Diagnosis of cholangiocarcinoma in primary sclerosing cholangitis

Introduction: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the hepatobiliary system characterized by chronic inflammation, progressive fibrosis, stricture formation and destruction of extrahepatic and intrahepatic bile ducts.

Areas covered: The increased incidence of cholangiocarcinoma (CCA) in PSC has been well documented and can be explained by the continuous inflammation in the biliary tree leading to an enhanced dysplasia–carcinoma sequence. Although PSC patients may progress to liver cirrhosis; CCA most commonly occurs between the ages of 30 and 45 years when cirrhosis has not yet developed. Therefore, CCA in patients with PSC occurs earlier than in patients without PSC.

Expert commentary: Despite improvement in diagnostic methods and devices, the dilemma of diagnosing CCA in patients with PSC has not been solved yet and needs further investigation.     

Treatment options for primary sclerosing cholangitis

Primary sclerosing cholangitis is a cholestatic liver disease characterized by inflammation and fibrosis of intra-/extrahepatic bile ducts, leading to multifocal strictures. Primary sclerosing cholangitis exhibits a progressive course resulting in cirrhosis and the need for liver transplantation over a median period of 12 years. The disease is frequently associated with inflammatory bowel disease and carries an increased risk of colorectal cancer and cholangiocarcinoma. Despite extensive research, there is currently no effective medical treatment. Multiple drugs are shown to be ineffective in halting disease progression, including ursodeoxycholic acid, the most widely evaluated drug. High-dose ursodeoxycholic acid (28–30 mg/kg/day) was recently shown to increase the adverse events rate. Endoscopic or radiological dilatation of a ‘dominant’ stricture may lead to symptomatic and biochemical improvement. However, liver transplantation is the only life-prolonging treatment for patients with end-stage disease. Studies with promising drugs, such as antibiotics, antifibrotic agents and bile acid derivatives, are eagerly awaited.     

Biliary dysplasia, cell proliferation and nuclear DNA-fragmentation in primary sclerosing cholangitis with and without cholangiocarcinoma

OBJECTIVES: To study the extent of biliary dysplasia, and the degree of cell proliferation and apoptosis in bile duct cells (BDC) from patients with primary sclerosing cholangitis (PSC), with and without cholangiocarcinoma (CC). METHODS: Specimens of liver tissue from 16 patients suffering from PSC and CC, and 16 patients with end-stage PSC without cancer, were investigated. Histological evaluation of presence of biliary dysplasia and bile duct proliferation was made. Immunohistochemistry, applying antibodies against Ki-67, p53 and bcl-2, was used. Nuclear DNA fragmentation was assessed by in situ DNA labelling (ApopTag). The numbers of positive cells expressed as a percentage of the total number of BDCs constituted the labelling index (LI). RESULTS: Bile duct dysplasia was significantly more frequent in nontumorous liver tissue from patients with PSC and CC than from patients having end-stage PSC without cancer (P < 0.05). Patients with biliary dysplasia had a higher frequency of marked bile duct proliferation (P < 0.01) than patients without dysplasia. In tumour tissue, the LI for Ki-67 positive nuclei was more than four times the LI of nuclear DNA fragmentation (P < 0.01). Ki-67, bcl-2, p53 or DNA fragmentation were not significantly different in nontumorous liver tissue from patients with and without CC. Immunohistochemical staining for p53 was positive in 75% of the tumours, whilst in nontumorous tissue no such overexpression was found. CONCLUSION: PSC patients with CC more often display biliary dysplasia than those with end-stage PSC, indicating that biliary dysplasia may be a precancerous stage in PSC. Additionally, p53 mutation seems to be a late event in tumour development, since no p53 expression was found in the premalignant areas with nontumorous BDC.     

Usefulness of transpapillary cytology and biopsy in diagnosing cholangiocarcinoma that mimics primary sclerosing cholangitis

Two patients with a sclerosing type of cholangiocarcinoma are reported. One, a 68-year-old male, presented with jaundice and mild right upper abdominal pain. Endoscopic retrograde cholangiography showed diffuse narrowing and irregularity of the intra- and extrahepatic bile ducts, suggestive of primary sclerosing cholangitis. The other patient was a 72-year-old female who complained of slight right upper abdominal pain, lassitude, and anorexia. Both ultrasonography and computed axial tomography demonstrated slight dilatation of the anterior branch of the right hepatic duct, but no mass. Endoscopic cholangiography revealed stenosis of that duct and diffuse irregularity of the other intrahepatic ducts, also suggestive of primary sclerosing cholangitis. In both patients, however, transpapillary cytology of bile demonstrated malignant cells, and biopsy from within the bile duct showed cholangiocarcinoma. Both transpapillary cytology and biopsy, especially the latter, are useful procedures for the diagnosis of this unique clinical entity.     

Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis

BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) is associated with a high risk of cholangiocarcinoma development. Efforts should be made to detect early neoplastic changes that can be radically treated by liver transplantation. METHODS: In this prospective case series we obtained brush cytology specimens from bile duct strictures in 61 consecutive PSC patients. The cytological classifications were compared with histopathological findings in bile ducts from explanted livers or clinical outcome. RESULTS: Among patients with cytological low-grade (n=9; 15%) or high-grade dysplasia/adenocarcinoma (n=13; 21%), 8 (36%) proved to have cholangiocarcinoma and 7 (32%) to have high-grade dysplasia (i.e. cholangiocarcinoma in situ) in bile ducts from explanted livers. The sensitivity, specificity, positive- and negative predictive values, and accuracy of brush cytology in diagnosis of biliary malignancy were 100%, 84%, 68%, 100%, and 88% for the combination of low-grade and high-grade dysplasia/adenocarcinoma and 73%, 95%, 85%, 91%, and 90% for high-grade dysplasia/adenocarcinoma only. All patients with high-grade biliary epithelial dysplasia in explanted bile ducts were tumour free at follow-up. CONCLUSIONS: Brush cytology from bile duct strictures in PSC patients can detect cholangiocarcinoma in situ. Patients with cytological low-grade and high-grade dysplasia/adenocarcinoma are currently referred for liver transplantation in our hospital.     

Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis

Cholangiocarcinoma (CCA) is a dreaded complication of primary sclerosing cholangitis (PSC); however, marked variability in the incidence of CCA in PSC is reported. Furthermore, limited information exists on risk factors for the development of CCA in PSC. The aim of this study was to determine the incidence of CCA in patients with PSC and to evaluate baseline risk factors for the later development of CCA. From a previous study of the natural history of PSC, we identified 161 patients with PSC who did not have CCA at study entry. Patients were followed until a diagnosis of CCA was established, liver transplantation was performed, or death occurred. Patients were followed for a median of 11.5 yr (interquartile range 4.0-16.1 yr). Fifty-nine patients (36.6%) died, 50 patients (31.1%) underwent liver transplantation, and 11 patients (6.8%) developed CCA. The rate of CCA developing was approximately 0.6% per year. Compared to the incidence rates of CCA in the general population, the relative risk of CCA in PSC was significantly increased (RR = 1,560; 95%CI = 780, 2,793; p < 0.0001). On univariate analysis, a history of variceal bleeding (p < 0.001), proctocolectomy (p= 0.01), and lack of symptoms (p= 0.02) were significant risk factors for CCA with the Mayo Risk Score being marginally significant (p= 0.051). Multivariate analysis determined only variceal bleeding to be a significant risk factor for CCA (RR 24.2; 95%CI: 3.3-67.1). No association was found between the duration of PSC and the incidence of CCA. In conclusion, approximately 7% of PSC patients later developed CCA over a mean follow-up of 11.5 yr, which is dramatically higher than the rates in the general population. Variceal bleeding is a major risk factor for the later development of CCA.     

Advanced cholangiocarcinoma in a patient with stage I primary sclerosing cholangitis

A 29‐year‐old woman presented with jaundice and fever in May 2001. Cholangiography showed multiple strictures and beading of the biliary tree, with a large stricture in the common bile duct and marked dilatation of the hilar bile ducts. Typical cholangiography findings and elevated hepatobiliary enzymes suggested primary sclerosing cholangitis (PSC). At the same time, computed tomography detected a 2‐cm tumor in the common bile duct, and angiography showed an encasement in the portal vein. Tumor markers, cytology, and biopsy were all negative for cancer. Although laparotomy showed a healthy liver and no lymph node metastasis was found, suggesting early‐stage PSC and a low likelihood of accompanying cholangiocarcinoma (CCA) reported so far, the tumor in the resected common bile duct was subsequently diagnosed as CCA. Therefore, pancreatoduodenectomy was performed combined with partial resection of the portal trunk. Histology also revealed invasion of the wall of the portal vein by cancer cells. The patient had a recurrence 5 months later and died 12 months after her operation. This is a rare case in which stage I PSC was complicated by advanced CCA.     

Liver transplantation for primary sclerosing cholangitis

Although the development of interventional radiology and biliary surgical techniques has prolonged the survival time of patients with primary sclerosing cholangitis, liver transplantation remains the only effective treatment for patients with primary sclerosing cholangitis with liver cirrhosis. Several prognostic survival models have been establised for this disease, and the efficacy of actual liver transplantations has been reported in comparison with these survival models. One- and 5-year actuarial patient survivals after liver transplantation for primary sclerosing cholangitis were shown to be greater than and approximately equal to 90%, respectively. An association with cholangiocarcinoma is the most adverse factor affecting survival after liver transplantation for primary sclerosing cholangitis, while the association of inflammatory bowel disease or previous bili-ary surgery does not adversely affect the outcome of the liver transplantation. Recurrent sclerosing cholangitis is an important issue for posttransplant patients with primary sclerosing cholangitis, and occurs in 10%—20% of such patients. Although our understanding of recurrent sclerosing cholangitis is still in the early stages, its potential occurrence indicates the need for a longer follow-up period after liver transplantation.     

Prospective surveillance for cholangiocarcinoma in unselected individuals with primary sclerosing cholangitis

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Health-related quality of life before and after liver transplantation in patients with primary sclerosing cholangitis

Abstract

Background and aims: Liver transplantation (LTx) remains the only curative treatment in patients with primary sclerosing cholangitis (PSC) and liver failure. In Helsinki we have also performed pre-emptive LTx in PSC patients without liver insufficiency but considered to have a high risk for cholangiocarcinoma. The present study evaluates the possible differences in health-related quality of life (HRQoL) in these two PSC groups before and after LTx.

Methods: The total study population was 48 patients, 16 were transplanted due to increased risk of cholangiocarcinoma without liver insufficiency (the premalignant group) and 32 patients with end-stage liver disease (the symptomatic group).

Results: HRQoL remained good after LTx in the premalignant group, and this difference was also clinically important compared with the symptomatic group, although not statistically significant. Both groups had slightly lower mean HRQoL scores after LTx than the age- and gender-standardized general population, and this difference was not clinically important in either group and statistically significant only in the symptomatic group.

Conclusions: HRQoL does not decrease markedly after LTx in the premalignant PSC group, and this group does cope better than the symptomatic PSC group. After LTx, mean HRQoL of the premalignant group stays close to that of the age- and gender-standardized general population.     

Outcome and prognostic factors of 391 Japanese patients with primary sclerosing cholangitis

Objectives: We performed a national survey in 2003, and demonstrated characteristic features of primary sclerosing cholangitis (PSC) patients in Japan. In this study, we aimed to clarify the outcome and prognostic factors of Japanese PSC patients. Methods: Questionnaires were sent to gastroenterologists in Japan, and 391 patients with PSC were registered and enrolled in the current study. The median follow‐up was 5.3 years (range 0.1–20.8 years). The cumulative incidence for survival was analysed using the Kaplan–Meier method. Univariate and multivariate analyses were performed using the Cox‐proportional hazards regression model for determining prognostic variables. Results: The estimated median survival of all patients was 13.1 years, with a 5‐year survival rate of 74.5%. Thirty‐eight patients (9.7%) who underwent liver transplantation (LT) had a 5‐year survival rate of 92.0%. Both univariate and multivariate analysis demonstrated that younger age [below 49 years old; odds ratio (OR)=1.76, 1.12–2.76, P=0.0136] and lower total bilirubin (below 3.0 mg/dl; OR=2.50, 1.60–3.89, P≤0.0001) were independent prognostic factors for LT‐free survival of PSC patients in Japan. Cholangiocarcinoma (CCA) was found in 14 (3.6%) patients, and only two out of 125 PSC patients exhibited a history of inflammatory bowel diseases. Conclusions: Although several characteristic features existed, the outcome as well as prognostic factors of Japanese PSC patients appeared to be similar to those from the United States and European countries. In contrast, the incidence of CCA in PSC appeared to be lower in Japan.     

Intrahepatic cholangiocarcinoma: indication for transplantation

Background/Purpose. Cholangiocarcinoma (CCC) is a rare malignant tumor of the biliary system with a poor prognosis that frequently presents in advanced unresectable stages. A discussion of the role of liver transplantation (LTx) for intrahepatic (IH)-CCC will be presented, based on a review of the international literature. Methods. A search of the international literature related to the topic was performed in the established online databases and databanks. Only those reports with patient series larger than ten were included. Results. The largest series of patients with IH-CCC (n = 186) was reported in the Data Analysis Booklet of the European Liver Transplant Registry (ELTR), revealing 1-, 3-, 5-, 8-, and 10-year survival rates of 58%, 38%, 29%, 23%, and 21%. Other single-center series had comparable or even worse outcomes. More recent experience identified a certain highly selected group of patients who could benefit from LTx in an otherwise unresectable state of disease. Several single-center studies found tumor stage or size, lymph node involvement, and positive surgical margins/contiguous organ infiltration to be predictors of outcome. The recently published Mayo Clinic protocol uses preoperative chemoirradiation and staging at laparotomy before proceeding to liver transplantation, resulting in an early experience with 100% 1-year survival. Conclusions. Generally speaking, IH-CCC is not a favorable indication for liver transplantation. However, there is a highly selected group of patients with early tumor stages potentially benefitting from LTx. Combination with neoadjuvant chemoirradiation may further improve results after LTx. Living-donation LTx may open new therapeutic possibilities to treat patients at an early stage of disease.     

Epidemiology,risk of malignancy and patient survival in primary sclerosing cholangitis: a population-based study in Finland

Abstract

Background: There are only a few and mostly small population-based epidemiological studies of primary sclerosing cholangitis (PSC).

Objective: We aimed to estimate prevalence and incidence rates of PSC, and survival and malignancy risk for PSC patients in a large population-based study.

Methods: We retrieved 632 PSC patients from 1990 to 2015 in the Hospital District of Helsinki and Uusimaa (HUS), comprising 29% of the Finnish population. Mortality information of the PSC patients was obtained from the national Population Registry, malignancy information from the Finnish Cancer Registry and the causes of death from the Statistics Finland. Standardized incidence ratio and standardized mortality ratio (SMR) were calculated for predefined malignancy types.

Results: The crude incidence of PSC in the HUS area was 1.58/100,000 person-years, and the point prevalence in 2015 was 31.7/100,000 inhabitants. The mean time from diagnosis to death was 21.9 years. The risk for any malignancy was three-fold and the risk for colorectal carcinoma was five-fold when comparing with the general population. During the first year after diagnosis of PSC, the risk for cholangiocarcinoma is 900-fold compared to the general population and after that 150-fold. SMR for all malignant neoplasms was 5.9 (95% CI 4.2–8.1).

Conclusion: We found that the incidence of PSC in the HUS area in Finland is similar or higher than previously reported from other countries. The prevalence is markedly higher than reported elsewhere, probably due to the active search of the disease, suggesting that the disease is underdiagnosed.     

Geoepidemiologic variation in outcomes of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, progressive, hepatobiliary disease characterized by inflammation and fibrosis of the intra- and extra-hepatic bile ducts. Its natural history is one that generally progresses towards cirrhosis, liver failure, cholangiocarcinoma, and ultimately disease-related death, with a median liver transplantation-free survival time of approximately 15-20 years. However, despite its lethal nature, PSC remains a heterogenous disease with significant variability in outcomes amongst different regions of the world. There are also many regions where the outcomes of PSC have not been studied, limiting the overall understanding of this disease worldwide. In this review, we present the geoepidemiologic variations in outcomes of PSC, with a focus on survival pre- and post-liver transplantation as well as the concurrence of inflammatory bowel disease and hepatobiliary neoplasia.     

Biliary brush cytology： Factors associated with positive yields on biliary brush cytology

AIM： To evaluate the yield of brushing biliary strictures and the factors associated with a positive result in biliary strictures. METHODS： Data on all consecutive patients （01/02 -10/05） who were identified to have a biliary stricture and who underwent biliary brush cytology were collected. The yield of positive biliary brush cytology was evaluated and compared to results with the gold standard for diagnosis （defined as either definitive surgical histology or clinical course）. Additionally, associated factors of positive results including stricture location, gender, age, mass size, length of stricture, and dilatation prior to brushing cytology were assessed. RESULTS： From 199 patients who had brushing cytology samples （10 patients were excluded due to lack of gold standard diagnosis）, 77 patients had positive brushing cytology （yield 41%）. Variables associated with positive cytology brushing on initial endoscopic retrograde cholangiography were age 1.02 （1.00-1.05）, mass size 〉 1 cm 2.22 （1.01-4.89） and length of stricture 〉 1 cm 3.49 （1.18-10.2）. The sensitivity of biliary brushing was 61%, its specificity 98%, the positive predictive value reached 99%, and the negative predictive value was 57%. CONCLUSION： Our results revealed a 41% positive yield from brushing cytology. The sensitivity of biliary brushing cytology in our center was 61% and the specificity was 98%. Predictors of positive yield include older age, mass size 〉 1 cm, and stricture length of 〉 1 cm.     

Etiology and natural history of primary sclerosing cholangitis

The etiology of primary sclerosing cholangitis remains unknown. Bacteria, toxins, viral infections, and immunological and genetic factors have all been proposed as etiological agents. Portal bacteremia, toxins absorbed from the diseased colon in inflammatory bowel disease, and cytomegalovirus and reovirus infections have been implicated by various investigators but there is little evidence to support these hypotheses. The close association between primary sclerosing cholangitis and various human leukocyte antigen haplotypes is now well established and lends support to the theory that immunologic and genetic mechanisms may be involved in its pathogenesis. Patients with primary sclerosing cholangitis may have elevated levels of circulating immune complexes, immunoglobulins, and non-organ specific autoantibodies. The association between ulcerative colitis and primary sclerosing cholangitis remains unexplained and both groups of patients have a high prevalence of antibodies to the perinuclear cytoplasmic antigen. The long-term prognosis in primary sclerosing cholangitis is tempered by the development of cholangiocarcinoma in 6%—30% of patients when followed over long periods of time. Detecting cholangiocarcinoma early in a patient with primary sclerosing cholangitis is one of the most frustrating problems faced by a clinician while caring for these patients. The long-term outlook for patients with primary sclerosing cholangitis and cholangiocarcinoma remains dismal, whatever the treatment modality employed. However, the development of a multivariate statistical survival model from long-term survival data from the Mayo Clinic and other centers has been a major step in identifying individual primary sclerosing cholangitis patients at low, moderate, and high risk of dying. Such models have been useful for stratifying patients in therapeutic trials, for in patient counseling, and in patient selection and timing of liver transplantation.