Atypical acinar cell nodules of the human pancreas

The earliest morphological evidence of altered growth potential of pancreatic acinar cells of the rats treated with carcinogen, such as azaserine, is the development of nodules of atypical acinar cells, some of which are considered to appear, eventually, as acinar cell carcinomas. On the other hand, there exist nodular lesions in the human pancreas, which are similar to atypical acinar cell nodules of the rats, in the sense of nodularity, multiplicity, size, and cytological features, such as pale cytoplasm. To clarify the plausibility of the human nodular lesions as a precursor of acinar cell carcinoma of the pancreas, light and electron microscopical studies were performed, using pancreases of 115 semi-consecutive series of autopsy cases and 20 surgical cases. Multiple nodular lesions were found in 3 autopsy cases and one surgical cases. Ultrastructurally, markedly dilated cysterna of rough-surfaced endoplasmic reticulum and intracisternal granules were the most prominent characteristics of the atypical cells of the nodules. These features are neither reported in chemically induced atypical acinar cell nodules and carcinomas nor in human acinar cell carcinomas. The human lesions were considered to be of degenerative nature rather than neoplastic.     

ATYPICAL ACINAR CELL NODULES OF THE HUMAN PANCREAS

The earliest morphological evidence of altered growth potential of pancreatic acinar cells of the rats treated with carcinogen, such as azaserine, is the development of nodules of atypical acinar cells, some of which are considered to appear, eventually, as acinar cell carcinomas. On the other hand, there exist nodular lesions in the human pancreas, which are similar to atypical acinar cell nodules of the rats, in the sense of nodularity, multiplicity, size, and cytological features, such as pale cytoplasm. To clarify the plausibility of the human nodular lesions as a precursor of acinar cell carcinoma of the pancreas, light and electron microscopical studies were performed, using pancreases of 115 semi-consecutive series of autopsy cases and 20 surgical cases. Multiple nodular lesions were found in 3 autopsy cases and one surgical cases. Ultrastructurally, markedly dilated cysterna of rough-surfaced endoplasmic reticulum and intracisternal granules were the most prominent characteristics of the atypical cells of the nodules. These features are neither reported in chemically induced atypical acinar cell nodules and carcinomas nor in human acinar cell carcinomas. The human lesions were considered to be of degenerative nature rather than neoplastic.     

Differentiation and cell proliferation patterns in rat exocrine pancreas: role of type I and type II injury

Fully differentiated and functionally specialized acinar cells of the rat pancreas are versatile and adaptable. Acinar cells can be stimulated to divide following administration of a mitogen or after inducing acinar cell necrosis. The degree of compensatory hyperplasia is dependent upon the extent of acinar cell necrosis. Type I injury (subtotal acinar cell necrosis) is followed by marked proliferation of acinar cells leading to complete restitution of the pancreas, whereas subsequent to type II injury (global acinar cell necrosis) there is no restitution of the pancreas because of lack of enough viable cells that have served as precursor cells. Associated with type Ii injury there is proliferation of ductular and periductular cells followed by the development of hepatocytes. In addition, during adverse conditions acinar cells undergo dedifferentiation and form pseudoductular structures. In rats, acinar tissue is a prime target for carcinogens. Transformed acinar cells form foci which are morphologically classified as acidophilic and basophilic lesions. Acidophilic foci which show increased cell proliferation progress to form nodules and acinar cell carcinomas.     

Characterization of preneoplastic and neoplastic lesions in the rat pancreas

Nodules of acinar cells with increased proliferative potential develop in the pancreas of carcinogen-treated rats and in untreated aged rats. Large nodules are classed as adenomas. Phenotypic and genotypic characteristics of nodule cells were compared with normal pancreas and transplantable acinar cell carcinomas by several methods. Nuclei of acinar cells from normal pancreas, adenomas, and three carcinomas in situ had normal diploid DNA content as determined by flow cytometry. One of two primary carcinomas had a hypodiploid DNA content. Two of three transplantable carcinomas were aneuploid with a DNA content in the tetraploid range. Explants from nodules and adenomas failed to grow in soft agar, whereas several carcinomas were positive in this assay. A primary carcinoma was serially transplanted, but transplantation of nodules or adenomas failed. Transfection of DNA from carcinomas in situ yielded a higher frequency of NIH 3T3 transformants than DNA from adenomas. DNAs from the transformants did not contain ras sequences. These studies indicate that cells from nodules and adenomas have low growth potential and lack critical phenotypic and genotypic characteristics of transformed malignant cells that were present in some primary and transplanted carcinomas.     

Preneoplastic and neoplastic lesions in the pancreas of rats fed choline-devoid or choline-supplemented diets

Groups of male Fischer 344 rats were chronically fed semipurified choline-devoid or choline-supplemented diets, high in fat (15%), and containing or not containing 0.06% phenobarbital. Atypical acinar cell nodules were observed in the pancreas of the rats, irrespective of the diet fed, with incidences varying from 38% to 100% in the various groups. No consistent differential effects of the dietary treatments on the incidence and growth of the nodules were evident, even though the diameter of the nodules tended to be greater in some of the groups fed the basal choline-devoid diet. The vast majority of the nodules were of the acidophilic type. More advanced pancreatic acinar cell lesions were observed in a few of the rats. Since the rats were not exposed to a chemical carcinogen(s), development of the nodules and of the more advanced lesions, even in rats fed the control diets, was most likely due to evolution of endogenous (spontaneous) initiated pancreatic cells, promoted primarily by the feeding of semipurified diets with a high fat content.     

Intrahepatic metastasis of hepatocellular carcinoma: a histopathologic study.

Developmental processes of intrahepatic metastasis were examined in 75 selected cases of hepatocellular carcinoma (HCC) arising in cirrhotic livers. According to their prevalent sites of formation, metastatic nodules were divided into the portal type (59 of 75, 78.7%) and the acinar type (16 of 75, 21.3%). In general the tumor histology was similar to that of primary lesions. The acinar type usually developed via coalescence of scattered tumor cell clusters formed within pseudolobules. In seven cases classified as acinar type, the nodules were composed of well-differentiated tumor cells which were arranged in trabeculae of almost normal thickness (normotrabecular subtype). In four out of these seven cases, the lesions could be clearly defined as metastatic. The subtype could not be determined when only a few discrete nodules were present, as in the remaining three cases. The nodules of the normotrabecular subtype tended to contain a central core of less-differentiated HCC in association with tumor growth, giving rise to a feature of nodule-in-nodule lesions. It is concluded that there do occur metastatic nodules showing well-differentiated, normotrabecular pattern and that these nodules are available for studying developmental steps of early HCCs.     

Immunohistochemical staining of Ha-ras oncogene product in normal, benign, and malignant human pancreatic tissues

We examined immunohistochemical staining with Ha-ras oncogene product in normal, benign, and malignant human pancreatic tissues. In cases of pancreatic cancer, its relation to histologic type was evaluated. Serous cystadenoma and atypical acinar cell nodules did not react with the Ha-ras oncogene product, and ductal cells and acinar cells in normal pancreas showed lower immunoreactivity than other benign or malignant lesions. However, the positive rate of islet cells in normal pancreas was almost the same in cases of pancreatic cancer. Strongest positivity was observed in cases of chronic pancreatitis, and islet cell tumors also showed high positive staining rates. In pancreatic cancer, the positive rate of well-differentiated adenocarcinomas was rather higher than that of poorly differentiated adenocarcinomas. Our study indicates that the Ha-ras oncogene p21 product does not correlate with neoplastic transformation in human pancreas, is not a useful marker for differentiating benign and malignant lesions, and cannot be used to determine the origin of differentiation in the pancreas.     

Acinar Cell Carcinoma of the Pancreas

A case of acinar cell carcinoma of the pancreas is presented. The differential diagnosis is discussed and includes endocrine neoplasm of the pancreas (islet cell and carcinoid tumor) and a poorly differentiated adenocarcinoma. The separation of the various entities by light microscopic, histochemical, immunocytochemical, and ultrastructural methods is described. The acinar cell carcinoma characteristically is positive for pancreatic digestive enzymes by immunocytochemistry, and at the ultrastructural level zymogen-type granules can be demonstrated; these have a tendency to aggregate in the apical region of acinar structures. Clinically the acinar cell carcinoma is an aggressive malignant neoplasm that may present with a characteristic syndrome of disseminated fat necrosis. Survival is generally less than 1 year.     

Acinar cell carcinoma of the pancreas.

A case of acinar cell carcinoma of the pancreas is presented. The differential diagnosis is discussed and includes endocrine neoplasm of the pancreas (islet cell and carcinoid tumor) and a poorly differentiated adenocarcinoma. The separation of the various entities by light microscopic, histochemical, immunocytochemical, and ultrastructural methods is described. The acinar cell carcinoma characteristically is positive for pancreatic digestive enzymes by immunocytochemistry, and at the ultrastructural level zymogen-type granules can be demonstrated; these have a tendency to aggregate in the apical region of acinar structures. Clinically the acinar cell carcinoma is an aggressive malignant neoplasm that may present with a characteristic syndrome of disseminated fat necrosis. Survival is generally less than 1 year.     

Proliferative exocrine pancreatic lesions in rats. The effect of sample size on the incidence of lesions

Pancreatic tissue from untreated and corn oil gavage control rats in four chronic (2-year) toxicity and carcinogenicity studies was examined microscopically for the presence of acinar hyperplasia, acinar adenoma, and acinar carcinoma. Formalin-fixed pancreatic tissue that had been saved from these rats was then examined for grossly visible lesions; and all additional available pancreatic tissue was embedded, routinely processed, and sectioned at 5-7 microns for histopathological examination. There were no additional gross lesions identified in the review of the residual tissues. However, microscopic examination of this additional tissue resulted in a marked increase in the number of proliferative lesions diagnosed. The incidence of acinar cell adenomas increased from 1/188 (0.5%) to 28/193 (15%) in untreated control male rats and from 8/194 (4%) to 73/195 (37%) in corn oil gavage vehicle control male rats. There were similar increases in hyperplasia in vehicle and untreated male rats, and similar but much less dramatic increases in hyperplasia and adenoma in vehicle and untreated control female rats. The previously reported effect of increased proliferative lesions of the exocrine pancreas of male rats given corn oil vehicle was confirmed. In addition, examination of a larger tissue sample identified a similar but smaller effect of the corn oil vehicle in female F344 rats that had not been detected by routine sampling of the pancreas.     

Pure pancreatic-type acinar cell carcinoma of the stomach: a case report

Acinar cell carcinoma is an uncommon carcinoma of the exocrine pancreas. On very rare occasions it has been reported in ectopic sites, sometimes with, but usually without contiguous heterotopic pancreatic tissue. Whilst mixed and composite glandular tumours have also been described, pure pancreatic-type acinar cell carcinomas arising in the stomach are very rare.     

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.     

Solid adenoma with exclusive hepatocellular differentiation: a new variant among pancreatic benign neoplasms?

We report a unique, previously unreported pancreatic tumor with hepatoid differentiation associated with serous microcystic adenoma in a 70-year-old man. These two lesions localized, respectively, at the body and the tail of the pancreas, were found incidentally on abdominal ultrasonography. Serum alpha-fetoprotein was not increased and no hepatic lesion was displayed on computed tomography. A subtotal pancreatectomy with splenectomy was performed. The patient is alive and well 12 months after resection. Pathological examination showed a very unusual encapsulated solid tumor with hepatocytic differentiation, bile production and immunoreactivity for hepatocyte paraffin-1 antibody. The tumor cells were negative for endocrine (neuron-specific enolase, chromogranin A, synaptophysin) and acinar (amylase, trypsin) markers. Ultrastructurally, zymogen and neurosecretory granules were absent. The features of the tumor were almost indistinguishable from those of hepatocellular adenoma; therefore, we believe that this solid hepatoid tumor may represent a variant of pancreatic adenoma. Recognition of this entity is important because the only reported pancreatic hepatoid tumors to date have been malignant. The main differential diagnoses include hepatoid ductal adenocarcinoma, hepatoid acinar cell carcinoma, primitive hepatoid endocrine tumor, and metastatic hepatocellular carcinoma.     

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.     

Acinar cell carcinoma of the pancreas

Four cases of acinar cell carcinoma of the pancreas are reported. An acinar cell carcinoma can resemble an islet cell tumor by routine light microscopy but the two differ considerably in their fine structure and immunostaining properties. Although cells of both tumors contain numerous dense-core granules, their size ranges are different, and atypical forms occur in the acinar cell tumors, including elongated bodies filled with filaments. Many mitochondria-rough endoplasmic reticulum complexes were present in one tumor. In a liver metastasis, nests of endocrine cells were discovered amid the groups of acinar cells, and some of the endocrine granules contained rectangular cores.     

Acinar Cell Carcinoma of the Pancreas

Four cases of acinar cell carcinoma of the pancreas are reported. An acinar cell carcinoma can resemble an islet cell tumor by routine light microscopy but the two differ considerably in their fine structure and immunostaining properties. Although cells of both tumors contain numerous dense-core granules, their size ranges are different, and atypical forms occur in the acinar cell tumors, including elongated bodies filled with filaments. Many mitochondria-rough endoplasmic reticulum complexes were present in one tumor. In a liver metastasis, nests of endocrine cells were discovered amid the groups of acinar cells, and some of the endocrine granules contained rectangular cores.     

Filamentous Inclusions in Acinar Cell Carcinoma of the Pancreas

Acinar cell carcinoma of the pancreas exhibits a spectrum of histologic appearances. Some tumors can be readily identified by light microscopy, but others resemble endocrine/neuroen-docrine neoplasms. Ultrastructurally, though large zymogen granules of acinar cells are usually distinctive, the zymogen granules of neoplastic acinar cells are sometimes abnormally small, overlapping in size with the granules of endocrine/neu-roendocrine neoplasms. Six cases of acinar cell carcinoma, two with a typical histologic appearance and four that resembled endocrine/neuroendocrine tumors, were studied ultrastructurally. In addition to zymogen granules and abundant rough endoplasmic reticulum, all cases of acinar cell carcinoma exhibited pleomorphic, membrane bound inclusions that contained filaments. Similar inclusions were not identified in islet cell or carcinoid tumors, and several findings indicate that the inclusions represent deranged zymogen granules. In the ultrastructural study of a pancreatic neoplasm with granules, these inclusions may provide a clue for the diagnosis of acinar cell carcinoma.     

Acinar cell neoplasms of the exocrine pancreas.

The pathological features of 12 acinar cell neoplasms of the pancreas are described; these comprise 11 carcinomas, of which seven were pure acinar cell growths and four were mixed acinar and ductal carcinomas, and one adenoma. These tumors occurred in a series of 105 during the period 162-75. Thrombotic endocarditis developed in three out the 11 carcinoma cases. The distinctive histological features of these neoplasms and the means of differentiating them from anaplastic carcinomas and certain other carcinomas, for example, islet cell carcinoma, oat cell carcinomas, and carcinoid tumours, are discussed. The poor prognosis of pancreatic cancers is emphasized, and reasons are put forward for believing that future epidemiological studies may need to take account of the histological types of pancreatic carcinoma.     

Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia

A number of studies have shown that pancreatic ductal adenocarcinoma develops through precursor lesions termed pancreatic intraepithelial neoplasia (PanIN). PanINs are thought to initiate in the small ducts of the pancreas through activating mutations in the KRAS proto-oncogene. What remains unanswered is the identification of the individual cell type(s) that contributes to pancreatic ductal adenocarcinoma formation. To follow the cellular and molecular changes that occur in acinar and duct cell properties on Kras(G12D) expression, we took advantage of LSL-Kras(G12D/+)/p48(Cre/+) mice, which faithfully mimic the human disease. In young animals (4 weeks), the predominant cellular alteration in the exocrine pancreas was acinar metaplasia in which individual acini consisted of acinar cells and duct-like cells. Metaplastic acinar structures were highly proliferative, expressed Notch target genes, and exhibited mosaic expression patterns for epidermal growth factor receptor, ErbB2, and pErk. This expression pattern paralleled the expression pattern detected in mouse PanINs, suggesting that mouse PanINs and acinar-ductal metaplasia follow similar molecular pathways. Indeed, immunofluorescence studies confirmed the presence of acinar cells within mPanIN lesions, raising the possibility that Kras(G12D)-induced mPanINs develop from acinar cells that undergo acinar-ductal metaplasia. Identification of an acinar contribution to PanIN formation offers new directions for successful targeted therapeutic approaches to combat this disease.