Primary Intrahepatic Stones

Hepatolithiasis, or primary intrahepatic stones, is prevalent in the Far East. This clinical syndrome has been previously referred to in the West as Oriental cholangiohepatitis. The majority of primary intrahepatic stones are calcium bilirubinate stones, but intrahepatic stones with high cholesterol purity have recently been recognized. Primary intrahepatic stones are formed de novo within the liver and can be distinguished from extrahepatic stones on the basis of a unique pathogenetic etiology, chemical composition, and clinical course. Patients with hepatolithiasis are often plagued by a progressive illness punctuated by multiple intrahepatic strictures, recurrent cholangitis, liver abscesses, and hepatic destruction. Advances in interventional radiological techniques, cholangioscopy, and novel surgical innovations have led to significant changes in the way these patients are now managed.     

Intrahepatic Cholangiocarcinoma: expert consensus statement

An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of intrahepatic cholangiocarcinoma (ICC) in order to establish practice guidelines and to agree on consensus statements. The treatment of ICC requires a coordinated, multidisciplinary approach to optimize survival. Biopsy is not necessary if the surgeon suspects ICC and is planning curative resection, although biopsy should be obtained before systemic or locoregional therapies are initiated. Assessment of resectability is best accomplished using cross-sectional imaging [computed tomography (CT) or magnetic resonance imaging (MRI)], but the role of positron emission tomography (PET) is unclear. Resectability in ICC is defined by the ability to completely remove the disease while leaving an adequate liver remnant. Extrahepatic disease, multiple bilobar or multicentric tumours, and lymph node metastases beyond the primary echelon are contraindications to resection. Regional lymphadenectomy should be considered a standard part of surgical therapy. In patients with high-risk features, the routine use of diagnostic laparoscopy is recommended. The preoperative diagnosis of combined hepatocellular carcinoma and cholangiocarcinoma (cHCC–CC) by imaging studies is extremely difficult. Surgical resection remains the mainstay of treatment, but survival is worse than in HCC alone. There are no adequately powered, randomized Phase III trials that can provide definitive recommendations for adjuvant therapy for ICC. Patients with high-risk features (lymphovascular invasion, multicentricity or satellitosis, large tumours) should be encouraged to enrol in clinical trials and to consider adjuvant therapy. Cisplatin plus gemcitabine represents the standard-of-care, front-line systemic therapy for metastatic ICC. Genomic analyses of biliary cancers support the development of targeted therapeutic interventions.     

Mucin Secreting Cholangiocarcinoma Associated with Clonorchiasis

Hepatic clonorchiasis is implicated in the pathogenesis of mucin secreting cholangiocarcinoma in the Far East. Obstructive jaundice is often associated with the malignant stricture. We present a case with recurrent cholangitis due to biliary obstruction caused by excessive mucus produced by the tumor. The excess mucus and infected bile led to early stent clogging within a few weeks after stent insertion. Intraductal 5-fluorouracil treatment resulted in an apparent reduction in mucus production. Apart from frequent admission for stent exchange, the patient has lived a reasonably good quality life for three years.     

Neoadjuvant and Adjuvant Therapy in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and causes major economic and health burdens throughout the world. Although the incidence of ICC is relatively low, an upward trend has been seen over the past few decades. Owing to the lack of specific manifestations and tools for early diagnosis, most ICC patients have relatively advanced disease at diagnosis. Thus, neoadjuvant therapy is necessary to evaluate tumor biology and downstage these patients so that appropriate candidates can be selected for radical liver resection. However, even after radical resection, the recurrence rate is relatively high and is a main cause leading to death after surgery, which makes adjuvant therapy necessary. Because of its low incidence, studies in both neoadjuvant and adjuvant settings of ICC are lagging compared with other types of malignancy. While standard neoadjuvant and adjuvant regimens are not available in the current guidelines due to a lack of high-level evidence, some progress has been achieved in recent years. In this review, the available literature on advances in neoadjuvant and adjuvant strategies in ICC are evaluated, and possible challenges and opportunities for clinical and translational investigations in the near future are discussed.     

肝内胆管细胞癌CT诊断及鉴别诊断

目的：探讨肝内胆管细胞癌的CT表现及其他肝内肿瘤的鉴别要点。方法：回顾性分析经手术及病理证实的18例肝内胆管细胞癌的CT资料，术前均经CT平扫和增强扫描，6例经延迟扫描。结果：18例CT平扫均表现为单发低密度病灶，密度均匀者3例，不均匀者15例；肝包膜回缩证10例；边缘清楚4例，不清楚14例；伴有肝内胆管扩张及肝内胆管结石8例；有脾肿大者3例，不均匀者15例；肝包膜回缩证10例；边缘清楚4例，不清楚14例；伴有肝内胆管扩张及肝内胆管结石8例；有脾肿大者3例。增强扫描病灶均匀为轻度强化，且不同程度地出现线样或网格状强化。结论：肝内胆管细胞癌有一定的CT特征，大多可与肝内其他占位病变鉴别。     

Expandable Metallic Stents: in the Benign Strictures of Intrahepatic Ducts in Patients with Primary Intrahepatic Stones

Abstract: In Korea there is a prevalence for primary intrahepatic stones. Patients with primary intrahepatic stones and oriental cholangiohepatitis ofen have accompanying intrahepatic strictures. Despite complete removal of the intrahepatic stones, sustained intrahepatic strictures will evoke bile stasis and impairment of liver function. So the correction of intrahepatic strictures in addition to the removal of the stones is important in the management of primary intrahepatic stones. We inserted self-expandable metallic stents in 16 patients with primary intrahepatic stones for the correction of intrahepatic strictures after complete removal of their intrahepatic stones. All of the patients had a previous history of abdominal surgery for the removal of intrahepatic stones. The criteria for insertion of expandable metallic stents was recurrent stenosis after successful balloon dilatation. The metallic stents inserted were Gianturco-Rosch stents (24F) and the stents were inserted via a T-tube or percutaneous transhepatic biliary drainage (PTBD) track. In the follow-up period of an average of 12 months (9–15 months), 14 (88%) out of 16 patients experienced relief of pruritus and improved liver function. But two patients (12%) with secondary biliary cirrhosis showed no improvement of their clinical symptoms and signs. In conclusion, these findings suggest that expandable metallic stents will be useful in the management of intrahepatic strictures, which recurred after successful balloon dilatation, in patients with primary intrahepatic stones.     

Prevalence,Risk Factors,and Survival of Patients with Intrahepatic Cholangiocarcinoma

PurposeTo investigate the prevalence, related risk factors, and survival of intrahepatic cholangiocarcinoma in a Mexican population.Material and methodsWe conducted a cross-sectional study at Medica Sur Hospital in Mexico City with approval of the local research ethics committee. We found cases by reviewing all clinical records of inpatients between October 2005 and January 2016 who had been diagnosed with malignant liver tumors. Clinical characteristics and comorbidities were obtained to evaluate the probable risk factors and the Charlson index. The cases were staged based on the TNM staging system for bile duct tumors used by the American Joint Committee on Cancer and median patient survival rates were calculated using the Kaplan-Meier method.ResultsWe reviewed 233 cases of hepatic cancer. Amongst these, hepatocellular carcinomas represented 19.3% (n = 45), followed by intrahepatic cholangiocarcinomas, which accounted for 7.7% (n = 18). The median age of patients with intrahepatic cholangiocarcinoma was 63 years, and most of them presented with cholestasis and intrahepatic biliary ductal dilation. Unfortunately, 89% (n = 16) of them were in an advanced stage and 80% had multicentric tumors. Median survival was 286 days among patients with advanced stage tumors (25th-75th interquartile range, 174-645 days). No correlation was found between the presence of comorbidities defined by the Charlson index, and survival. We evaluated the presence of definite and probable risk factors for the development of intrahepatic cholangiocarcinoma, that is, smoking, alcohol consumption, and primary sclerosing cholangitis.DiscussionWe found an overall prevalence of intrahepatic cholangiocarcinoma of 7.7%; unfortunately, these patients were diagnosed at advanced stages. Smoking and primary sclerosing cholangitis were the positive risk factors for its development in this population.     

Cholangiocarcinoma as Related to Chronic Intrahepatic Cholangitis and Hepatolithiasis

A case of cholangiocarcinoma is described in a patient with underlying hepatic lithiasis and cholangitis. The possible pathogenesis of cholangiocarcinomas is discussed and the importance of endoscopic retrograde cholangiography in the diagnosis of this malignancy is emphasized.     

Case Report: Primary Biliary Cirrhosis Associated with Cholangiocarcinoma

Primary biliary cirrhosis (PBC) is a chroniccholestatic liver disease of unknown etiology with anumber of immunological abnormalities. Althoughmalignant liver tumors associated with PBC wereconsidered rare in the past, recent studies havedemonstrated that the development of hepatocellularcarcinoma (HCC) in PBC is common, particularly inpatients with virus-related liver cirrhosis (1-7). Toour knowledge, the association of PBC with cholangiocarcinomahas not been previously reported.     

Segmental Bile Duct-Targeted Liver Resection for Right-Sided Intrahepatic Stones

Hepatectomy is a safe and effective treatment for intrahepatic stones (IHSs). However, the resection plane for right-sided stones distributed within 2 segments is obstacle because of atrophy-hypertrophy complex formation of the liver and difficult dissection of segmental pedicle within the Glissonean plate by conventional approach. Thus, we devised segmental bile duct-targeted liver resection (SBDLR) for IHS, which aimed at completely resection of diseased bile ducts. This study aimed to evaluate the outcomes of SBDLR for right-sided IHSs.From January 2009 to December 2013, 107 patients with IHS treated by SBDLR in our center were reviewed in a prospective database. Patients’ intermediate and long-term outcomes after SBDLR were analyzed.A total of 40 (37.4%) patients with localized right-sided stone and 67 (62.7%) patients with bilateral stones underwent SBDLR alone and SBDLR combined with left-sided hepatectomy, respectively. There was no hospital mortality of this cohort of patients. The postoperative morbidity was 35.5%. The mean intraoperative blood loss was 414 mL (range: 100–2500). Twenty-one (19.6%) patients needed red blood cells transfusion. The intermediate stone clearance rate was 94.4%; the final clearance rate reached 100% after subsequent postoperative cholangioscopic lithotomy. Only 2.8% patients developed stone recurrence in a median follow-up period of 38.3 months.SBDLR is a safe and effective treatment for right-sided IHS distributed within 2 segments. It is especially suitable for a subgroup of patients with bilateral stones whose right-sided stones are within 2 segments and bilateral liver resection is needed.     

Intrahepatic,Perihilar and Distal Cholangiocarcinoma: Management and Outcomes

Introduction and aimsCholangiocarcinomas are a heterogeneous group of tumors that can be classified into three clinically distinct types of cancers, intrahepatic, perihilar and distal cholangiocarcinoma. The inconsistent use of nomenclature for these cancers has obscured a true knowledge of the epidemiology, natural history and response to therapy of these cancers. Our aims were to define demographic characteristics, management and outcomes of these three distinct cancer types.Materials and methodsA retrospective study of patients enrolled in an institutional cancer registry from 1992 to 2010. Median survival was compared between different treatment modalities over three time periods for the three types of cholangiocarcinoma at different stages of the disease using Kaplan Meyer analysis.Results242 patients were identified. All cases were reviewed and classified into intrahepatic (90 patients), distal (48 patients) or perihilar (104 patients) cholangiocarcinomas. These cancers differed in median age of onset, gender distribution, median survival and stage. 13.8% of patients presented with stage I, 5.8% with stage II, 9.6% with stage III, 28% with stage IV, with 41.8% having unknown stage. The overall median survival was 15.8 months, and was 23, 25, 14, and 4.5 months for stages I, II, III, and IV respectively. Surgery improved survival in both early and advanced stages. Multimodality therapies further improved outcomes, particularly for perihilar cholangiocarcinoma.ConclusionPerihilar, distal and intrahepatic cholangiocarcinoma vary in their presentation, natural history and therapeutic approach to management. A consistently applied classification is essential for meaningful interpretation of studies of these cancers.     

A New Prognostic Model Covering All Stages of Intrahepatic Cholangiocarcinoma

Background and Aims: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malig-nancy that causes a poor survival. We aimed to identi...     

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.     

Extensive Portal Tumor Thrombi with Portal Hypertension in an Autopsy Case of Intrahepatic Cholangiocarcinoma

Vascular invasion is not a prominent feature of cholangiocarcinoma (CCC), in contrast to hepatocellular carcinoma (HCC), which frequently shows extensive vascular tumor thrombi. We report an autopsy case of CCC with extensive portal tumor thrombi and portal hypertension. A 57-yr-old man presented with abdominal pain. Liver imaging revealed no tumors, but showed intrahepatic portal venous obstruction. HCC with portal tumor thrombi was suspected clinically. His clinical course was rapid; he died of hepatic failure 50 days after admission. At autopsy, the liver (2,700 g) was studded with diffuse whitish yellow granular areas with flecks of coalescent granules. Intrahepatic portal veins were diffusely occluded by tumor thrombi. Microscopically, the tumor was poorly differentiated adenocarcinoma with mucin; tumor cells were immunohistochemically positive for carcinoembryonic antigen, CA 19-9, DU-PAN-2, and biliary type cytokeratins, but negative for alpha-fetoprotein. Tumor cells were diffuse in the liver, and there were numerous tumor thrombi in the small portal veins. Hepatic veins and small arteries were occasionally occluded by tumor thrombi. There was ascites, splenomegaly and tumor thrombi in the gastric and esophageal veins, suggesting that portal hypertension had been present. This tumor seemed to have marked affinity to invade portal veins. It must be stressed that there are CCCs with extensive portal tumor thrombi and resultant portal hypertension.     

Combined Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Outcome After Liver Transplantation

Background  

Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma is a rare hepatobiliary malignancy incorporating components derived from both hepatocyte and intrahepatic bile duct epithelium. The natural history, treatment, and prognosis of this distinct cancer differ from hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC) and are not completely understood. There is considerable controversy about the classification, treatment, and survival, which in turn is related to the rarity of the condition. Treatment options include surgical resection and the prognosis is believed to be better than CC but worse than HCC alone.     

Association between Repeated Praziquantel treatment and Papillary,and Intrahepatic Cholangiocarcinoma

Introduction and aim. The carcinogenesis of tubular and papillary cholangiocarcinoma (CCA) differ. The available epidemiologic studies about risk factors for CCA do not differentiate between the tubular and papillary type. The current study investigated the relationship between the number of repeated use of Praziquantel (PZQ) treatments and each type of CCA.Material and methods. This was a hospital-based, matched, case-control study of patients admitted to Srinagarind Hospital, Khon Kaen University. The patients were 210 pathologically-confirmed cases of CCA, while the controls were 840 subjects diagnosed with other diseases. The 4 controls were individually matched with each case by sex, age, and date of admission. The cases were classified according to location (intrahepatic vs. extrahepatic) and cell type (papillary vs. tubular). Multivariable conditional logistic regression was used for the analysis.Results. After adjusting for confounders, there were statistically significant associations between intrahepatic and papillary CCA and repeated use of PZQ treatment. The respective odds of developing intrahepatic CCA for those who used PZQ once, twice, or more was 1.54 (95%CI:0.92-2.55 ), 2.28 (95%CI:0.91-5.73), and 4.21 (95%CI:1.61-11.05). The respective odds of developing papillary CCA for those who used PZQ once, twice, or more was 1.45 (95%CI:0.80-2.63), 2.96 (95%CI:1.06-8.24), and 3.24 (95%CI:1.09-9.66). There was no association between number of uses of PZQ treatment and developing extrahepatic or tubular CCA.Conclusion. The current study found an association between papillary and intrahepatic CCA and repeated use of PZQ treatment. We suggest further study on the risk factors for papillary and tubular CCA should be performed separately.     

Genetic,Clinicopathological, and Radiological Features of Intrahepatic Cholangiocarcinoma with Ductal Plate Malformation Pattern

Background/AimsIntrahepatic cholangiocarcinoma (iCCA) with a ductal plate malformation (DPM) pattern is a recently recognized rare variant. The genomic profile of iCCA with DPM pattern needs to be elucidated.MethodsCases of iCCA with DPM pattern were retrospectively reviewed based on the medical records, pathology slides, and magnetic resonance imaging (MRI) reports collected between 2010 to 2019 at a single center. Massive parallel sequencing was performed for >500 cancer-related genes.ResultsFrom a total of 175 iCCAs, five (2.9%) cases of iCCA with DPM pattern were identified. All cases were of the small duct type, and background liver revealed chronic B viral or alcoholic hepatitis. Three iCCAs with DPM pattern harbored MRI features favoring the diagnosis of hepatocellular carcinoma, whereas nonspecific imaging features were observed in two cases. All patients were alive without recurrence during an average follow-up period of 57 months. Sequencing data revealed 64 mutated genes in the five cases, among which FGFR2 and PTPRT were most frequently mutated (three cases each) including an FGFR2-TNC fusion in one case. Mutations in ARID1A and CDKN2A were found in two cases, and mutations in TP53, BAP1, ATM, NF1, and STK11 were observed in one case each. No IDH1, KRAS, or PBRM1 mutations were found.ConclusionsiCCAs with DPM pattern have different clinico-radio-pathologic and genetic characteristics compared to conventional iCCAs. Moreover, FGFR2 and ARID1A variants were identified. Altogether, these findings further suggest that iCCA with DPM pattern represents a specific subtype of small duct type iCCA.