Including Intrahepatic Cholangiocarcinoma Research Articles

The epidemiological trends of biliary tract cancers in the United States of America

BackgroundBiliary tract cancers (BTCs) are a series of heterogeneous malignancies that are broadly grouped based on the anatomical site where they arise into subtypes including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC).Methods and ResultsThe present study provides an overview of the epidemiology of the various BTCs based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2018. Distinct differences in both incidence and mortality rates were observed for these BTCs as a function of age, sex, ethnicity, and calendar year. In 2018, BTCs emerged as the fifth most prevalent form of alimentary tract cancer in the USA. While the incidence and mortality of ICC appear to be increasing, the incidence rates of GBC, ECC, and AVC have remained stable, as have the corresponding mortality rates. The most common and deadliest BTCs in 2018 were ICC and GBC among males and females, respectively. The ethnic groups exhibiting the highest incidence rates of these different BTCs were American Indians and Alaska Natives for GBC, and Asian and Pacific Islanders for ICC, ECC, and AVC. The incidence of all of these forms of BTC rose with age. There were some variations in BTCs in terms of staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes from 2000 to 2018.ConclusionsThe epidemiological characteristics, staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes were distinct for each of these BTCs.

The clinical implications and molecular features of intrahepatic cholangiocarcinoma with perineural invasion

BackgroundPerineural invasion (PNI) is associated with metastasis in malignancies, including intrahepatic cholangiocarcinoma (ICC), and is correlated with poor prognosis.MethodsThe study included three large cohorts: ZS-ICC and TMA cohorts from our team, MSK cohort from a public database, and a small cohort named cohort 4. Prognostic implications of PNI were investigated in MSK cohort and TMA cohort. PNI-related genomic and transcriptomic profiles were analyzed in MSK and ZS-ICC cohorts. GO, KEGG, and ssGSEA analyses were performed. Immunohistochemistry was used to investigate the relationship between PNI and markers of neurons, hydrolases, and immune cells. The efficacy of adjuvant therapy in ICC patients with PNI was also assessed.ResultsA total of 30.6% and 20.7% ICC patients had PNI in MSK and TMA cohorts respectively. Patients with PNI presented with malignant phenotypes such as high CA19-9, the large bile duct type, lymph node invasion, and shortened overall survival (OS) and relapse-free survival (RFS). Nerves involved in PNI positively express tyrosine hydroxylase (TH), a marker of sympathetic nerves. Patients with PNI showed high mutation frequency of KRAS and an immune suppressive metastasis prone niche of decreased NK cell, increased neutrophil, and elevated PD-L1, CD80, and CD86 expression. Patients with PNI had an extended OS after adjuvant therapy with TEGIO, GEMOX, or capecitabine.ConclusionOur study deciphered the genomic features and the immune suppressive metastasis-prone niche in ICC with PNI. Patients with PNI showed a poor prognosis after surgery but a good response to adjuvant chemotherapy.Graphical abstract

Combination of TACE and Lenvatinib as a promising option for downstaging to surgery of initially unresectable intrahepatic cholangiocarcinoma.

Conversion therapy has been widely applied in various cancer types including intrahepatic cholangiocarcinoma (ICC). The aim of this retrospective study was to evaluate the efficacy and safety of transarterial chemoembolization combined with lenvatinib (TACE-L) as a novel conversion therapy in patients with initially unresectable ICC. Enrolled in this retrospective study were patients with unresectable ICC who received TACE-L between January 2015 and May 2018. The patients were evaluated every 2 months for possible secondary resection. Of the 44 eligible patients, 28 (63.6%) were successfully downstaged to receive surgical resection and the other 16 patients were included into the unsuccessfully downstaged group. The overall adverse events during TACE-L were moderate, including 12 patients (27.3%) with Grade 3 or 4 toxicities. Of the 28 downregulated patients, 23 (82.1%) achieved an R0 resection, and 6 (21.4%) had Clavien-Dindo grade ≥ 3 complications, including one postoperative death. Kaplan-Meier curves showed that the successfully downstaged patients had better overall survival (OS) than the unsuccessfully downstaged patients (P = 0.006). Multivariable analysis identified successful TACE-L conversion therapy as a significantly favorable prognostic factor for OS. TACE-L proves to be a safe and efficacious conversion therapy modality that allows for secondary resectability in patients with initially unresectable ICC.

Abstract 2710: The MD Anderson patient-derived xenograft series for modeling precision oncology in biliary tract cancers

Abstract Purpose: Biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), are rare malignancies which frequently present at advanced stage and have a poor survival. Incorporation of next-generation sequencing into clinical care has provided an avenue for the development of targeted therapies in BTCs which are rich in actionable mutations. However, clinically relevant models for BTC are limited, representing a major challenge in the field. We sought to develop a catalog of BTC patient-derived xenograft (PDX) models and representing diverse molecular profiles to create a resource for the modeling of precision oncology. Methods: Tumor tissue from surgical specimens or image-guided biopsies was collected from consenting patients at MD Anderson Cancer Center with histologically-confirmed BTCs for PDX development. Tumor fragments were implanted in the flank of NSG mice and passaged into nude mice. Whole-exome sequencing (WES) was performed on tumors from early-passage (P1-P2) PDXs and matching patient blood to determine somatic mutations/indels and copy number variations. Functional alterations in cancer-related genes that are targetable directly or indirectly with approved or investigational agents were considered “actionable”. Results: Samples were obtained from 97 patients undergoing image-guided biopsy (86/97, 89%) or surgical resection (11/97, 11%). Out of 97 tumors implanted, 33 (34%) PDXs from 30 patients were successfully established: 74% (24/33) ICC, 15% (5/33) ECC, and 12% (4/33) GBC. Relative take rates for PDX development were 34% (29/86) for those developed from biopsy samples and 36% (4/11) for those developed from surgical samples. In two patients, multiple PDXs were developed from biopsies at different time points during their care. WES demonstrated that the PDXs captured several key actionable alterations including alterations in ERRB2, FGFR2, IDH1, ATM, PIK3CA, PTEN and KRAS. Conclusion: Here, we describe a unique collection of clinically and molecularly annotated BTC PDX models which reflect the genomic heterogeneity present in ICC, ECC, and GBC. WES of early-passage PDXs provides evidence that these models capture the variety of actionable alterations harbored in the parental tumor and may enable the development of novel, biomarker-driven treatment strategies and rational combination therapies. To date, this is one of the largest collections of BTC PDX models available and will serve as an invaluable resource to guide the development of personalized treatments for patients with these aggressive malignancies. Citation Format: Timothy Philip DiPeri, Kurt W. Evans, Ching-Wei D. Tzeng, Lawrence Kwong, Michael P. Kahle, Xiaofeng Zheng, Dali Li, Hop S. Tran Cao, Thuy Vu, Sunhee Kim, Fei Su, Bryce Kirby, Chetna Wathoo, Gabriela Raso, Yasmin Rizvi, Huamin Wang, Filip Janku, Kenna Shaw, Timothy Yap, Milind Javle, Jordi Rodon, Funda Meric-Bernstam. The MD Anderson patient-derived xenograft series for modeling precision oncology in biliary tract cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2710.

Clinical outcomes and prognostic analysis of conversion surgery for initially unresectable biliary tract cancer: Japan-Korea collaboration study

There are small scale retrospective studies showing efficacy of conversion surgery for initially unresectable biliary tract cancer (UR BTC) patients who responded long-term chemotherapy or radiation therapy. This study aimed to establish new evidence by evaluating effect of conversion surgery for UR-LA BTC from Japan and Korea. Patients with initially UR BTC including intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PHCC), distal bile duct cancer (DBC), and gallbladder cancer (GBC) and Amplla of vater cancer (AVC) who underwent conversion surgery between January 2013 to December 2017 following chemotherapy or radiotherapy were retrospectively collected from Japanese and Korean institutes. A total of 91 patients, including 27 ICC, 24 PHCC, 32 GBC, 7 DBC and 1 AVC cases, were enrolled. The reasons for unresectability were local progression without distant metastasis in 66 cases (73%) and distant metastasis in 25 cases (27%). As preoperative chemotherapy, gemcitabine-based multidrug therapy was performed for 70 patients (77%), and radiation therapy was performed for 19 patients (21%). The result of evaluation of the responses using RECIST showed 5 CR cases (5%), 52 PR cases (57%), 27 SD cases (30%) and 1 PD case (1%). The median interval from the induction of treatment to surgical resection was 6.4 months. The surgical procedures comprised hepatectomy with bile duct resection in 56 cases (62%), pancreaticoduodenectomy in 7 cases (8%) and hepatopancreatoduodenectomy in 8 cases (9%). Combined vascular resection was performed 25 patients (27%). Postoperative complication over Clavian-Dindo Grade III occurred in 48 cases (53%). There were 5 mortality cases (5%). R0 resection was performed for 74 cases (81%). Pathologically CR was achieved for 13 cases (14%). Five year survival rate of initially UR-BTC patients who underwent conversion surgery after preoperative therapy was 43.9% (median survival time: 39.2 months). Selected patients diagnosed with initially unresectable bile duct cancer are able to undergo conversion surgery and may have long-term survival after potentially curative resection.

Intrahepatic cholangiocarcinoma induced M2-polarized tumor-associated macrophages facilitate tumor growth and invasiveness

BackgroundM2-polarized tumor-associated macrophages (M2-TAMs) have been shown to correlate with the progression of various cancers, including intrahepatic cholangiocarcinoma (ICC). However, the interactions and mechanism between M2 macrophages and ICC are not completely clear. We aimed to clarify whether M2 macrophages promote the malignancy of ICC and its mechanism.MethodsTwo progressive murine models of ICC were used to evaluate the alterations in different macrophage populations and phenotypes. Furthermore, we assessed M2 macrophage infiltration in 48 human ICC and 15 normal liver samples. The protumor functions and the underlying molecular mechanisms of M2 macrophages in ICC were investigated in an in vitro coculture system.ResultsWe found that the number of M2 macrophages was significantly higher in ICC tissues than in normal bile ducts in the two murine models. M2 macrophage infiltration was highly increased in peritumoral compared with intratumoral regions and normal liver (p < 0.01). ICC cells induced macrophages to differentiate into the M2-TAM phenotype, and coculture with these M2 macrophages promoted ICC cell proliferation, invasion and epithelial–mesenchymal transition (EMT) in vitro. Mechanistically, M2-TAM-derived IL-10 promoted the malignant properties of ICC cells through STAT3 signaling. Furthermore, blockade of IL-10/STAT3 signaling partly rescued the effects of M2 macrophages on ICC.ConclusionOur results indicated that M2-polarized macrophages induced by ICC promote tumor growth and invasiveness through IL-10/STAT3-induced EMT and might be a potential therapeutic target for ICC.

Asbestos and Intrahepatic Cholangiocarcinoma.

The link between asbestos exposure and the onset of thoracic malignancies is well established. However epidemiological studies have provided evidences that asbestos may be also involved in the development of gastrointestinal tumors, including intrahepatic cholangiocarcinoma (ICC). In line with this observation, asbestos fibers have been detected in the liver of patients with ICC. Although the exact mechanism still remains unknown, the presence of asbestos fibers in the liver could be explained in the light of their translocation pathway following ingestion/inhalation. In the liver, thin and long asbestos fibers could remain trapped in the smaller bile ducts, particularly in the stem cell niche of the canals of Hering, and exerting their carcinogenic effect for a long time, thus inducing hepatic stem/progenitor cells (HpSCs) malignant transformation. In this scenario, chronic liver damage induced by asbestos fibers over the years could be seen as a classic model of stem cell-derived carcinogenesis, where HpSC malignant transformation represents the first step of this process. This phenomenon could explain the recent epidemiological findings, where asbestos exposure seems mainly involved in ICC, rather than extrahepatic cholangiocarcinoma, development.

NTRK gene fusions in biliary tract cancers.

574 Background: Gene fusions involving one of the 3 neurotrophic tyrosine receptor kinases ( NTRK) have been identified in approximately 1% of solid tumors and inhibitors of TRK (e.g. larotrectinib) have been shown to have anti-tumor activity regardless of tumor type. NTRK gene fusions have been previously reported in bilio-pancreatic cancers. It is of interest therefore to determine the incidence and molecular characteristics of NTRK gene fusions in patients with bilio-pancreatic cancers. Methods: Formalin-fixed paraffin-embedded archival blocks from surgical resections, biopsies or cytological samples of biliary tract tumors including intra-hepatic cholangiocarcinoma (IH), extra-hepatic cholangiocarcinoma (EH), perihilar cholangiocarcinoma (PH) and gallbladder tumors (G) were selected/retrieved from the tumor bank of the CUB Hôpital Erasme between January 2010 and July 2019. A two-step diagnostic method incorporating immunohistochemistry (IHC) screening followed by NGS analysis was used. Pan–TRK IHC (monoclonal antibody clone EPR17341 [AbCam, Cambridge, MA]) was used for the screening method. Staining intensity (negative, weak, moderate or strong) and localization (cytoplasmic or nuclear) were evaluated. The presence of at least weak staining tumor cells led to testing by a RNA-based NGS panel (Oncomine Focus Assay, ThermoFisher scientific). Results: 145 archival tumors samples (81 surgical resections, 48 biopsies and 16 cytology) have been selected, including 61 IH, 32 PH, 26 EH and 26 G (67 female and 78 male). 134 samples were suitable to perform IHC. 17 samples were IHC positive. Intensity of staining was weak in 16 samples and moderate in one. Staining location was cytoplasmic (14/17), nuclear (2/17), and nuclear+cytoplasmic (1/17). NGS testing of the 17 IHC positive samples revealed a single NTRK3 gene fusion ( ETV6(4)- NTRK3(14)). In this case (female patient with a poorly differentiated PH, deceased), IHC had a weak focal cytoplasmic and nuclear staining. Overall in the patients screened by IHC and confirmed by NGS, the percentage of NTRK fusions was 0.75%. Conclusions: NTRK gene fusions are rare in biliary cancers but testing is of high interest due to the emergence of possible treatment with specific TRK inhibitors.

Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation

Metabolism is a critical regulator of cell fate determination. Recently, the significance of metabolic reprogramming in environmental adaptation during tumorigenesis has attracted much attention in cancer research. Recurrent mutations in the isocitrate dehydrogenase (IDH) 1 or 2 genes have been identified in several cancers, including intrahepatic cholangiocarcinoma (ICC). Mutant IDHs convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which affects the activity of multiple α-KG-dependent dioxygenases including histone lysine demethylases. Although mutant IDH can be detected even in the early stages of neoplasia, how IDH mutations function as oncogenic drivers remains unclear. In this study, we aimed to address the biological effects of IDH1 mutation using intrahepatic biliary organoids (IBOs). We demonstrated that mutant IDH1 increased the formation of IBOs as well as accelerated glucose metabolism. Gene expression analysis and ChIP results revealed the upregulation of platelet isoform of phosphofructokinase-1 (PFKP), which is a rate-limiting glycolytic enzyme, through the alteration of histone modification. Knockdown of the Pfkp gene alleviated the mutant IDH1-induced increase in IBO formation. Notably, the high expression of PFKP was observed more frequently in patients with IDH-mutant ICC compared to in those with wild-type IDH (p < 0.01, 80.9% vs. 42.5%, respectively). Furthermore, IBOs expressing mutant IDH1 survived the suppression of ATP production caused by growth factor depletion and matrix detachment by retaining high ATP levels through 5ʹ adenosine monophosphate-activated protein kinase (AMPK) activation. Our findings provide a systematic understanding as to how mutant IDH induces tumorigenic preconditioning by metabolic rewiring in intrahepatic cholangiocytes.

Expression of fatty-acid-binding protein 5 in intrahepatic and extrahepatic cholangiocarcinoma: the possibility of different energy metabolisms in anatomical location.

The biliary tract cancer (BTC) covers a range of carcinomas, including intrahepatic cholangiocarcinoma (ICC), cholangiolocellular carcinoma (CoCC), perihilar cholangiocarcinoma (perihilar CC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), defined according to the anatomical location. These adenocarcinomas mostly comprise biliary epithelial cell-derived malignant cells. In addition to anatomical differences, there are morphological and biological differences in BTC starting from embryonic development of the tissues extending to physiological differences. Fatty acid-binding proteins (FABPs) are closely associated with the energy metabolism. Using surgical specimens from 74 BTCs, we performed immunohistochemistry for FABP5 and its associated molecules, including peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator 1 (PGC-1), and estrogen-related receptor α (ERRα). We found that the expression patterns of small BTCs (ICC and CoCC) considerably differed from those of large BTCs (perihilar CC, ECC, and GBC). Expression of FABP5 and PGC-1 in large BTCs was high compared with those of small BTCs, but no difference in the expression of PPARγ and ERRα was observed. FABP5 appears to play a role in malignant progression in large BTCs. Small and large BTCs possess different energy metabolism systems owing to their different anatomical locations and course of carcinogenesis, although all BTCs originate from biliary epithelial cells.

ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma.

Cancer stem cells contribute to a high rate of recurrence and chemotherapeutic resistance in many types of cancer, including intrahepatic cholangiocarcinoma (ICC). Inhibitor of differentiation 3 (ID3) has been reported to promote cancer stem cells, but its role in ICC is obscure. In this study, we identified that ID3 is highly expressed in human ICC tissues compared with matched normal tissues and correlates with poor prognosis. Functional studies demonstrate that ID3 is required for stemness maintenance in cholangiocarcinoma both in vitro and in vivo. Consistent with the regulation of cancer stem cell features by ID3, transgenic expression of ID3 enhances chemoresistance of cholangiocarcinoma cells. Moreover, we found that ICC patients with low ID3 levels benefited from postoperative transarterial chemoembolization, whereas patients with high ID3 levels did not, indicating the significance of ID3 in individualized ICC therapy. Mechanistically, ID3 could interact with E47 and block E47 recruitment to the promoter of β-catenin, which leads to activation of Wnt/β-catenin signaling. Conclusion: Our results show that ID3 could promote the stemness of ICC by increasing the transcriptional activity of β-catenin and could serve as a biomarker in predicting ICC patients' response to adjuvant chemotherapeutics.

Programmed death ligand 1 expression in human intrahepatic cholangiocarcinoma and its association with prognosis and CD8+ T-cell immune responses.

BackgroundAgents targeting the programmed death ligand 1 (PD-L1)/programmed death receptor 1 immune checkpoint exhibited promising clinical outcomes in a variety of malignant tumors, including intrahepatic cholangiocarcinoma (ICC). However, the relationship between PD-L1 expression and CD8+ T-cell immune responses is not well defined in ICC.Patients and methodsWe investigated PD-L1 expression immunohistochemistry in formalin-fixed, paraffin-embedded tissues from 192 ICC patients undergoing curative resection and correlated our results with the clinicopathologic features and prognosis. We also quantified CD8+ T-cell infiltration in ICC specimens and evaluated the relationship between PD-L1 expression and CD8+ T-cell infiltration. After incubating human ICC cell lines (HCCC9810 and RBE) with interferon (IFN)-γ, we measured the PD-L1 expression of these ICC cells by Western blot and flow cytometry.ResultsOnly 34 patients (17.7%) showed ≥5% membranous PD-L1 expression on tumor cells, and tumoral PD-L1 overexpression (≥5%) was significantly associated with superior overall survival (P=0.012) and disease-free survival (P=0.018). A significant positive association was found between PD-L1 expression and the presence of CD8+ T-cells. In fresh frozen ICC specimens, IFN-γ was found to be significantly correlated with PD-L1 and CD8A gene expression, as evaluated by reverse transcription-polymerase chain reaction. Moreover, stimulation of the HCCC9810 and RBE cells with recombinant IFN-γ, secreted by CD8+ T-cells rapidly induced PD-L1 upregulation in these cell lines in vitro.ConclusionTumor PD-L1 overexpression is mainly stimulated by activated CD8+ T-cells pre-existing in the ICC microenvironment, and PD-L1 is a favorable prognostic factor for the patients. These observations suggest that anti-PD-L1/programmed death receptor 1 therapy may benefit ICC patients with tumor cell PD-L1 expression and the presence of CD8+ T-cells.

4:21 PM Abstract No. 331 Quantitative analysis of Lipiodol washout rates in intrahepatic cholangiocarcinoma and hepatic metastasis from neuroendocrine tumors and colorectal cancer after chemoembolization

To evaluate Lipiodol washout time after conventional transarterial chemoembolization (cTACE) in different hepatic malignancies including intrahepatic cholangiocarcinoma (ICC) as well as hepatic metastatic neuroendocrine tumors (NET) and colorectal carcinoma (CRC). This retrospective study included 41 patients, who underwent cTACE for the treatment of ICC (n = 9), NET (n = 14) or CRC metastases to the liver (n = 12). Lipiodol volume (LV) in cm3 was analyzed on follow-up non-contrast CT imaging obtained within 24 hours (LV1) as well as 40-220 days (LV2) after cTACE using a volumetric segmentation and image analysis software (qEASL; Medisys, Philips Research, Suresnes, France). The lipiodol washout rate was calculated as the ratio of (LV1-LV 2) to the interval (in days) between both CT scans. Additionally, tumor response on contrast-enhanced MRI was assessed 1 month after cTACE according to qEASL criteria. Lipiodol was visible on all follow-up CT scans. The LV2 was significantly lower than LV1 in all three tumors types (p<0.001). The mean lipiodol washout rate was -0.034 for ICC, -0.045 for NET, and -0.034 cm3/day for CRC metastases. No significant difference in lipiodol washout rates was observed between the three types of tumors (p>0.05). As for tumor response, 2/9 ICC patients, 4/14 NET patients and 5/18 CRC patients demonstrated response to cTACE according to qEASL criteria. However, no difference in lipiodol washout rate was revealed between responders and non-responders (p>0.05). This study showed that lipiodol washout rates after cTACE were similar for different hepatic malignancies including ICC, NET and CRC metastases. All observed tumors showed consistent washout regardless of response suggesting that lipiodol washout rate may not be predictive of tumor response to treatment.

Intrahepatic cholangiocarcinoma frequently shows loss of BAP1 and PBRM1 expression, and demonstrates specific clinicopathological and genetic characteristics with BAP1 loss

BAP1 and PBRM1 expression loss has been observed in multiple cancers, including intrahepatic cholangiocarcinoma (ICC). We investigated BAP1 and PBRM1 expression in ICC using immunohistochemistry, and analysed its association with clinicopathological and genetic features, including two histological subtypes. Whole-section slides of 108 consecutive primary ICC cases were immunostained against BAP1 and PBRM1. Complete loss of BAP1 and PBRM1 was observed in 21 (19.4%) and 25 (23.1%) cases, respectively, and partial loss was identified in four (3.7%) and nine (8.4%) cases. In all cases, normal bile ducts were strongly and diffusely positive for both BAP1 and PBRM1. ICC with BAP1 loss showed lower serum CA19-9 levels, less perineural invasion, rare mucin production, weaker immunoreactivity against S-100P and stronger immunoreactivity against N-cadherin and NCAM. IDH mutations were identified more frequently in ICCs with BAP1 loss. All ICC with BAP1 loss corresponded to small-duct type ICC. Multivariate Cox regression analysis showed that BAP1 loss was an independent prognostic factor for both overall and recurrence-free survival (P < 0.05). Conversely, PBRM1 loss was found in both small-duct type and large-duct type ICC, and was not associated significantly with any specific characteristics, including prognosis. BAP1 and PBRM1 loss is seen frequently in ICC. ICC with BAP1 loss shares features of small-duct type ICC.

Ring finger protein 43 expression is associated with genetic alteration status and poor prognosis among patients with intrahepatic cholangiocarcinoma

Ring finger E3 ligases have roles in processes central to maintenance of genomic integrity and cellular homeostasis. Many ring finger E3 ligases are implicated in malignancy. Ring finger protein 43 (RNF43) is a ring finger E3 ligase that negatively regulates the Wnt/β-catenin signaling pathway. RNF43 is frequently mutated in several types of malignancy, including intrahepatic cholangiocarcinoma (ICC). The significance of its expression in ICC has not, however, been reported. We determined RNF43 expression and identified RNF43 polymorphisms in ICC tissues. We also investigated the correlation between RNF43 expression and RNF43 mutation status, RNF43 polymorphisms, clinicopathological features, and prognosis of ICC patients. RNF43 reduced expression in ICC, and the reduction of RNF43 messenger RNA expression was significantly correlated with the presence of rs2257205 and RNF43 somatic mutations, confirming that all RNF43 somatic mutations in ICC are inactivating. Overall survival was worst in patients with down-regulation of RNF43. Univariate and multivariate analyses revealed that RNF43 expression was an independent prognostic factor. There was no statistically significant association between RNF43 messenger RNA and protein expression nor any clinicopathological features or RNF43 polymorphisms. The results imply that RNF43 is down-regulated in ICC and may play a crucial role during development of ICC.

Loss of BAP1 Expression Occurs Frequently in Intrahepatic Cholangiocarcinoma.

BRCA1-associated protein 1 (BAP1) is a deubiquitinating enzyme that functions as a tumor suppressor gene. Double hit BAP1 inactivation has been reported in a range of tumor types, including intrahepatic cholangiocarcinoma (ICC), sometimes in association with germline mutation.We performed immunohistochemistry for BAP1 on a well-characterized cohort of 211 ICC patients undergoing surgical resection with curative intent at 3 institutions based in 3 different countries. The median age at diagnosis was 65 years (range, 36.5–86) and 108 (51%) were men. Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in nonneoplastic cells) occurred in 55 ICCs (26%). BAP1 loss predicted a strong trend toward improved median survival of 40.80 months (95% CI, 28.14–53.46) versus 24.87 months (95% CI, 18.73–31.01), P = 0.059). In a multivariate model including age, sex, BAP1 status, tumor stage, tumor grade, lymphovascular invasion, and tumor size, female sex was associated with improved survival (hazard ratio [HR] 0.54; 95% CI, 0.34–0.85), while advanced tumor stage and lymphovascular invasion (HR 1.89; 95% CI, 1.09–3.28) correlated with decreased survival. In a multivariate analysis, high grade tumors were associated with BAP1 loss (odds ratio [OR] 3.32; 95% CI, 1.29–8.55), while lymphatic invasion was inversely associated with BAP1 loss (OR 0.36; 95% CI, 0.13–0.99).In conclusion, we observed a trend toward improved prognosis in ICC associated with absent expression of BAP1 and an association of BAP1 loss with higher histological grade and absent lymphatic invasion. Female sex was associated with improved survival while advanced tumor stage and lymphatic invasion were associated with decreased survival.

Treating primary liver cancer with hepatic arterial infusion of floxuridine and dexamethasone: Does the addition of systemic bevacizumab improve results?

e14658 Background: Unresectable primary liver cancer (UPLC), including intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), has poor median survival, typically 10 to 11 months....

A pilot study of external beam radiotherapy for unresectable primary liver cancer

4220 Background: Radiotherapy is used to treat patients with unresectable primary liver cancer, including intrahepatic cholangiocarcinoma (IHC) and hepatocellular carcinoma (HCC), but the efficacy has never been examined well. The purpose of this study was to clarify the efficacy and feasibility of external beam radiotherapy (EBRT) alone in such patients. Methods: Twenty-one patients with unresectable primary liver cancer, 11 with IHC and 10 with HCC were enrolled in this prospective trial between June 1998 and August 2003. The eligibility criteria were: clinical target volume that encompassed gross tumor volume plus lateral margin of 1 to 2 cm can receive more than 95% of prescribed dose; no distant metastasis; performance status 0, 1 or 2; Child-Pugh classification A or B; no massive ascites or pleural effusion; no serious complications; and written informed consent of the patient. We performed EBRT (50 Gy in 25 fractions, 5 times/week) and evaluated its efficacy and adverse effects during a 3- to 34-months follow-up period. Time to progression (TTP) and survival time (ST) were calculated by the Kaplan-Meier method from the date of starting radiotherapy. Results: The full irradiation dose was administered in 19 of 21 patients. Irradiation was discontinued after 8 Gy because of obstructive jaundice in 1 patient with IHC, and after 36 Gy because of massive ascites in 1 patient with HCC. Grade 3 or 4 toxicity was observed in 6 of the 21 patients (28.6%), i.e., 5 with HCC and one with IHC; ascites developed in all 6 of them and total-bilirubin elevation in 2 of them. There were no direct treatment-related deaths. Overall response rate (OR) in assessable 19 patients was 47% (95% CI, 27–68%), including 2 CR, 7PR, 8SD, and 2 PD. The OR of the HCC patients was 50% (2 CR, 3 PR, 4 SD, 2 PD), and the OR of the IHC patients was 44% (4 PR, 4 SD, 1 PD). The median TTP and ST of the 21 patients were 4.4 months and 9.9 months, respectively. The 1- and 3-year survival rates were 38% and 19%, respectively. Conclusions: Raidotherapy with 50 Gy was tolerated except for the development of ascites in HCC. It is effective against primary liver cancer and warrants further investigation to determine the survival benefit. No significant financial relationships to disclose.

Striking trends in the cholangiocarcinoma incidence and mortality in the United States of America 1979–1998

Background and Methods: Cholangiocarcinoma (CCA) arises from both intra and extrahepatic bile ducts and has been considered a rare tumor in the United States. Recently, worldwide rising mortality due to primary liver tumors including intrahepatic cholangiocarcinoma (IHCC) has been reported. We have analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database to determine the age-adjusted incidence of cholangiocarcinoma and data from the U.S. Vital-Statistics database to determine age-adjusted mortality rates. Results: The incidence of I HCC (leD-9 155.1) progressively increased from 0.12 to 0.81 per 100,000 population between 1979 and 1996 (Figure) associated with a rise in mortality from 0.2 to 0.9 during 1979-1998. Increase in mortality was higher in men (0.2 to 1.1) compared with women (0.2 to 0.8). The percent change in mortality was higher in those aged >75 years. In contrast, the incidence of extrahepatic cholangiocarcinoma (EHCC lOB-9 156.1) decreased from 1.1 to 0.7 (Figure) and the mortality reduced from 0.6 to 0.3 associated with a similar reduction in mortality secondary to gall bladder cancer (iCD-9 156.B} from 1.2 to 0.7 per 100,000 population during this period. Conclusions: The incidence and mortality of intrahepatic cholangiocarcinoma in the USA has increased five fold in the last two decades, the rate of rise of which far exceeds that of hepatocellular carcinoma. This is not readily explained by diagnostic transfer from other tumors or improved diagnosis. Opposing trends in intra and extra hepatic cholangiocarcinoma suggest dissimilar pathogenesis.