Complications of colonoscopy surveillance of patients with Lynch syndrome - 33 years of follow up.

BACKGROUND AND STUDY AIMS: Lynch syndrome (LS) is a hereditary autosomal dominant condition, with an increased lifetime risk of developing malignancies including colorectal cancer (CRC). Current guidelines differ in recommended colonoscopy-surveillance intervals from 1 to 2 years. Although colonoscopy is considered a safe procedure, there are risks of severe adverse events (SAEs), such as perforation and bleeding, as well as adverse events (AEs), such as abdominal discomfort and post-colonoscopy gastrointestinal infections. Colonoscopy-related bleeding and perforation rates have been reported 0.17% and 0.11%, respectively. However, there are insufficient data regarding complications of colonoscopy-surveillance for LS patients. This study aims to investigate the risk of AEs among LS patients during colonoscopy in the Stockholm region. PATIENTS AND METHODS: This retrospective cohort study includes 351 LS patients undergoing endoscopic surveillance at the Karolinska University Hospital, August 1989 - April 2021. Data from endoscopic surveillance colonoscopies were extracted from patients' medical records. RESULTS: Of 1873 endoscopies in 351 LS patients, 12 complications (AEs) were documented within 30 days (0.64%) and with a total of 3 bleedings (SAEs, 0.16%). No perforations were identified. CONCLUSION: Colonoscopy surveillance for LS patients shows a comparatively low risk of AEs per-examination. Colonoscopy complications per-patient, including both SAEs and AEs, show a significantly higher risk. Colonoscopy complications only including SAEs, show a comparatively low risk. Understanding the lifetime risk of surveillance-related colonoscopy complications is important when designing targeted surveillance programmes.

Quality of endoscopic surveillance of Lynch syndrome patients in a Swedish cohort.

Background and study aims Risk factors for colorectal cancer (CRC) in Lynch syndrome (LS) include sex, age, smoking, high body mass index (BMI), surveillance interval length, and risk genotype. The Boston Bowel Preparation Scale (BBPS) produces a standardized bowel cleanliness rating. A low BBPS score might be a risk factor for missed early lesions. The aim of this study was to investigate the correlation between BBPS score and adenoma detection (with known risk factors for CRC) and surveillance interval with CRC detection in LS patients. Methods A retrospective cohort study including 366 LS patients with 1,887 colonoscopies under surveillance in Stockholm, Sweden from 1989 to 2021 was conducted. Associations were tested using linear and logistic regression. Results We found no association between BBPS score and number of adenomas detected. A low BBPS score was found to be associated with older age (regression coefficient (coeff) -0.015; 95% confidence interval [CI] -0.026 to -0.004; P = 0.007) and obesity (coeff = -0.48; 95% CI: -0.89 to -0.062; P = 0.024). A higher number of detected adenomas was associated with older age (coeff = 0.008; 95% CI 0.004 to 0.012; P < 0.001), male sex (coeff = 0.097; 95% CI 0.008 to 0.19; P = 0.033) and CRC (coeff = 0.28; 95% CI 0.061 to 0.50; P = 0.012). Surveillance interval length was not significant in CRC detection. Conclusions Bowel cleanliness was not associated with adenoma detection and was less likely achieved in patients who were older and had higher BMI. Adenoma detection was associated with older age and male sex. The results indicate the need for better adherence to guidelines and attention to older age groups, men, and patients with obesity.

Endoscopic surveillance of Lynch syndrome at a highly specialized center in Sweden: An observational study of interval colorectal cancer and individual risk factors.

Introduction: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC). In order to detect CRCs amongst LS patients, regular colonoscopies are recommended. However, an international agreement on an optimal surveillance interval has not yet been reached. In addition, few studies have investigated factors that could potentially increase the CRC risk amongst LS patients. Aims: The primary aim was to describe the frequency of CRCs detected during endoscopic surveillance and to estimate the interval from a clean colonoscopy to CRC detection amongst LS patients. The secondary aim was to investigate individual risk factors, including sex, LS genotype, smoking, aspirin use and body mass index (BMI), on CRC risk amongst patients that develop CRC before and during surveillance. Material and methods: Clinical data and colonoscopy findings from 366 LS patients' 1437 surveillance colonoscopies were collected from medical records and patient protocols. Logistic regression and Fisher's exact test were used to investigate associations between individual risk factors and CRC development. Mann-Whitney U test was used to compare the distribution of TNM stages of CRC detected before surveillance and after index. Results: CRC was detected in 80 patients before surveillance and in 28 patients during surveillance (10 at index and 18 after index). During the surveillance programme, CRC was detected within 24 months in 65% of the patients, and after 24 months within 35% of the patients. CRC was more common amongst men, previous and current smokers, and the odds of developing CRC also increased with an increasing BMI. CRCs were more often detected amongst MLH1 and MSH2 carriers during surveillance, compared to the other genotypes. Conclusions: We found that 35% of the CRC cases detected during surveillance were found after 24 months. MLH1 and MSH2 carriers were at higher risk of developing CRC during surveillance. Additionally, men, current or previous smokers, and patients with a higher BMI were at higher risk of developing CRC. Currently, LS patients are recommended a "one-size-fits-all" surveillance program. The results support the development of a risk-score whereby individual risk factors should be taken into consideration when deciding on an optimal surveillance interval.

Exome sequencing in a Swedish family with PMS2 mutation with varying penetrance of colorectal cancer: investigating the presence of genetic risk modifiers in colorectal cancer risk.

OBJECTIVE: Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes, such as the PMS2 gene, and is characterised by a familial accumulation of colorectal cancer. The penetrance of cancer in PMS2 carriers is still not fully elucidated as a colorectal cancer risk has been shown to vary between PMS2 carriers, suggesting the presence of risk modifiers. METHODS: Whole exome sequencing was performed in a Swedish family carrying a PMS2 missense mutation [c.2113G>A, p.(Glu705Lys)]. Thirteen genetic sequence variants were further selected and analysed in a case-control study (724 cases and 711 controls). RESULTS: The most interesting variant was an 18 bp deletion in gene BAG1. BAG1 has been linked to colorectal tumour progression with poor prognosis and is thought to promote colorectal tumour cell survival through increased NF-κB activity. CONCLUSIONS: We conclude the genetic architecture behind the incomplete penetrance of PMS2 is complicated and must be assessed in a genome wide manner using large families and multifactorial analysis.

[Updated Swedish guidelines for endoscopic surveillance after colorectal polypectomy]. / Nya riktlinjer: endoskopisk kontroll efter kolorektal polypektomi.

These new guidelines are based on the recommendations published by European Society of Gastrointestinal Endoscopy (ESGE) in 2020. Low risk patients, i.e. after removal of 1-4 <10 mm adenomas with low grade dysplasia (irrespective of villous components), or any serrated lesion (hyperplastic polyp, sessile serrated lesion, or traditional serrated adenoma) <10 mm without dysplasia, are not recommended a surveillance colonoscopy. High-risk patients, i.e. after removal of at least one adenoma ≥10 mm or with high grade dysplasia or any serrated lesion ≥10 mm or with dysplasia, should undergo a surveillance colonoscopy after 3 years. If high-risk lesions are detected at surveillance colonoscopy, a 3-year repetition of the next endoscopic examination is recommended. If a high-risk patient has no high-risk lesions at surveillance colonoscopy, a 5-year period is recommended until the next surveillance colonoscopy. In general, follow-up should be terminated at 80 years of age.

Room for improvement: One third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer.

BACKGROUND: Lynch syndrome is caused by germline mutations in the mismatch repair genes and is characterised by a familial accumulation of colorectal and other cancers. Earlier identification of Lynch syndrome patients enables surveillance and might reduce the risk of cancer. It is important to explore whether today's clinical care discovers patients with Lynch syndrome suitable for surveillance in time. This study aimed to describe what led to a diagnosis of Lynch syndrome in the cohort referred to the Hereditary Gastrointestinal Cancer Unit, Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance. METHODS: This was a descriptive study. Data from 1975 to 2018 were collected and compiled as a database. Age at diagnosis was calculated from the date when a pathogenic MMR gene mutation was confirmed, from the period June 1994-September 2018. Data were collected from patient protocols prospectively during patient consultations and medical records retrospectively. Criteria for inclusion were registration at the outpatient clinic and a confirmed mismatch repair gene mutation. RESULTS: A total of 305 patients were eligible for inclusion. Three major reasons for diagnosis were identified: 1. Predictive testing of a previously known mutation in the family (62%, mean age 37), 2. A family history of Lynch associated tumours (9%, mean age 37), 3. A diagnosis of cancer (29%, mean age 51). The proportion diagnosed due to cancer has not changed over time. CONCLUSION: A high proportion of patients (29%) were identified with Lynch syndrome after they had been diagnosed with an associated cancer, which suggests that there is significant room for improvement in the diagnosis of patients with Lynch syndrome before cancer develops.

Older age is a risk factor for inadequate energy intake during acute, severe IBD and is associated with shorter time to relapse.

BACKGROUND: Effects of nutritional intake on inflammatory bowel disease (IBD) flare resolution are unknown. We hypothesised that nutritional factors during hospitalisation for acute severe IBD are associated with risk of subsequent relapse. We also studied risk factors for inadequate energy intake. METHODS: Patients admitted to the Karolinska Hospital Gastroenterology ward with IBD flare during 2015-2016 were retrospectively identified. In total, 91 patients were included. Data on nutrition, disease factors, inflammatory markers, and daily energy requirement were extracted. Requirement of new systemic steroid prescription, intensification of biological therapy, readmission, surgery, and calprotectin level were individually used as proxies for disease relapse. Follow-up was one year after discharge. Adjustments for age and sex were made where appropriate. RESULTS: Overall, 19%, 31%, and 45% of patients had days with energy intake <30, <50, and <70% of calculated requirement. Older age was associated with a higher number of days with energy intake <30, <50, and <70% of calculated requirement (regression coefficient 0.03, 0.04, 0.06 respectively, p = .012, .017, .008). The number of days with energy intake <30 and <70% of the calculated requirement and the length of the hospitalisation were associated with shorter time to new steroid prescription (hazard ratio 1.3, 1.1, 1.04 respectively, p = .016, .034, .011). CRP and calprotectin were not associated with relapse. CONCLUSION: Older age is a predictor of inadequate energy intake during hospitalisation for acute severe IBD. Inadequate energy intake adjusted for age and sex during IBD flare was better predictor of time to the next steroid-requiring relapse than inflammatory markers.

[Lynch syndrome is a major cause of monogenetic familial colorectal cancer]. / Många fall av Lynchs syndrom upptäcks först vid cancerdiagnos - Ökad medvetenhet om ärftlig cancer och regelbunden kontroll av anlagsbärare kan minska mortalitet och morbiditet.

Individuals with a history of colorectal or endometrial cancer younger than 50 years of age or with relatives younger than 50 years of age with a history of any of these malignances should be referred to clinical genetics for further diagnostic examinations and genetic counseling. Lynch syndrome is caused by mutations in mismatch repair genes and implicates an increased risk for colorectal cancer as well as endometrial cancer. Routine surveillance for this group of individuals regarding colorectal cancer by means of colonoscopy and endometrial cancer by means of transvaginal ultrasound as well as endometrial biopsies is recommended annually or biennially. Several preventive measures are under development, such as chemoprevention and vaccination. During 2015 we investigated reasons for diagnosis among those registered at Karolinska University Hospital. We found that a substantial part of this group of individuals was diagnosed in conjunction with their diagnosis of cancer; a prerequisite in order to offer at-risk individuals preventive measures is to improve identification of these individuals and offer them presymptomatic genetic testing in order to identify predisposing mutations.

Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort.

Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patient's germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.