Intrahepatic Bile Duct Tumors Research Articles

Non-primary solid malignancies of breast in needle core biopsy: a clinicopathological analysis of 23 cases

Objective: To investigate the accurate diagnosis and differential diagnosis of non-primary solid malignant tumors in breast needle core biopsy. Methods: Twenty-three cases of breast, axilla or neck lymph nodes pathologically diagnosed as non-primary solid malignant tumors were collected at the First Affiliated Hospital of Nanjing Medical University, Nanjing, China from January 2013 to March 2023. The differential diagnoses and diagnostic features were analyzed, based on combining clinical data, histology, and expression characteristics of biomarkers. Results: All patients were female, with age ranging from 29 to 75 years (average 56 years). The average time from the diagnosis of primary tumor to the current diagnosis was 21 months (0 to 204 months).The primary sites included the ovary (9 cases), the lung (5 cases), the gastrointestinal tract (4 cases), the pancreas, intrahepatic bile duct, thyroid gland, nasal cavity and forearm skin (1 case each). No carcinoma in situ was found in any of the cases. The morphological differences were significant among the tumors, but similar to the primary tumors. The tumors of neuroendocrine and female reproductive tract had great morphological and immunophenotypic overlaps with breast cancer. Metastatic lung cancer cells showed obvious atypia and tumor giant cells. The morphology and immunophenotype of metastatic serous carcinoma of female reproductive system might resemble invasive micropapillary carcinoma of the breast. Metastatic adenocarcinoma of the gastrointestinal tract often had features of mucous secretion. Metastatic neuroendocrine tumors were bland in appearance and morphologically similar to solid papillary carcinoma of breast, but negative for ER. TRPS1 was mostly negative (18/23) and variably positive in ovarian (4/9) and intrahepatic bile duct (1/1) tumors. Conclusions: The diagnosis of breast needle core biopsy specimen should be combined with clinical history, imaging study, and careful examination of histological features, such as presence of in situ component, morphological similarity between the primary and metastatic tumors, and using appropriate markers to differentiate the primary from metastatic tumors.

PTH-114 Usefulness of pre-treatment serum CA19-9 concentration in prediction of prognosis for patients with intrahepatic bile duct tumours

Introduction Serum concentration of Carbohydrate Antigen 19-9 (CA19-9) has been related to survival of patients with Cholangiocarcinoma (CCA). We evaluated the cut-off value of serum CA19–9 to define predictive management strategies in patients with CCA. Method Three hundred and forty-one (341) Patients were retrospectively reviewed at a regional hepatobiliary centre in Liverpool, UK. The hospital integrated database was used to extract clinical and laboratory data. The receiver operating characteristic curve (ROC) of serum concentration of CA19–9 by location of tumour and type of treatment offered were assessed. The cut-off value of CA19–9 providing optimal prognosis was used to evaluate differences in survival of the patients using Kaplan-Meier survival log-rank test. Results One hundred and sixty-four (48%) patients had valid pre-treatment CA19–9 measurements. Among treatment groups; biliary stent was placed in 67(41%); surgical resection in 43 (26.2%); chemotherapy in 36 (22.0%); while 18 (11%) had supportive care. For site of lesion, ROC for CA19–9 was 0.74 (95% CI: 0.62–0.84; sensitivity: 80.9%; specificity: 60.0%, p = 0.0002). For prognosis of intrahepatic disease and ROC for hilar lesions was 0.62 (95% CI: 0.51–0.71; sensitivity: 90.2%; specificity: 36.1%, p = 0.05). By treatment modality, surgical resection showed significant relationship with pre-treatment CA19–9 value (ROC: 0.75; 95% CI: 0.60–0.87). Serum concentration of >34 IU/ml was defined as the cut-off predictive of prognosis for those who had surgical resection (sensitivity: 76.9% and specificity: 73.3%, p = 0.001). The median survival of patients who had surgical resection with serum CA19–9 >34 IU/ml was 18 months whereas for those with a value ≤34 IU/ml, 5 year survival was 80%. Conclusion Serum CA19–9 concentration is a useful predictor of prognosis in patients with intrahepatic lesions as well as those undergoing resection for IHBD tumours. Validation of this cut-off value requires further studies. Disclosure of interest None Declared.

Incidence and mortality of primary liver cancer in England and Wales: Changing patterns and ethnic variations

To explore recent trends, modes of diagnosis, ethnic distribution and the mortality to incidence ratio of primary liver cancer by subtypes in England and Wales. We obtained incidence (1979-2008) and mortality (1968-2008) data for primary liver cancer for England and Wales and calculated age-standardised incidence and mortality rates. Trends in age-standardised mortality (ASMR) and incidence (ASIR) rates and basis of diagnosis of primary liver cancer and subcategories: hepatocellular carcinoma, intrahepatic bile duct and unspecified liver tumours, were analysed over the study period. Changes in guidelines for the diagnosis of primary liver cancer (PLC) may impact changing trends in the rates that may be obtained. We thus explored changes in the mode of diagnosis as reported to cancer registries. Furthermore, we examined the distribution of these tumours by ethnicity. Most of the statistical manipulations of these data was carried out in Microsoft excel® (Seattle, Washington, United Sttaes). Additional epidemiological statistics were done in Epi Info software (Atlanta, GA, United Sttaes). To define patterns of change over time, we evaluated trends in ASMR and ASIR of PLC and intrahepatic bile duct carcinoma (IHBD) using a least squares regression line fitted to the natural logarithm of the mortality and incidence rates. We estimated the patterns of survival over subsequent 5 and 10 years using complement of mortality to incidence ratio (1-MIR). Age-standardised mortality rate of primary liver cancer increased in both sexes: from 2.56 and 1.29/100000 in 1968 to 5.10 and 2.63/100000 in 2008 for men and women respectively. The use of histology for diagnostic confirmation of primary liver cancer increased from 35.7% of registered cases in 1993 to plateau at about 50% during 2005 to 2008. Reliance on cytology as a basis of diagnosis has maintained a downward trend throughout the study period. Although approximately 30% of the PLC registrations had information on ethnicity, there was a relatively higher registration of the major tumour subtypes in patients whose ethnic backgrounds were from high incident regions of the world. Survival from PLC is estimated to get poorer in 10 years (2018) relative to 2008, particularly as a result of IHBD. Incidence and mortality of PLC, and particularly IHBD, have continued to rise in England and Wales. Changes in the modes of diagnosis may be contributing.

PWE-268 Recent trends in primary liver cancer in England and Wales

IntroductionMortality and incidence rates of Primary Liver Cancer (PLC) have been rising in England and Wales towards the end of the last century. The current trend and ethnic distribution of...

N-cadherin serves as diagnostic biomarker in intrahepatic and perihilar cholangiocarcinomas

As a definite immunoprofile of this tumor is missing, the histopathologic diagnosis of intrahepatic cholangiocarcinoma is difficult. The aim of this study was to explore E- and N-cadherin expressions in intrahepatic bile duct tumors, and to determine their potential interest in differential diagnosis. Normal liver tissue, 5 cirrhosis with ductular reaction, 5 focal nodular hyperplasia, 5 bile duct hamartomas, 5 bile duct adenomas, and 45 intrahepatic cholangiocarcinomas from Causasian patients were studied. Tissue-microarrays including 20 esophageal, 86 gastric, 8 small bowel, 64 colonic, 18 pancreatic, 6 gallbladder, and 7 extrahepatic biliary tract adenocarcinomas, 22 hepatocellular carcinomas, and normal tissues were constructed. Immunohistochemistry was performed using E-cadherin, N-cadherin, NCAM, Hep Par1, and cytokeratins 7, 19 and 20. Immunoblot analysis of frozen liver tissues was performed to control the specificity of E- and N-cadherin antibodies used. In normal liver, epithelial cells of intrahepatic bile ducts, whatever their caliber, as well as hepatocytes, coexpressed E- and N-cadherins at their plasma membranes. In cirrhosis, ductular reactions completely expressed E- and N-cadherins. All the benign lesions and 30 of the 45 intrahepatic cholangiocarcinomas (23/29 peripheral and 7/16 hilar) also expressed N-cadherin. E-cadherin was detected in all the lesions. The expression of N-cadherin at the plasma membrane of tumor cells was significantly more frequent in peripheral than in hilar intrahepatic cholangiocarcinomas (P=0.003). Among noncholangiocarcinomas, only 1% gastric and 66% gallbladder adenocarcinomas and all the hepatocellular carcinomas expressed N-cadherin at the membrane of tumor cells. Finally, for the diagnosis of intrahepatic cholangiocarcinomas, the specificity value of membranous expression of N-cadherin was 88%, whereas that of the combination cytokeratin 7/membranous N-cadherin was 98%. In the gastrointestinal and liver tract, membranous N-cadherin is restricted to the hepatocytes and intrahepatic biliary cells. In combination with cytokeratin 7 and Hep Par1, N-cadherin is a reliable tool for the histopathological diagnosis of primary hepatic tumors.

P53 mutations in human cholangiocarcinoma: a review

The reported mortality from intrahepatic bile duct tumours is increasing markedly in industrialised countries, for reasons that remain unknown. Inactivation of the tumour suppressor gene p53, is the commonest genetic abnormality in human cancer and has been implicated in the genesis of cholangiocarcinoma in various immunohistochemical and molecular epidemiological investigations, including gene sequencing studies. The structure and function of p53 and its role in linking cancer to specific carcinogens by way of mutational signatures is reviewed. The findings of previous p53 studies and their relevance in human cholangiocarcinoma are summarised.

Time trends in incidence and mortality for chronic liver disease and liver cancer in the interval 1980-1997 in Catalonia, Spain.

It has been reported that the incidence of liver cancer and intrahepatic bile duct tumours might be increasing in some developed countries. The purpose of this study was to examine time trends of incidence and mortality rates of liver cirrhosis and liver cancer for the period 1980-1997 in Catalonia, Spain. Data were obtained from the Catalan Mortality Registry and the Tarragona Cancer Registry. Joinpoint analysis was used to detect time-related changes in incidence and mortality of liver diseases. The cohort effect on mortality and incidence rates was explored by an age-period-cohort model. Mortality from liver cirrhosis decreased during the study period for both sexes and all age groups, with the exception of men aged between 25 and 35 years. No changes in incidence or mortality rates were observed for liver cancer. Mortality rates for intrahepatic bile duct tumours increased in men and women, while incidence rates remained stable. This study identified in Catalonia an increase in mortality due to liver cirrhosis among 25-35-year-old men. Mortality rates for intrahepatic bile duct tumours increased for all age groups and both sexes. The former could be related to hepatitis C or B viruses and human immunodeficiency virus co-infection, while the latter remains unexplained.

Transcriptional Activation of the MUC2 Gene by p53

MUC2 is one of the major components of mucins that provide a protective barrier between epithelial surfaces and the gut lumen. We investigated possible alterations of MUC2 gene expression by p53 and p21(Sdi1/Waf1/Cip1) in a human colon cancer cell line, DLD-1, establishing subclones in which a tetracycline-regulatable promoter controls exogenous p53 and p21 expression. MUC2 mRNA more significantly increased in response to p53 than to p21. Unexpectedly, MUC2 expression was also induced in human osteosarcoma cells, U-2OS and Saos-2, by exogenous p53. We next performed a reporter assay to test the direct regulation of MUC2 gene expression by p53. Deletion and mutagenesis of the MUC2 promoter region showed that it contains two sites for transactivation by p53. Furthermore, an electrophoretic mobility shift assay indicated that p53 binds to those elements. We analyzed MUC2 expression in other cell types possessing a functional p53 after exposure to various forms of stress. In MCF7 breast cancer and A427 lung cancer cells, MUC2 expression was increased along with the endogenous p53 level by actinomycin D, UVC, and x-ray, but not in RERF-LC-MS lung cancer cells carrying a mutated p53. These results suggest that p53 directly activates the MUC2 gene in many cell types.

Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998

BACKGROUNDThe age standardised mortality rate per 100 000 population for all causes of liver tumours (International Classification of Disease 9 (ICD-9) 155) has almost doubled in England and Wales during...

Anatomy and pathology of intrahepatic and extrahepatic bile duct tumors

Adenocarcinomas of the intra- and extrahepatic bile ducts are rare tumors that begin with malignant transformation of the bile duct epithelia. Intrahepatic cholangiocarcinomas derive from the small bile ducts located proximally to the right and left hepatic ducts. Extrahepatic bile duct carcinomas originate in the right or left hepatic duct, the cystic duct, or the choledochal duct. Tumors located at the bifurcation are called Klatskin tumors. The intrahepatic cholangiocarcinomas are classified according to the TNM classification of liver tumors, while the extrahepatic bile duct tumors have their own TNM classification. Several factors, accompanied by a chronic inflammatory reaction, have been discussed in the etiopathogenesis of these tumors: schistosomiasis, ulcerative colitis with primary sclerosing cholangitis, and inborn bile duct cysts of the liver as a consequence of a disturbance of the ductal plate formation. Over 95% of bile duct tumors are adenocarcinomas. In the nomenclature of precursor lesions a two-grade classification of dysplasia (low-grade versus high-grade) has been found to be more reproducible.

Expression of MUC1 and MUC2 mucin antigens in intrahepatic bile duct tumors: its relationship with a new morphological classification of cholangiocarcinoma.

Our previous immunohistochemical study on intrahepatic bile duct tumors showed that invasive cholangiocarcinoma (ICC) with a poor outcome expressed MUC1 mucin but was negative for MUC2 mucin, whereas bile duct cystadenocarcinoma (BDCC) with a favorable outcome was MUC1 negative and MUC2 positive. In the present study, ICC was further subdivided into 2 subtypes: intraductal growth type and/or periductal infiltrating type (ICC-IP) and mass forming type (ICC-M). The survival of patients with BDCC or ICC-IP is significantly better than that of patients with ICC-M. We examined these subtypes (ICC-IP and ICC-M) and BDCC for their expression of MUC1 mucins of different glycoforms. ICC-M showed significantly higher MUC1 expression rates (90%, 95%, and 85% positive rates as measured with the DF3, MY.1E12, and MUC1-Glycoprotein antibodies, respectively) than BDCC and ICC-IP (14% and 33%, 58% and 58%, and 0% and 50% positive respectively, as measured by the same antibodies). In contrast, BDCC (86% positive) and ICC-IP (67% positive) showed significantly higher MUC2 expression rates than ICC-M (25% positive) as measured with the anti-MRP antibody. Thus, the immunohistochemical staining pattern of ICC-IP resembled the pattern of BDCC more than they resembled ICC-M. In general, MUC1 expression is associated with poor patient outcome, irrespective of the glycosylation status. In particular, high expression of more sialylated forms of MUC1 mucins was correlated with poor survival. In contrast, expression of non-sialylated MUC2 mucin is a favorable prognostic indicator. These results suggest that ICC-IP is a different entity from ICC-M. This reclassification may have value in determining prognosis and treatment method.

Expression of mucin antigens in human cancers and its relationship with malignancy potential.

Mucins are high molecular weight glycoproteins having oligosaccharides attached to the apomucin protein backbone by O-glycosidic linkages. Biochemical studies on the structures and the organ specificities of several mucin core proteins (MUC1-MUC7) have been reported during the past several years. In the present study of pancreas and intrahepatic bile duct tumors, MUC1 mucin (membrane bound mucin detected by monoclonal antibody, DF3) was highly expressed in invasive ductal carcinomas of the pancreas (IDC) and invasive cholangiocarcinomas of the liver (ICC), which show invasive growth and a poor prognosis, but it was rarely expressed in intraductal papillary mucinous tumors of the pancreas (IPMT) and bile duct cystadenocarcinomas of the liver (BDCC), which show a favorable prognosis. In contrast, MUC2 mucin (intestinal type secretory mucin detected by polyclonal antibody, anti-MRP) was rarely expressed in IDC and ICC, whereas it was highly expressed in IPMT and BDCC. The results suggest that the differences in the expression of MUC1 and MUC2 mucins are a useful prognostic indicator of malignancy potential in the neoplasms of the pancreas and intrahepatic bile duct. Moreover, the expression of MUC1 and MUC2 mucins was a useful indicator of the malignancy potential of tumors derived from other organs, such as the ampulla of Vater, stomach and breast. In another study on the expression of several MUC1 mucin antigens with different patterns of glycosylation, sialylated-MUC1 mucin detected by monoclonal antibody, MY.1E12, was found to be expressed in all the invasive carcinomas (IDC and ICC) but was not frequently seen in the non-invasive type tumors (IPMT and BDCC), although the other types of MUC1 mucins did not show such contrast between the invasive and non-invasive type tumors. The results suggest that sialylation of MUC1 mucin is associated with invasive growth of neoplasms. In contrast, our study of the expression of MUC2 mRNA (transcript of intestinal type mucin) and MUC5AC mRNA (transcript of gastric type mucin) by in situ hybridization in the tumors of the pancreas and intrahepatic bile duct found that the non-invasive type tumors (IPMT and BDCC) synthesize MUC2 mRNA and MUC5AC mRNA, whereas most of the invasive carcinomas (IDC and ICC) do not. Furthermore, patients positive for MUC2 mRNA or MUC5AC mRNA expression in the tumors showed significantly better survival than the patients with no expression. The production of MUC2 or MUC5AC, an abundant extracellular intestinal or gastric type secretory mucin with high viscosity may be correlated, by a majority of the non-invasive type tumors, with the expansive growth of the tumors that display lower levels of invasion and metastasis.

K-ras gene mutations in intrahepatic bile duct tumors of Syrian golden hamsters.

In our laboratory, we have developed a new model of carcinoma of the bile duct in Syrian golden hamsters, using N-nitrosobis(2-oxopropyl)amine (BOP). Morphologic and biologic characteristics of the carcinoma induced in this model are similar to those seen in humans. In order to examine the gene-related carcinogenesis of intrahepatic bile duct carcinoma, we investigated mutations in the K-ras gene in various early hyperplastic and neoplastic lesions of these hamsters, according to the original sites of the lesions. Inbred female hamsters were given a subcutaneous injection of N-nitrosobis(2-oxopropyl)amine (BOP) following dissection of the extrahepatic bile duct on the distal end of the common duct and preparation of a cholecystoduodenostomy (CDDB) or simple laparotomy (SL). Neoplastic lesions arising from the intrahepatic bile duct were histologically examined, and K-ras mutations were investigated. Mutations of K-ras codon 12 were evident in 12% of tubular hyperplasias, 19% of tubular adenocarcinomas, 15% of papillary hyperplasias and 36% of papillary adenocarcinomas. In papillary adenocarcinoma arising from a large bile duct, K-ras mutations occurred more frequently than in tubular adenocarcinoma arising from ductule or ductular proliferation. K-ras mutations were present even in a hyperplasia; the positive rates of the mutations increased in the presence of a carcinoma. Genetic changes in carcinoma of the intrahepatic bile duct varied based on sites of the duct and the histological type. A part of the hyperplastic lesions of the intrahepatic bile duct presented K-ras gene mutation. This suggests that K-ras gene mutation is an early event in the carcinogenic process. In carcinoma of the intrahepatic bile duct, the lesion arising from a large bile duct of the hepatic hilum tended to exhibit a higher frequency of K-ras gene mutation than did a tubular lesion arising from ductule or ductal proliferation. This hamster model is useful to examine the carcinogenesis of human intrahepatic bile duct carcinoma.

Immunohistochemical studies of mucin antigens in pancreas and intrahepatic bile-duct tumors

Our previous studies of pancreatic and intrahepatic bile-duct tumors revealed that MUC2 mucin (“secretory mucin”, detected by a polyclonal antibody, anti-MRP) was highly expressed in intraductal papillary-mucinous tumors of the pancreas (IPMTs) and bile duct cystadenocarcinomas of the liver (BDCs) with expansive growth pattern and favorable prognosis, whereas it was rarely or not expressed in invasive ductal carcinomas of the pancreas (IDCs) and cholangiocarcinomas of the liver (CCs) with invasive growth pattern and poor prognosis. In contrast, MUC1 mucin (“membrane-bound mucin” detected by the monoclonal antibody, DF3) was rarely or not expressed in IPMTs and BDCs, but was always expressed in IDCs and CCs (Cancer 71:2191–2199, 1993;Int J Cancer 55:82–91, 1993). The results of these studies suggest that the difference in the expression of MUC1 and MUC2 mucins is a useful indicator of malignant potential in neoplasms of the pancreas and intrahepatic bile duct. This article is a review of our previous studies described above. In addition, we present longer-term follow-up data for the cases reported in our previous studies as well as demonstrating pathological prognostic factors, such as lymph node status, lymphatic infiltration, and perineural invasion. We also examined several additional cases of IPMTs and analyzed the same prognostic factors. We could confirmed the findings of our previous studies, and found that most IPMTs and BDCs with a MUC1(−) and MUC2(+) expression pattern showed less aggressive pathological factors than most IDCs and CCS with a MUC1(+) and MUC2(−) expression pattern.

Tumour induction in Syrian hamsters fed a combination of aminopyrine and nitrite.

Hamsters fed a aminopyrine/sodium nitrit mixture in drinking water showed a high incidence of intrahepatic bile duct tumours. Chenodeoxycholic acid was not found to have any promoting effect on the liver carcinogenicity induced by this combination of aminopyrine and sodium nitrit in hamsters.