (From reference 53, with permission).

In humans, 60­80% of patients with pancreatic cancers have diabetes or an altered glucose tolerance (74-76). Epidemiological studies suggest that this may in part be due to the fact that diabetics are at higher risk for developing pancreatic cancer (7-10). Other lines of evidence imply that an abnormality seen in the glucose tolerance is a consequence of pancreatic cancer. For example, the abnormality is seen in patients with localized small pancreatic cancers (77) which are not associated with widespread parenchymal damage. In one study (77), in 25 patients with pancreatic carcinoma smaller than 2 cm, alteration of glucose metabolism was found in 9 patients (36%); in 7 patients with tumors smaller than 1 cm, a glucose tolerance test showed an abnormality in 2 (28%); and in 18 patients with tumors between 1.1 and 2 cm, impaired glucose tolerance was found in 7 (39%); in 260 patients with tumors larger than 2 cm, the prevalence of alteration was 56.1% (77). Hence, it is evident that even small and localized pancreatic cancers cause a glucose metabolic abnormality. In many patients, the altered glucose tolerance and diabetes are first detected at the time of diagnosis of pancreatic cancer (77-84). Although impaired glucose tolerance has been reported in up to 30% of patients with different types of cancer, in pancreatic cancer patients the frequency and the magnitude of impaired glucose tolerance is higher (80-84). In a study by Permert et al., nearly half of pancreatic cancer patients had frank diabetes (80,81). The diabetes was seen in patients who did not have advanced disease or evidence of metastasis (80-81). In addition, in these patients the metabolic abnormality improved or was cured after tumor resection, suggesting that the diabetes was due to the presence of cancer.

Ishikawa et al. showed that, during an oral glucose tolerance test, the plasma C­peptide level was lower, and the proinsulin level and the total proinsulin/total C­peptide ratio was significantly higher in pancreatic cancer patients than in controls (84). Because the ratio was higher in patients with tumors, where many intact islets were left around the tumors, than in those patients with fewer islets left, the authors speculated that in the islets left in cancer stroma the activity of proinsulin converting enzymes decreases or the proinsulin production and release is stimulated (84). Because proinsulin accounts for only 5-10% of insulin activity, glucose intolerance occurs despite the higher immunoreactive insulin levels, which usually are measured by antibodies against insulin that crossreact with proinsulin. The alteration of islets around the tumor could be related directly to the neoplastic process that also affects the islets or indirectly by factors released from the nearby cancer.