Lynch syndrome diagnosis is based on the application of Amsterdam criteria, which applies the “3-2-1 Rule”, and the Amsterdam second classification, which includes non-colorectal cancers: endometrial, small intestine, ureteral, and kidney cancers . The “3-2-1 Rule” criteria include ≥ 3 affected family members, one of whom is a first-degree relative of the other two, across at least 2 generations with at least 1 of them presenting with hereditary non polyposis colorectal cancer (HNPCC) before the age of 50. The familial adenomatous polyposis should be excluded. Lynch syndrome is caused by germline mutations in one of four DNA mismatch repair genes that lead to microsatellite instability and/or loss of mismatch repair protein expression at immunohistochemistry [1, 2]. In 90% of cases, mutations can be found in MLH1 or MSH2 genes, while mutations in MSH6 and PMS2 genes are less frequent [1, 2].
The etiology of tumors that are usually rare in the HNPCC tumor spectrum is still controversial. Here, we report the case of a 33-year-old woman with a family history of Lynch syndrome, due to a germline MLH1 gene mutation, who developed a papillary thyroid carcinoma.
Only a few cases of thyroid cancer have been reported in patients with Lynch syndrome, mostly associated with an MSH2 germline mutation (Table 1). Interestingly, Aswath K et al., described a family with the co-occurrence of familial non-medullary thyroid cancer (FNMTC) and HNPCC. Two out of five relatives affected by PTCs were analyzed and both carried the germline MSH2 p.C707Y variation. Although the clinical significance of the MSH2 variant is uncertain, it may suggest a role in PTC predisposition.
To our knowledge, only one thyroid cancer associated with a germline MLH1 mutation has been previously described in a patient with Lynch syndrome. The patient was a 43-year-old female who developed PTC a few years after the uterine and ovarian adenocarcinomas and colon cancer. Unfortunately, we have no data about the genetic analysis on thyroid cancer tissue.
Here, we report a second patient carrying a germline MLH1 mutation. The MLH1 c.545+3A>G variation is known to be pathogenic leading to the skipping of exon 6. The genetic analysis of the thyroid cancer tissue showed the coexistence of BRAF p.V600E and TERTC228T promoter mutations.Notably, this is the first case in whom papillary thyroid carcinoma has been diagnosed as the first and isolated neoplastic disease in a Lynch syndrome family member. During the 4 years follow-up the patient didn’t develop any Lynch-associated cancers.
Genes involved in DNA repair pathways have a pivotal role in preserving genomic integrity upon exposure to genotoxic agents and the impairments in these mechanisms are related to increases in mutation frequency, genomic instability, and finally to cancer susceptibility[10,11].
Although thyroid cancer is not considered as part of Lynch syndrome, several reports have indicated an association between MMR deficiency and thyroid cancer.
Lu Y et al. found a lower expression of MLH1 protein in thyroid cancer tissues, both papillary and follicular cancers, compared with normal tissues . Moreover, MLH1 germline and somatic mutations have been described in PTCs [10, 12].
The defective DNA repair system in a condition of excessive oxidative stress that promotes the DNA oxidation and subsequent lesions may have an important role in the PTC tumorigenesis [9, 13]. It is therefore reasonable to suppose that MMR impairment, including that induced by MLH1 mutations, may increase the chance of somatic genetic alterations. Our patient follows this hypothesis being a carrier of two somatic driver mutations in the PTC tissue. Moreover, in all analyzed PTC tissues of patients with Lynch Syndrome, including our patient, it has been found a somatic BRAF p.V600E mutation (Table 1). Interestingly, the association between the aberrant MLH1 methylation and expression and the presence of the BRAF p.V600E mutation has been described in thyroid cancer cell lines and PTC tissues .
In conclusion, although we cannot exclude an incidental occurrence of PTC in Lynch syndrome patients, our study underlines the need to follow-up LS patients for the development of rare associated cancers, including thyroid cancers.