Lynch syndrome (LS) is a hereditary cancer predisposition condition associated with elevated risk of several cancers, primarily colorectal (CRC)(15-80%), but also endometrial-ovarian (15-60%) and urothelial carcinoma (UC)(1-28%). It results from a mutation of a mismatch repair (MMR) gene. LS has autosomal dominant inheritance. MSH2 subtype mutations are found in 39.3% of all LS and this subtype carries a significantly elevated risk of UC, in particular of the upper tracts (UTUC) with a lifetime risk of up to 28% in carriers. As such, MSH2 carriers represent a significant risk burden for UC. There is no consensus on UC surveillance in LS patients. Current LS guidelines recommend annual urinalysis, with cystoscopy reserved for high-risk cases, but adherence varies due to invasiveness, cost, and logistical burden. CT urography (CTU) and voided cytology are the standard for UTUC detection, and cystoscopy for bladder UC, but these carry radiation exposure, cost, are invasive and lack sensitivity. Biomarker-based testing could reduce dependence on imaging and cystoscopy, with improved sensitivity. The Cxbladder Triage Plus test is a non-invasive voided urine test that integrates five mRNA biomarkers and FGFR3 and TERT DNA mutations, which are associated with UC. In a U.S. Veterans Affairs study, Cxbladder Triage Plus showed 94% sensitivity, 77% specificity, and a 99.3% negative predictive value.

A review of New Zealand’s LS surveillance guidelines was conducted, assessing adherence to international recommendations. Numbers of at-risk patients were calculated using data from the NZ Familial GI Cancer Service database. Studies on urinary biomarkers were evaluated to determine their utility for LS-associated UC and UTUC detection. We reviewed our experience using Cxbladder for surveillance in LS carriers.

Our review highlights significant challenges in LS UC surveillance. We estimate that very few LS patients at risk for UC receive screening for UC. Annual Cxbladder testing was performed on 17 LS patients without personal history of UC to assess UC risk, with follow up <7 years. During the review period, two patients returned elevated Cxbladder results proceeding to cystoscopy and CTU. One other patient had atypia on voided urine cytology and another patient requested standard investigations despite a normal Cxbladder level. No patient in the surveillance cohort developed UC. Compliance with Cxbladder testing in this small cohort was high.

Emerging evidence suggests that specific urinary biomarkers provide high sensitivity and specificity, allowing earlier intervention in LS patients. Cxbladder Triage Plus is a clinically validated, non-invasive tool for stratifying hematuria patients in UC evaluation. Annual testing integrated into LS patients surveillance protocols may streamline risk stratification and improve early UC detection, reducing imaging and invasive investigations.