Despite the increasing number of individuals diagnosed with Lynch syndrome, few studies have reported prospective follow-up data in this high-risk population. While colorectal surveillance is well established, international consensus remains limited regarding optimal surveillance strategies for other organ systems, largely due to a lack of robust evidence.

This study is based on a retrospective analysis of prospectively collected data from a single prevention-oriented center. All included individuals were confirmed carriers of a pathogenic or likely pathogenic variant in one of the mismatch repair (MMR) genes associated with Lynch syndrome and were followed according to a structured surveillance protocol.

The primary objective of this study was to estimate the incidence of cancers diagnosed during prospective follow-up in this genetically defined population.

The secondary objective was to assess the concordance between observed cancers and current organ-specific surveillance recommendations as outlined in regional French guidelines.

517 patients carrying a P/LP variant in an MMR gene and enrolled in prospective follow-up. A total of 201 cancers were diagnosed during prospective follow-up. 

203 patients (39.3%) carried MSH2 or EPCAM P/LP variant, 181 had MLH1 (35%), 90 (17.4%) had MSH6  and 42 (8.1%) had PMS2. One patient carried two distinct variants affecting both EPCAM and MLH1. The median age at inclusion was 43 years (IQR: 32–52 years), and was 52 years (IQR: 40–64 years) at last follow-up. 52.8% were males and 47.2% were females, with a median follow-up duration of 8 years (IQR: 4–13 years). A total of 281 patients were cancer-free at the start of surveillance.

132 were subject to specific recommendations based on the underlying genetic predisposition. These included tumors of the upper and median GI tract (stomach, duodenum, jejunum, n=14), lower GI tract (colon and rectum, n=84), urinary tract (renal, bladder, and urothelial tumors, n=27), and gynecologic cancers (n=7). 

The organ-specific incidence rates were as follows:

– Lower GI tract (n = 84): 1.74% (95% CI, 1.37–2.11)

– Urinary tract (n = 27): 0.56% (95% CI, 0.35–0.77)

– Upper and median GI tract (n = 14): 0.29% (95% CI, 0.14–0.44)

– Gynecologic cancers (n = 7): 0.15% (95% CI, 0.04–0.25)

Outside of the recommended surveillance organs, 69 cancers were diagnosed (1.43%; 95% CI 1.09–1.77). The most frequent sites were skin-related tumors (cutaneous, sebaceous, basal cell, or melanoma; n = 26; 0.54%; 95% CI 0.33–0.75), followed by breast (n = 12; 0.25%; 95% CI 0.11–0.39), pancreas (n = 7; 0.15%; 95% CI 0.04–0.25), and prostate (n = 6; 0.12%; 95% CI 0.03–0.22).

Urinary tract tumors were predominantly diagnosed in an asymptomatic setting (n=21) through surveillance imaging, cytology, or incidental findings, while 2 cases were diagnosed due to symptoms. Among upper GI tumors (n=14), 6 were detected during routine endoscopic surveillance, and the remaining 8 were identified in symptomatic contexts. Of the 84 lower GI tumors, the vast majority (n=71) were diagnosed during scheduled surveillance colonoscopies, with only 11 cases detected due to symptoms. Gynecologic cancers (n=7) included 2 asymptomatic and 5 symptomatic cases.

Characteristics of the study population

This study provides robust prospective evidence supporting the value of structured, multidisciplinary surveillance in patients with Lynch syndrome. The majority of cancers covered by recommendations were detected at an asymptomatic stage, particularly in the lower GI and urinary tracts—underscoring the effectiveness of current surveillance protocols. The high rate of symptomatic upper and median GI tumors highlights the need to reassess surveillance strategies for this site. In addition, our findings support the integration of dedicated skin, breast, and prostate surveillance into personalized and comprehensive care plans for patients with Lynch syndrome.