Diagnosis of cholangiocarcinoma in primary sclerosing cholangitis: finding a needle in a haystack

Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree, characterized by fibrosis and stricturing of the bile ducts and leading to cirrhosis [1]. It is a premalignant disease that confers a significant risk for the development of cholangiocarcinoma (CCA) [2] [3]. The risk of CCA among patients with PSC is increased 400-fold compared with the general population, with a 20 % lifetime risk, and CCA remains one of the leading causes of liver-related mortality in this patient population [2] [3].

The clinical features and cholangiographic findings of CCA are nonspecific and difficult to differentiate from benign bile duct strictures. Noninvasive diagnostic modalities such as magnetic resonance cholangiopancreatography (MRCP) or tumor markers such as carbohydrate antigen 19 – 9 (CA 19 – 9) have not been proven to be useful for detection of CCA in patients with PSC [2] [4]. Early diagnosis is important because surgical resection or liver transplantation in early stage remains the only cure [5]. Because of the limitations of current imaging modalities, endoscopic retrograde cholangiopancreatography (ERCP) with cytology is proposed as an initial diagnostic strategy for early diagnosis of CCA. However, the underlying chronic inflammation decreases the diagnostic sensitivity of brushings to less than 45 % [6].

In this issue of Endoscopy, Boyd et al. [7] investigated the utility of biliary brush cytology for screening of PSC and biliary dysplasia in patients referred for their first ERCP, irrespective of the presence of symptoms or dominant stricture. During each ERCP, both the intra- and extracellular bile ducts were sampled when possible using a simultaneous suction and brushing technique to increase the cellular yield. Over a median follow-up time of 4.7 years, CCA was detected in seven patients (2.7 %). In this study, 43.3 % of patients referred for their first ERCP already had advanced disease, and suspicious or malignant cytology was present in 6.9 %. None of the patients with mild disease and benign cytology developed CCA, while 15 patients with severe disease developed biliary dysplasia or CCA. This study delivers an important message: CCA in PSC arises from a field defect and brushings need to be obtained from multiple areas of the biliary tree, regardless of stricture location or presence of a dominant stricture. In addition, identifying high-risk PSC patients who may need close surveillance is critical. The authors report that patients with severe disease at clinical presentation may require closer surveillance.

How do we evaluate the findings of the present study and what are the implications for clinical practice and future research? The goal of surveillance in patients with PSC is not only to identify CCA but perhaps to identify those with a predisposition to CCA irrespective of the presence or absence of dominant strictures.

Biliary brush for cytology is an established initial diagnostic technique for surveillance of CCA; however, it is limited by poor sensitivity (43 %) and the potential for false-negative results [6]. Because of the limitations of biliary cytology, fluorescence in situ hybridization (FISH) has been evaluated to improve the diagnosis of CCA [8]. FISH assesses the presence of chromosomal aneuploidy (increase or decrease in chromosome number) and uses fluorescence-labeled probes to evaluate samples obtained by biliary brushings. The FISH assay in patients with PSC evaluates three centromeric probes that target chromosomes 3, 7, and 17, and a locus-specific probe to 9p21. FISH polysomy (five or more cells show gains of two or more of the four probes), indicating duplication of more than one chromosome, is a marker for chromosomal instability and a hallmark of CCA. In a recent study evaluating the performance of FISH in 690 patients with PSC, the pooled sensitivity and specificity of polysomy for CCA was 51 % and 93 %, respectively [8]. Some could argue that this study did not take into account the clinical picture along with laboratory evaluation. Nevertheless, the lack of widespread availability, only marginal improvement in diagnostic sensitivity beyond brush cytology, and additional cost has limited the application of FISH to select tertiary care centers.

Expert recommendations for CCA surveillance in patients with PSC are to obtain liver tests every 3 – 6 months, and annual MRCP and CA 19 – 9 [2]. ERCP with brushings for cytology and FISH is recommended for individuals with suspicious imaging features such as a new dominant stricture, or with symptoms that suggest biliary obstruction or worsening laboratory tests [2]. The problem with this surveillance strategy is that only patients with suspected dominant biliary stricture will be evaluated with brushings for cytology. However, the authors have clearly highlighted that performing brushings irrespective of the presence or absence of dominant stricture is important in order to identify field defects and diagnose CCA. The other problem with this ERCP-based surveillance strategy is that patients will require multiple repeat ERCPs. ERCP is associated with adverse events such as pancreatitis and bacterial cholangitis. Although ERCP in PSC patients is safe overall, with a low prevalence of adverse events, it is rather an unfavorable, invasive routine surveillance strategy – certainly in asymptomatic patients [9]. The authors did not report their incidence of ERCP-associated adverse events in their study.

Because of the limitations of brush cytology and FISH, advanced techniques for biliary imaging have been studied in patients with PSC. Probe-based confocal laser endomicroscopy followed by targeted biopsies yielded a diagnostic sensitivity of 83 % and a specificity of 88 % for CCA [10]. Narrow-band imaging in combination with cholangioscopy was subsequently studied and did not improve CCA diagnosis in the setting of PSC [11]. Although advanced biliary imaging techniques hold promise, their utility is limited by the lack of tissue diagnosis. Single-operator cholangioscopy (Spyglass; Boston Scientific Inc., Marlborough, Massachusetts, USA) provides the opportunity for direct visualization of bile ducts with targeted biopsies of suspicious lesions. Early experience with this technology is exciting, with improved sensitivity and specificity for CCA diagnosis [12].

Even with the incorporation of all of the above-mentioned technologies, the accuracy for diagnosing CCA is still suboptimal. A better understanding of CCA has led to a series of studies that have examined the role of novel biomarkers. We studied volatile organic compounds (VOCs) in the headspace (gas above the sample) of bile aspirated during ERCP and developed a model that yielded a diagnostic sensitivity and specificity of 91 % and 73 %, respectively for CCA [13]. In addition to VOCs, we studied the bile lipid profile among those with de novo CCA and benign biliary conditions including PSC, and found that a combination of oxidized phosphatidylcholines was able to distinguish benign from malignant strictures with a sensitivity and specificity of 100 % and 83 %, respectively [14]. Another study highlighted a panel of 22 peptides to identify 80 % of CCA associated with PSC [15]. These studies highlight the methods in evolution for diagnosing early CCA in patients with PSC.

Three factors are critical for the development of effective surveillance strategies for CCA in patients with PSC: clinical performance, the availability of technology, and cost effectiveness. In terms of clinical performance, the current technologies are suboptimal. In addition, they are not universally available and are not cost effective. If surveillance is going to be a realty in PSC patients, we need to develop and apply noninvasive biomarkers to risk stratify patients and perform ERCPs in only high-risk cases. Irrespective of the limitations of the present study, the authors have made a significant contribution that will help the development of effective surveillance strategies for diagnosing CCA in patients with PSC. Until the role of biomarkers is better defined, we need to continue to employ brushings judiciously in PSC patients to hopefully find the needle of CCA in the PSC haystack.

• References

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