Clinical and Pathological Characterization of Lynch-Like Syndrome

Abstract

BACKGROUND: Lynch syndrome (LS) is characterized by mismatch repair (MMR) deficiency. However, there is a group of patients where LS is suspected because of MMR deficiency but there is no germinal mutation in MMR genes.These patients are known as Lynch-like syndrome (LLS) and there is no consensus about their management. The aim of this study is to describe a large series of LLS patients and to analyze if there are clinical, pathology or molecular differences in patients with suspected hereditary or sporadic origin.METHODS: Patients with colorectal cancer (CRC) were included in a national registry when their tumors show immunochemical loss of MSH2, MSH6, PMS2 or loss of MLH1 with BRAF-wild type and/or no MLH1 methylation and absence of pathogenic mutation in these genes. Demographic, clinical and pathological variables, as well as family history of neoplasms were registered. RESULTS: We included 160 patients with LLS. Mean age at diagnosis of CRC was 55 years. A total of 66 patients were female (41%). Amsterdam I and II criteria were fulfilled by 11%, revised Bethesda guidelines by 65% of cases and 24% were diagnosed because of universal screening. There were no differences in sex, indication for colonoscopy, immunochemistry, pathology findings or personal history of CRC or other LS related tumors between patients fulfilling Amsterdam or Bethesda guidelines and patients diagnosed because of universal screening of LS without family history.

Risk of Cancer in Family Members of Patients with Lynch-Like Syndrome

“…With the implementation of universal tumor screening for LS in all patients with CRC [3], an increase in the number of patients with LLS has been shown. These patients represent a heterogeneous population where sporadic and truly LS cases are mixed [10]. This fact makes the adequate follow-up of these patients and their FDR difficult as, in the majority of cases, they are not appropriately diagnosed and classified.…”

“…Data were extracted from a descriptive, observational, multicenter, nationwide registry (EPICOLON III) on familial CRC, involving 25 Spanish hospitals [10]. We studied a cohort of patients with CRC and LS (with confirmed germline pathogenic mutation in mismatch repair (MMR) genes) and patients with CRC and LLS.…”

What Is Lynch-like Syndrome and How Should We Manage It?

“…Here, we must start with Lynch syndrome. A brief tour of the history of our ability to recognize, understand, and name Lynch syndrome 1 provides the context for the current report on the clinical and pathological characteristics of Lynch-like syndrome by Pico et al 2 -and it is a fitting tribute to Henry T. Lynch, considered the father of cancer genetics, who died at the age of 91 on June 2, 2019. 3 Lynch syndrome is defined today as the autosomaldominant predisposition to colorectal cancer (CRC) and other cancers that is caused by germline mutations in a DNA mismatch repair (MMR) gene-a molecular definition.…”

“…The key messages are that most CRCs are MMR proficient, and most are sporadic; family history of CRC is common, but most cases of familial cancer aggregation are currently not explained by germline mutations in single or multiple genes; Lynch syndrome accounts for 2%-3% of all CRCs, and most, but not all, of these are MMR deficient; MMR-deficient tumors owing to a somatic mechanism, and not to Lynch syndrome, are relatively common; and MMR-deficient tumors with no identified somatic cause or germline MMR gene mutation (Lynch-like syndrome) are rare. In the study by Pico et al, 2 CRCs were not studied for the presence of biallelic somatic mutations in MMR genes. Such biallelic mutations may account for over half of CRCs that might be labeled as Lynch-like syndrome.…”

“…The reason is that, rare as the clinical scenario may be, we need to be able to advise our patients and their families intelligently in order to manage their future cancer risk. This brings us to the findings, interpretation, and implications of the study by Pico et al 2 Pico et al 2 separate their cohort of 160 patients with CRC and Lynch-like syndrome into 2 subcohorts, designed to try to create one group of patients suspected of having cancer of hereditary origin and another group of patients suspected of having cancer of sporadic origin.…”