In 21 patients who had undergone total pancreatectomy for pancreatic head carcinoma, the uninvolved pancreas was examined with regard to the type, incidence and regional distribution of duct epithelial proliferation. The results were compared with those in 37 operative specimens from patients with chronic pancreatitis, in 46 normal pancreases from autopsies and with findings in experimental pancreatic carcinogenesis. While the incidence of squamous metaplasia and non-papillary epithelial hypertrophy varied little in the different groups, papillary epithelial hyperplasia was found three times more often in cases of carcinoma, with associated mild duct obstruction. Atypical epithelial proliferation was only detected in the vicinity of carcinomas. Unequivocal transition from papillary hyperplasia to atypical proliferation was not observed. In hamsters treated with dihydroxy-di-n-propylnitrosamine (DHPN) for induction of pancreatic duct carcinomas, the early duct lesions closely resembled atypical epithelial proliferation of human pancreas. It is concluded that (1) papillary epithelial hyperplasia is probably only indicative of early duct obstruction and/or a general neoplastic stimulus, (2) intraductal epithelial proliferation with atypia is a true precursor of duct carcinoma, and (3) chronic pancreatitis lacks atypical duct lesions.

The endocrine pancreatic tissue from patients with severe primary chronic pancreatitis (n=6). secondary chronic pancreatitis due to duct obstruction by carcinoma (n=6) and non-diabetic, non-pancreatitic controls (n=4) was studied qualitatively and quantitatively using specific immunocytochemistry and electron microscopy. Grouping of variously sized islets in the sclerotic tissue (sclerosis islets), islet neoformation by ductuloinsular proliferation, and intrainsular fibrosis were the main qualitative findings. Immunocytochemical quantitation of the distribution of insulin (B), glucagon (A), somatostatin (D) and pancreatic polypeptide (PP) producing cells revealed a significant relative increase in the number of A cells and a decrease in the number of B cells of the sclerosis islets in primary chronic pancreatitis ((B-44.1+/-9.3%:A-38.3+/-2.4%:D-8.6+/-5.1%:PP-4.6+/-4.1%) as well as in secondary chronic pancreatitis B-38.0+/-14.3%:A-38.4+/-19.0%:D-9.1+/-5.8%:PP-14.5+/-23.4%) compared with controls (B-71.1+/-8.1%:A-24.3+/-5.5%:D-8.0+/-2.8%:PP-0.5+/-0.4%). The number of PP cells was significantly increased in primary chronic pancreatitis only. It is suggested that scarring of the exocrine pancreas affects islet composition, probably by impairment of the local circulation and of glucose diffusion, thus leading to reduction of the number and glucose sensitivity of B cells. The hyperplasia of A and PP cells appears to be a secondary phenomenon due to the loss of B cells.

The action of diazoxide, an antidiuretic agent, and diphenylhydantoin, an antiepileptic (DPH), both with strong hyperglycemic side effects on the pancreatic B cells, was examined by electron microscopy and cytochemistry, with the following findings. 1. Effects on secretory apparatus: the severe hyperglycemic syndrome following a single injection of diazoxide (200 mg/kg) or DPH (150 mg/kg) did not change the granularity of the B cells. Ultrastructurally a marked increase of lysosomal digestion of secretory granules (crinophagy) was observed in almost all B cells. Crinophagy may be regarded as a result of an impaired discharge of secretory granules during simultaneous maintenance of biosynthesis. It is also possible that changes of the electrophysical properties of the granule surfaces may play an additional role in crinophagy. 2. Effect on synthesizing apparatus: in B cells subtotally degranulated by the injection of anti-insulin serum (AIS), regranulation occurred more rapidly after the additional administration of diazoxide or DPH than without these compounds. This fact may imply that, under the hyperglycemic conditions tested, diazoxide or DPH have no effect on the synthesizing capacity of the B cells.

Calcium distribution in B cells of the isolated perfused rat pancreas was examined by the pyroantimonate precipitation technique in relation to the insulin secretory pattern of the perfused pancreas in response to 3 mM or 20 mM D-glucose or 20 mM D-glucose in calcium-depleted ethylene glycol tetra-acetic acid (EGTA) medium. Perfusion fixation after various time intervals from 3 to 30 min allowed appropriate relation to secretory phases. Qualitative and quantitative evaluation of the precipitation patterns revealed a significant increase in cell membrane associated percipitates after 3--5 min of perfusion with 20 mM glucose compared with the results after perfusion with 3 mM glucose. After 10--30 min of perfusion with 20 mM glucose there was an additional significant increase in precipitates located in the cytoplasm and the halos of the secretory granules. Perfusion with 20 mM glucose in calcium-deprived EGTA medium strongly reduced the number of precipitates within the B cells. The results suggest that cell membrane associated calcium may be involved in exocytosis, and by its sudden increase may trigger the first phase of insulin secretion. The calcium stores in the cytoplasm and the granules may be of importance for long-term regulation of insulin release.

A recurred and metastasized hemangiopericytoma of menigeal origin caused a terminal hypoglycemia syndrome in a 40 year old man. The disease had been observed over a period of 10 years. The total weight of the tumour metastases was 1800 g. Electron microscopical examination of the tumour cells revealed, in particular, a markedly developed ergastoplasm, prominent Golgi complexes surrounded by many microvesicles, round to ovoid electron dense bodies and fine fibrillar structures. Furthermore, large deposits of basement membrane-resembling material were found in the pericapillary and intercellular spaces. On the basis of the structural characteristics which indicate distinct synthesizing capacity of the cells, an excessive glucose consumption by the tumour is suggested to be an important factor in the pathogenesis of tumour hypoglycemia. The question whether the ultrastructure of the tumour also exhibits secretory processes, which may be related to the release of a presumed inhibitor of hepatic gluconeogenesis and/or glycogenolysis, remains open. Typical granules as in polypeptide hormon secreting cells were not observed. The possibility that the demonstrated electron dense membrane limited bodies represent atypical secretory granules is discussed.