Common Cholangiocarcinoma Research Articles

Transcriptome analysis of human cholangiocytes exposed to carcinogenic 1,2-dichloropropane in the presence of macrophages in vitro

1,2-Dichloropropane (1,2-DCP), a synthetic organic solvent, has been implicated in causality of cholangiocarcinoma (bile duct cancer). 1,2-DCP-induced occupational cholangiocarcinoma show a different carcinogenic process compared to common cholangiocarcinoma, but its mechanism remains elusive. We reported previously that exposure of MMNK-1 cholangiocytes co-cultured with THP-1 macrophages, but not monocultured MMNK-1 cholangiocytes, to 1,2-DCP induced activation-induced cytidine deaminase (AID) expression, DNA damage and ROS production. The aim of this study was to identify relevant biological processes or target genes expressed in response to 1,2-DCP, using an in vitro system where cholangiocytes are co-cultured with macrophages. The co-cultured cells were exposed to 1,2-DCP at 0, 0.1 or 0.4 mM for 24 h, and then the cell lysates were assessed by transcriptome analysis. 1,2-DCP upregulated the expression of base excision repair genes in MMNK-1 cholangiocytes in the co-cultures, whereas it upregulated the expression of cell cycle-related genes in THP-1 macrophages. Activation of the base excision repair pathway might result from the previously observed DNA damage in MMNK-1 cholangiocytes co-cultured with THP-1 macrophages, although involvement of other mechanisms such as DNA replication, cell death or other types of DNA repair was not disproved. Cross talk interactions between cholangiocytes and macrophages leading to DNA damage in the cholangiocytes should be explored.

Intraductal Papillary Adenocarcinoma Of The Bile Duct With Associated Invasive Neuroendocrine Component: Case Report

Abstract Casestudy Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma that is characterized by intraductal growth and better outcomes compared with common cholangiocarcinoma. IPNBs are mainly found in patients from Far Eastern countries, where hepatolithiasis and clonorchiasis are endemic. Approximately 40%-80% of IPNBs are associated with invasive carcinoma. The invasive carcinomas are most often tubular or mucinous type. Invasive neuroendocrine component has not been previously described. We present a case of 69 year-old African American male who presented with worsening abdominal pain and jaundice over few months. Computed tomography showed 4 cm mass near the porta hepatis with massive ductal dilatation. A fine needle aspiration of the mass was performed and a diagnosis of adenocarcinoma was made. Subsequently, the patient underwent Right Trisegmentectomy. Conclusion Histologic sections revealed intraductal papillary neoplasm in the bile duct lumina. The papillae were lined by columnar epithelial cells with delicate fibrovascular cores. The tumor cell nuclei were slightly elongated, hyperchromatic and basally located without significant multilayering. The cytoplasm was eosinophilic with occasional intestinal differentiation. Frank invasion of the stalk and underlying periductular tissues was identified. Interestingly; the invasive component had different cytological features than the intraductal component, it was composed of small to medium sized cells with granular cytoplasm. The nuclei were uniform and round with “salt and pepper” chromatin. The invasive component stained positively for the neuroendocrine markers (Synaptophysin, Chromogranin and CD56), whereas the intraductal component stained positively for CK7, CK20 and CDX2 and negative for neuroendocrine markers. Three years later, a recurrent tumor was found in the left lobe on imaging. Biopsy of the lesion showed metastatic neuroendocrine carcinoma. The intraductal papillary neoplasm with invasive neuroendocrine component is very unusual tumor, we think more studies are warranted to best evaluate the treatment options and the prognosis of such neoplasms.

Probing the Tumor Suppressor Function of BAP1 in CRISPR-Engineered Human Liver Organoids.

The deubiquitinating enzyme BAP1 is a tumor suppressor, among others involved in cholangiocarcinoma. BAP1 has many proposed molecular targets, while its Drosophila homolog is known to deubiquitinate histone H2AK119. We introduce BAP1 loss-of-function by CRISPR/Cas9 in normal human cholangiocyte organoids. We find that BAP1 controlsthe expression of junctional and cytoskeleton components by regulating chromatin accessibility. Consequently, we observe loss of multiple epithelial characteristics while motility increases. Importantly, restoring the catalytic activity of BAP1 in the nucleus rescues these cellular and molecular changes. We engineer human liver organoids to combine four common cholangiocarcinoma mutations (TP53, PTEN, SMAD4, and NF1). In this genetic background, BAP1 loss results in acquisition of malignant features upon xenotransplantation. Thus, control of epithelial identity through the regulation of chromatin accessibility appears to be a key aspect of BAP1's tumor suppressor function. Organoid technology combined with CRISPR/Cas9 provides an experimental platform for mechanistic studies of cancer gene function in a human context.

18F-FDG PET/CT may be a suitable method for preoperative diagnosis and evaluation of Chinese older patients with hilar cholangiocarcinoma

BackgroundAs the most common cholangiocarcinoma, hilar cholangiocarcinoma (HCCA) is a challenge in hepatobiliary surgery and causes a very poor prognosis. This study was designed to explore whether 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) may be a suitable method for preoperative diagnosis and evaluation of Chinese older patients with hilar cholangiocarcinoma.MethodsThis study enrolled 53 patients (≥ 65 years) with HCCA. 18F-FDG PET/CT scan was performed in all patients within one week before operation.Results18F-FDG PET/CT identified the tumors in all patients (100%). There were 48 patients (90.6%) with the same Bismuth-Corlette classifications determined by 18F-FDG PET/CT and operative pathology, whereas Bismuth-Corlette classifications of 5 patients (9.4%) were underestimated by 18F-FDG PET/CT compared with that determined by operative pathology. 18F-FDG PET/CT identified 19 patients (sensitivity: 67.9%) in 28 patients with lymph node metastases, and 22 patients (specificity: 88.0%) in 25 patients without lymph node metastases, with an accuracy of 77.4%. 18F-FDG PET/CT identified 8 patients (sensitivity: 47.1%) in 17 patients with liver, peritoneal or other distant metastases, and 35 patients (specificity: 97.2%) in 36 patients without liver, peritoneal or other distant metastases, with an accuracy of 81.1%. 18F-FDG PET/CT identified 17 patients (sensitivity: 73.9%) in 23 patients with unresectable tumors, and 24 patients (specificity: 80.0%) in 30 patients with resectable tumors, with an accuracy of 77.4%.Conclusions18F-FDG PET/CT may be a suitable method for preoperative diagnosis and evaluation, and offer valuable information for effective operation in Chinese older patients with HCCA.

Diagnosis and treatment of intraductal papillary neoplasm of the bile duct

Intraductal papillary neoplasm of the bile duct (IPNB) is a rare tumor arising from epithelia of bile duct, with a better prognosis compared with common cholangiocarcinoma. IPNB can occur anywhere along the biliary tree, and cause the dilation of the bile duct and acute cholangitis. Recent large case series of this peculiar disease in the far eastern countries showed greater incidences of hepatolithiasis and clonorchiasis compared with Western series. According to the immunochemistry features, IPNB can be classified into four subtypes, pancreaticobiliary, intestinal, gastric and oncocytic types. The pancreaticobiliary type is the most common and is usually associated with invasive lesions. Patients without distant metastasis can undergo surgical resection, surgical procedures include pancreaticoduodenectomy, hemihepatectomy, segmental liver resection and liver transplantation, and regional lymphectomy is necessary. Key words: Bile tract neoplams; Papillary neoplasms; Diagnosis; Therapy

CXCL7 promotes proliferation and invasion of cholangiocarcinoma cells

CXCL7 is an important chemoattractant cytokine, which signals through binding to its receptor CXCR2. Recent studies have demonstrated that the CXCL7/CXCR2 signaling plays a promoting role in several common malignancies, including lung, renal, colon, and breast cancer. However, the regulatory role of CXCL7, in cholangiocarcinoma, as well as the underlying mechanism, has not been previously reported. Herein, we found more positive expression of CXCL7 in cholangiocarcinoma tissues compared to adjacent non-tumor tissues. High CXCL7 expression was significantly correlated with poor differentiation, lymph node metastasis, vascular invasion and advanced clinical stage, but was not associated with age, gender, or tumor size. Besides, the expression of CXCL7 was significantly associated with the Ki67 expression, but not associated with CA199, AFP, or P53 expression in cholangiocarcinoma. Moreover, the overall survival of cholangiocarcinoma patients with high CXCL7 expression was significantly shorter than those with low CXCL7 expression. Invitro study indicated that CXCL7 and CXCR2 were also positively expressed in several common cholangiocarcinoma cell lines, including HuCCT1, HuH28, QBC939, EGI-1, OZ and WITT. SiRNA-induced inhibition of CXCL7 significantly reduced the proliferation and invasion of QBC939 cells. On the contrary, overexpression of CXCL7 markedly promoted these malignant phenotypes of QBC939 cells. Of note, the conditioned medium of CXCL7-overexpresing human hepatic stellate cells could also promote the proliferation and invasion of QBC939 cells, suggesting that CXCL7 may also play an oncogenic role in cholangiocarcinoma in a paracrine-dependent manner, not only in an autocrine-dependent manner. Molecular assay data suggested that the AKT signaling pathway was involved in the CXCL7-mediated malignant phenotypes of QBC939 cells. In summary, our study suggests that CXCL7 plays a promoting role in regulating the growth and metastasis of cholangiocarcinoma.

Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes.

Cholangiocarcinoma is a relatively rare cancer, but its incidence is increasing worldwide. Although several risk factors have been suggested, the etiology and pathogenesis of the majority of cholangiocarcinomas remain unclear. Recently, a high incidence of early-onset cholangiocarcinoma was reported among the workers of a printing company in Osaka, Japan. These workers underwent high exposure to organic solvents, mainly haloalkanes such as 1,2-dichloropropane (1,2-DCP) and/or dichloromethane. We performed whole-exome analysis on four cases of cholangiocarcinoma among the printing workers. An average of 44.8 somatic mutations was detected per Mb in the genome of the printing workers' cholangiocarcinoma tissues, approximately 30-fold higher than that found in control common cholangiocarcinoma tissues. Furthermore, C:G-to-T:A transitions with substantial strand bias as well as unique trinucleotide mutational changes of GpCpY to GpTpY and NpCpY to NpTpY or NpApY were predominant in all of the printing workers' cholangiocarcinoma genomes. These results were consistent with the epidemiological observation that they had been exposed to high concentrations of chemical compounds. Whole-genome analysis of Salmonella typhimurium strain TA100 exposed to 1,2-DCP revealed a partial recapitulation of the mutational signature in the printing workers' cholangiocarcinoma. Although our results provide mutational signatures unique to occupational cholangiocarcinoma, the underlying mechanisms of the disease should be further investigated by using appropriate model systems and by comparison with genomic data from other cancers.

Intraductal papillary neoplasm of the bile duct

Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma that is characterized by intraductal growth and better outcomes compared with common cholangiocarcinoma. IPNBs are mainly found in patients from Far Eastern areas, where hepatolithiasis and clonorchiasis are endemic. According to the immunohistochemical profiles of the mucin core proteins, IPNBs are classified into four types: pancreaticobiliary, intestinal, gastric, and oncocytic. Approximately 40%-80% of IPNBs contain a component of invasive carcinoma or tubular or mucinous adenocarcinoma, suggesting that IPNB is a disease with high potential for malignancy. It is difficult to make an accurate preoperative diagnosis because of IPNB's low incidence and the lack of specificity in its clinical manifestation. The most common abnormal preoperative imaging findings of IPNB are intraductal masses and the involvement of bile duct dilation. Simultaneous proximal and distal bile duct dilation can be detected in some cases, which has diagnostic significance. Cholangiography and cholangioscopy are needed to confirm the pathology and demonstrate the extent of the lesions. However, pathologic diagnosis by biopsy cannot reflect the actual stage in many cases because different foci may be of different stages and because mixed pathologic findings may exist in the same lesion. Surgical resection is the major treatment. Systematic cholangioscopy with staged biopsies and frozen sections is recommended during resection to ensure that no minor tumors are left and that curative resection is achieved. Staging, histologic subtype, curative resection and lymph node metastasis are factors affecting long-term survival.

Adenosquamous carcinoma of the liver

The clinicopathologic characteristics, biologic behavior, and histogenesis of primary adenosquamous carcinoma (ASC) of the liver have yet to be fully clarified. Eight cases of ASC of the liver were analyzed both clinicopathologically and immunohistochemically using antibodies of cytokeratin (CK) 7, CK 8, CK 18, CK 19, and CK 903 (CK 5, CK 10, CK 11, and CK 14). The survival curve of the 6 patients with surgically resected ASC was compared with that of the 32 patients with common cholangiocarcinoma (CC). Most ASCs had invasive pathologic features, including venous invasion, lymphatic permeation, and intrahepatic metastases. There were lymph node metastases from 7 tumors (88%), and most of the metastases were adenocarcinoma. All adenocarcinoma (AC) components were positive for both CK 7 and CK 19. The squamous cell carcinoma (SCC) components were positive for CK 7 in all cases but were positive for CK 19 in only 5 cases (62.5%). The ACs were positive for CK 903 in only 3 cases (37.5%), whereas all SCCs were positive for CK 903. Almost all ACs were positive for both CK 8 and CK 18, whereas the SCCs were positive for CK 8 in only 3 cases (37.5%) and for CK 18 in no cases. All 6 patients with surgically resected ASC died of the disease within 1 year postoperatively. Their survival curve was significantly worse than that of the 32 patients with common CC (P < 0.001). The two patients on whom autopsy was performed also died within 1 year after diagnosis. ASC tended to have more aggressive biologic behavior and a poorer prognosis than common CC. The authors' immunohistochemical analysis of CK expression indicated that most of the ASCs of the liver that were studied developed from a squamous transformation of the preexisting CC.

A clinicopathologic study of intrahepatic cholangiocarcinoma containing a component of squamous cell carcinoma

Eleven cases of cholangiocarcinoma containing a component of squamous cell carcinoma (CC-SCC) were reviewed clinicopathologically in comparison with 82 cases of common cholangiocarcinoma presenting as a pure form of adenocarcinoma (CC-AC). The former type was prone to develop in a rather advanced stage of the disease, as indicated by short survival time, large tumor size, aggressive modes of intrahepatic spreading, and frequent metastasis. Histologically, the area of squamous cell carcinoma ranged from focal to overwhelming. The occurrence of the squamous element could be interpreted as the result of the metaplastic transformation of adenocarcinoma cells because of the intimate coexistence of the two types in the primary and metastatic lesions. It also was suggested that anaplastic carcinoma cells could sometimes differentiate into squamous cell carcinoma. In no instances was there any squamous metaplasia of the bile ducts demonstrated; therefore, there was no supporting evidence for the possibility of squamous metaplasia of the bile duct epithelium and subsequent malignant transformation.