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Comparison of the novel quantitative ARMS assay and an enriched PCR–ASO assay for K-ras mutations with conventional cytology on endobiliary brush cytology from 312 consecutive extrahepatic biliary stenoses

¹ Department of Pathology, Academic Medical Centre Amsterdam, 1100 DD Amsterdam, The Netherlands
² AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK

Correspondence to:
Dr G J A Offerhaus
Department of Pathology, Academic Medical Center, Amsterdam, PO Box 22660, 1100 DD, Amsterdam, The Netherlands; g.j.offerhaus{at}amc.uva.nl Background: Extrahepatic biliary stenosis (EBS) has malignant and benign causes. Patients with EBS are at risk of having or developing malignancy. Accurate diagnostic tests for early detection and surveillance are needed. The sensitivity of biliary cytology for malignancy is low. K-ras mutation analysis on brush cytology is a valuable adjunct, but specificity is low. A quantitative test for K-ras mutations has been developed: the amplification refractory mutation system (ARMS).

Aim: To assess the test characteristics and additional value of ARMS in diagnosing the cause of EBS.

Methods: Brush samples from endoscopic retrograde cholangiopancreatography were collected from 312 patients with EBS. K-ras mutation analysis was performed using ARMS—allele specific amplification was coupled with real time fluorescent detection of PCR products. Results were compared with conventional cytology and K-ras mutation analysis using allele specific oligonucleotide (ASO) hybridisation, and evaluated in view of the final diagnosis.

Results: The test characteristics of ARMS and ASO largely agreed. Sensitivity for detecting malignancy was 49% and 42%, specificity 93% and 88%, and positive predictive value (PPV) 96% and 91%, respectively. The sensitivity of ARMS and cytology combined was 71%, and PPV was 93%. The specificity of ARMS could be increased to 100% by setting limits for the false positives, but reduced sensitivity from 49% to 43%.

Conclusions: ARMS can be considered supplementary to conventional cytology, and comparable to ASO in diagnosing malignant EBS. A specificity of 100% can be achieved with ARMS, which should be considered in the surveillance of patients at risk for pancreatic cancer.

Abbreviations: ARMS, amplification refractory mutation system; ASO, allele specific oligonucleotide; EBS, extrahepatic biliary stenosis; ERCP, endoscopic retrograde cholangiopancreatography; PCR, polymerase chain reaction

Keywords: K-ras; amplification refractory mutation system; allele specific oligonucleotide; brush cytology; extrahepatic biliary stenosis

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