3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Endometrial carcinomas: microsatellite instability and and suspected lynch syndrome in the greater Johannesburg area(2019) Wadee, ReubinaEndometrial 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.Item The histopathological analysis of cellular elements, accessory molecules and cytokines in mycobacterial granulomas from HIV positive and negative individuals(2014-03-31) Wadee, ReubinaThe immune response to infection with Mycobacterium tuberculosis (Mtb) involves complex interactions between macrophages, T-cells, cytokines and accessory molecules. Mycobacteria evade the host’s immune response by interfering with cell mediated immune systems. Granulomas are central to the host’s defenses against Mtb. These responses may be modified by immune alterations especially in patients co-infected with Human Immunodeficiency Virus (HIV). This study investigated the immunohistochemical profile of CD4+, CD8+, CD68+, Th-17 (also known as Interleukin-17 cells) and Forkhead box (FOXP3) cells, accessory molecule expression (HLA Class I and II) and selected cytokines (Interleukin 2, 4, 6 and Interferon-) of various cell types within mycobacterial granulomas, in lymph nodes from ten HIV negative and ten HIV positive patients. Tissue from a foreign body granuloma in skin was utilised for comparison. This study illustrated retention of CD4+ lymphocyte numbers within granulomas from HIV negative (-) patients but documented a reversal in the ratio of CD4+ to CD8+cells in granulomas from HIV positive (+) patients. Similar IL-17 cell counts were noted in mycobacterial granulomas from both HIV (-) and HIV (+) patients. CD68 was identified in all macrophages and HLA Class II stained 100% of cells. Mycobacterial granulomas from HIV (-) patients showed marginally lower numbers of HLA Class I cells when compared to those from HIV (+) patients. The percentage of FOXP3 positive cells differed significantly between mycobacterial granulomas from HIV (-) and HIV (+) patients. This study highlights the complex interplay between different cell types and cytokines secreted into the microenvironment that ultimately results in containment of the organism or disease progression. Tuberculosis mono-infection causes variation in the expression of cell markers such as FOXP3 with accompanying noteworthy changes in cytokine production in areas of granuloma formation. The alterations noted in TB and HIV co-infection are even greater and point toward evolution of micro-organism synergism with host demise.