Lynch Syndrome: Its Impact on Urothelial Carcinoma.

Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.

Risk factors for metachronous colorectal cancer in Lynch syndrome patients: a registry-based observational mono-institutional study cohort.

BACKGROUND: Risk factors for metachronous colorectal cancer (mCRC) in Lynch Syndrome (LS) patients are essential for colorectal cancer (CRC) treatment strategy to perform not only a curative but also preventive surgery. The aim of this study was to evaluate the risk factors for mCRC development in LS patients to define the patient subset that may benefit an extended curative and preventive surgical resection. METHODS: Patient's clinical history, oncological, molecular and follow-up were collected retrospectively from the Hereditary Digestive Tumors Registry at the National Cancer Institute of Milan. The age-related cumulative risk of mCRC was calculated using the Kaplan-Meier method. Factors significantly associated with mCRC were analyzed with a Cox regression model. Overall and specific competitive risks were also calculated. RESULTS: In a total of 1346 CRC patients, 159 (11.8%) developed a mCRC after a mean follow-up of 138 months from the primary tumor. The independent risk factors reported by a multivariate analysis were: pathogenetic variants in MLH1 and MSH2 (HR 2.96 and 1.91, respectively) and history of colorectal adenomas (HR 1.54); whereas female sex and extended surgery were protective (HR 0.59 and 0.79, respectively). CONCLUSIONS: Among a high-risk population for CRC, in particular LS, an extended surgery may be considered in CRC patients with specific risk factors (MLH1 or MSH2 germline pathogenic variants, history of colorectal adenomas) to reduce the risk of mCRC development.

[Muir-Torre syndrome and Turcot syndrome]. / Syndrome de Muir-Torre et syndrome de Turcot.

INTRODUCTION: Lynch syndrome (LS) is a syndrome that carries a genetic predisposition to certain cancers associating, either in a single individual or in a family, a visceral tumour, mainly colorectal, with a high risk of other synchronous or metachronous cancers. LS is linked with mutations in the genes coding for proteins in the DNA repair system. Phenotypic variants of SL exist, including Muir-Torre syndrome (MTS) and Turcot syndrome (TS), both of which predispose to colorectal cancer. They may be distinguished by the presence of benign or malignant sebaceous tumours in MTS, and tumours of the central nervous system in TS. PATIENTS AND METHODS: A 59-year-old man, with a history of right colon cancer at the age of 36 years, consulted for a nose lesion shown by histopathological examination to be a sebaceous tumour. Immunohistochemistry revealed loss of expression of proteins MSH2 and MSH6, strongly suggesting a diagnosis of MTS. Eight years earlier, the man's son had developed a fatal glioblastoma; given the paternal phenotype of MTS, the hypothesis of TS in the son is probable. DISCUSSION: This case suggests that several variants of Lynch syndrome may be seen within the same family. It raises the issue of screening for cerebral tumours in patients with MTS and in their family members, even though such a recommendation does not exist; current recommendations in fact consist primarily of gastrointestinal and gynaecological monitoring.

[Muir-Torre syndrome associated with Waldenstrom's macroglobulinemia]. / Syndrome de Muir-Torre chez un patient atteint de maladie de Waldenström.

BACKGROUND: Muir-Torre syndrome (MTS), a cutaneous variant of Lynch syndrome, consists of hereditary predisposition to cutaneous tumours and gastrointestinal and gynaecological neoplasms, with autosomal dominant transmission. It is associated with mutations in genes coding for proteins in the DNA mismatch repair system. PATIENTS AND METHODS: Herein, we report a case of a male patient presenting Waldenstrom's macroglobulinemia since the age of 50 and which, after the age of 65 years, developed into sebaceous tumours (5 sebaceous adenomas, 1 sebaceoma, 1 sebaceous carcinoma) and colonic lesions (4 adenomas). The clinical phenotype was consistent with MTS. Somatic analysis carried out on one sebaceous tumour showed instability of the microsatellites with loss of expression of MSH2 and MSH6 although constitutional genetic analysis showed no germline mutations known to be harmful. DISCUSSION: This noteworthy case raises a number of questions, including the possibility of association between STM and Waldenstrom's macroglobulinemia, which is discussed herein.

Epigenetic mechanisms in the pathogenesis of Lynch syndrome.

Inherited defects in the DNA mismatch repair (MMR) system, MLH1, MSH2, MSH6, and PMS2 genes, underlie Lynch syndrome, one of the most prevalent cancer syndromes in man. The syndrome offers a model for cancers arising through MMR defects and microsatellite instability, which applies to ~ 15% of all colorectal, endometrial, and other cancers. Lynch syndrome also illustrates the significance of the epigenetic component in cancer development. Inactivation of tumor suppressor genes by epigenetic mechanisms is an acquired property of many tumors developing in Lynch syndrome. Furthermore, constitutional epimutations of MMR genes may explain a proportion of mutation-negative families lacking MLH1 or MSH2 protein expression in tumor tissue. This review provides an update of the molecular basis of Lynch syndrome by focusing on the role of epigenetic mechanisms in the pathogenesis of the disease.

Histopathological Predictors of Microsatellite Instability in Colorectal Cancer-a Tertiary Care Center Experience.

Microsatellite instability (MSI) has a therapeutic and prognostic implication in colorectal carcinomas (CRCs). It can be detected either by immunohistochemistry (IHC) or molecular studies. In developing countries, a significant proportion of the patients experience financial constraints limiting the utilization of healthcare facilities. We aimed to identify the possible clinicopathological variables which can be used as predictors of microsatellite instability in such patients. CRC cases received for MSI detection by IHC (for 1 and 1/2 years) were included. A panel of four IHC markers (anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6) was used. Confirmation by the molecular study was recommended in all the IHC-proven MSI cases. Various clinicopathological parameters were evaluated as predictors of MSI. Microsatellite instability was detected in 40.6% (30/74) cases with MLH1 and PMS2 dual loss in 27% cases, MSH2 and MSH6 dual loss in 6.8%, loss of all four MMR proteins in 2.7%, and isolated PMS2 loss in 4.1%. MSI-H expression was shown by 36.5% cases with only 4.1% cases showing MSI-L expression. The age cut-off value to differentiate both the study groups (MSI vs MSS) was 63 years with a sensitivity of 47.7% and specificity of 86.7%. ROC curve showed an area under the curve of 0.65 (95% CI, 0.515-0.776; p-value = 0.03). On univariate analysis, age < 63 years, colon site, and absence of nodal metastasis were significantly higher in the MSI group. However, on multivariate analysis, only the age < 63 years was found to be significantly higher in the MSI group. Confirmation was molecular study could only be obtained in 12 cases and was completely concordant with MSI detection by IHC. MSI detection can be performed either by IHC or by molecular study. In this study, no histological parameter appeared to be the independent predictor of MSI status. The age < 63 years might predict the microsatellite instability, yet larger studies are needed for its validation. Thus, we recommend that IHC testing should be performed in all CRC cases.

Lynch-like Syndrome: Potential Mechanisms and Management.

Lynch syndrome is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) system genes, such as MLH1, MSH2, MSH6, or PMS2. It is the most common hereditary colorectal cancer syndrome. Screening is regularly performed by using microsatellite instability (MSI) or immunohistochemistry for the MMR proteins in tumor samples. However, in a proportion of cases, MSI is found or MMR immunohistochemistry is impaired in the absence of a germline mutation in MMR genes, BRAF mutation, or MLH1 hypermethylation. These cases are defined as Lynch-like syndrome. Patients with Lynch-like syndrome represent a mixture of truly hereditary and sporadic cases, with a risk of colorectal cancer in first-degree relatives that is between the risk of Lynch syndrome in families and relatives of sporadic colon cancer cases. Although multiple approaches have been suggested to distinguish between hereditary and sporadic cases, a homogeneous testing protocol and consensus on the adequate classification of these patients is still lacking. For this reason, management of Lynch-like syndrome and prevention of cancer in these families is clinically challenging. This review explains the concept of Lynch-like syndrome, potential mechanisms for its development, and methods for adequately distinguishing between sporadic and hereditary cases of this entity.

Intraductal sebaceous papilloma of a meibomian gland: a new entity possibly associated with the MSH6 subtype of the Muir-Torre syndrome.

Over several months, a painless, multinodular, non-erythematous swelling of the deep tissues of his left upper eyelid developed in a 63-year-old man. An excisional biopsy with histopathologic evaluation disclosed a unique sebaceous papilloma within a cyst lined by non-keratinizing squamous epithelium that focally displayed a variably thick, superficial, eosinophilic cuticular layer. Immunohistochemical staining demonstrated that the tumor and its epithelial cystic lining had a profile consistent with Meibomian gland duct epithelium. Adipophilin highlighted cytoplasmic vacuolar lipid positivity. The encapsulation of the lesion, absence of nuclear atypia, and Ki-67 nuclear positivity restricted to the basilar cells established its intrinsically benign nature. The patient's clinical history was remarkable for pulmonary and colonic carcinomas resected, respectively, 20 years and 8 years earlier. DNA mismatch repair protein expression studies disclosed loss of nuclear immunostaining of MSH6 protein, pointing to the possibility of an underlying rare MSH6 variant of the Muir-Torre syndrome, not yet described in the ophthalmic literature. p16 nuclear positivity was also found in the tumor cells, indicating the possible role of high-risk human papillomavirus as an additional factor in the genesis of the tumor. Genetic evaluation of normal and tumoral tissues in future similar cases will detect if there is an underlying germline mutation versus a somatic mutation limited to the tumor. This will be required to fully establish a predictable linkage with this new subtype of the Muir-Torre syndrome.

Targeted next generation sequencing screening of Lynch syndrome in Tunisian population.

A high colorectal cancer (CRC) incidence is observed in Tunisia, with a relatively high proportion of patients developing CRC before the age of 40. While this suggests a genetic susceptibility, only a few Tunisian Lynch Syndrome families have been described. In this study we aimed to identify the underlying genetic cause in 32 patients with early onset CRC and/or a positive family history. Of twenty-four patients' tumor or biopsies could be analyzed with immunohistochemical staining to detect loss of expression of one of the MMR proteins. Ten tumors showed loss of expression, of which one tumor was from a patient where a germline pathogenic MSH2 variant was detected previously with Sanger sequencing. Next generation sequencing of the MMR, POLE and POLD1 genes was performed in leukocyte and tumor DNA of the remaining nine patients, as well as in two patients with MMR-proficient tumors, but with severe family history. In six of 11 patients a germline variant was detected in MLH1 (n = 5) or MSH2 (n = 1). Two of six patients were from the same family and both were found to carry a novel in-frame MLH1 deletion, predicted to affect MLH1 function. All MLH1 variant carriers had loss of heterozygosity with retention of the variant in the tumors, while a somatic pathogenic variant was detected in the patient with the germline MSH2 variant.

Comparison of screening strategies for Lynch syndrome in patients with newly diagnosed endometrial cancer: a prospective cohort study in China.

BACKGROUND: The prevalence of Lynch syndrome and screening strategies for this disorder in Chinese patients with endometrial cancer have seldom been investigated. Such data would be essential for the screening, prevention, genetic counseling, and treatment of Lynch syndrome. The purpose of this prospective study was to determine the accuracy of the mismatch repair (MMR) protein immunohistochemistry (IHC), microsatellite instability (MSI) test, and clinical diagnostic criteria in screening for Lynch syndrome-associated endometrial cancer (LS-EC) in a prospective Chinese cohort. METHODS: All patients with newly diagnosed endometrial cancer (EC) were evaluated using clinical diagnostic criteria (Amsterdam II criteria and the revised Bethesda guidelines), MSI test, and IHC of MMR proteins in tumor tissues. For all patients, the screening results were compared with results of germline sequencing for pathogenic variants of MMR genes. RESULTS: Between December 2017 and August 2018, a total of 111 unselected patients with newly diagnosed EC were enrolled. Six patients (5.4%) harbored a pathogenic germline mutation of MMR genes: 1 had a mutation in MutL homolog 1 (MLH1), 2 in MutS homolog 2 (MSH2), and 3 in MutS homolog 6 (MSH6). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for identifying LS-EC were 33.3%, 88.6%, 14.3%, and 95.9%, for the clinical criteria, 66.7%, 75.0%, 14.3%, and 97.3% for IHC of MMR proteins, 100%, 89.9%, 33.3%, and 100% for MSI test, and 100%, 72.4%, 20.0% and 100% for combined IHC and MSI test, respectively. The combination of IHC and MSI test had higher sensitivity and PPV than the clinical criteria (p = 0.030). MSI test and IHC were highly concordant for LS-EC screening (73/77, 94.8%). CONCLUSION: The accuracy of the combination of IHC of MMR proteins and MSI test for screening LS among Chinese patients with EC was superior to that of the clinical criteria. Trial registration NCT03291106. Registered on September 25, 2017.

Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines.

BACKGROUND: Pancreatic cancer (PC) is categorized as a neoplasm associated with Lynch syndrome; however, the precise proportion of PC patients harboring DNA mismatch repair genes (MMR genes) remains unclear, especially in the Asian population. METHODS: Among 304 Japanese patients with pathologically proven pancreatic ductal adenocarcinoma, we selected 20 (6.6%) patients with a personal or family history involving first- or second-degree relatives fulfilling the revised Bethesda guidelines (RBG), defined as RBG-compatible cases. We analyzed germline variants in 21 genes related to a hereditary predisposition for cancer as well as clinical features in all 20 cases. RESULTS: The RBG-compatible cases did not show any unique clinicopathological features. Targeted sequencing data revealed three patients carrying deleterious or likely deleterious variants. Specifically, these three patients harbored a nonsense variant in ATM, a frameshift variant in ATM, and a concurrent nonsense variant in PMS2 and missense variant in CHEK2 (double-mutation carrier), respectively. Although an MMR gene mutation was identified in only one of the 20 patients, up to 15% of the RBG-compatible PC cases were associated with germline deleterious or likely deleterious variants. CONCLUSIONS: These findings showed that these guidelines could be useful for identifying PC patients with DNA damage repair genes as well as MMR genes.

Primary mucinous adenocarcinoma of the vermiform appendix with high grade microsatellite instability.

Primary adenocarcinoma of the vermiform appendix is a rare entity and is frequently discovered by the pathologist following appendectomy for suspected appendicitis.We present a 42-year-old male with primary mucinous adenocarcinoma of the appendix initially presenting symptoms of acute appendicitis. Histological investigation of the appendectomy specimen showed a mucinous adenocarcinoma and the patient was treated by secondary right hemicolectomy giving the final histopathological classification of an UICC IIIC tumor. Since the patient fulfills the revised Bethesda criteria analysis of immunoreactivity of DNA mismatch repair proteins was performed showing loss of MLH1 and MSH2 expression associated with high microsatellite instability (MSI-H), not yet reported for primary mucinous appendiceal carcinoma. Further genetic analysis for DNA mismatch repair gene mutations were negative. The patient received intensified adjuvant chemotherapy according to the FOLFOX-4-scheme, since MSI-H colorectal carcinomas might show lower response rates following standard 5-FU-based adjuvant chemotherapy.