Original Article: Laboratory Investigation Clinicopathological characteristics of patients with upper urinary tract urothelial cancer with loss of immunohistochemical expression of the DNA mismatch repair proteins in universal screening Shinji Urakami, 1,2 Naoko Inoshita, 3 Suguru Oka, 1 Yu Miyama, 3 Sachio Nomura, 4 Masami Arai, 4 Kazushige Sakaguchi, 1 Kazuhiro Kurosawa 1 and Toshikazu Okaneya 1 1 Department of Urology, Toranomon Hospital, 2 Okinaka Memorial Institute for Medical Research, 3 Department of Pathology, Toranomon Hospital, and 4 Department of Clinical Genetic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan Abbreviations & Acronyms HNPCC = hereditary non- polyposis colorectal cancer LS = Lynch syndrome IHC = immunohistochemical MLPA = multiplex ligation- dependent probe amplification MMR = mismatch repair MSI = microsatellite instability UUTC = upper urinary tract urothelial cancer Correspondence: Shinji Urakami M.D., Ph.D., Department of Urology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. Email: shinurakami@ybb.ne.jp Received 19 April 2017; accepted 11 September 2017. Online publication 22 November 2017 Objectives: To assess the detection rate of putative Lynch syndrome-associated upper urinary tract urothelial cancer among all upper urinary tract urothelial cancers and to examine its clinicopathological characteristics. Methods: A total of 143 patients with upper urinary tract urothelial cancer who had received total nephroureterectomy were immunohistochemically stained for the expression of mismatch repair proteins MLH1, PMS2, MSH2 and MSH6. For all suspected mismatch repair-deficient cases, MMR genetic testing was recommended and clinicopathological features were examined. Results: Loss of mismatch repair proteins was found in seven patients (5%) who were thus categorized as putative Lynch syndrome-associated upper urinary tract urothelial cancer. Five of these patients showed dual loss of MSH2/MSH6. Two patients were confirmed to be MSH2 germline mutation carriers. Histologically, all seven tumors were low-grade atypical urothelial carcinoma and showed its unique histological features, such as an inverted papilloma-like growth pattern and a villous to papillary structure with mild stratification of tumor cells. Six tumors had no invasion of the muscularis propria. No recurrence or cancer-related deaths were reported in these seven patients. Just three patients met the revised Amsterdam criteria. Conclusions: This is the first report that universally examined mismatch repair immunohistochemical screening for upper urinary tract urothelial cancers. The prevalence (5%) of putative Lynch syndrome-associated upper urinary tract urothelial cancers is much higher than we had expected. We ascertained that putative Lynch syndrome-associated upper urinary tract urothelial cancers were clinically in the early stage and histologically classified into low-grade malignancy with its characteristic pathological features. The clinicopathological characteristics that we found in the present study could become additional possible markers in the diagnosis of Lynch syndrome- associated upper urinary tract urothelial cancers. Key words: DNA mismatch repair proteins, immunohistochemistry, Lynch syndrome, universal screening, upper urinary tract cancer. Introduction LS is an autosomal dominant inherited cancer syndrome caused by germline mutations in DNA MMR genes including MLH1, MSH2, MSH6 and PMS2. 1 Mutations in the MMR gene occur in 0.2% of the general population. 2,3 Their inactivation results in a large increase in spontaneous mutability and a direct cellular oncogenic effect. 1 LS carriers are thus prone to various malignancies including cancers of the colon, rectum, endometrium, ureter, renal pelvis and small bowel. LS has also been referred to as HNPCC syndrome. 4 Many detailed epidemi- ological studies have reported on HNPCC. 5,6 HNPCC develops with early onset and involves multiple cancers. The lifetime risk of colorectal cancers in patients with LS is thought to exceed 50%. 7 Furthermore, it has been reported that approximately 1–5% of all colorectal cancers are caused by LS. 8,9 In addition, LS-related colorectal cancers have unusual © 2017 The Japanese Urological Association 151 International Journal of Urology (2018) 25, 151--156 doi: 10.1111/iju.13481