Pituitary proliferative lesions in aging male Long-Evans rats. A model of mixed multiple endocrine neoplasia syndrome

The incidence of spontaneous pituitary nodules in rats increases progressively with age. In a colony of male Long-Evans rats, 50 per cent of the 2- to 3-year-old animals harbored pituitary nodules which were composed almost exclusively of sparsely granulated prolactin (PRL) cells. Sixty per cent of the PRL nodules were multicentric and in most instances were associated with diffuse hyperplasia of PRL cells adjacent to the nodules. A progressive increase with age in the population of PRL cells was also observed. These findings suggest that the pituitary nodules may have originated from foci of PRL hyperplasia. Furthermore, five of these glands contained additional nodules of other hormonal cell types, including mixed PRL/gonadotropins (two animals), mixed PRL/thyrotropin-stimulating hormone (one), gonadotropins (one), and adrenocorticotropic hormone (one). These animals also demonstrated a high incidence of thyroidal C cell nodular hyperplasia and/or medullary thyroid carcinoma (42 per cent), adrenal medullar nodules (31 per cent), and parathyroid nodular hyperplasia (30 per cent). In human kindreds with multiple endocrine neoplasia syndromes, concomitant thyroidal C cell and adrenal medullary proliferative lesions, as well as parathyroid abnormalities, are found in type II phenotype patients, whereas pituitary, pancreatic islet, and parathyroid abnormalities develop in patients with type I phenotype. The Long-Evans rat strain, with concomitant proliferative lesions in these four endocrine organs, may provide a useful model system of a mixed multiple endocrine neoplasia syndrome and, also, of prolactin-secreting pituitary adenomas.     

Islets of Langerhans from prohormone convertase‐2 knockout mice show α‐cell hyperplasia and tumorigenesis with elevated α‐cell neogenesis

Antagonism of the effects of glucagon as an adjunct therapy with other glucose‐lowering drugs in the chronic treatment of diabetes has been suggested to aggressively control blood glucose levels. Antagonism of glucagon effects, by targeting glucagon secretion or disabling the glucagon receptor, is associated with α‐cell hyperplasia. We evaluated the influence of total glucagon withdrawal on islets of Langerhans using prohormone convertase‐2 knockout mice (PC2‐ko), in which α‐cell hyperplasia is present from a young age and persists throughout life, in order to understand whether or not sustained glucagon deficit would lead to islet tumorigenesis. PC2‐ko and wild‐type (WT) mice were maintained drug‐free, and cohorts of these groups sampled at 3, 12 and 18 months for plasma biochemical and morphological (histological, immunohistochemical, electron microscopical and image analytical) assessments. WT mice showed no islet tumours up to termination of the study, but PC2‐ko animals displayed marked changes in islet morphology from α‐cell hypertrophy/hyperplasia/atypical hyperplasia, to adenomas and carcinomas, these latter being first encountered at 6–8 months. Islet hyperplasias and tumours primarily consisted of α‐cells associated to varying degrees with other islet endocrine cell types. In addition to substantial increases in islet neoplasia, increased α‐cell neogenesis associated primarily with pancreatic duct(ule)s was present. We conclude that absolute blockade of the glucagon signal results in tumorigenesis and that the PC2‐ko mouse represents a valuable model for investigation of islet tumours and pancreatic ductal neogenesis.     

Major histocompatibility complex protein expression on pancreas and pancreatic islet endocrine cell subsets

To determine which cells in the human and rat pancreas and islets express class I and II histocompatibility complex proteins, double indirect immunofluorescence and the Staphylococcus aureus rosette method were used. Islet preparations used permitted positive endocrine and class I or II protein identification. Class I and II proteins were expressed in pancreatic vascular endothelium and passenger cells of the mononuclear cell type. Antibodies directed to class I or beta 2 microglobulin reacted with dispersed islet B, A, and D cells, whereas class II protein antibodies were associated with only islet B and A cells. Islet B-cell class II proteins decreased after 20 days of in vitro culture. These results suggest that 1) a variety of pancreas and islet nonendocrine cells can express class I and II proteins, 2) normal pancreatic islet endocrine cells not only express class I proteins but also class II proteins, and 3) in vitro islet culture results in reduced expression of class II proteins by islet B cells.     

MULTIPLE NONFUNCTIONAL PANCREATIC ISLET CELL TUMOR IN MULTIPLE ENDOCRINE NEOPLASIA TYPE I

A case of multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type I (MEN I) is reported. The patient was a 41-year-old woman who had a past history of thyroid cancer (papillary carcinoma) and hyperparathyroidism due to parathyroid adenoma. Later, a nonfunctional pituitary tumor and Ave nonfunctional pancreatic tumors were found simultaneously and the patient was finally diagnosed as having MEN I. Following surgical enucleation, the pancreatic tumors were histopathologlcally diagnosed as benign islet cell tumors. One of them (tumor 3) exhibited a solid nodular pattern while the others showed gyriform patterns. They were divided histochemlcally and immunohistochemically into three types: two (tumors 1 and 2) produced a single hormone (glucagon), one (tumor 3) produced five (Insulin, glucagon, somatostatin, gastrin and pancreatic polypeptide) and the remaining two (tumors 4 and 5) produced two (glucagon and pancreatic polypeptide). Electron microscopically, three types of endosecretory granules were found in the tumor cells of tumor 3 but only one type was found in tumor 4. However, in the tumor 4 extract, glucagon, pancreatic polypeptide, C-peptlde, somatostatin, vasoactive intestinal peptide and growth hormone releasing factor were detected by radioimmunoassay. These findings suggest that these pancreatic tumors were both multicellular and multihormonal.     

Nesidioblastosis and endocrine hyperplasia of the pancreas: a secondary phenomenon

Diffuse endocrine cell proliferation (nesidioblastosis) and islet cell hyperplasia are considered causes of organic hyperinsulinism but have not been distinguished (by histometric or immunohistologic methods) from the normally variable pancreatic islet cell population during development and in adults. Therefore, in this study morphologic, immunohistologic (to detect insulin, glucagon, somatostatin, and pancreatic polypeptide), and morphometric features were evaluated in 1) normal pancreases (from fetal to adult; n = 49); 2) pancreases from patients with nesidioblastosis (n = 5); and 3) tumor-associated pancreases (TAP) from patients with insulin-producing islet cell tumors (n = 8). The study of normal postnatal development revealed that all features of fetal development remain present after birth and that the diagnosis of any diffuse endocrine disorder should therefore be based essentially on quantitative histometric parameters (total endocrine area, islet size distribution, distribution of each endocrine cell type). With these parameters endocrine cell hyperplasia was demonstrated in TAP from adults due to increased numbers of A and D cells. However, in the cases previously diagnosed as pathologic nesidioblastosis, all parameters were within the normal range. Thus, nesidioblastosis does not appear to be a pathologic entity. Careful re-examination of the pancreases, prompted by these data, revealed small islet cell tumors in three of these five cases. It is concluded that the endocrine pancreas can react rapidly, both morphologically and functionally, to changes in hormonal feedback, e.g., islet cell tumors. Therefore, the observation of a diffuse islet cell disorder in a patient with hyperinsulinism should not be considered an indication that an islet cell tumor is not present.     

Studies on co-localization of 7B2 and pancreatic hormones in normal and tumoural islet cells

Summary The distribution of protein 7B2, a protein with structural characteristics of GTP-binding proteins, has been studied in normal pancreatic islets and in a series of 70 pancreatic endocrine tumours with emphasis on the co-localization of 7B2 and the different pancreatic hormones. Although all cell types of normal islets were found to store 7B2, variations from intense expression to absence of reaction were seen within each cell type. In particular, B cells showed intense immunostaining for 7B2 in small compact islets and weak or no staining in larger islets with lobular arrangement. Pancreatic polypeptide (PP) cells expressed 7B2 intensely in the PP-rich area of ventral embryological origin, but were mostly non-reactive in the PP-poor area. The A cells, located along intralobular blood vessels, were more frequently immunoreactive for 7B2 than those at the periphery of the islets. Immuno-electron microscopy revealed a preferential localization of 7B2 in secretory granules of islet cells, with more intense localization in the peripheral halo of alpha granules. Benign islet cell tumours more frequently expressed 7B2 than their malignant counterparts. Although often expressed in a lower number of tumour cells than the tumour-specific hormone, 7B2 was usually co-localized with the latter. In contrast, no relationship was found with the localization of proinsulin. It is concluded that 7B2 is a non-permanent component of the cell granule compartment, probably involved in events related to exocytosis and without relationship to intracellular prohormone processing.     

胰岛肿瘤及胰岛增生的免疫组化研究

应用免疫组化ＡＢＣ及ＬＳＡＢ法，对２７例胰岛肿瘤和３例胰岛增生进行Ｉｎｓ，Ｇａｓ，Ｇｌｕ，Ｓｏｍ，Ｓｅｒ，ＶＩＰ，ＰＰ，ＮＳＥ，ＣＨＧ，ＳＹＰ，ｈＣＧ，ＥＭＡ，Ｋ及ＣＫ的研究。结果显示：胰岛素瘤及胰岛增生Ｉｎｓ均阳性，Ｉｎｓ阳性程度与临床症状的轻重无关。胰岛素肿瘤多数为混合性的，而增生基本上是单一的，免疫反应强度与细胞分化程度有关，而与组织学类型无关；无功能性肿瘤仅表现个别激素的弱阳性。ＮＳＥ，ＣＨＧ及ＳＹＰ均是胰岛肿瘤的良好标记，它们与ＥＭＡ及Ｋ（ＣＫ）联合使用，有助于胰岛内分泌肿瘤与外分泌肿瘤的鉴别；ｈＣＧ有助于鉴别胰岛素肿瘤的良恶性。     

Duct-Islet Cell Tumor of the Pancreas. A Case Report with Immunohistochemical and Electron Microscopic Findings

A case of pancreatic tumor with features of both duct and islet cell components was found incidentally at autopsy in a 76 year old male who had died of intrahepatic cholan-giocarcinoma. The tumor, measuring about l.0cm in diameter, was located in the pancreatic tail. The tumor was composed of two distinct cell populations, islet cells and duct cells. Immunocytochemically, nearly all of the former cells were positive for insulin but negative for cytokeratin, carcinoembryonic antigen (CEA) and mucin, while the latter were positive for cytokeratin, CEA and mucin but negative for insulin. Additionally, a majority of the tumor cells that had formed islet-like structures were positive for neuron specific enolase (NSE), whereas NSE-positive cells were found only rarely in duct components. Electron microscopy confirmed the presence of two cell populations. Simultaneous occurrence of duct and islet cell components in a single pancreatic tumor indicates an intimate histogenetic relationship between pancreatic endocrine and duct cells. Acta Pathol Jpn 39: 328 335, 1989.     

Cyclin-dependent kinase (cdk6) and p16 in pancreatic endocrine neoplasms

AIMS: p16 and p27, the inhibitors of cyclin-dependent kinases, have been reportedly decreased in certain human tumours, including a few endocrine tumours. The current study used immunocytochemical staining to compare the staining intensity of cdk6 and its inhibitor, p16, in pancreatic endocrine neoplasms with normal pancreatic islets. METHODS: Twenty-four primary pancreatic endocrine neoplasms, consisting of 12 insulinomas, one glucagomoma, three pancreatic polypeptide (PP)-omas, five gastgrinomas and three non-fuctioning tumours, were immunocytochemically studied for cdk6 and p16 compared with the adjacent non-neoplastic islets. RESULTS: In the normal islets, cdk6 staining was strongly positive for islet cell nuclei and cytoplasms, whereas p16 was strongly positively stained for islet cell cytoplasms. Insulinomas, glucagonoma, PP-omas and non-functioning tumours were weakly stained for cdk6 and p16. Among five gastrinomas, three tumours were moderately stained and two tumours were more weakly stained for cdk6 and p16. Thus, tumour cells were weaker stained for cdk6 and p16 compared with the strong staining of normal islet cells. No distinct immunostaining difference was observed among five kinds of pancreatic endocrine neoplasms. CONCLUSIONS: The decreased immunocytochemical staining for cdk6 and p16 is consistently observed in five kinds of pancreatic endocrine neoplasms. This decreased cdk6 and p16 in pancreatic endocrine neoplasms may be a part of the cell cycle event in tumour transformation and progression, and the same process may involve other endocrine tumours.     

Neuropilin-2 is a novel marker expressed in pancreatic islet cells and endocrine pancreatic tumours

Neuropilin-2 (NP-2) is a cell surface transmembrane protein originally characterized as a receptor for the type 3 semaphorins, and more recently for a number of vascular endothelial growth factor (VEGF) isoforms. NP-2 expression has been recently localized to a subset of neuroendocrine cells in the gastrointestinal tract. The aim of this study was to define the expression pattern of NP-2 in normal pancreatic islets and to determine the utility of NP-2 expression as a diagnostic marker of pancreatic endocrine tumours. Paraffin-embedded tissue sections from 30 endocrine pancreatic tumours (EPTs) and from normal pancreas were immunostained with a rabbit polyclonal antibody generated towards NP-2. Nineteen of the tumours were hormonally functional (nine insulinomas, nine gastrinomas, and one glucagonoma). The NP-2 staining pattern was correlated with islet cell hormone expression. In addition, NP-2 expression was evaluated in other normal neuroendocrine tissues and neuroendocrine neoplasms. In normal pancreas, NP-2 stained a distinct subset of islet cells situated primarily at the islet periphery. Double immunohistochemical staining revealed co-localization with glucagon-expressing cells. Moderate to strong NP-2 staining was present in 27 of 30 EPTs. Serial staining of the pancreatic tumours with insulin, gastrin, glucagon, pancreatic polypeptide (PP) or somatostatin did not reveal a distinct pattern of co-localization. NP-2 expression was not detected in neuroendocrine cells outside the gastroenteropancreatic system, or in their corresponding neoplasms, except for focal staining in one bronchial carcinoid tumour. In conclusion, the vast majority of EPTs examined expressed NP-2, suggesting its utility as a diagnostic marker for these tumours. The function of NP-2 in islet cell biology or tumourigenesis remains to be elucidated.     

C. L. Oakley lecture (1987). The pathogenesis of beta cell destruction in type I (insulin-dependent) diabetes mellitus

In a study of pancreases from 75 patients who died at presentation of Type I diabetes there was selective destruction of beta cells associated with islet inflammation (insulitis). According to a recent hypothesis, aberrant expression of Class II major histocompatibility complex (MHC) products on a target cell may allow presentation of organ specific surface antigen(s) to potentially autoreactive T helper lymphocytes and thus lead to autoimmunity. Aberrant expression of Class II MHC was demonstrated immunohistochemically on beta cells in 21 out of 23 patients with recent onset diabetes. No such expression was seen on the other pancreatic endocrine cells. Ninety-four per cent of insulin-containing islets in these patients had marked hyperexpressions of Class I MHC affecting all endocrine cells in these islets. Insulin deficient islets were not thus affected. Both these abnormalities of MHC expression appeared to precede insulitis within a given islet and appeared to be unique to Type I diabetes, being absent in pancreases of patients with Type II diabetes, chronic pancreatitis, cystic fibrosis, graft-versus-host disease and Coxsackie B viral pancreatitis. The development of autoimmunity to beta cells in Type I diabetes may be a 'multistep' process in which abnormalities of MHC expression are crucial events.     

Pancreatic endocrine pathology in von hippel-lindau disease: An expanding spectrum of lesions

A 41-yr-old patient with a history of von Hippel-Lindau (VHL) disease with previously removed bilateral pheochromocytomas and renal cell carcinoma presented with progressive obstructive jaundice due to multiple lesions in the pancreas. The pancreatectomy specimen showed a range of endocrine lesions including islet hyperplasia, nesidioblastosis, microadenomas, and endocrine carcinoma. In addition, some of the non-tumorous islets displayed peliosis. The endocrine carcinoma showed a biphasic pattern composed of typical endocrine cells and oncocytes. The oncocytic component showed widespread lymphovascular invasion and lymph node metastasis. Immunohistochemistry and electron microscopy confirmed that the oncocytic cells were endocrine. Focal areas contained cells with foamy cytoplasm, a feature that is associated with pancreatic endocrine tumors in VHL. This case expands the spectrum of lesions seen in the pancreas of VHL patients. There is some overlap with lesions encountered in multiple endocrine neoplasia type I. In addition, the endocrine lesions were composed of two main cell types (typical and oncocytic cells) with the oncocytic component invading lymphatic channels and spreading to regional lymph nodes.     

Comparative immunocytochemical study of MHC class II expression in human donor pancreas and isolated islets

Expression of major histocompatibility complex (MHC) molecules by pancreatic islets may influence the survival of pancreas or islet grafts in allogeneic recipients. This study compares the presence of MHC class II (HLA-DP, DQ, DX and DR)-positive cells in 27 pancreases and in 10 isolated islet preparations from human donors. Cells expressing MHC class II were present in all tissues examined as histiocytes located in interstitial areas in both the endocrine and nonendocrine components and as endothelial cells in the nonendocrine part. Endocrine, acinar and duct cells were MHC class II negative. In pancreases from donors under the age of 7 years the frequency of MHC class II-positive histiocytes was only one third of that in adults, and they rarely contained MHC class II-positive endothelial cells. The MHC class II-positive hisiocytes were further phenotyped as macrophages positive for LCA and acid phosphatase, or dendritic cells negative for the latter markers. Dendritic cells were frequent in adult organs but rare in organs from donors under 7 years of age. In freshly isolated islet preparations from adult donors, less than 1% of the cells were MHC class II positive. These were identified as resident macrophages and dendritic cells. No MHC class II positive cells were encountered in the islet capillaries. The putative role of MHC class II-positive donor cells in allograft rejection suggests that these differences in MHC class II expression influence the immunogenicity of pancreatic and islet grafts in an age-dependent manner.     

Differential expression and regulation of MHC products in the endocrine and exocrine cells of the human pancreas.

Inappropriate expression of HLA Class II (D/DR) molecules has been detected in the target cells of most autoimmune diseases including Type I (insulin-dependent) diabetes. The possibility that this phenomenon is due to the action of lymphocytes or some of their products has been investigated by analysing in vitro the modulation of HLA products in Beta cells. Monolayer cultures from 25 human pancreatic glands were supplemented with alpha-interferon (IFN), beta-IFN or gamma-IFN, interleukin 2 (IL-2) and supernatants from activated lymphocytes. In addition, lectins and a variety of other hormones, biological products and chemicals were tested. Major histocompatibility complex (MHC) expression was assessed by double immunofluorescence technique using monoclonal antibodies to non-polymorphic determinants of Class I and Class II molecules and the pancreatic cells were identified by antibodies to islet hormones and other cytoplasmic antigens. gamma-IFN and lectins produced a parallel enhancement of HLA-A,B,C expression in islet, exocrine/ductal cells and fibroblasts. HLA-D/DR was inducible in all pancreatic cell types, except endocrine islet cells which did not produce Class II molecules in response to any of the stimuli including supernatants from activated lymphocytes. Exocrine/ductal cells from glands of patients with chronic pancreatitis spontaneously expressed Class II products, but islet cells were devoid of any detectable D/DR. These data are consistent with recent observations which have indicated that in the 'diabetic' pancreas inappropriate Class II expression in the Beta cells occurs independently of the presence of lymphocytes infiltrating the islets, and make it necessary to postulate that other factors are responsible for the Class II induction in Beta cells in human Type I diabetes.     

Concurrent gastrinoma and somatostatinoma in a 10-year-old Portuguese water dog

Severe hypergastrinaemia in the dog is considered a strong indicator for a gastrin-producing pancreatic islet cell tumour. In human medicine, gastrinomas are described as enteropancreatic neuroendocrine tumours that cause the Zollinger-Ellison syndrome. However, in contrast to the supposed origin of canine gastrinomas in pancreatic islets, gastrinomas in human beings arise predominantly in the duodenum and gastric antrum, and are often a component of the syndrome of multiple endocrine neoplasia type I. This report is of a canine case of multiple endocrine neoplasms, consisting of a pancreatic islet cell somatostatinoma, and a gastrinoma in the mesenteric lymph nodes and liver. From the literature and the authors' findings, it is concluded that the clinical diagnosis of hypergastrinaemia is not pathognomonic for a gastrin-producing islet cell tumour. Furthermore, the presence of an islet cell tumour in the face of hypergastrinaemia does not warrant a diagnosis of an islet cell gastrinoma. Immunohistochemistry is necessary to confirm the diagnosis of a pancreatic islet cell gastrinoma.     

Islet cell carcinomas in dogs

Summary Seven cases of dog islet cell carcinomas were studied by conventional and immunohistochemical light- and electron-microscopy. Antisera to insulin, pancreatic polypeptide, somatostatin and glucagon were used. In 6 tumours several hormones were demonstrated. Glucagon never occurred. Insulin was the only hormone present in every tumour, thus it seems to be a good marker for these neoplasmas.Liver metastases contained less immunoreactive cells than primary tumours and cell types found in primary carcinomas were sometimes not present in liver metastases.In two cases a degenerative neuropathy occurred.     

Characterization of the endocrine cells in the pancreatic-bile duct system of the rat

Six types of endocrine cells showing immunolabelling against gut or pancreatic islet hormones were identified in the pancreatic-bile duct system of the normal adult rat at the light and electron microscopic levels. They were located within the epithelial lining of the duct system from the intercalated portion to its duodenal opening. However, the distribution and frequency of each endocrine cell varied along the length of the duct system. While insulin, glucagon, somatostatin, and pancreatic polypeptide cells were widely distributed along the entire duct system, small numbers of cholecystokinin and serotonin cells were confined to the terminal portion. A considerable number of somatostatin cells were concentrated in gland-like pouches of the terminal portion of the common pancreatic-bile duct. When the accessory pancreatic duct was present, insulin, glucagon, and somatostatin cells were also found in its epithelial lining. Electron microscopically, the specific content of the secretory granules of all endocrine cells was confirmed by immunolabelling or cytochemical staining. Further the characteristics of the secretory granules of each endocrine cell type corresponded to those present in the same kind of endocrine cells in gut or pancreatic islet. The duct endocrine cells displayed a particular ultrastructural appearance. The “open type cells” were highly polarized, with their apical cytoplasmic process reaching the duct lumen, whereas “closed type cells” showed long basal cytoplasmic processes with no connection with the duct lumen. In general, insulin, and somatostatin cells were of the “open type,” while no morphological connection with the duct lumen was found for glucagon and pancreatic polypeptide cells. The presence of various duct endocrine cells with their particular ultrastructural appearance implies that they may take part in modulating the function of the duct system.     

Cystatin C in the human pancreas and gut: An immunohistochemical study of normal and neoplastic tissues

Summary The occurrence of immunoreactive cystatin C (CC) in normal and neoplastic cells of the human pancreas and gut was investigated using an indirect streptavidin-biotin method on formaldehyde-fixed and paraffin-embedded tissues. Virtually all pancreatic islet cells and many neuroendocrine cells throughout the gastrointestinal tract showed strong CC immunoreactivity and a granular cytoplasmic staining pattern. All 14 endocrine pancreatic tumours (insulinomas, glucagonomas, gastrinomas and non-producing tumours), as well as 16 of 17 gut carcinoid tumours, were also strongly CC immunoreactive. In addition, non-endocrine epithelial cells of pancreatic ducts and the gastrointestinal mucosa and 20 of the 24 adenocarcinomas from these sites showed weak CC immunoreactivity. Thus, CC cannot be used as a reliable immunohistochemical marker for endocrine gastro-entero-pancreatic tumours despite the fact that the protein is strongly expressed in a majority of such tumours.     

Characterization of the endocrine cells in the pancreatic-bile duct system of the rat.

Six types of endocrine cells showing immunolabelling against gut or pancreatic islet hormones were identified in the pancreatic-bile duct system of the normal adult rat at the light and electron microscopic levels. They were located within the epithelial lining of the duct system from the intercalated portion to its duodenal opening. However, the distribution and frequency of each endocrine cell varied along the length of the duct system. While insulin, glucagon, somatostatin, and pancreatic polypeptide cells were widely distributed along the entire duct system, small numbers of cholecystokinin and serotonin cells were confined to the terminal portion. A considerable number of somatostatin cells were concentrated in gland-like pouches of the terminal portion of the common pancreatic-bile duct. When the accessory pancreatic duct was present, insulin, glucagon, and somatostatin cells were also found in its epithelial lining. Electron microscopically, the specific content of the secretory granules of all endocrine cells was confirmed by immunolabelling or cytochemical staining. Further the characteristics of the secretory granules of each endocrine cell type corresponded to those present in the same kind of endocrine cells in gut or pancreatic islet. The duct endocrine cells displayed a particular ultrastructural appearance. The "open type cells" were highly polarized, with their apical cytoplasmic process reaching the duct lumen, whereas "closed type cells" showed long basal cytoplasmic processes with no connection with the duct lumen. In general, insulin, and somatostatin cells were of the "open type", while no morphological connection with the duct lumen was found for glucagon and pancreatic polypeptide cells. The presence of various duct endocrine cells with their particular ultrastructural appearance implies that they may take part in modulating the function of the duct system.     

Expression of intermediate filaments in neuroendocrine tumors

Expression of 160-kilodalton (kd) neurofilament, cytokeratin, and vimentin was immunohistochemically investigated in 45 pheochromocytomas, 12 medullary thyroid carcinomas, and 12 pancreatic islet cell tumors. Four mixed neuroendocrine-neural tumors, two multiple endocrine neoplasia type I tumors, and two multiple endocrine neoplasia type II tumors were included in this study. Neurofilament immunoreactivity was demonstrated in 45 (100%) of the pheochromocytomas, 10 (83%) of the medullary thyroid carcinomas, and 11 (92%) of the islet cell tumors. Cytokeratin and vimentin were detectable in 29% and 24% of the pheochromocytomas, 100% and 25% of the medullary thyroid carcinomas, and 67% and 25% of the islet cell tumors, respectively. Neurofilament was the most frequently detected intermediate filament in the neuroendocrine tumors. Cytokeratin was seen in the intra-adrenal but not the extra-adrenal pheochromocytomas. Coexpression of neurofilament and cytokeratin was common in the neuroendocrine tumors, and occasionally vimentin was also expressed simultaneously. There were no characteristic differences in the expression of intermediate filaments between multiple endocrine neoplasia type I or II tumors and sporadic-type tumors or between metastatic tumors and nonmetastatic tumors.