Pancreaticobiliary maljunction and choledochal cysts: from embryogenesis to therapeutics aspects

Pancreaticobiliary maljunction (PBM) and choledochal cysts (CC) are rare and little-known diseases. Several definitions have been proposed for the PBM, but the most widely accepted is an excessive length of the common pancreaticobiliary duct due to the abnormal convergence of the pancreatic and biliary ducts out of the duodenal wall. This anomaly, thought to develop during embryogenesis, is associated with a loss of regulation of the Oddi’s sphincter leading to a pancreaticobiliary or biliopancreatic backflow. This reflux could be responsible, or associated with cystic dilatation of the bile ducts and biliary tract cancers, to various biliary or pancreatic events such as cholangitis or pancreatitis. For the diagnosis of PBM, magnetic resonance cholangiopancreatography has now become the gold standard as a noninvasive imaging tool. However, the main risk of PBM is the development of bile duct cancer, most often on a distended area. PBM without CC increase the occurrence of gallbladder cancer and require a preventive cholecystectomy. Surgical treatment of PBM with concomitant CC is more complex and depends on localization of the dilatation(s) as reported in the Todani’s classification. This review describes the pathogenesis, embryogenesis, clinical features, investigation and management of PBM and CC.     

胰胆管合流异常与肝外胆系癌的相关性探讨

目的　探讨胰胆管合流异常与肝外胆道系统癌（胆囊癌和肝外胆管癌）的相关性。 方法　回顾性分析2008年1月～2009年12月连续857例患者行磁共振胰胆管造影的临床及影像学资料,测量其胆胰汇合角度及共同管长度,确诊胰胆管合流异常67例。随机在790例不伴有胰胆管合流异常的病例中抽取78例为对照组,与67例胰胆管合流异常的病例行对照研究,分析胰胆管合流异常与肝外胆道系统癌的相关性。 结果　67例胰胆管合流异常的患者中发生胆系癌56.72%（38例),对照组中发生胆系癌 14.10% (11例),两组病例中胆系癌发生率存在显著性差异（χ2=22.27, P<0.05）。胰胆管合流异常并发胆系癌的病例中,胰胆管汇合类型对胆系癌的分化程度无显著影响（χ2=2.70, P>0.05）。 结论　胰胆管合流异常与肝外胆道系统癌发生有显著相关性,而胰胆管汇合类型对胆系癌的分化程度无显著影响。     

A Rare Case Report: Carcinoma Pancreas with Hepatocellular Carcinoma

Synchronous double malignancies involving different organs are relatively rare and uncommon finding. We report an interesting case of double malignancy in which a patient exhibited synchronous two separate carcinomas, pancreatic and hepatocellular carcinoma (HCC). Patient was a 64-year-old male who presented primarily with symptoms pertaining to the biliary obstruction and ultrasound of abdomen revealing pancreatic head mass. HCC was detected incidentally during the investigations for carcinoma pancreas.     

Histologic and genetic analysis of the gallbladder in patients with occult pancreatobiliary reflux

Recent studies have suggested that pancreatobiliary reflux occurs not only in patients with pancreaticobiliary maljunction (PBM), but also in patients without PBM and thereby possibly causes biliary tract disease. In this study, we examined prospectively histological findings and genetic analysis in the non-cancerous epithelium of the gallbladder in patients with high biliary amylase levels and a normal pancreaticobiliary junction. Ki-67 L.I of non-cancerous epithelium was 14.4 and 3.5% in the high biliary amylase levels (HBA) group and the low biliary amylase levels (LBA) group, respectively (p<0.01). There was no case showing p53 overexpression regardless of amylase levels of bile. COX-2 expression was detected in the cytoplasm of non-cancerous epithelium in 9 cases in the HBA group and 5 cases in the LBA group. The positive rate of COX-2 overexpression was significantly higher in the HBA group than in the LBA group (p<0.05). COX-2 overexpression cases showed higher Ki-67 L.I than COX-2 non-overexpression cases (21.2 vs. 7.9%, p<0.05). Mutations of the K-ras gene were detected in non-cancerous gallbladder epithelium in 3 cases, only in the HBA group. Patterns of K-ras mutation at codon 12 were GAT in two cases and GTT in one case. Three cases showing COX-2 overexpression also showed K-ras mutation. These three cases showing K-ras mutation had comparatively high cellular proliferative activity (28, 26 and 14%). In conclusion, our data suggest that occult pancreaticobiliary reflux, especially with high biliary amylase levels, represents an important risk factor for the development of gallbladder carcinoma as well as PBM, and it may be possible to detect patients with such high biliary amylase levels by ERCP.     

Carcinoma in situ of the cystic duct

Cholelithiasis and cholesterolosis associated with carcinoma in situ of the cystic duct epithelium was observed in a male patient. Ultrastructurally, small acini-like lined a thickened, reduplicated basal lamina encompassing a pleiomorphic population of cells, including typical chole-cystocytes, a poorly differentiated type, and cells containing modified mucous vesicles with heterogeneous fatty deposits. Even though the etiology of this apparent neoplastic epithelium and of its thickened basal lamina is unclear, it is hypothesized to be the result of an altered control of cell adhesion mechanisms, resulting from a repeated renewal of the typical epithelium abraded by the passage of the stones and the biliary sludge, associated with inflammatory stimuli that accompany cholecystolithiasis. Based on recent studies, it is suggested that investigations of molecular markers in extrahepatobiliary tract lesions and retrospective studies of these archival tissues could clarify the association of these neoplastic changes with other hepato-biliary lesions.     

The PDZ domain binding motif (PBM) of human T-cell leukemia virus type 1 Tax can be substituted by heterologous PBMs from viral oncoproteins during T-cell transformation

Several tumor viruses, such as human T-cell leukemia virus (HTLV), human papilloma virus (HPV), human adenovirus, have high-oncogenic and low-oncogenic subtypes, and such subtype-specific oncogenesis is associated with the PDZ-domain binding motif (PBM) in their transforming proteins. HTLV-1, the causative agent of adult T-cell leukemia, encodes Tax1 with PBM as a transforming protein. The Tax1 PBM was substituted with those from other oncoviruses, and the transforming activity was examined. Tax1 mutants with PBM from either HPV-16 E6 or adenovirus type 9 E4ORF1 are fully active in the transformation of a mouse T-cell line from interleukin-2-dependent growth into independent growth. Interestingly, one such Tax1 PBM mutant had an extra amino acid insertion derived from E6 between PBM and the rest of Tax1, thus suggesting that the amino acid sequences of the peptides between PBM and the rest of Tax1 and the numbers only slightly affect the function of PBM in the transformation. Tax1 and Tax1 PBM mutants interacted with tumor suppressors Dlg1 and Scribble with PDZ-domains. Unlike E6, Tax1 PBM mutants as well as Tax1 did not or minimally induced the degradations of Dlg1 and Scribble, but instead induced their subcellular translocation from the detergent-soluble fraction into the insoluble fraction, thus suggesting that the inactivation mechanism of these tumor suppressor proteins is distinct. The present results suggest that PBMs of high-risk oncoviruses have a common function(s) required for these three tumor viruses to transform cells, which is likely associated with the subtype-specific oncogenesis of these tumor viruses.     

Production of interleukin 2 by human lymph nodes

Perigastric lymph node cells (LNC) from patients with gastric carcinoma or benign lesions were tested for interleukin 2 (IL 2) production upon stimulation with phytohemagglutinin (PHA), in comparison with that of peripheral blood mononuclear cells (PBM) or spleen cells (SPC). IL 2 activity in the supernatants of LNC cultures from patients with either carcinoma or benign lesions was significantly higher than that of PBM cultures from the same person. There was no significant difference in IL 2 activity between PBM cultures or LNC cultures from patients with carcinoma and patients with benign lesions. Supernatants from LNC cultures were also more active than those obtained from SPC cultures. The production of interleukin 1 (IL 1) in LNC was lower than that in PBM. In LNC, the proportion of OKT3+ cells was similar to that found in PBM, with a prevalence of OKT4+ cells over OKT8+ cells. No differences were found between lymphatic cells from patients with carcinoma and from patients having benign lesions.     

Thrombosis and Pancreatic Carcinoma Revisited

A case of recurrent pulmonary embolism from thrombophlebitis associated with pancreatic carcinoma is reported. There is an increased incidence of thrombophlebitis with all tumors, but carcinoma of the pancreas is statistically more frequently responsible. The higher incidence of thrombophlebitis with tumors of the body and tail of the pancreas is probably due to the low trypsin levels associated with these tumors. Trypsin levels are directly related to plasma antithrombin levels and mucinous adenocarcinomas are more commonly associated with thrombus formation.     

Biliary stricture due to hepatocellular carcinoma: Diagnosis by bile duct brushing cytology

Bile duct brushing cytology is a useful technique in the diagnosis of malignant biliary strictures. Adenocarcinoma is the usual type of carcinoma diagnosed in these brushing specimens. This report details the bile duct brushing cytology findings in an unusual case of hepatocellular carcinoma which presented with obstructive jaundice due to invasion of the biliary tract. A striking feature of the brushing was the prominent capillary vascular pattern associated with the tumor cells. This is a cytologic feature which has been noted in fine-needle aspirates of hepatocellular carcinoma as well, and is distinct from the expected findings in adenocarcinoma. Diagn. Cytopathol. 16:55–56, 1997. © 1997 Wiley-Liss, Inc.     

Expression of MUC1 and MUC2 and carbohydrate antigen Tn change during malignant transformation of biliary papillomatosis

AIM: Biliary papillomatosis is characterized by papillary proliferations of biliary lining cells without invasion or metastasis. The neoplastic character and biological behaviour of this disease remain still speculative. These issues were examined in this study. METHODS AND RESULTS: Mucin core protein MUC1, MUC2, MUC3, MUC5AC and carbohydrate antigens (T, Tn and sialosyl Tn) were immunohistochemically examined, using 11 lesions of biliary papillomatosis from seven patients, and five lesions of biliary papillomatosis with foci of carcinoma from four patients. Five cases of papillary intrahepatic cholangiocarcinoma and 12 histologically normal livers were used as a control. Patients with biliary papillomatosis alone or with carcinoma were middle-aged or elderly (five men and six women). Microscopically, biliary papillomatosis showed a villous, papillo-tubular, papillary, or papillo-villous pattern with a thin fibrovascular core. Cytologically, they were classifiable into biliary epithelial or pyloric gland-like type. The former was frequent in the cases associated with carcinoma. Expression of MUC1, Tn antigen and sialosyl Tn antigen was frequent and marked in biliary papillomatosis alone and with carcinoma and also intrahepatic papillary carcinoma. In addition, marked expression of MUC1 and Tn antigen were rather frequent in biliary papillomatosis with carcinoma and intrahepatic biliary papillary carcinoma compared with biliary papillomatosis. MUC2 was rather frequent and marked in biliary papillomatosis alone compared to other two disease groups. Focal expression of MUC5AC and MUC2 was rather frequent and infrequent irrespective of disease group, respectively. Focal expression of T antigen was frequent in papillary ICC. CONCLUSION: Biliary papillomatosis could undergo overt malignant transformation along with altered phenotypic expression of MUC proteins and mucin carbohydrate antigens.     

Enhanced production of interleukin 1 and tumor necrosis factor by peripheral monocytes after lentinan administration in patients with gastric carcinoma.

The effect of intravenous administration of lentinan, an immunopotentiating polysaccharide, on the production of interleukin 1-alpha (IL 1-alpha), interleukin 1-beta (IL 1-beta) and tumor necrosis factor-alpha (TNF-alpha) by monocytes in peripheral blood mononuclear cells (PBM) was studied in patients with gastric carcinoma. Peripheral blood samples were obtained from 10 patients before and 3, 5 and 7 days after a single dose of 2 mg lentinan injection. The ability of monocytes in PBM to produce IL 1-alpha was significantly augmented 3 and 5 days after lentinan administration, as compared with that before treatment. IL 1-beta production was also significantly increased 3, 5 and 7 days after the drug injection. Further, the capacity to produce TNF-alpha was significantly enhanced 3, 5 and 7 days after the drug administration. Thus, it is likely that the augmentation of these cytokine's production may contribute to the antitumor action of lentinan in patients with gastric carcinoma.     

Carcinoma of the extrahepatic biliary tract: a clinicopathological and immunohistochemical study

The clinical and histological findings in 15 cases of carcinoma arising from the extrahepatic biliary tract are reviewed. The clinical findings are in agreement with previously reported series and the dismal prognosis is confirmed. The prognosis does not appear to be related to tumour size, site, mitotic count or laboratory data on presentation. Only histological grading of the tumour is related to prognosis. Perineural tumour infiltration was a prominent feature and dysplasia within adjacent bile duct epithelium was present in five cases. The value of carcinoembryonic antigen (CEA) as a histological tumour marker was investigated. All tumours from the upper and middle biliary tree expressed this antigen. Although immunocytochemistry is seldom needed to assess malignancy in large surgical resection specimens anti-CEA helps delineate the extent of tumour infiltration and discriminates between normal and dysplastic or malignant epithelium; anti-CEA may also be helpful in identifying foci of malignancy in small sclerotic biopsy specimens.     

Double common bile duct with ectopic drainage into the stomach. Case report and review of the literature

Abstract: A rare abnormal biliary tract consisting in a double common bile duct with an ectopic biliary tree draining into the stomach is described. This congenital anomaly, associated with lithiasis in the ectopic duct, was detected for the first time on MR-cholangiopancreatography. Only 23 cases of abnormal biliary drainage into the stomach have been reported in the literature. Embryogenesis and potential risks, such as lithiasis in the ectopic duct and the development of gastric carcinoma, are discussed.     

Solid Adenosquamous Carcinoma of the Liver A Case Report and Review of the Literature

This is a report of a fatal case of a primary and solid adenosquamous carcinoma (ASC) of the liver in a 58-yearold Japanese woman. There was no association with biliary cysts. Histochemistry and immunohistochemistry support the contention that the neoplasm arose from squamous metaplasia of a mucus-secreting adenocarcinoma (MSA) of intrahepatic biliary duct epithelium.     

Squamous Differentiation in Thyroid Carcinoma With Special Reference to Histogenesis of Squamous Cell Carcinoma of the Thyroid

Squamous differentiation of thyroid carcinoma was studied clinicopathologically and immunohistochemically in 29 autopsy cases. Tumor cell nests with squamous differentiation (CNSD), which histologically resembled squamous cell carcinoma, were found in 6 cases (20.7%). All of these 6 cases with CNSD had areas of undifferentiated carcinoma, representing 31.6% of 19 cases with undifferentiated carcinoma, and all but one case also showed coexisting papillary carcinoma. The CNSD were histologically associated with undifferentiated carcinoma in 5 cases, and with papillary carcinoma in one case; the CNSD were occasionally intermingled with these types of carcinoma, and there were findings suggesting a histological transition between the CNSD and undifferentiated carcinoma or papillary carcinoma. Immunohistochemistry revealed that all the CNSD were reactive with antibodies for keratin and vimentin, whereas thyroglobulin and desmin were not expressed. It was concluded that the CNSD examined here were most probably due to extensive squamous differentiation (squamous metaplasia) in undifferentiated carcinoma and papillary carcinoma. In addition, the present results may explain the fact that cases diagnosed solely as squamous cell carcinoma sometimes show a prognosis similar to that of undifferentiated carcinoma, and may well represent extensive squamous differentiation in such tumors rather than true squamous cell carcinoma of the thyroid. Acta Pathol Jpn 39: 306 312, 1989.     

Carcinoma of the breast with choriocarcinomatous features

Choriocarcinomatous differentiation has been described in tumors arising from many organs including lung, rectum, colon, stomach, bladder, and rarely breast. Mammary carcinoma with choriocarcinomatous features is a rare variant of breast metaplastic carcinoma characterized by malignant cells morphologically resembling choriocarcinoma cells in which reactivity with human placental lactogen and human chorionic gonadotropin can be demonstrated by immunohistochemistry. The characteristic syncytiotrophoblast-like giant cells seen in these neoplasms are more commonly associated with moderately to poorly differentiated carcinomas with or without a clear-cut mesenchymal component. Most of the reported cases have behaved very aggressively. The reason for this poor prognosis remains unclear. Because of the small number of cases, special treatment protocols have not been developed and these patients are treated surgically and with the standard chemotherapeutic agents available for other types of carcinoma of the breast. Pathologically, these tumors must be distinguished from metastatic choriocarcinoma to the breast.     

Different carcinogenic process in cholangiocarcinoma cases epidemically developing among workers of a printing company in Japan

Recently, cholangiocarcinoma has epidemically developed among young adult workers of a printing company in Japan. Exposure to organic solvents including 1,2-dichloropropane and/or dichloromethane is supposed to be associated with the carcinoma development. The metabolism of dichloromethane proceeds through a Theta-class glutathione S-transferase (GST) T1-1-catalyzed pathway, where its reactive intermediates have been implicated in genotoxicity and carcinogenicity. This study examined features of the carcinogenic process of the cholangiocarcinoma developed in the printing company. Surgically resected specimens of the cholangiocarcinoma cases were analyzed, where all cases were associated with precursor lesions such as biliary intraepithelial neoplasia (BilIN) and/or intraductal papillary neoplasm of the bile duct (IPNB). Immunohistochemical analysis confirmed constitutional expression of GST T1-1 in normal hepatobiliary tract. Immunostaining of γ-H2AX, a marker of DNA double strand break, showed that its expression was significantly increased in foci of BilIN, IPNB and invasive carcinoma as well as in non-neoplastic biliary epithelial cells of the printing company cases when compared to that of control groups. In the printing company cases, immunohistochemical expression of p53 was observed in non-neoplastic biliary epithelial cells and BilIN-1. Mutations of KRAS and GNAS were detected in foci of BilIN in one out of 3 cases of the printing company. These results revealed different carcinogenic process of the printing company cases, suggesting that the exposed organic solvents might act as a carcinogen for biliary epithelial cells by causing DNA damage, thereby contributing to the carcinoma development.     

Enhanced induction of lymphokine-activated killer activity after lentinan administration in patients with gastric carcinoma.

In 15 patients with gastric carcinoma, peripheral blood mononuclear cells (PBM) were obtained serially before and 3, 5 and 7 days after lentinan administration. The generation of lymphokine-activated killer (LAK) activity, induced by in vitro activation of PBM with interleukin 2 (IL 2), was significantly augmented 5 days after a single intravenous dose of 2 mg lentinan, when compared with that before lentinan injection. Natural killer (NK) activity of PBM was also significantly enhanced 7 days after the drug injection. However, the distribution of lymphocyte subsets exhibited no significant change following lentinan administration.     

DNA Copy Number Changes in Thyroid Carcinoma

The genetic changes leading to thyroid cancer are poorly characterized. We studied DNA copy number changes by comparative genomic hybridization (CGH) in 69 primary thyroid carcinomas. In papillary carcinoma, DNA copy number changes were rare (3 of 26, 12%). The changes were all gains, and they were associated with old age (P = 0.01) and the presence of cervical lymph node metastases at presentation (P = 0.08). DNA copy number changes were much more frequent in follicular carcinoma (16 of 20, 80%) than in papillary carcinoma (P < 0.0001), and follicular carcinomas had more often deletions (13/20 versus 0/26, P < 0.0001). Loss of chromosome 22 was common in follicular carcinoma (n = 7, 35%), it was more often seen in widely invasive than in minimally invasive follicular carcinoma (54% versus 0%, P = 0.04), and it was associated with old age at presentation (P = 0.01). In three of the four patients with follicular carcinoma who died of cancer, the tumor had loss of chromosome 22. DNA copy number changes were found in 5 (50%) of the 10 medullary carcinomas studied. Four of these five carcinomas had deletions, and in two of them there was deletion of chromosome 22. Eleven (85%) of the thirteen anaplastic carcinomas investigated had DNA copy number changes, of which five had deletions, and one had deletion of chromosome 22. The most common gains in anaplastic carcinoma were in chromosomes 7p (p22-pter, 31%), 8q (q22-qter, 23%), and 9q (q34-qter, 23%). We conclude that DNA copy number changes are frequent in follicular, medullary, and anaplastic thyroid carcinoma but rare in papillary carcinoma when studied by CGH. Loss of chromosome 22 is particularly common in follicular carcinoma, and it is associated with the widely invasive type.     

Differential Expression of VLAβ1 (CD29) on Monocytes From Patients With Endometriosis

PROBLEM : Previous studies have established that in vitro proliferation of endometrial cells is enhanced by peripheral blood monocytes (PBM) and suppressed by peritoneal macrophages (PM) from patients with endometriosis but only suppressed by PBM and PM obtained from normal subjects. The functional activity of PBM and PM is influenced by the engagement of numerous cell surface receptors with their respective physiological ligands. METHOD : In this study, PBM and PM from fertile women (Group 1), women with unexplained infertility (Group 2), and women with limited (Group 3) or severe (Group 4) endometriosis were isolated in order to analyze these cells for the expression of CD54, CD58 and HLA-DR (immunoglobulin supergene antigens) CD18 and CD29 (integrins) and CD44 (an addresin). These cell surface antigens are involved in monocyte/macrophage trafficking, activation, signal transduction and/or adhesion. RESULTS : No differences were detected in the percentage of PBM expressing CD18, CD44, CD54, CD58, or HLA-DR among the four groups of subjects. Furthermore, the density of these antigens expressed on PBM was identical in patients and control subjects. In contrast, the percentage of PBM expressing CD29 (also known as VLAβ1) and the density of CD29 expressed per cell were significantly reduced (P < 0.01) in patients with limited endometriosis compared to controls and patients with severe disease. Interestingly, although the percentage of CD29+ PBM from women with severe endometriosis was not statistically different from the percentage of CD29+ PBM from controls, the density of CD29 expressed per cell was significantly elevated among patients with severe disease. Analysis of PM from the four subject groups revealed no differences in CD29 expression or density. However, the percentage of PM expressing CD18 was significantly decreased in patients with limited (but not severe) endometriosis. CONCLUSION : Since both CD18 and CD29 play a role in cell trafficking and/or adhesion, alterations in their expression among patients with endometriosis suggest that these integrin β chains may play a role in the pathogenesis of the disease.