Endometrial carcinomas: microsatellite instability and and suspected lynch syndrome in the greater Johannesburg area

Wadee, Reubina
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Endometrial carcinomas are common malignancies of the female genital tract, with endometrioid endometrial carcinoma (EEC) being the most common histological subtype. Microsatellite instability is a molecular abnormality that is often documented in EEC and most tumours associated with Lynch syndrome (LS). This study assessed 145 cases of EEC for the 4 mismatch repair markers by immunohistochemistry (IHC) and for microsatellite instability (MSI) by PCR. There were 41 cases that showed MMR deficiency, of which 37 demonstrated MLH1 loss. Forty-six cases were microsatellite unstable by PCR. The 37 MLH1 deficient cases and 25 cases illustrating discordance between IHC and PCR results underwent methylation studies, which revealed that over 80% of the 37 MHL1 deficient cases were hypermethylated. Furthermore, of the 25 cases showing discordant MMR IHC and MSI PCR results, 68% were hypermethylated. Of the remaining 8/25 cases, 7 were unmethylated whilst 1 case had insufficient DNA for methylation assessment. BRAF assessment by IHC, PCR and Sanger sequencing was performed which showed that using all 3 tests; 6 out of 37 cases had BRAF mutations, which is higher than studies from western societies, but less than that noted in an eastern study. Similar to western studies, however, the present study showed that BRAF mutations are uncommon in EECs and should therefore not be included in the workup of EEC patients. This study illustrated that a possible 13 of 145 (8.97%) patient cases are suspected of having potential germline mutations, which is double the expected frequency noted in the developed nations. This suggests that there may be a higher incidence of LS in South Africa than in western countries and highlights the need for screening tests in our patient population. It is thus incumbent on histopathologists to undertake screening tests to identify females who may be affected by LS so that such patients, and their relatives; may be offered genetic counselling with a view to germline mutational assessment. Patients and relatives with suspected LS may then undergo surveillance for the development of other possible tumours in an attempt to decrease the menace of morbidity and mortality associated with this tumour syndrome.
A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for Doctor of Philosophy, in the branch of Anatomical Pathology. Johannesburg, 2019