Undifferentiated thyroid carcinoma is not commonly associated with Lynch syndrome. In our patient the immunohistochemical loss of expression for the MSH2 and MSH6 protein suggested that this tumour was not coincidental, but due to the underlying mutation in the MSH2
gene. Loss of MSH6
expression in tumours is often observed in case of germline MSH2
mutations and can be explained by loss of its stabilizing partner MSH2. Broaddus et al. [18
] contended that for both an adrenal and a thyroid carcinoma an MSH2
gene mutation was causally linked because the tumour showed loss of MSH2 protein with immunohistochemical staining, but retained expression of MLH1
. This staining pattern was similar to that seen in the more common Lynch syndrome related malignancies in these families. Although both adrenal and thyroid carcinoma showed loss of MSH2
immunohistochemical expression, neither tumour was microsatellite instable (MSI-high). Loss of protein expression in the absence of MSI has been observed before in Lynch syndrome, most notably in patients with MSH6
In the past, the Lynch syndrome tumour spectrum has primarily been defined through an epidemiological and statistical approach. From a clinical point of view this approach is of course still very valid as many clinicians will be primarily interested in tumours that have a significantly increased risk of developing in their patients. Cumulative cancer risks for Lynch syndrome were usually based on retrospective cohort analysis of families meeting the Amsterdam criteria, often including families without proven mutations and untested first-degree relatives. More recently studies have focused on proven mutation carriers only. The risk figures listed in Table are based on the latter type of studies [8
]. Interestingly, the risk for gastric, ovarian, ureter/renal pyelum and brain tumours appears to be higher for carriers of MSH2
mutations than for carriers of MLH1
mutations. In addition to the statistical approach, the tumour spectrum can be broadened through analysis of tumours occurring in MMR gene mutation carriers. Again, patients with atypical Lynch syndrome tumours as listed in Table more often have been reported to carry an MSH2
than an MLH1
mutation. Also a wider range of tumours is observed for MSH2
than for MLH1
in these patients. At this point we can only speculate on the reason for these differences. MLH1
each create a heterodimer with different partners and have different roles in the detection and repair of DNA mismatches. For each of these protein complexes, deficiency might have a different impact on types and quantity of mismatches left unrepaired and the effect deficiency has on different target genes. The absence of MSH6
mutations in Table might simply be caused by the fact that these mutations have been less frequently observed in Lynch syndrome in general. Ascertainment bias, however, cannot be excluded as laboratories did not test MSH6
in their analyses of Lynch syndrome suspected patients until fairly recently. Nevertheless, the absence of MSH6
from the listed reports might also reflect a true difference in associated tumour spectrum.
The tumours listed in Table are not known to develop significantly more frequently in MMR gene mutation carriers than in the general population. Loss of MMR function may or may not have contributed significantly to tumour development in these particular cases. Generally, in these organs loss of the wild type allele in MMR gene mutation carriers and/or subsequently the accumulation of clinically important unrepaired mutations in cancer-associated target genes are apparently relatively rare. It is interesting to look at the types of cancer that develop in patients who have inherited bi-allelic MMR gene mutations (Tabele .). These patients are born with a mismatch repair deficiency and can present with tumours that rarely occur in carriers of single allele MMR gene mutations who need to lose their WT allele in their tissues first. Several studies have demonstrated that these bi-allelic mutations can lead to a phenotypically distinct recessive syndrome with predominantly childhood onset brain tumours, leukaemia and lymphoma, bowel tumours and endometrial carcinoma [20
]. A striking feature of these patients is that nearly all of them display some features, spotty hyperpigmentation of the skin and Lisch nodules of the irides, usually observed in neurofibromatosis type I. Some of the reported tumour types, sarcoma, NHL and early-onset breast cancer match the types incidentally reported in patients with single allele MMR gene mutations, which further supports the notion that these tumour types could be causally linked to inherited MMR gene mutations.
Whether or not MMR deficiency contributed significantly to development of the types of cancer occasionally seen in Lynch syndrome patients remains to be determined. From a practical point of view, we conclude that unusual tumours in Lynch syndrome can show loss of immunohistochemical staining that corresponds to the MMR germline mutation. Therefore these tumours, especially of those types that rarely occur in the general population, could be useful when trying to predict MMR gene mutations in Lynch syndrome suspected families for mutation analysis [6
] if the typical Lynch syndrome-associated tumours are unavailable.