Multiple atypical acinar cell nodules of the pancreas

Although acinar cell nodules of the pancreas have been described in rats given carcinogenic chemicals, similar nodules have not been reported in humans. This report describes two cases of nodular acinar cell lesions in the pancreas in patients who died of insulin secreting islet cell adenoma and of bronchogenic carcinoma. The lesions consisted of multiple nodules that were well demarcated from the surrounding acinar tissue and were composed of zymogen granule containing acinar cells with a pale to pink cytoplasm. The significance of these atypical acinar cell nodules in regard to their being possible precursor lesions of acinar cell carcinoma of the pancreas is discussed.     

Unilocular acinar cell cystadenoma of the pancreas an unusual acinar cell tumor

We report an unusual case of acinar cell cystadenoma of the pancreas in a 52-year-old man treated for pulmonary adenocarcinoma. The lesion, located in the body of the pancreas, was revealed incidentally by abdominal computed tomography during follow-up for a pulmonary neoplasm. A left pancreatectomy was performed. The unilocular cystic lesion measured 5 cm and was lined by a single layer of columnar acinar cells with eosinophilic granular cytoplasm, faintly stained by periodic acid-Schiff. Immunohistochemical analysis showed the lining cells were positive for cytokeratin and trypsin, and electronic microscopy showed that they contained zymogen granules. Acinar cell tumors of the pancreas are rare and include acinar cell carcinomas, acinar cell cystadenocarcinomas, and acinar cell adenomas. We report a case of cystic acinar cell tumor of the pancreas with benign gross and histologic features that could be added to the list of cystic neoplasms of the pancreas as acinar cell cystadenoma.     

Intraductal acinar cell carcinoma of the pancreas

We describe a purely intraductal acinar cell carcinoma involving branch ducts of the pancreas in a 74-year-old man, which presented as recurrent episodes of acute pancreatitis. Endoscopic ultrasound examination revealed an intraductal mass bulging into the main pancreatic duct suggesting, pre-operatively, an intraductal mucinous papillary tumour. Gross examination showed several dilated branch ducts that contained haemorrhagic tumour material without any solid or true cystic formation within the pancreatic parenchyma. Using histology, a purely intraductal acinar cell carcinoma was observed, involving branch ducts only, associated with foci of carcinoma in situ in adjacent exocrine parenchyma. The main pancreatic duct was free of disease except for its communication with a cancerous branch duct. A concomitant neuroendocrine microadenoma was incidentally found during slide screening. Immunohistochemistry performed on the intraductal proliferation confirmed zymogen secretion with positive staining for alpha-1 anti-chymotrypsin and anti-trypsin and the persistence of diastase-periodic acid-Schiff positive granules in the apical pole of the tumour cells. Neuroendocrine markers were negative in the acinar cell carcinoma and positive in the neuroendocrine microadenoma. To our knowledge, this is the first report of an intraductal acinar cell carcinoma of the pancreas involving branch ducts and sparing the main pancreatic duct.     

Alpha-fetoprotein-producing acinar cell carcinoma of the pancreas.

A pancreatic carcinoma and liver metastases associated with marked elevation of the serum alpha-fetoprotein (AFP) level were resected from a 57-year-old man. On microscopic examination, the tumor cells showed a predominantly acinar arrangement, with tubular and trabecular structures; in some foci it had features of a medullary pattern. Alpha-fetoprotein, lipase, trypsin, chymotrypsin, and alpha 1-antitrypsin were strongly demonstrated in tumor tissue by immunohistochemical techniques. A biochemical analysis of AFP on affinity sepharose columns revealed that the AFP derived from the tumor tissues was similar to that of hepatocellular carcinoma. Ultrastructural study showed that most of the tumor cells had abundant rough endoplastic reticulum and numerous zymogen granules. No squamoid corpuscles, neuroendocrine granules, bile production, or bile canaliculi were recognized. These findings suggest that this unique tumor originated from acinar cells.     

Solid and cystic acinar cell tumour of the pancreas

Summary The clinico-pathological features of five cases with a distinctive pancreatic tumour are presented. The tumours, which occurred only in young women and an adolescent girl, were of large size (2.5–10 cm), had an uncharacteristic symptomatology and showed fibrous encapsulation with no evidence of metastases. The histological features include (1) solid areas with a monomorphic cell pattern and intracellular PAS positive globules, and (2) large foci of degeneration with cystic necroses, haemorrhages and cholesterol granulomas. Some tumour cells were positive for ₁-antitrypsin. The ultrastructural demonstration of zymogen-like granules suggests an acinar origin for the tumours. We therefore propose the term solid and cystic acinar cell tumour. This tumour resembles the so called pancreatoblastomas in small children in some respects. It must be clearly distinguished, on the other hand, from acinar cell carcinoma with its acinic structures and poor prognosis. This lesion is not included in the WHO classification of pancreatic neoplasms.Dedicated to Prof. Dr. G. Seifert in honour of his sixtieth birthday     

Ex vivo analysis of acinar and endocrine cell development in the human embryonic pancreas.

In contrast to the considerable body of data on pancreas development in rodents, information on pancreas development in humans is scant. We previously described a model in which mature beta cells developed from human embryonic pancreas: human embryonic pancreas was grafted under the kidney capsule of scid mice, beta cells were then seen to develop in the graft. Here, we showed that not only beta cells, but also other endocrine cells, acinar cells and ducts develop in this model. We then used this model to probe the mechanisms underlying acinar and beta cell development in the human embryonic pancreas. BrdU pulse/chase experiments produced evidence of clonal acinar cell development: the first acinar cells to appear proliferated, thereby expanding the acinar cell population. In contrast, beta cell development was regulated by the proliferation of pancreatic progenitor cells, followed by beta-cell differentiation. We then showed that early progenitors expressing PDX1 proliferated, whereas late endocrine progenitors expressing Ngn3 did not. This proliferative capacity of early endocrine progenitor cells in embryonic human pancreas may hold promise for obtaining human beta-cell expansion.     

Atypical acinar proliferations of the prostate

Small acinar lesions of the prostate may mimic prostate cancer. In the central and transition zone of the prostate, atypical adenomatous hyperplasia (AAH) must be differentiated from low grade carcinoma (Gleason score 2-5). In the dorso-peripheral zone, high grade prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferations (ASAP) are the most important lesions mimicking carcinoma. Further differentiation is necessary between high grade PIN and intraductal carcinoma. ASAP, on the other hand, may mimic low grade carcinoma. The significance of basal cell type cytokeratin immunohistochemistry (IHC) in the differentiation between ASAP and low grade carcinoma of the prostate was substantiated by additional MIB-1 IHC. The status of the basal cell layer in ASAP was found to be variable (complete, fragmented and absent). Independent of the status of the basal cell layer, the mean MIB-1 proliferation index of ASAP was significantly higher than that of clearly benign lesions and did not differ from that of low grade carcinoma. As carcinoma is frequently detected in rebiopsies, close clinical follow up of patients with ASAP is advisable.     

Brush cytology of acinar cell carcinoma of the pancreas with intraductal growth

We describe a rare case of pancreatic acinar cell carcinoma (ACC) with intraductal growth in a 77‐year‐old man, which was diagnosed by endoscopic brush cytology. Preoperative imaging revealed an ill‐defined mass involving the main pancreatic duct of the body, which was suspected to be an invasive ductal carcinoma. Endoscopic brush cytology showed several thick, small to large clusters of tumor cells. However, a loosely cohesive or individual cell arrangement was more prominent. Singly dispersed naked nuclei, occasionally with crush artifact, were frequently observed. The nuclear contour was smooth and chromatin was finely clumped. The cytoplasm contained many coarse D‐PAS‐positive granules. Histologically, the tumor expansively invaded to parenchyma and expanded to fill the pancreatic ducts. Ultrastructurally, the tumor cells were less cohesive with scarce tight junctions, and their cytoplasm contained numerous zymogen granules and filamentous inclusions. Although ACCs usually show expansive growth, the incidence of intraductal extension may be higher than previously considered. A few of the characteristic cytomorphological features described here may be useful for differential diagnosis of this tumor from malignant epithelioid neoplasms involving the large pancreatic ducts. Diagn. Cytopathol. 2014;42:321–324. © 2013 Wiley Periodicals, Inc.     

Alpha fetoprotein-producing acinar cell carcinoma of the pancreas showing multiple lines of differentiation

An alpha fetoprotein (AFP)-producing tumour occurring in the head of the pancreas of a 30-year-old woman is reported. Histological examination revealed a markedly solid proliferation of tumour cells with prominent nucleoli and occasional luminal structures, some of which contained mucinous material stained with mucicarmine and alcian blue. No squamoid corpuscles were recognized. Immunohistochemistry showed intense positivity for lipase trypsin, and AFP basically, and single cells were also positive for carcino-embryonic antigen, CA19-9, synaptophysin and neuron-specific enolase. Pancreatic hormone-positive cells were absent. Electron microscopical examination revealed numerous granules of variable sizes in the tumour cells, which were considered to be zymogen. The tumour is an acinar cell carcinoma with multi-directional differentiation including the ability to produce AFP. Among AFP-positive pancreatic tumours, acinar cell carcinoma and pancreatoblastoma seem to be the most frequent.     

Solid cystic acinar cell tumor of the pancreas. Immunohistologic studies of histogenesis

A case of a very rare solid and cystic tumor of the pancreas in a 25-year-old woman was examined by immunohistochemical methods, e.g. antiglucagon, antisomatostatin, antivip etc. The stainings by the PAP- or biotin-avidin-method were negative and also those with S-100 protein and especially with chromogranin. A tumor of the endocrine system was therefore excluded. Some areas of the tumor showed positive staining with alpha-1-antitrypsin as is known in acinar cell carcinoma. The classification of the neoplasm as an acinar adenoma of the pancreas seems to be well established, mainly because several authors electronmicroscopically demonstrated structures resembling acini and zymogen granules.     

Derivation of ductlike cell lines from a transplantable acinar cell carcinoma of the rat pancreas.

Two cell lines were derived from a transplantable acinar cell carcinoma that had been established from a primary carcinoma of the pancreas in an azaserine-treated Lewis rat. The cultured tumor cells initially produced amylase, but production of exocrine enzymes ceased after 1-2 weeks in culture. The cultured cells were tumorigenic in Lewis rats, and one line produced solid tumors composed of ductlike structures surrounded by dense fibrous tissue. The second cell line produced partially solid and partially cystic tumors with a mixed phenotype of squamous, mucinous, and glandular areas when it grew in vivo following regrafting. Both cell lines lost structural and immunohistochemical acinar cell markers while acquiring duct cell markers during culture and regrafting. These studies provide strong support for the hypothesis that ductlike carcinomas can arise from neoplastic pancreatic acinar cells in rats.     

Rapid acinar to ductal transdifferentiation in cultured human exocrine pancreas.

Experiments have been performed to define conditions for the primary culture of human exocrine pancreas, as a first step towards molecular reconstruction experiments of pancreatic neoplasia. Normal human exocrine pancreas was digested using collagenase and dispase and the resulting cellular aggregates were cultured in vitro. The phenotype of the digested pancreatic cells was almost exclusively acinar (amylase-positive, keratin 19 and mucin antigens-negative), yet within 4 days of culture the cells had taken on a ductal phenotype (amylase-negative, keratin 19 and mucin antigens-positive). The kinetics of these observations exclude the possibility of overgrowth of the acinar population by a ductal sub-population, and selective adherence is excluded by examination of those cells that do not adhere, which are representative of the initiating population. We interpret these data as indicating that, under the conditions of culture, the acinar cell phenotype is not stable and can transdifferentiate to a ductal phenotype. Taken together with recent data from transgenic animals, this in vitro observation has possible implications for our view of the pathogenesis of pancreatic neoplasia.     

Effects of dietary fatty acids on the early stages of neoplastic induction in the rat pancreas. Changes in fatty acid composition and development of atypical acinar cell nodules.

Diets enriched with fat, especially unsaturated fat, promote experimental pancreatic carcinogenesis, but little is known of the effects of individual fatty acids. The effect of stearic and oleic acid on pancreatic fatty acids and atypical acinar cell nodules (preneoplastic lesions) was studied in 14-day-old weanling male Leeds strain rats (n = 60) given the carcinogen azaserine. Rats were allocated to one of six groups: untreated controls (n = 10), 20% stearic acid diet (n = 10), 20% oleic acid diet (n = 10), carcinogen alone (n = 10), carcinogen plus 20% stearic acid diet (n = 10) or carcinogen plus 20% oleic acid diet (n = 10). Azaserine was administered by intraperitoneal injection in a dose of 30 mg/kg at 2, 3 and 4 weeks of age. When total lipid extracts of pancreas were examined, there was an increase in stearic acid in the stearic acid fed group and an increase in oleic acid in the oleic acid fed group, irrespective of carcinogen treatment. The relative content of all other pancreatic fatty acids was suppressed by feeding oleic acid. At 26 weeks, the number and volumetric indices of pancreatic atypical acinar cell nodules was increased only in rats given azaserine and oleic acid. The enhancing effect of oleic acid on pancreatic carcinogenesis may be associated with pancreatic fatty acid changes.     

Atypical dermal nodules in benign melanocytic naevi

Aims : The prognosis of deeply invasive melanoma can be poor and to a large extent it is unresponsive to treatment once metastases have occurred. It is therefore important that any dermal melanocytic lesions that have some features suggestive of melanoma but are nevertheless benign, should be identified. Methods and results : A series of 40 benign melanocytic naevi is described in which the clinical presenting feature was a central focus of increased pigmentation. This was found histologically to correspond to dermal nodules of large melanocytes showing some, usually mild, nuclear atypia but low indices of cellular proliferation. The nodules are found within otherwise typical melanocytic naevi. The clinical and histological differential diagnosis included invasive melanoma but in follow-up, which is admittedly short (mean 24 months), none have recurred or metastasized. Conclusions : It is suggested that the nodules represent terminal differentiation of melanocytes rather than proliferative changes. They should be distinguished from melanoma and regarded as a variant of benign melanocytic naevi.     

Beta cell regeneration in human pancreas

The issue of beta cell regeneration in human pancreas is probably one of the most controversial aspects of type 1 diabetes research. In this review, we will first describe the known mechanisms underlying beta cell development and expansion in normal human pancreatic development because it is likely that such mechanisms might also play a role in beta cell regeneration. The sensu strictiori definition of beta cells implies replacement of lost beta cell mass by new beta cells. In our discussion, however, we will use the term in a more general way, defining as regeneration the formation of new beta cells, whether or not a loss of beta cells has actually occurred. The potential mechanisms of beta cell regeneration in the human pancreas will be discussed in the second part of this review. In particular, we will analyze beta cell regeneration through proliferation of beta cells, neogenesis from non-beta cell precursors, and transdifferentiation from alpha cells. In the third part of this review, we will explore the arguments for and against the ability of the human pancreas to regenerate functional beta cells in the context of type 1 diabetes and in other pathological conditions.