Genetic Abnormalities in Biliary Brush Samples for Distinguishing Cholangiocarcinoma from Benign Strictures in Primary Sclerosing Cholangitis

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Abstract

Background . Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and is strongly associated with cholangiocarcinoma (CCA). The lack of efficient diagnostic methods for CCA is a major problem. Testing for genetic abnormalities may increase the diagnostic value of cytology. Methods. We assessed genetic abnormalities for CDKN2A , TP53 , ERBB2 , 20q , MYC , and chromosomes 7 and 17 and measures of genetic clonal diversity in brush samples from 29 PSC patients with benign biliary strictures and 12 patients with sporadic CCA or PSC-associated CCA. Diagnostic performance of cytology alone and in combination with genetic markers was evaluated by sensitivity, specificity, and area under the curve analysis. Results . The presence of MYC gain and CDKN2A loss as well as a higher clonal diversity was significantly associated with malignancy. MYC gain increased the sensitivity of cytology from 50% to 83%. However, the specificity decreased from 97% to 76%. The diagnostic accuracy of the best performing measures of clonal diversity was similar to the combination of cytology and MYC . Adding CDKN2A loss to the panel had no additional benefit. Conclusion . Evaluation of MYC abnormalities and measures of clonal diversity in brush cytology specimens may be of clinical value in distinguishing CCA from benign biliary strictures in PSC.

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Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis.

Phunchai Charatcharoenwitthaya, Keith D. Lindor, C Halling … (2008)

There is limited information on test performance for detecting cholangiocarcinoma in primary sclerosing cholangitis (PSC), particularly when used sequentially. This study aimed to characterize diagnostic performance of serum carbohydrate antigen 19-9 (CA 19-9), ultrasonography, computed tomography, magnetic resonance imaging, cholangiography, and biliary cytologic techniques for detecting cholangiocarcinoma in PSC. All consecutive patients with PSC were screened and followed for development of cholangiocarcinoma from 2000 through 2006. Of 230 patients, 23 developed cytopathologically confirmed cholangiocarcinoma with an annual incidence of 1.2%. The optimal cutoff value for serum CA 19-9 was 20 U/mL, which yielded a sensitivity of 78%, specificity of 67%, positive predictive value (PPV) of 23%, and negative predictive value (NPV) of 96%. Serum CA 19-9 combined with either ultrasonography, computed tomography, or magnetic resonance imaging provided a sensitivity of 91%, 100%, and 96%, specificity of 62%, 38%, and 37%, PPV of 23%, 22%, and 24%, and NPV of 98%, 100%, and 98%, respectively, if at least one method was positive. Subsequent cholangiographic examinations in these patients increased specificity to 69% and PPV to 42% while maintaining sensitivity of 91% and NPV of 96%. Following this group, conventional cytology, aneuploidy detection by digital imaging analysis, and aneusomy detection by fluorescence in situ hybridization in brushing samples of biliary strictures had a sensitivity of 50%, 57%, and 86%, specificity of 97%, 94%, and 83%, PPV of 86%, 89%, and 80%, and NPV of 83%, 74%, and 88%, respectively, for detecting cholangiocarcinoma. Tumor serology combined with cross-sectional liver imaging may be useful as a screening strategy and cholangiography with cytologic examination is helpful for the diagnosis of cholangiocarcinoma in patients with PSC.

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The ups and downs of Myc biology.

Laura Soucek, Gerard Evan (2010)

The basic helix-loop-helix protein Myc is a renowned transcription factor controlling disparate aspects of cell physiology that, together, allow efficient proliferation of somatic cells. This ability, together with the observation that its deregulated expression occurs in the majority of human cancers, suggests that Myc could be a good therapeutic target. However, several aspects of Myc biology remain elusive: what is the major difference between oncogenic and physiological Myc? How does oncogenic Myc evade the intrinsic tumor surveillance pathways provided by evolution? If Myc inhibition were even possible, what would be the consequences for the homeostasis of normal proliferating tissues versus the fate of cancer cells? Here we summarize the latest works addressing these issues. Copyright 2009 Elsevier Ltd. All rights reserved.

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Cholangiocarcinoma and dominant strictures in patients with primary sclerosing cholangitis: a 25-year single-centre experience.

Michael H Chapman, George J. Webster, Selina Bannoo … (2012)

Dominant biliary strictures occur commonly in patients with primary sclerosing cholangitis (PSC), who have a high risk of developing cholangiocarcinoma (CC). The natural history and optimal management of dominant strictures remain unclear, with some reports suggesting that endoscopic interventions improve outcome. We describe a 25-year experience in patients with PSC-related dominant strictures at a single tertiary referral centre. A total of 128 patients with PSC (64% men, mean age at referral 49 years) were followed for a mean of 9.8 years. Eighty patients (62.5%) with dominant biliary strictures had a median of 3 (range 0-34) interventions, compared with 0 (0-7) in the 48 patients without dominant strictures (P<0.001). Endoscopic interventions included the following: (i) stenting alone (46%), (ii) dilatation alone (20%), (iii) dilatation and stenting (17%) and (iv) none or failed intervention (17%, of whom most required percutaneous transhepatic drainage). The major complication rate for endoscopic retrograde cholangiopancreatography was low (1%). The mean survival of those with dominant strictures (13.7 years) was worse than that for those without dominant strictures (23 years), with much of the survival difference related to a 26% risk of CC developing only in those with dominant strictures. Half of those with CC presented within 4 months of the diagnosis of PSC, highlighting the importance of a thorough evaluation of new dominant strictures. Repeated endoscopic therapy in PSC patients is safe, but the prognosis remains worse in the subgroup with dominant strictures. In our series, dominant strictures were associated with a high risk of developing CC.