Endocrine aspect of exocrine pancreatic cancer

Abstract

Our studies have shown that almost all preneoplastic and neoplastic tumors induced in hamsters contain endocrine cells. Because the induced pancreatic cancer resembles the human disease in many respects, it was of interest to find out whether human pancreatic cancer also produce endocrine cells. To examine the participation of the endocrine cells in the exocrine pancreatic cancer, we first examined 32 human pancreatic cancers with the antibodies against insulin, glucagon, somatostatin, PP, VIP, gastrin, and calcitonin or by argyrophilic reaction (1). Thirty (79%) cancers showed ei therfew or many ceils immunoreactive with all but anti-gastrin-, -VIP, and -calcitoniu. Many cells showed an argyrophilic reaction. In 17 cases, the number of stained cells was excessive and the morphology of tumors was consistent with mixed ductal-islet tumor. Argyrophilic ceils and cells immunoreactive with antiinsulin and -glucagon were the predominant in such cases. However, becat~se the biopsy material we used was small and only a few sections from each tumor were examined, it was not possible to determine whether several types of immunoreactive cells reside at the same location, or whether some cells produce more than one peptide. In subsequent studies, we examined larger sections of surgical material from 9 pancreatic cancer patients by serial sections and by using a multilabeled immunohistochemical technique developed at our institute. With this method, we visualized 4 peptides in the same islet. In this study, we also included antibodies against other pancreatic hormones, including pancreastatin, chromogranin A, serotonin, and neuron-specific enolase (NSE). We found that all 9 cancers contained cells immunoreactive with all of the antibodies used, except for pancreastatin, which was missing in 3 cases ,and for PP, which was not detectable in two cases, Here again, insulin was the predominant cell type, followed by glucagon and somatostatin ceils. Many of these hor-mones were found within the same glands. Colocalization of some hormones, such as insulin and serotonin and NSE and glucagon, was indicated. Similar to the situation in hamsters, most endocrine cells were localized on the base of the glands, but many were also within the epithelium and some seem to reach the lumen by a slender neck. In several cases, accumulation of endocrine cells was found in the papillary projections of the malignant epithelium. Because endocrine cells are found at different levels of the malignant epithelium and within the lumen, it seemed that the endocrine ceils migrated within the epithelium, were shed into the lumen like the tumor cells and were replaced by new endocrine cells at the base of the malignant glands. Although many of these endocrine cells resembled the corresponding endocrine cells in the normal islets, some of these endocrine cells were atypical. Some had granules on the supranuclear cell portion. A few endocrine cells were found in the invasive portion of the cancers, including those that had invaded the periuneural space. There were also atypical cells with cytoplasmic vacnolization and irregular granular distribution, possibly as a reflection of the altered synthesis, storage, or release of the granules. On the other hand, differences in the staining intensity could indicate their endocrine activity. Consequently, it appears that in both humans and hamsters, endocrine cells participate in the development of exocrine pancreatic cancer, and these endocrine cells seem to be malignant and have endocrine activity. Nevertheless, participation of endocrine cells in the exocrine pancreatic cancer is conceptually and practically important, particularly in view of epidemiological studies, which link pancreatic cancer with diabetes. In fact, it has been established that more than 80% of pancreatic cancer patients develop frank diabetes or altered glucose tolerance. Our immunohistochemical and experimental studies, as well as clinical studies by Permert and associates (2-4), have led us to believe that endocrine cell proliferation in exocrine pancreatic cancer may cause alteration in hormonal homeostasis leading to glucose metabolic abnormalities. However, studies are required to substantiate this view.