Masaru Takase

Histopathologic characteristics of autoimmune pancreatitis based on comparison with chronic pancreatitis.

Objectives: To clarify the histopathologic characteristics of autoimmune pancreatitis (AIP), based on comparison with both chronic alcoholic pancreatitis (CAP) and chronic obstructive pancreatitis (COP). Methods: Three AIP patients, 17 CAP patients, and 19 COP patients were studied histopathologically. Results: There was a dense lymphoplasmacytic infiltrate, especially within and around the pancreatic ducts, and fibrosis associated with AIP, while there was fibrosis accompanied by mild inflammatory infiltration in both CAP and COP. Inter- and intralobular fibrosis admixed with acinar atrophy was observed in both AIP and COP, while interlobular fibrosis combined with a “cirrhosis-like” appearance was found in CAP. Obliterative phlebitis was found in AIP, while thrombosis of the splenic vein was exhibited in CAP. Conclusion: Autoimmune pancreatitis was histologically characterized by dense lymphoplasmacytic infiltrate combined with fibrosis, acinar atrophy, obliterative phlebitis, and ductal involvement.

Autoimmune pancreatitis can be classified into early and advanced stages.

Objectives: Although a number of pathological studies using various names/synonyms for autoimmune pancreatitis (AIP) have been reported, they do not mention the pathological staging related to origin/pathogenesis. Here, we propose a pathological staging for AIP lesions. Methods: We histopathologically examined pancreatic tissue specimens of 31 AIP patients (14 pancreatectomized and 17 needle-biopsied materials) provided by 15 hospitals in Japan and studied the relevance of clinical manifestations to the pathological stage of AIP. Results: Based on the presence or absence of acinar cells in AIP lesions, pancreatic tissue specimens were successfully divided into 20 cases in the early stage and 11 cases in the advanced stage, respectively. In the early stage, fibrosis was distributed in the interlobular and intralobular areas, admixed with acinar atrophy. Lymphoplasmacytic infiltration caused the narrowing of the ductal lumen and obliterative phlebitis. The common bile duct wall was also involved. In the advanced stage, the lesion was replaced by massive/extensive interlobular fibrosis with lymphoplasmacytic infiltrates to various degrees. Phlebitis was mild. Comparative analysis of clinical parameters between the early and advanced stages showed a significantly higher prevalence of jaundice and positive antinuclear antibodies in the early stage, and decreased serum lipase levels in the advanced stage. Conclusions: Autoimmune pancreatitis can be divided into early and advanced stages according to the presence or absence of acinar cells. Our pathological staging will facilitate understanding and evaluation of the clinical course in AIP.Abbreviations: AIP = autoimmune pancreatitis, ANA = antinuclear antibody, CAP = chronic alcoholic pancreatitis, COP = chronic obstructive pancreatitis

Case of combined adrenal cortical adenoma and myelolipoma

We report a case of myelolipoma 10 mm in size within a functional cortical adenoma that was 33 × 22 × 17 mm in size. A 29‐year‐old woman was referred to hospital for transient hypertension. A right adrenal tumor was detected by computed tomography (CT) scan and magnetic resonance imaging (MRI). Her cortisol levels indicated a loss of the normal diurnal pattern, and urinary 17‐hydroxycorticosteroids was elevated. She underwent a right adrenalectomy under the diagnosis of adrenal adenoma with Cushings syndrome. The tumor was fairly well encapsulated by a thin layer of connective tissue. The major tumor portion was composed of two distinct cell types, clear cells and eosinophilic cells, arranged in an alveolar structure. These findings were representative of cortical adenoma. The adrenal cortical adenoma centrally included well‐demarcated adipose tissue admixed with scattered islands of myelopoietic elements: erythroblasts, myeloid cell series and lymphocytic cells, which was eventually recognized as myelolipoma. Recently, adrenal myelolipoma has commonly been found because of the ease of detecting it as an incidentaloma by CT scan or MRI. However, the present adrenal myelolipoma case is uncommon because it is combined with a functioning cortical adenoma. Only six similar cases have previously been reported in English and Japanese publications. Furthermore, in the present case, the myelolipoma formed a tumor nodule, and to our knowledge, this is the first reported case of a radiographically recognizable tumor nodule. We discuss the etiology of myelolipoma and suggest that myelolipoma can develop in the course of endocrine hyperfunction.

Development and Congenital Anomalies of the Pancreas

Understanding how the pancreas develops is essential to understand the pathogenesis of congenital pancreatic anomalies. Recent studies have shown the advantages of investigating the development of frogs, mice, and chickens for understanding early embryonic development of the pancreas and congenital anomalies, such as choledochal cysts, anomalous pancreaticobiliary junction, annular pancreas, and pancreas divisum. These anomalies arise from failure of complete rotation and fusion during embryogenesis. There are many theories in the etiology of congenital anomalies of the pancreas. We review pancreas development in humans and other vertebrates. In addition, we attempt to clarify how developmental failure is related to congenital pancreatic anomalies.

Histopathological study on mechanism and background of tumor-forming pancreatitis.

Fifteen cases of tumor‐forming pancreatitis, detected as tumors by diagnostic imaging or by physical examination were histologically examined. Eleven of the 15 patients were heavy drinkers. Tumorous lesions were located in the head of the pancreas in 11 cases and in the body or tail of the pancreas in four cases. Macroscopic examination revealed tumorous swelling or sclerotic appearance in the pancreatic tissue. Histologically, these lesions showed tumorous swelling with (n= 12) or without (n= 3) a background of chronic pancreatitis. In the former, the tumorous lesions consisted of extensive fibrosis, including necrosis or abscesses, stones and reparative granulation tissue, and there was a successive transition to the surrounding chronic pancreatitis pattern. The latter three tumorous lesions presented with inter‐ and intralobular fibrosis with lymphoid hyperplasia or lymphoplasmacytic infiltration and were adjacent to normal pancreatic tissue. Therefore, tumor‐forming pancreatitis shows at least two distinct types: a reparative tumorous swelling with a background of chronic pancreatitis, which is considered to have given rise to the tumor at some stage; and a lymphoid and fibrous proliferation in normal pancreatic tissue, which is considered to represent an autoimmune‐related disease process.

Histopathologic Study of Coexistent Pathologic States in Pancreatic Fibrosis in Patients with Chronic Alcohol Abuse: Two Distinct Pathologic Fibrosis Entities with Different Mechanisms

The distribution and clinicopathologic features of pancreatic fibrosis were studied histopathologically in 137 autopsy cases of chronic alcohol abuse. Fibrosis was observed in 90 of the cases and was classified as perilobular sclerosis (PS) and intralobular sclerosis (IS). Fibrosis of the PS type was irregular and sometimes patchy and extended into the intralobular area in advanced cases. In some advanced cases, complete replacement of the pancreatic tissue by extensive fibrosis was seen. Fibrosis of the IS type was uniformly distributed. The tissues in some cases showed prominently periacinar fibrosis. In these cases, the pancreatic parenchyma had not been completely replaced by extensive fibrosis. Clinicopathologic comparisons revealed the following results: accompanying liver cirrhosis was greater in the IS than in the PS of fibrosis. However, a higher frequency of protein plugs, pancreatic stones, extensive fibrosis replacement, peripancreatic fibrosis, splenic vein involvement, choledochus involvement, pseudocyst, and ductal hyperplasia was found in the PS type compared to the IS type. In conclusion, the findings on the perilobular and intralobular distribution of fibrosis and differences in various components or accompanying diseases in pancreatic fibrosis suggest that this entity shows two distinct pathologic patterns with differing mechanisms.

Histopathologic and Immunohistochemical Studies on the Mechanism of Interlobular Fibrosis of the Pancreas

OBJECTIVE To elucidate the mechanism of interlobular fibrosis of the pancreas, which is categorized as chronic alcoholic pancreatitis. METHODS Forty pancreatic tissue samples from patients with ampullary carcinomas, which cause various degrees of stricture of the main pancreatic duct, and 20 patients with chronic alcoholic pancreatitis were studied histopathologically and immunohistochemically. RESULTS Fibrosis was observed in 23 of 40 patients with ampullary carcinomas and was classified into 3 categories: mild changes (10 cases), moderate changes (9 cases), and marked changes (4 cases). In the mild change cases, mild fibrosis was diffusely distributed in the interlobular areas, with scant immunoreactivity of anti-alpha-smooth muscle actin (alpha-SMA) and an expansive lobular appearance, whereas moderate and marked change cases showed interlobular and intralobular fibrosis with marked anti-alpha-SMA immunoreactivity and lobular atrophy. By quantitative analysis, the mild change cases showed both higher MIB1-positive and lower apoptotic acinar cell ratios than those of moderate and marked changes. Anti-alpha-SMA immunoreactivity in the patients with chronic alcoholic pancreatitis was found in interlobular fibrosis. Hence, mild changes in cases of ampullary carcinomas had histologic findings similar to chronic alcoholic pancreatitis, except for excessive fibrosis cases with patchy distribution. CONCLUSION Incomplete obstruction of the main pancreatic duct caused the beginning of interlobular fibrosis, which is categorized as chronic alcoholic pancreatitis.

Pathology of autoimmune pancreatitis and tumor-forming pancreatitis

The most frequently recognized presentation of autoimmune pancreatitis (AIP) is that mimicking pancreatic cancer. It is also known that at some stage during the disease process chronic pancreatitis clinically presents as a tumorous swelling, often suspected of being a carcinoma. In Japan, this stage has also been proposed clinically to be tumor-forming pancreatitis. Hence, tumor-forming pancreatitis shows at least two distinct types: a reparative process for centriductal acute inflammation with a background of chronic pancreatitis, which is considered to have given rise to the tumor at some stage of chronic pancreatitis, and a lymphoplasmacytic infiltration with lymphoid and fibrous proliferation in normal pancreatic tissue, which corresponds to autoimmune pancreatitis. These tumorous lesions may be changeable along the disease process.

Expression of Transforming Growth Factor β by Small Duct Epithelium in Chronic, Cancer-associated, Obstructive Pancreatitis: An In Situ Hybridization Study and Review of the Literature

Objectives: Transforming growth factor β (TGF-β) is a dominant mediator of pancreatic fibrosis. The objective of this study was to identify cellular sources of TGF-β mRNA and compare the results with previous immunohistochemical/in situ hybridization studies. Methods: In situ hybridization of TGF-β was conducted for 9 human tissues of chronic obstructive pancreatitis (COP) and 2 control specimens. By classifying these 9 COP tissues into 3 fibrosis phases by the amount of fibrotic space, histopathologic changes were examined for each fibrosis phase. Whether or not TGF-β-positive cells were closely distributed to fibrosis was also investigated in control and COP cases. Results: Three cases were categorized in early, intermediate, and advanced stages of fibrosis. Transforming growth factor β mRNA was identified for a part of small duct epithelia, that is, intercalated ductule cells, centroacinar cells, and/or metaplastic ductal structures adjacent to acinar cells. The number of TGF-β-positive cells was greater in COP cases than in controls. In controls and in the early stage of fibrosis, no fibrosis was seen near TGF-β-positive cells. Conclusions: Small duct epithelia are the main cellular sources of TGF-β in COP, and many of them may be working for COP fibrosis either directly or indirectly.

Pre-existing histological type and developmental mechanism of mucinous noncystic carcinoma of pancreas

Eleven cases with mucinous noncystic carcinoma (MC) of the pancreas were studied by histology and mucin immunohistochemistry, to elucidate the mechanism, or route of development, and pre-existing histological type of MC of the pancreas. These MCs were observed in close approximation to, or surrounding, intraductal papillary-mucinous carcinomas (IPMCs), and were centrally situated among ductal adenocarcinomas (DAs). Hence, the 11 cases originated from 8 IPMCs and 3 DAs. The mechanism and routes to MC were divided into four types as follows: IPMC directly invaded the stroma (4 cases), over-production of mucin in IPMC expanded the branches of the pancreatic duct possibly resulting in rupture (3 cases), DA underwent extreme mucinous degeneration (3 cases), and a recurrent form, as MC, at the surgical stump of IPMC (one case). The outcomes of MC cases with IPMC had variable survival rates, while those from DA had short durations. MUC immunoreactivity in MC was divided into three categories; anti-MUC1-positive only (2 IPMCs, 2 DAs), mixed anti-MUC1 and anti-UC2-positive (3 IPMCs, one DA) and anti-MUC-positive only (3 IPMCs). Pre-existing MC histological types included both IPMC and DA. These two pre-existing types of MC involved mucin overproduction and mucinous degeneration. MUC immunoreactivity in MC revealed three patterns, which may be related to variable outcomes.