Introduction

Lynch syndrome (LS) is a hereditary cancer syndrome, with an increased lifetime risk of developing colorectal cancer (CRC). Current guidelines recommend colonoscopy intervals of 2 years which requires high procedural quality for the patient’s safety. Although colonoscopy is a relatively safe procedure, there are risks of adverse events (AEs) such as perforation, bleeding, splenic injury and death. Thulin et al 2019, showed that the relative frequency of bleeding and perforation varies in Sweden (bleeding: 0.02%–0.27%; perforation: 0.02%–0.27%). There are insufficient data regarding safety and quality of coloscopy surveillance for LS patients. The aim of this study was to investigate the risk of AEs amongst LS patients during colonoscopy.

Aims & Methods

There are insufficient data regarding safety and quality of coloscopy surveillance for LS patients. The aim of this study was to investigate the risk of AEs amongst LS patients during colonoscopy.

Retrospective cohort study including 366 LS patients in endoscopic surveillance at the Karolinska University Hospital, August 1989-April 2021. Data from endoscopic surveillance colonoscopies were extracted from standardized protocols and medical records.

Results

Out of 1,887 endoscopies, 11 complications were documented within 30 days (0,58%). In this study 5/1887 (0,26%; 5/366 pts, 1,3%) endoscopies led to a documented complication of bleeding or perforation. Total number of colonoscopies per patient leading to occurrence of one complication were 6 (mean, 0-12).

Conclusion

Complications were higher compared to previously described data regarding AEs in Sweden. Due to high number of performed colonoscopies of LS patients, the lifetime risk for participation in a surveillance program needs to be considered in health economic risk-benefit analyses. Experienced high-volume endoscopists at selected centers and adherence to appropriate surveillance intervals may decrease the risk of complications.

References

Jamizadeh N, Walton Bernstedt S, Haxhijaj A, Andreasson A, Björk J, Forsberg A, Backman AS. Endoscopic surveillance of Lynch syndrome at a highly specialized center in Sweden: An observational study of interval colorectal cancer and individual risk factors. Front Oncol. 2023 Feb 20;13:1127707. doi: 10.3389/fonc.2023.1127707. PMID: 36890827; PMCID: PMC9987586.
Thulin T, Hammar U, Ekbom A, Hultcrantz R, Forsberg AM. Perforations and bleeding in a population-based cohort of all registered colonoscopies in Sweden from 2001 to 2013. United European Gastroenterology Journal. 2019;7(1):130-137. doi:10.1177/2050640618809782.

Introduction

Lynch syndrome is a hereditary cancer predisposition syndrome associated with a significantly increased risk of colorectal cancer (CRC). Despite regular colonoscopic surveillance, patients remain at considerable risk of developing CRC. Surgical resection has long been the cornerstone of curative treatment, but it often comes with substantial morbidity. Endoscopic en-bloc resection techniques such as endoscopic submucosal dissection (ESD) and endoscopic full-thickness resection (eFTR) may offer effective, organ-sparing alternatives for early invasive cancers, but data on their safety and oncological outcomes in Lynch syndrome patients are lacking.

Aims & Methods

We conducted a multicenter, multinational retrospective case series including Lynch syndrome patients with confirmed pathogenic variants in MLH1, MSH2, MSH6, PMS2, or EPCAM deletions who underwent endoscopic en-bloc resection for malignant colorectal lesions between 2010 and 2024. Clinical, procedural, histological, and follow-up data were collected from medical records. The primary outcome was the rate of curative endoscopic resection, defined as radical resection without the need for surgery and no locoregional recurrence or distant metastasis at 6 months. Secondary outcomes included locoregional recurrence or distant metastasis at 24 and 60 months, along with the number of additional resections performed.

Results

A total of 38 patients (mean age 61.3 ± 15 years, 50% female) underwent 17 ESDs, 19 eFTRs, 1 endoscopic intermuscular dissection (EID), and 1 hybrid procedure (Combined ESD + eFTR). The R0 resection rate was 89% (34/38). Thirteen (34%) patients underwent additional surgery, with 12 cases due to T1CRC with high risk features (including all 4 cases with R1 resection) and 1 case due to perforation. In 25 patients (66%), curative treatment was achieved through endoscopic resection alone. Of these, 18 completed at least 6-months of follow-up, all of whom were disease-free. At 24 months, endoscopy was performed in nine patients, all of whom remained disease-free. Two patients completed 60-months of follow-up with no recurrences.

Conclusion

This is the first and largest case series of patients with Lynch syndrome treated with en bloc endoscopic resection. In 7 out of 10 patients, curative treatment was achieved through endoscopic resection alone without exposing patients to the morbidity of oncological surgery. These findings suggest that ESD and eFTR are safe and could serve as minimally invasive alternatives to surgery for selected patients, warranting further prospective evaluation.

Introduction

Lynch Syndrome (LS), the most common hereditary colorectal cancer (CRC) syndrome, is associated with increased adenoma and carcinoma risks. Colonoscopy surveillance recommendations generally consider MMR gene-specific risk but remain largely standardized in terms of surveillance intensity and frequency. However, accumulating evidence suggests that genotype-specific differences in neoplasia risk may warrant more tailored approaches.

Aims & Methods

This study evaluated trends in adenoma and CRC incidence across surveillance visits stratified by genotype among LS patients. We analyzed 318 LS patients with pathogenic variants in MLH1, MSH2, MSH6, PMS2 or EPCAM each with ≥2 surveillance colonoscopies between 2015–2025 at MD Anderson Cancer Center in Texas, USA. Individuals with prior colorectal surgery, inflammatory bowel disease, incomplete colonoscopy, or sigmoidoscopy-only exams were excluded. Adenoma (tubular, tubulovillous [TVA], SSA) and advanced neoplasia (advanced adenoma or CRC) rates were assessed over three follow-up visits. Statistical comparisons used Kruskal-Wallis and Fisher’s exact tests (α=0.05).

Results

Among 205 patients with follow-up (median age 43.4, median follow-up 1089 days), tubular adenomas (TA) were observed in 58.8%, sessile serrated adenomas (SSA) in 16.2%, and advanced neoplasia (AN) in 7.8%. Five CRCs (2.4%) were identified overall. MSH2/EPCAM carriers (n=79) had the highest neoplasia burden, with TA in 57.0%, SSA in 20.3%, and 3 of 5 CRCs. MLH1 carriers (n=50) had TA in 43.4%, SSA in 2.0%, and 2 CRCs (4.0%). PMS2 (n=37) had the lowest burden (TA 21.6%, SSA 5.4%) and no CRCs. While per-visit incidence trends were not statistically significant, total adenoma count across genotypes differed significantly (p<0.05). Additionally, TA and TVA incidence at first follow-up varied significantly by genotype (p = 0.036 and 0.037, respectively).

Table: Neoplasia Outcomes by LS Genotype (n = patients with ≥1 follow-up)

Conclusion

These findings highlight important genotype-specific differences in cumulative adenoma and CRC burden among LS carriers. While MSH2/EPCAM and MLH1 carriers exhibited the highest neoplasia rates, PMS2 carriers demonstrated consistently low lesion and cancer incidence. These results support the need for genotype-based surveillance strategies to reduce unnecessary procedures while preserving cancer prevention.

Disclosure

The authors declare that they have no conflicts of interest related to this work.

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)

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

Colonoscopic surveillance reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. Still, its invasiveness and high costs highlight the need for a non-invasive approach to predict the presence of neoplastic lesions.

Aims & Methods

This study aimed to identify faecal bacterial biomarkers to discern between carriers with colorectal lesions and those with normal colon.
Two independent Spanish cohorts (a training and a validation cohort) were recruited through two multicenter studies (Table 1). Participants provided a faecal sample before surveillance colonoscopy to quantify the abundance of F. prausnitzii (FPRA) and its phylogroups I and II (PHGI and PHGII), P. stomatis (PTST), B. fragilis (BCTF), B. thetaiotaomicron (BCTT), B46 (best BLAST match S. variabile), G. morbillorum (GMLL), B48 (best BLAST match R. faecis), and E. coli (ECO) through qPCR. Eubacteria (EUB) was quantified as the total bacterial load. Participants were classified based on colonoscopy findings as normal colonoscopy (NC), non-advanced adenoma (NAA), and advanced neoplasia (AN, including advanced adenoma and CRC). A bacterial signature for neoplasia prediction was defined and validated in the training and validation cohorts, respectively.

Table 1. Main characteristics of the study participants. NC, normal colonoscopy; NAA, non-advanced adenoma; AA, advanced adenoma; CRC, colorectal cancer.

Results

The bacterial abundances were analysed in the training cohort according to age, sex, body mass index (BMI), germline mutation, and colonoscopy findings. Significant moderate positive correlations were identified between the abundances of BCTF and age (r=0.325, p=0.040), and PHGII and BMI (r=0.399, p=0.010). A significant negative correlation was identified between GMLL abundance and BMI (r=-0.331, p=0.036). Patients harbouring MLH1 mutations exhibited a significantly higher abundance of FPRA compared to PMS2 carriers (p=0.048). Patients with neoplasia (NAA+AN) presented significantly lower abundances of BCTF (p=0.027) and B48 (p=0.038) than patients with NC. Patients with AN presented a significantly lower abundance of PTST compared to patients with NC or NAA (p=0.032).
Although all the bacterial markers achieved a sensitivity of 100% to predict the presence of neoplasia, none of them presented a specificity higher than 25% by itself. To maintain sensitivity and increase specificity a bacterial signature was defined including ECO, BCTF, GMLL, FPRA, PHGI, PHGII, and B46 combined with the inherited mutation. The signature showed 100% sensitivity (SS), 52.50% specificity (SP), 34.48% positive predictive value (PPV), and 100% negative predictive value (NPV). This signature was subsequently validated demonstrating 100% SS, 56.45% SP, 53.44% PPV, and 100% NPV.

Conclusion

A new faecal bacterial signature to predict the presence of colorectal neoplasia in LS carriers has been identified, showcasing its potential usefulness to improve and personalise LS surveillance, optimising endoscopic resources, and providing a less invasive and cost-effective approach.

Disclosure

S. Taboada-López, M. Malagón, S. Ramió-Pujol and M. Serra-Pagès are employees of GoodGut.

Introduction

Lynch syndrome (LS) is the most frequent hereditary cancer syndrome, responsible for 3-5% of all colorectal cancer (CRC) cases. Patients with LS are at increased risk for metachronous CRC, influenced by the specific gene involved and the extent of prior surgical intervention¹. However, the impact of colonoscopy surveillance on metachronous CRC incidence in LS carriers has not been clearly defined.

Aims & Methods

To characterize LS carriers at risk of developing metachronous CRC based on the affected gene and the extent of prior surgery. To describe follow-up characteristics, particularly the rate of colonoscopy surveillance. To report the incidence of metachronous CRC according to surgical extent and gene mutation. To analyze potential risk factors associated with metachronous CRC development.
This retrospective multicenter study included 583 LS carriers diagnosed with CRC; 43 were excluded due to missing surgical or follow-up data, resulting in 540 patients analyzed. Patients were categorized by high-risk genes (MLH1, MSH2) or low-risk genes (MSH6, PMS2) and by surgical extent (extensive or partial colectomy). Colonoscopy surveillance was defined as at least one colonoscopy following the initial CRC diagnosis or between successive CRC events in cases of metachronous CRC. Survival analysis assessed the incidence of metachronous CRC.

Results

Among the 540 included carriers, 247 (45.7%) had MLH1 mutations, 181 (33.5%) MSH2, 80 (14.8%) MSH6, and 32 (5.9%) PMS2. Participants were grouped into four categories: high-risk/extensive colectomy (N=58), high-risk/partial colectomy (N=370), low-risk/extensive colectomy (N=9), and low-risk/partial colectomy (N=103). Age at first CRC diagnosis was significantly higher in high-risk groups compared to low-risk groups. No differences were found between groups regarding sex, tumor location, or tumor stage. Median follow-up duration was 8.6 years (IQR 4.5-14.6), with no significant differences among groups. During follow-up, 107 cases of metachronous CRC occurred. Survival analysis revealed significant differences in metachronous CRC incidence (Log-rank test: p=0.006), with 10-year incidence rates of 6.4% for high-risk/extensive colectomy, 17.9% for high-risk/partial colectomy, 0% for low-risk/extensive colectomy, and 4.8% for low-risk/partial colectomy groups. Risk factors significantly associated with metachronous CRC included high-risk gene mutations (HR 2.49, 95% CI 1.2-4.77) and initial CRC diagnosis before the year 2000 (HR 1.61, 95% CI 1.02-2.55). Colonoscopy surveillance was associated with a reduced risk of metacronous CRC (HR 0.06, 95% CI 0.04-0.09).

Table 3. Metachronous CRC risk factors

Conclusion

Individuals carrying pathogenic variants in MLH1 or MSH2 who undergo partial colectomy face a markedly increased risk of developing metachronous CRC. Nonetheless, the introduction of structured colonoscopic surveillance and optimized management strategies after the year 2000 has significantly mitigated this risk. These findings are essential for informing surgical decision-making in patients with LS and CRC, particularly when evaluating the most appropriate extent of colectomy.

References

Eikenboom EL, Moen S, Van Leerdam ME, Papageorgiou G, Doukas M, Tanis PJ, et al. Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study. The Lancet Gastroenterology & Hepatology. 2023 Dec;8(12):1106–17.