Low prevalence of biliary tract cancer with defective mismatch repair genes in a Japanese hospital-based population

Abstract

Recent studies have reported that immune checkpoint inhibitors are effective against various defective mismatch repair (dMMR)/microsatellite instability-high (MSI-H) cancers. A limited number of reports are available on the frequency of dMMR/MSI-H carcinoma in biliary tract cancer (BTC), describing its clinicopathological characteristics and prognosis. The latter carcinoma is also associated with Lynch syndrome (LS). The present study was performed to investigate the frequency of patients with dMMR/MSI-H in BTC and the clinical characteristics of BTC with dMMR/MSI-H in a single institution in Japan. A total of 116 patients with BTC who underwent curative surgical resection at Kagawa University Hospital between January 2008 and December 2017 were included. The protein expression levels of the mismatch repair (MMR) genes [mutL homolog 1 (MLH1), mismatch repair endonuclease PMS2 (PMS2), MutS homolog (MSH)2 and MSH6] were assessed by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded tissue specimens. Subsequently, MSI testing was performed on patients who exhibited loss of MMR protein expression. Loss of expression of one or more proteins was detected in five cases (4.3%). Loss of MLH1/PMS2 expression was observed in one case of intrahepatic cholangiocarcinoma, whereas loss of PMS2 expression was noted in one case of perihilar cholangiocarcinoma. Loss of MSH2/MSH6 and MSH6 expression was noted in two cases of distal cholangiocarcinoma and loss of PMS2 expression in one case of ampullary carcinoma. Out of the five patients, two demonstrated MSI-H. Microsatellite stability was observed in two cases and for one case, no data were available. Two MSI-H cases were patients with loss of expression of MLH1/PMS2 and MSH2/MSH6. None of the five patients exhibited a past medical history or family history of suspected LS. The frequency of dMMR in BTC was ~5%, which was similar to that reported by similar studies performed in other countries. In the present study, IHC appeared to be more useful than MSI testing for detecting MMR abnormalities with regards to the detection rate. Furthermore, there may only be a limited number of patients with BTCs who are likely to benefit from the therapeutic effects of treatment with immune checkpoint inhibitors.

Keywords: Lynch syndrome; biliary tract cancer; defective mismatch repair; immunohistochemistry; microsatellite instability-high.

Figure 1.

Expression pattern of MMR proteins in tissues from patients with biliary tract cancer and defective MMR. In case 1, loss of MLH1 and PMS2 was observed in the nuclei of cancer cells, while loss of MSH2 and MSH6 was observed in case 2. In case 3, loss of MSH6 was observed in the nuclear region of the cancer cells, while loss of PMS2 was observed in cases 4 and 5. The arrowheads indicate cancer cells (magnification, ×200). MMR, mismatch repair; MLH1, mutL homolog 1; PMS2, mismatch repair endonuclease PMS2; MSH, MutS homolog.

Figure 2.

Representative electropherograms of the cancer tissues exhibiting MSI-H. The presence of MSI for (A) case 1 and (B) case 2 is indicated. MSI-H is present when the maximal peak at each marker is situated outside the quasi-monomorphic variation range (gray zone). In cases 1 and 2, different-sized peaks were observed other than a distinctive peak from an allele (plus). Different-sized peaks were described as ‘positive’ and the results that did not yield peaks as ‘negative’. Five mononucleotide microsatellite markers: BAT25, BAT26, NR21, MONO-27 and NR24. MSI-H, MSI-high; MSI, microsatellite instability.