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

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

5. PATTERNS OF ISLETS DURING PANCREATIC CARCINOGENESIS

The existence of an endocrine­exocrine interaction is convincingly demonstrated in some pancreatic diseases, especially in pancreatic cancer. In the hamster pancreatic cancer model, which in morphological, molecular biological, clinical, and immunological aspects mimics the human disease (29,34-43), the participation of endocrine cells in the development of exocrine cancer begins very early during carcinogenesis. In this model, various numbers and types of islet cells are found within the hyperplastic, preneoplastic and neoplastic cells forming ductal and ductular structures (Fig. 2; 29,34,37,44-48). These endocrine cells are primarily located in the basal aspect of the glands. However, they can be found scattered at different levels of the multilayered epithelium (Fig. 3). The pattern of their distribution within the malignant epithelium and the presence of exfoliated endocrine cells and material immunoreactive with anti­insulin in the lumen of these glands indicates that, like malignant ductal/ ductular cells, the endocrine cells are renewed and shed. This phenomenon could explain the higher level of islet hormones which exist in the pancreatic juice of animals with pancreatic cancer than in normal control hamsters (45). Another interesting phenomenon in this pancreatic cancer model is an exaggerated formation of periinsular and intrainsular ductules, which otherwise are rarely seen in control animals (29,34,46-48). In fact, these intrainsular ductular structures are the earliest lesions induced, whereas alterations of ductal and ductular epithelium occur later. Depending on the dose of the carcinogen, these periinsular and intrainsular ductules gradually become visible in some or many islets. Within the islets, they expand, ramify (Figs. 4,5), and ultimately form either microcystic structures resembling human serous cystadenomas (Fig. 6) or become increasingly hyperplastic and atypical and finally transform to malignant structures which are indistinguishable from similarly altered ductal cells (Figs. 7,8). These malignant intrainsular and periinsular ductules gradually replace the islets and leave only a small group or single islet cells which can best be demonstrated immunohistochemically (Fig. 9). Similar, randomly scattered islet cells can also be found within the invasive well-differentiated cancers. With decreasing differentiation of cancer cells, the numbers of endocrine cells decrease, but they may still be found in some invasive and metastasizing tumors (45). These findings indicate that certain cells, within or around islets, possibly correspond to the "Trübe Zelle" (49), "inselpotente Zelle" (50), "nesidioblasts" (51), "immature b-cells" (52), or "islet precursor cells," which have been recognized in the pancreas of many species, including the hamster (47), and represent tumor progenitor cells. These pluripotent cells, which obviously are also distributed randomly along the pancreatic ductal system, seem to be particularly responsive to carcinogenic insult. Within the islets, where they presumably present a source of new islet cells, they lose their ability to differentiate into islet cells and resume the undifferentiated, duct­like phenotype and undergo malignant transformation the same way as do the corresponding cells within the ductal/ductular epithelium. As discussed below, the expression of tumor­associated carbohydrate antigens, such as CA 19-9, DU-PAN-2 and TAG-72, by islet cells in the immediate vicinity of pancreatic cancer (53), is in line with the differentiation failure of these precursor cells. It is, nevertheless, ironic to see that endocrine tissue "gives rise" to exocrine pancreatic cancer.

Fig. 2. Early stage in the development of pancreatic cancer. Cells immunoreactive for somatostatin (red) are seen within the hyperplastic epithelium of a ductule. X 210.

Fig. 3. Somatostatin (red) and insulin immunoreactive cells (brown) in a pancreatic cancer. Nothe the distribution of the endocrine cells in all layers of the malignant epithelium. X 210. (From reference 53, with permission).

Fig 4. Distended and ramified intrainsular ductules in a pancreas of a hamster treated with the pancreatic carcinogen, BOP. This was the only microscopic finding in the pancreas of this animal. H&E, X 210.

Fig. 5. Ramified and distended intrainsular ductules at early stages of pancreatic carcinogenesis. There were no changes in the exocrine pancreas. H&E, X 120.

Fig. 6. Convergence of cystic intrainsular ductules of neighboring islets forming a pattern resembling microcystic adenoma. Remnants of islet cells are marked by arrows. H&E, X 75.

Fig. 7. Proliferation and distention of intrainsular ductules with a hyperplastic epithelium. H&E. X 120.

Fig.8. Malignant alterations of one segment of intrainsular ductules with invasion of the surrounding tissue. H&E, X 120. (From reference 29, with permission).

Fig . 9. A moderately - differentiated pancreatic adenocarcinoma containing cells immunoreactive with chromogranin A (red) X 210.