Malignant potential of colorectal neoplasms in Lynch syndrome: an analysis of 325 lesions endoscopically treated at a single institute.

BACKGROUND: Patients with Lynch syndrome are at an increased risk of developing colorectal cancer, and the adenoma-carcinoma sequence is accelerated in these patients. However, the clinicopathological characteristics of colorectal neoplasms in Lynch syndrome patients are not well-known. METHODS: A total of 325 consecutive colorectal neoplasms were endoscopically removed from 68 patients with Lynch syndrome between June 2005 and May 2018 and retrospectively reviewed. RESULTS: Of the 325 lesions, 94 (29%), 220 (68%) and 11 (3%) were from patients with MLH1, MSH2 and MSH6 mutations, respectively. The median lesion size was 5 mm (range 2-40 mm), with 229 (71%) lesions having a non-polypoid morphology. The frequencies of advanced neoplasms, including high-grade adenomas, intramucosal carcinomas and submucosal invasive carcinomas were 14, 34, 97 and 93% for lesions with diameters of <5, ≥5 and <10, ≥10 and <20, and ≥20 mm, respectively. The frequencies of advanced neoplasms in the proximal colon, distal colon and rectum did not significantly differ (36, 35 and 41%, respectively). CONCLUSIONS: Our results suggest that the malignant transformation interval from low-grade adenomas to advanced neoplasms is similar in all parts of the colon. Furthermore, since one-third of neoplastic lesions with diameters of ≥5 and <10 mm and most of those ≥10 mm were advanced neoplasms, we recommend that in Lynch syndrome patients, careful colonoscopic surveillance should be performed throughout the colon, and all neoplastic lesions, regardless of the size, should be subjected to detailed endoscopic examination, complete resection and detailed pathological examination.

p53, Cyclin-D1, ß-catenin, APC and c-myc in Tumor Tissue from Colorectal and Gastric Cancer Patients with Suspected Lynch Syndrome by the Bethesda Criteria.

Colorectal cancer (CRC) is one of the most frequent neoplasms worldwide, and up to 15% have a family history. Lynch syndrome (LS) is a hereditary cause of CRC and gastric (GC). Individuals with LS have mutations in mismatch genes repair. p53, cyclin D1, ß-catenin, APC and c-myc proteins are involved in the cell cycle and carcinogenesis. OBJECTIVE: To study the expression of p53, Cyclin D1, ß-catenin, APC and c-myc proteins in patients with CRC and GC with at least one of the Bethesda positive criteria. Compare the expression of these proteins with the presence or absence of expression of the DNA repair proteins. PATIENTS AND METHODS: We included 70 individuals with CRC or GC with at least one of the Bethesda positive criteria. Protein expression of MLH1, MSH2, MSH6, PMS2, p53, cyclin D1, ß-catenin, APC and c-myc were analized by immunohistochemistry tumours tissues. RESULTS: Deficient expression of MLH1, MSH2, MSH6 and PMS2 were respectively 38.7%; 17.7%; 26.22% and 48.38%. We found a negative association between deficiency of PMS2 and age, and positive association between PMS2 deficiency and APC positive. The positive imunoexpression of APC increases by 4 times the chance of having deficiency of PMS2. CONCLUSIONS: Patients with loss of expression of PMS2 had a higher risk of mutation or deletion of APC and tumours with positive immunoexpression of cyclin D1 had an increased risk of loss of expression of MSH2. These results suggest that tumours with loss of expression of DNA repair proteins had a higher loss of cell control cycle.
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The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis.

PURPOSE: Endometrial cancer (EC) is often the sentinel cancer in women with Lynch syndrome (LS). However, efforts to implement universal LS screening in EC patients have been hampered by a lack of evidence detailing the proportion of EC patients that would be expected to screen positive for LS. METHODS: Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science. Proportions of test positivity were calculated by random and fixed-effects meta-analysis models. I2 score was used to assess heterogeneity across studies. RESULTS: Fifty-three studies, including 12,633 EC patients, met the inclusion criteria. The overall proportion of endometrial tumors with microsatellite instability or mismatch repair (MMR) deficiency by immunohistochemistry (IHC) was 0.27 (95% confidence interval [CI] 0.25-0.28, I2: 71%) and 0.26 (95% CI 0.25-0.27, I2: 88%), respectively. Of those women with abnormal tumor testing, 0.29 (95% CI 0.25-0.33, I2: 83%) had LS-associated pathogenic variants on germline testing; therefore around 3% of ECs can be attributed to LS. Preselection of EC cases did increase the proportion of germline LS diagnoses. CONCLUSION: The current study suggests that prevalence of LS in EC patients is approximately 3%, similar to that of colorectal cancer patients; therefore our data support the implementation of universal EC screening for LS.

A framework to build capacity for a reflex-testing program for Lynch syndrome.

PURPOSE: Lynch syndrome (LS) is the most common inherited cause of colorectal cancer. Although testing all colorectal tumors for LS is recommended, the uptake of reflex-testing programs within health systems has been limited. This multipronged study describes the design of a provincial program for reflex testing in Ontario, Canada. METHODS: We recruited key stakeholders to participate in qualitative interviews to explore the barriers and facilitators to the implementation of a reflex-testing program. Data were analyzed in an iterative manner, key themes identified, and a framework for a proposed program developed. RESULTS: Twenty-six key informants participated in our interviews, and several themes were identified. These included providing education for stakeholders (patients, primary care providers, surgeons); challenges with sustaining various resources (laboratory costs, increased workload for pathologists); ensuring consistency of reporting test results; and developing a plan to measure program success. Using these themes, a framework for the reflex-testing program was developed. At a subsequent stakeholder meeting, the framework was refined, and recommendations were identified. CONCLUSIONS: This study identifies factors to ensure the effective implementation of a population-level program for reflex LS testing. The final product is a prototype that can be utilized in other jurisdictions, taking into account local environmental considerations.

Tumor development in Japanese patients with Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) patients have a high risk of developing various tumors. This study aimed to clarify the characteristics of tumors developing in LS patients. METHODS: This is a retrospective review of 55 LS patients treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital. RESULTS: The median age at the diagnosis of the first malignant tumor and first LS-related tumor was 44 (range, 19-65) and 44 (range, 24-66) years, respectively. Of the 55 LS patients with developing malignant tumors, 45 (93.8%) developed an LS-related tumor as the first malignant tumor. Colorectal cancer (CRC) developed in 47 patients (85.4%), followed by endometrial cancer (n = 13, 56.5%) in females and gastric cancer (n = 10, 18.1%). In 6 gastric cancer patients, Helicobacter pylori was detected in resected specimens. Twenty-nine patients (52.7%) developed CRC and extra-colonic tumors; of these, 15 patients (48.3%) had mutations in MLH1, 10 (58.8%) in MSH2, and 4 (57.1%) in MSH6. At the age of 50, the cumulative incidence was 50.9% [95% confidence interval (CI), 36.9-63.3%] for CRC, 17.4% (95% CI, 5.2-35.6%) for endometrial cancer, and 5.5% (95% CI, 1.4-13.8%) for gastric cancer. Eight gastric cancer, one breast cancer patient, five bladder cancer patients, and one prostate cancer patient demonstrated loss of expression of the mismatch repair (MMR) protein; patients with thyroid cancer, spindle cell sarcoma, and giant cell tumors did not demonstrate this. CONCLUSION: Gastric cancer incidence was high in Japanese patients with LS and associated with H. pylori infection. MMR protein deficiency caused the development of malignant tumors in LS patients.

Update on Hereditary Colorectal Cancer.

In the past two decades, significant advances have been made in our understanding of colorectal (CRC) tumors with DNA mismatch (MMR) repair deficiency. The knowledge from molecular and genetic alterations in a variety of clinical conditions has refined the disease terminology and classification. Hereditary non-polyposis colorectal cancer (HNPCC) encompasses a spectrum of conditions that have significant phenotypic overlapping that makes clinical diagnosis a challenging task. Distinguishing among the HNPCC disorders is clinically important, as the approach to surveillance for patients and their at-risk family members differs according to risks for colonic and extracolonic cancer associated with each syndrome. Prospective and next-generation studies will provide valuable clinical information regarding the natural history of disease that will help differentiate the Lynch syndrome mimics and guide diagnosis and management for heterogeneous conditions currently grouped under the category of familial CRC. The review is intended to present and discuss the molecular nature of various conditions related to MMR deficiency and discusses the tools and strategies that have been used in detecting these conditions.

Clinicopathological Features and Type of Surgery for Lynch Syndrome: Changes during the Past Two Decades.

PURPOSE: The Korean Hereditary Tumor Registry, the first and one of the largest registries of hereditary tumors in Korea, has registered about 500 families with hereditary cancer syndromes. This study evaluates the temporal changes in clinicopathologic features and surgical patterns of Lynch syndrome (LS) patients. MATERIALS AND METHODS: Data on 182 unrelated LS patients were collected retrospectively. The patients were divided into the period 1 group (registered in 1990-2004) and 2 (registered in 2005-2014). The clinical characteristics of the two groups were compared to identify changes over time. RESULTS: The period 1 group included 76 patients; the period 2 group, 106 patients. The mean ages at diagnosis were 45.1 years (range, 13 to 85 years) for group 1 and 49.7 years (range, 20 to 84 years) for group 2 (p=0.015). The TNM stage at diagnosis did not differ significantly-period 1 group: stage 0-I (n=18, 23.7%), II (n=37, 48.7%), III (n=19, 25.0%), and IV (n=2, 2.6%); period 2 group: stage 0-I (n=30, 28.3%), II (n=35, 33.0%), III (n=37, 34.9%), and IV (n=4, 3.8%). Extended resection was more frequently performed (55/76, 72.4%) in the period 1 group than period 2 (49/106, 46.2%) (p=0.001). CONCLUSION: Colorectal cancer in patients with LS registered at the Korean Hereditary Tumor Registry is still diagnosed at an advanced stage, more than two decades after registry's establishment. Segmental resection was more frequently performed in the past decade. A prompt nationwide effort to raise public awareness of hereditary colorectal cancer and to support hereditary cancer registries is required in Korea.

Novedades en el cáncer colorrectal hereditario / New advances in hereditary colorectal cancer

El cáncer colorrectal es la neoplasia más frecuente en ambos sexos en España. Entre el 20-25% de los casos presentan historia familiar de dicho tumor y un 5-6% se presentan en el contexto de una mutación germinal, es decir, en el contexto de un síndrome hereditario. La importancia de identificar a los pacientes con síndromes hereditarios que predisponen a cáncer colorrectal radica en la posibilidad de poder aplicar medidas preventivas, de cribado y un manejo más adecuado tanto para ellos como para sus familiares. A continuación se detallan los estudios más relevantes sobre el cáncer colorrectal hereditario que fueron presentados este año en el congreso de la American Gastroenterological Association

Colorectal cancer is the most frequent malignancy in both sexes in Spain. Between 20% and 25% of affected individuals have a family history of the disease, and 5% to 6% have a germ mutation, i.e. the disease develops in the context of a hereditary syndrome. The importance of identifying patients with hereditary syndromes predisposing them to colorectal cancer lies in the possibility of applying preventive measures, screening, and more appropriate management of both patients and their families. The present article outlines the most important studies presented at the congress of the American Gastroenterological Association

The role of religious and existential well-being in families with Lynch syndrome: prevention, family communication, and psychosocial adjustment.

This study explored the role of religious (RWB) and existential well-being (EWB) on psychosocial factors, support network characteristics, and screening practices in families with Lynch syndrome, also referred to as hereditary nonpolyposis colon cancer (HNPCC). Participants were individuals with Lynch syndrome associated cancers and their first-degree relatives at risk of inheriting an identified deleterious mutation. Analyses considered both family RWB and EWB norms and individual deviations from that norm. Analyses controlled for age, gender, cancer diagnosis, number of respondents, and network size. Higher family RWB was associated with increased depressive symptoms (p < .05) and avoidant cognitions (p < .05). Higher family EWB was related to decreased depression symptoms (p < .001). Higher family EWB was associated with fecal occult blood testing (p < .01), and family communication about genetic counselling and testing (p < .01). Analyses pointed to individual effects of EWB above and beyond family-level effects. Individuals with lower EWB than their family had lower perceived risk for colorectal cancer (p < .05), communicated disease risk information to less family members (p < .05), and were less likely to undergo recent colonoscopies (p < .05). Participants with lower EWB than their family also had higher cancer worry (p < .01) and increased depressive symptoms (p < .001). Findings indicate the importance of assessing individuals within the context of their family network and being aware of family characteristics which may impact individual adjustment to disease risk. Interventions considering family-level factors may provide efficient pathways to improving psychosocial factors, screening practices, communication about disease risk and genetic testing, and cancer prevention.

Quality of life after surgery for colon cancer in patients with Lynch syndrome: partial versus subtotal colectomy.

BACKGROUND: Lynch syndrome is a disorder caused by mismatch repair gene mutations. Mutation carriers have a high risk of developing colorectal cancer. In patients with Lynch syndrome in whom colon cancer has been diagnosed, in general, subtotal colectomy instead of partial colectomy is recommended because of the substantial risk of metachronous colorectal cancer. However, the effect of more extensive surgery on quality of life and functional outcome is unknown. OBJECTIVE: The aim of this study was to investigate quality of life and functional outcome in patients with Lynch syndrome after partial colectomy and subtotal colectomy. DESIGN: This is a nationwide cross-sectional study in the Netherlands. SETTINGS: Two quality-of-life questionnaires (Short Form-36 and The European Organization for Research and Treatment of Cancer Colorectal Cancer-specific Quality of Life Questionnaire Module) and a functional outcome questionnaire (Colorectal Functional Outcome) were used. PATIENTS: Patients with Lynch syndrome who underwent surgery for colon cancer were included. MAIN OUTCOME MEASURES: The primary outcomes measured were quality of life and functional outcome. RESULTS: Questionnaires were sent to 192 patients with Lynch syndrome who underwent surgery for colorectal cancer. A total of 136 patients returned the questionnaire (response rate, 71%). Eighteen patients with rectal cancer, 9 patients with a permanent ileostomy, and 5 patients with an IPAA were excluded. Fifty-one patients underwent partial colectomy, and 53 underwent subtotal colectomy. None of the scales of the Short Form-36 survey showed a significant difference. Analysis of the Colorectal Functional Outcome questionnaire revealed that, after subtotal colectomy, patients have a significantly higher stool frequency (p ≤ 0.01) and a significantly higher score on stool-related aspects (p = 0.06) and social impact (p = 0.03). The European Organization for Research and Treatment of Cancer Colorectal Cancer-specific Quality of Life Questionnaire Module presented more problems with defecation after subtotal colectomy (p ≤ 0.01). LIMITATIONS: Certain selection bias cannot be ruled out. CONCLUSIONS: Although functional outcome is worse after subtotal colectomy than after partial colectomy, generic quality of life does not differ after the 2 types of surgery in Lynch syndrome. When discussing the options for surgery with the patient, all advantages and disadvantages of both surgical procedures, including quality of life and functional outcome, should be discussed.

Identification of patients at-risk for Lynch syndrome in a hospital-based colorectal surgery clinic.

AIM: To determine the prevalence of a family history suggestive of Lynch syndrome (LS) among patients with colorectal cancer (CRC) followed in a coloproctology outpatient clinic in Southern Brazil. METHODS: A consecutive sample of patients with CRC were interviewed regarding personal and family histories of cancer. Clinical data and pathology features of the tumor were obtained from chart review. RESULTS: Of the 212 CRC patients recruited, 61 (29%) reported a family history of CRC, 45 (21.2%) were diagnosed under age 50 years and 11 (5.2%) had more than one primary CRC. Family histories consistent with Amsterdam and revised Bethesda criteria for LS were identified in 22 (10.4%) and 100 (47.2%) patients, respectively. Twenty percent of the colorectal tumors had features of the high microsatellite instability phenotype, which was associated with younger age at CRC diagnosis and with Bethesda criteria (P < 0.001). Only 5.3% of the patients above age 50 years had been previously submitted for CRC screening and only 4% of patients with suspected LS were referred for genetic risk assessment. CONCLUSION: A significant proportion of patients with CRC were at high risk for LS. Education and training of health care professionals are essential to ensure proper management.

Validation of a self-concept scale for Lynch syndrome in different nationalities.

Learning about hereditary cancer may influence an individual's self-concept, which otherwise represents a complex but stable cognitive structure. Recently, a 20-statement self-concept scale, with subscales related to stigma-vulnerability and bowel symptom-related anxiety, was developed for Lynch syndrome. We compared the performance of this scale in 591 mutation carriers from Denmark, Sweden and Canada. Principal component analysis identified two sets of linked statements-the first related to feeling different, isolated and labeled, and the second to concern and worry about bowel changes. The scale performed consistently in the three countries. Minor differences were identified, with guilt about passing on a defective gene and feelings of losing one's privacy being more pronounced among Canadians, whereas Danes more often expressed worries about cancer. Validation of the Lynch syndrome self-concept scale supports its basic structure, identifies dependence between the statements in the subscales and demonstrates its applicability in different Western populations.

F18-FDG-PET/CT in a patient affected by Lynch syndrome.

Lynch syndrome (LS) is the most common hereditary syndrome that predisposes patients to colorectal cancer, and it accounts for 2-5% of the total burden of colorectal cancer. We report a case of a 61-year-old female affected by Lynch syndrome who underwent multiple adenocarcinoma resections, studied by F18-FDG-PET/CT for 5 years. This case report suggests a potential role of F18-FDG-PET/CT in the evaluation of patients affected by Lynch syndrome.

A novel complex mutation in MSH2 contributes to both Muir-Torre and Lynch Syndrome.

Mutations in mismatch repair genes lead to Lynch Syndrome, the most common form of inherited colorectal cancer. In this report, we describe a novel complex germline mutation c.[1601_1661+92dup; 1591_1611del] of the mismatch repair gene, MSH2. This mutation, which segregates with the disease phenotype, was discovered in a Lynch syndrome kindred that also shows a history of the Muir-Torre syndrome. Interestingly, several tumors from this family displayed microsatellite instability, a hallmark of Lynch syndrome tumors but no consistent, concomitant loss of MSH2 protein expression. In addition, a subset of tumors showed neither prototypical feature of microsatellite instability nor immunohistochemistry deficiency, highlighting the importance of a detailed molecular analysis of rare genetic alterations. This mutation and the atypical clinical manifestations observed underscore the genetic complexity underlying Lynch syndrome, and the importance of comprehensive molecular screening in the diagnosis and early detection of colorectal and other associated cancers.

A review on the molecular diagnostics of Lynch syndrome: a central role for the pathology laboratory.

Lynch syndrome (LS) is caused by mutations in mismatch repair genes and is characterized by a high cumulative risk for the development of mainly colorectal carcinoma and endometrial carcinoma. Early detection of LS is important since surveillance can reduce morbidity and mortality. However, the diagnosis of LS is complicated by the absence of a pre-morbid phenotype and germline mutation analysis is expensive and time consuming. Therefore it is standard practice to precede germline mutation analysis by a molecular diagnostic work-up of tumours, guided by clinical and pathological criteria, to select patients for germline mutation analysis. In this review we address these molecular analyses, the central role for the pathologist in the selection of patients for germline diagnostics of LS, as well as the molecular basis of LS.

Surgical management of hereditary colorectal cancer: surgery based on molecular analysis and family history

The importance of colorectal cancer (CRC) is increasing. Aproportion show a hereditary component, as in Lynch syndromeand Familial Adenomatous Polyposis, and a recently defined entityas well, namely, Familial Colorectal Cancer type X. The highprobability to develop CRC in these groups may, at the time ofrecognition, change surgical management, including its timing oreven the surgical technique. In some cases prophylactic surgerycan play an important role. The possibility of using tools that allowrecognition of the aforementioned syndromes, including microsatelliteinstability, immunohistochemistry for DNA mismatchrepair system proteins, and especially their mutations, is on thebasis of therapeutic strategies that differ from those employed insporadic CRC cases(AU)