Introduction

Lynch syndrome (LS) is a heritable autosomal dominant genetic condition caused by mutations in several DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, PMS2 and EPCAM. Affected individuals have an increased life-long risk of developing cancers especially colorectal cancer (CRC) and endometrial cancer (EC). LS accounts for approximately up to 3% of all CRC. Traditionally, diagnosis was based on clinical criteria (Amsterdam II, Bethesda and revised Bethesda), which have proven to be of limited applicability in clinical practice. In recent years tumor testing via immunohistochemistry (IHC) of all CRCs for the expression of MMR proteins has successfully integrated into clinical care. Universal screening through IHC of CRC tumor samples is cost-effective and recommended by major guidelines, which also recommend its application to endometrial cancers.

Aims & Methods

Our aim was to assess the main differences between LS families where the first individual received a genetic diagnosis after IHC on tumor sample and LS families where the first individual received a genetic diagnosis due to meeting the Amsterdam II or revised Bethesda criteria. We obtained data (year of genetic test confirmation, first tumor diagnosis, family tree) of all our single center’s LS patients who undergo surveillance in our Institute (n = 101 patients). Accordingly, we grouped patients by family and identified each family’s index case-defined as the first individual to receive a genetic diagnosis - and relatives of index cases. Therefore, we divided the cohort into two groups: families whose the index case was identified after IHC on tumor sample and families whose the index case was identified due to meeting the Amsterdam II or revised Bethesda criteria. We subsequently evaluatedwhether patients identified through IHC would have also met the revised Bethesda or Amsterdam II criteria for genetic testing.

Results

We found that index cases identified through IHC (n =16; of which 8 on CRC tissue, 7 on EC tissue and 1 on lung cancer tissue) had a mean age of 57.93 years at the time of genetic diagnosis, whereas those identified through clinical criteria (n = 20) had a mean age of 46.35 years. As for the relatives, those whose index case was identified via IHC (n = 11) had a mean age of 45.72 years, while relatives of individuals diagnosed based on clinical criteria (n= 54) had a mean age of 37.96 years. Patients carrying pathogenic variants in MSH6 and PMS2 (leading to lower penetrance and a late onset of LS related cancers) were 8 out of 16 (50 %) in the IHC group and 1 out of 20 (5 %) in the clinical criteria group. Furthermore 8 out of 16 (50%) index patients diagnosed through IHC did not meet the Amsterdam II criteria.

Conclusion

The mean age of index cases diagnosed due to clinical criteria is lower than that of cases identified through IHC, probably because of the early onset of LS related cancers in these patients and since the clinical criteria require at least one case to be diagnosed at a young age (<50 years old). In contrast, universal immunohistochemistry (IHC) screening enables the detection of all patients with mismatch repair-deficient tumors, including those diagnosed later in life and those without an evident family history of cancer or carrying pathogenic variants in genes such as MSH6 and PMS2 with a lower penetrance. Our data strengthen the important role of IHC screening for MMR proteins loss of expression both in CRC and EC to find LS families that would not be possible to identify with clinical criteria only.

Introduction

Lynch syndrome (LS) is a hereditary condition associated with an increased risk of early colorectal cancer (CRC), due to mutations in DNA mismatch repair (MMR) genes, accounting for 3-5% of all CRC. High-definition screening colonoscopies in specialized centers reduce CRC mortality in this setting.

Aims & Methods

We conducted a clinical audit in a large cohort of these patients, ultimately to enhance the quality of care provided. We performed a retrospective evaluation of the clinical characteristics and risk factors of LS patients under surveillance at our reference center. CRC surveillance program includes colonoscopy every 2 years, starting at ages 20–25 for MLH1/MSH2 carriers and 30–35 for MSH6/PMS2 carriers. We further analyzed compliance to surveillance protocol and its clinical outcomes – our primary endpoint was mortality rate due to CRC and secondary endpoints were time to first advanced colorectal lesion and CRC staging at diagnosis.

Results

A total of 508 patients were included (44% MSH2, 23% MLH1, 20% MSH6, and 13% PMS2). The mean age at surveillance initiation was 44.4 years, with 35.6% starting after the diagnosis of a Lynch syndrome-associated neoplasia. The mean surveillance duration was 5.6 years. Each patient underwent an average of four colonoscopies, with 50% performed within the recommended surveillance intervals.
During the follow-up period, 35 patients were diagnosed with CRC, with a mean time to first advanced colorectal polyp of 3.7 years and for the first CRC diagnosis of 4.8 years. Having any colonoscopy outside the established interval was not associated with higher CRC incidence (p = 0,647). CRC cases diagnosed prior to surveillance initiation (n=143) were more advanced (58.1% stage ≥ II) and were treated with segmental colectomy in 80% of cases. In contrast, CRC cases diagnosed during surveillance (n=48) were detected at earlier stages (64.6% Tis/T1) and managed with endoscopic resection (29%) or total colectomy (56%) (p < 0.001).
The incidence of CRC was higher in MLH1/MSH2 carriers compared to MSH6/PMS2 carriers (36% vs. 22%, p = 0.0020). The mean age at first CRC diagnosis was 45.6 years for MLH1/MSH2 carriers and 49.9 years for MSH6/PMS2 carriers (p = 0.053). The CRC-related mortality rate was 0.6% (n=3), all cases diagnosed before surveillance initiation.

Conclusion

Although adherence to the CRC surveillance program in LS patients can be optimized, our findings underscore its importance in specialized reference centers. Surveillance was associated with earlier CRC detection, less invasive therapeutic approaches, and reduced CRC-related mortality. Our results also show a lower incidence of CRC and an higher age at first CCR diagnosis in MSH6/PMS2 carriers, strengthening the personalized surveillance recommendations dependent on gene specificities.

References

Castillo-Iturra, J., Sánchez, A. and Balaguer, F. (2024) ‘Colonoscopic surveillance in Lynch Syndrome: Guidelines in perspective’, Familial Cancer [Preprint]
del Carmen, G. et al. (2023) ‘Colorectal surveillance outcomes from an institutional longitudinalcohort of Lynch syndrome carriers’, Frontiers in Oncology, 13
Kastrinos, F. et al. (2021) ‘Gene-specific variation in colorectal cancer surveillance strategies for Lynch syndrome’, Gastroenterology, 161(2)