Toshio Morohoshi

ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells1

The ABCA3 gene, of the ABCA subclass of ATP‐binding cassette (ABC) transporters, is expressed exclusively in lung. We report here the cloning, molecular characterization, and distribution of human ABCA3 in the lung. Immunoblot analysis using the specific antibody reveals a 150‐kDa protein in the crude membrane fraction of human lung. Immunohistochemical analyses of alveoli show that ABCA3 is expressed only in the type II cells expressing surfactant protein A. At the ultrastructural level, ABCA3 immunoreactivity was detected mostly at the limiting membrane of the lamellar bodies. Since members of the ABCA transporter family are known to be involved in transmembrane transport of endogenous lipids, our findings suggest that ABCA3 plays an important role in the formation of pulmonary surfactant in type II cells.

Exocrine pancreatic tumours and their histological classification. A study based on 167 autopsy and 97 surgical cases.

Based on histopathological examination of 264 exocrine pancreatic tumours (167 autopsy and 97 surgical) from the files of the Institute of Pathology, University of Hamburg, over a 15‐yr period (1966–1980), a histogenetic classification is proposed. In addition to the more common neoplasms this also includes rarer and more recently defined entities. Of the 264 tumours, 250 were of duct origin, 10 acinar and four of uncertain histogenesis. Ductal adenocarcinoma, subdivided into a well‐differentiated and a poorly‐differentiated type, was most frequent (81.1%), followed by its variants: pleomorphic giant cell carcinoma 5·3%, adenosquamous carcinoma 3·8%, and mucinous carcinoma 1.1%. All these had a poor prognosis. Serous cystadenoma (1.1%), mucinous cystic tumour (1.5%) and intraductal papilloma (0.8%), which were rare tumours and mostly apparent in surgical material, proved to be benign or of only latent malignancy. The group of tumours of acinar cell origin consisted of the solid and cystic tumour (2.7%) with favourable prognosis and the acinar cell carcinoma (1.1%). No pancreatoblastoma was observed. The pleomorphic carcinomas of the small cell type (1.5%) were classed as tumours of uncertain histogenesis.

Intraductal papillary neoplasms of the pancreas. A clinicopathologic study of six patients.

A clinicopathologic study was conducted on six patients with intraductal papillary neoplasms of the pancreas. The patients were of both sexes and their ages ranged from 64 to 79 years. Three patients had a long history of symptoms mimicking chronic pancreatitis. The tumors involved the main pancreatic duct in the head‐‐body region either diffusely or focally. Histologic examination showed papillary proliferations of well‐differentiated, mucus‐secreting cells that occasionally stained for carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19‐9). The proliferations filled the main pancreatic duct, and extended into smaller ducts in some cases. In three patients, the lesions contained foci of pronounced to severe cellular atypia and carcinoma in situ. None of our series or any similar cases reported in the literature has shown invasion into peripancreatic tissue, metastasis, or tumor recurrence after pancreatectomy. Because of their favorable prognosis, intraductal papillary neoplasms should be considered low‐grade malignancies that must not be confused with the common ductal adenocarcinoma.

Prognostic relevance of morphological types of intraductal papillary mucinous neoplasms of the pancreas

Objective The clinicopathological significance of four morphological types of intraductal papillary mucinous neoplasms of the pancreas (IPMNs; gastric, intestinal, pancreatobiliary and oncocytic) was assessed. Design Retrospective multicentre analysis of 283 surgically resected IPMNs. Results Of the 283 IPMNs, 139 were of the gastric type, 101 were intestinal, 19 were pancreatobiliary and 24 were oncocytic. These types were significantly associated with clinicopathological factors including sex (p=0.0032), age (p=0.00924), ectatic duct size (p=0.0245), detection of mural nodules (p=4.09×10−6), histological grade (p<2.20×10−16), macroscopic types with differential involvement of the pancreatic duct system (p=3.91×10−5), invasive phenotypes (p=3.34×10−12), stage (p<2.20×10−16) and recurrence (p=0.00574). Kaplan–Meier analysis showed significant differences in patient survival by morphological type (p=5.24×10−6). Survival rates at 5 and 10 years, respectively, were 0.937 (95% CI 0.892 to 0.984) for patients with gastric-type IPMNs; 0.886 (95% CI 0.813 to 0.965) and 0.685 (95% CI 0.553 to 0.849) for those with intestinal-type IPMNs; 0.839 (95% CI 0.684 to 1.000) and 0.734 (95% CI 0.526 to 1.000) for those with oncocytic-type IPMNs; and 0.520 (95% CI 0.298 to 0.909) and undetermined for those with pancreatobiliary-type IPMNs. Analysis by the Cox proportional hazards model comparing prognostic risks determined by stage and the morphological and macroscopic types indicated that staging was the most significant predictor of survival (p=3.68×10−8) followed by the morphological type (p=0.0435). Furthermore, the morphological type remained a significant predictor in a subcohort of invasive cases (p=0.0089). Conclusion In this multicentre retrospective analysis, the morphological type of IPMN appears to be an independent predictor of patient prognosis.

Immunocytochemical markers of uncommon pancreatic tumors. Acinar cell carcinoma, pancreatoblastoma, and solid cystic (papillary‐cystic) tumor

Nine acinar cell carcinomas of the pancreas, 2 pancreatoblastomas, 16 solid‐cystic (papillary‐cystic) tumors, and 20 ductal adenocarcinomas were immunocytochemically investigated using antisera against four pancreatic enzymes (alpha‐amylase, lipase, trypsinogen, chymotrypsinogen), four pancreatic hormones, neuron specific enolase (NSE), alpha‐1‐antitrypsin (AAT), carcinoembryonic antigen (CEA), and CA 19–9. Lipase, trypsinogen, and chymotrypsinogen, but no alpha‐amylase were detected in all acinar cell carcinomas and pancreatoblastomas. In contrast, solid‐cystic tumors (SCT) were negative for pancreatic enzymes but 2 of 16 stained with NSE. No neuroendocrine granules or pancreatic hormones could be demonstrated. AAT was found in all tumors except ductal adenocarcinomas, which stained with CEA and CA 19–9. The study established pancreatic enzymes (except alpha‐amylase) as immunocytochemical markers for acinar cell carcinomas and pancreatoblastomas. There is as yet no marker specific for SCT, which would elucidate the obscure histogenetic origin and phenotypic differentiation of these tumors. Cancer 59:729‐747, 1987.

Solid and cystic acinar cell tumour of the pancreas

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 α1-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.

Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells.

Autoimmune pancreatitis (AIP) is a newly recognized disease. The presence of IgG4 positive plasma cells is thought to be of diagnostic help. In a surgical series of chronic pancreatitis cases, we determined the relative frequency of AIP before and after 1990, analyzed the diagnostic significance of IgG4 expression and examined the presence of oligoclonal T or B-cell populations. The histopathology of 202 surgical specimens of chronic pancreatitis removed between 1975 and 2004 was reviewed and 2 groups were distinguished, 1 of AIP cases and the other of nonautoimmune chronic pancreatitis (non-AIP CP). The intensity of infiltration of pancreatic tissue by IgG4 positive plasma cells and other immune cells was studied immunohistochemically. Finally, T and B-cell clonality was tested by polymerase chain reaction-based analysis. Except for 1 case in 1978, all cases of AIP were observed after 1990. IgG4 positive plasma cells were detected in 72.5% of AIP cases and in 63.1% of non-AIP CP cases. More than 20 cells per high power field were only seen in AIP (sensitivity 43%, specificity 100%). This finding was associated with higher age and grade. Polyclonal T and B-cell populations were found in both AIP and non-AIP CP except for 1 AIP case showing an oligoclonal IgGH-FR3 gene rearrangement. AIP seems to have increased considerably in frequency in the last 2 decades. High density infiltrates of IgG4 positive plasma cells are diagnostic for AIP, but are seen in less than half of the cases. T or B-cell oligoclonality could not be established as a feature of AIP.

Intraductal Tubular Neoplasms of the Pancreas : Histogenesis and Differentiation

Objectives: Intraductal neoplasms of the pancreas are generally referred to as intraductal papillary mucin-producing neoplasms (IPMNs), according to the WHO classification system. Herein, we report that morphologic and immunohistochemical features of intraductal tubular carcinoma (ITC) are quite different from those of intraductal papillary mucinous carcinoma (IPMC). Methods: We analyzed histogenesis and differentiation of ITC by light microscopy and immunohistochemistry. Results: Histologically, ITC was characterized as an intraductal nodular appearances with a monotonous tubular growth pattern without papillary projection. ITC showed de novo-like appearance without sequential progression usually observed in IPMC, suggesting that ITC is a homogeneous neoplasm. Cuboidal tumor cells in ITC resembled normal pancreatic duct epithelia, and the characteristic growth pattern of ITC replaced that of normal pancreatic duct epithelium. Immunohistochemically, ITC cells were positive for MUC-1 on the apical side of the cell membrane. In contrast to ITC cells, IPMC cells were negative for MUC-1, and ductal adenocarcinoma cells were strongly positive for MUC-1, as was the stroma around the cancer. The immunohistochemical staining pattern of DUPAN-2 resembled that of MUC-1. Interestingly, localization of MUC-1 and DUPAN-2 staining in ITC cells was similar to that in normal pancreatic ductules. ITC cells were negative for MUC-2 and MUC-5AC. In contrast, most IPMC cells were positive for MUC-2 and MUC-5AC. Conclusion: Based on our histologic and immunohistochemical findings, the intraductal pancreatic neoplasm (IPN) can be classified into 2 groups: IPN with gastrointestinal differentiation and IPN with pancreatic duct differentiation. Our present data indicated that ITC cells may arise directly from duct epithelia without progression and possessed pancreatic duct differentiation. On the basis of our data, we suggest that classification of pancreatic neoplasms in the WHO and The Armed Forces Institute of Pathology (AFIP) systems should be reconsidered.

The significance of alpha-fetoprotein and other tumour markers in differential immunocytochemistry of primary liver tumours.

One hundred benign and malignant primary liver tumours were screened immunocytochemically for alpha‐fetoprotein (AFP), α1‐antitrypsin, alpha‐human chorionic gonadotropin, carcinoembryonic antigen (CEA), keratin and vimentin. Alphafetoprotein was found in 16/63 (24%) hepatocellular carcinomas and in two hepatoblastomas. When comparing tissue positivity for AFP with tumour differentiation, grade 1 hepatocellular carcinomas were found to be negative, while 21% of grade 2, 36% of grade 3 and 16% of grade 4, respectively, stained positively. Alphafetoprotein positive cells were present in 9/10 hepatocellular carcinomas with serum levels exceeding 5000 ng/ml, but were absent in 17 tumours with serum AFP levels below 5000 ng/ml. All tumours other than hepatocellular carcinomas and hepatoblastomas were AFP negative. Carcinoembryonic antigen was present in 72% of cholangiocarcinomas, but was demonstrated in only one hepatocellular carcinoma. This exception was a combined hepatocellular‐cholangiocarcinoma in which CEA expression was restricted to the cholangiocellular part. α1‐antitrypsin was found in 4/63 hepatocellular carcinomas, in 2/2 fibrolamellar carcinomas and in 2/18 cholangiocarcinomas. Alpha‐human chorionic gonadotropin was detected in one hepatocellular carcinoma and was strongly expressed in both fibrolamellar carcinomas. Weak staining for keratin was seen in most tumours with hepatocellular differentiation. All cholangiocarcinomas, in contrast, were strongly labelled with the keratin antibody. Co‐expression of keratin and vimentin was observed in seven poorly differentiated hepatocellular carcinomas and three cholangiocarcinomas as well as in the two hepatoblastomas. The findings suggest that AFP is a diagnostic but rather insensitive immunocytochemical marker for hepatocellular differentiation in malignant liver tumours; CEA and keratin may help in discriminating cholangiocarcinomas from hepatocellular carcinomas.

Epidermoid Cyst Derived from an Accessory Spleen in the Pancreas

A rare case of splenic epidermoid cyst (SEC) of the pancreas discovered in a 32‐year‐old Japanese female is reported. The lesion, 5x6cm in size including caseous material and serous fluid in the lumen, was discovered by ultrasonography and computed tomography at the tail of the pancreas and was easily removed. Histopathologically, the cystic wall consisted of three components: the inside was lined by mature squamous epithelium with keratinization, the middle layer consisted of splenic pulp with a sinus structure, and the peripheral layer was dense fibrous connective tissue in which some involutional pancreatic ducts and islets were recognized. The literature about SEC of the pancreas is discussed in comparison with other types of epidermoid cyst including lymphoepithelial cyst and dermoid cyst in the pancreas. Acta Pathol Jpn 41: 916 921, 1991.