Introduction and objective
Lynch syndrome (LS) is an autosomal dominant disorder caused by mutations in DNA mismatch repair (MMR) genes that predisposes affected individuals to a variety of cancers. LS is currently believed to occur in about 1 in 300 people in the general population. An increased risk of upper tract urothelial carcinoma (UTUC) in LS has been well described in the literature, specifically in those with MSH2 gene mutation. Our group and others have also described an increased risk of bladder urothelial cancer (UC) in this population. However, little is known about the pathological features and clinical behavior of LS associated bladder cancer.
Methods
Bladder UC data between 1980 to 2019 were evaluated in MMR gene (MSH2, MLH1, MSH6, PMS2, EPCAM) mutation carriers within the Familial Gastrointestinal Cancer Registry (FGICR) in Toronto, Canada. Pathology, recurrences, and progression data were obtained. The American Urological Association (AUA) risk stratification for non-muscle invasive bladder cancer (NMIBC) was used to risk-stratify cases.
Results
Among 32 bladder UC patients with confirmed MMR mutations, 28 patients after an initial transurethral resection of bladder tumor (TURBT) had available data for review only. All cases were found with NMIBC on pathology, none with muscle invasive or metastatic disease. 12 cases (43%) were classified as low-risk, 6 (21%) were intermediate, and 10 (36%) were high-risk. 12/28 cases were high grade (HG) (5 TaHG and 7 T1HG). Eleven (39%) patients had recurrences, and 6 of these patients had worse pathology (grade and/or stage) on recurrence. Median time to recurrence was 28.5 months (IQR38.5). With a median follow up time of 5.3 years, 5 (18%) patients progressed to muscle invasive bladder cancer (2 from the low-risk group, 1 from the intermediate group, and 2 from the high-risk group). Median time to progression was 36 months (IQR 42.3).
Conclusions
At the time of the initial presentation, NMIBC accounted for 100% of all LS-associated UC, in sharp contrast with the 25-30% of muscle-invasive disease expected in most series of sporadic tumors. Ta was observed in 75%, of tumors, similar to what would be expected for sporadic cases, although over half of these patients had either intermediate or high-risk NMIBC as per the AUA risk stratification. A worrisome 18% of NMIBC patients progressed to muscle-invasive disease. Interestingly, 20% of these came from a low-risk group, which is intriguing and unexpected. Our finding suggests a possible more aggressive clinical behavior of bladder UC in the LS population.