Masters Degrees (Anatomical Pathology)
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- ItemAnalysis of hereditary haemochromatosis and clinical correlations in the elderly(Stellenbosch : Stellenbosch University, 2000-12) Bouwens, C. S. H.; Kotze, Maritha J.; Maritz, F. J.; De Villiers, J. N. P.; Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Pathology.ENGLISH ABSTRACT: Hereditary haemochromatosis (HH) is an autosomal recessive iron storage disease where the accumulation of iron in parenchymal organs may lead to diabetes, heart failure, liver cirrhosis, arthropathy, weakness and a variety of other ailments if preventive measures are not taken. HH is often not considered as a cause of these conditions, particularly not in the elderly where the background frequencies of type II diabetes, osteoarthritis and heart failure are generally high. Heterozygosity for C282Y, the HFE-mutation causing HH in approximately 80% of affected individuals worldwide, has been linked to a raised incidence of malignancies of the colon and rectum, stomach and the haematological system. One of the highest carrier-frequencies (116) in the world for this mutation has been reported in the South-African Afrikaner population, resulting in C282Y-homozygosity in approximately 1 in every 115 people in this group. A sample of 197 elderly Afrikaner volunteers was recruited for genotype/phenotype association studies. Their clinical presentation was denoted, biochemical iron-status determined and HFE genotyping performed. Either an increase or decrease in survival, or both, were proposed, depending on possible gender effects. HH has been positively associated with various cancer types, but may also protect against iron-deficiency anaemia which is by far the most frequent cause of anaemia in the older person. This study has led to the following findings: 1. The carrier frequency of mutation C282Y was found to be 1/8 in the elderly population (similar in males and females), which is slightly lower than the 1/6 reported in younger adults from the same population. Only one C282Y homozygote and two C282YIH63D compound heterozygotes were detected, all of them female. 2. The prevalence of diabetes, heart disease, arthropathy or a combination of these conditions did not differ significantly in C282Y heterozygotes and the mutationnegative group. 3. Among 24 C282Y heterozygotes only one individual with rectal carcmoma was detected compared with two cases with rectal- and seven with colonic malignancies in 153 mutation-negative individuals. The single female C282Y homozygote identified suffered from both rectal and colon carcinoma and died approximately 6 months ago as a consequence of her colon malignancy. 4. Serum ferritin appears to be a highly unreliable parameter of iron status, particularly in the elderly where a variety of factors that may influence the levels are often present in elderly individuals. This may be due to ageing alone or as a result of multiple comorbidities. 5. Serum ferritin levels were lower than expected in elderly subjects with mutation C282Y and compound heterozygotes with both C282Y and H63D, which may be related to a variable penetrance of the HFE gene mutations. It is possible that variation in other genes exist that confer protection against iron-loading by gene-gene interaction. The probability that environmental factors (e.g. a low iron diet) are more important in this respect cannot be excluded, although this is considered less likely in the light of the fact that the same trend was observed in all mutation-positive elderly individuals. It is therefore highly likely that C282Y -positive subjects with significant iron loading have died before reaching their seventies, particularly since none of the males included in this study were homozygous or compound heterozygous for the mutations analysed. In conclusion, possession of a mutant HFE gene does not appear to confer a survival advantage in old age, neither does it seem that mutation carriers with significant ironloading are overlooked by the medical fraternity. Further investigations are warranted to shed more light on the contributions of gene-gene and gene-environment interaction in the clinical manifestation of Hll, and how these processes can be manipulated to prevent the symptoms of this largely underdiagnosed disease.
- ItemAutomated sputum screening using the BD FocalPointTM Slide Profiler : correlation with transbronchial and transthoracic needle aspirates in a high risk population(Stellenbosch : Stellenbosch University, 2014-04) Neethling, Greta Sophie; Schubert, Pawel T.; Koegelenberg, C. F. N.; Diacon, A. H.; Wright, C. A.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology, Division of Anatomical Pathology.ENGLISH ABSTRACT: Background: Sputum is a non-invasive, economic investigation whereby bronchogenic carcinoma can be identified. Manual cytological screening is labour intensive, time-consuming and requires a continuous high level of alertness. Automation has recently been successfully introduced in gynaecological cytology. Since sputum samples are similar to cervical smears, the question arises as to whether they are also suitable for automated screening. Objective: This study presented with various objectives: 1) To test automated sputum screening using the BD FocalPoint™ Slide Profiler (FP) and compare with manual sputum screening. 2) To determine the sensitivity and specificity of sputum in identification of bronchogenic carcinoma. 3) To ascertain if any clinical, radiological or bronchoscopy findings would be predictors for bronchogenic carcinoma. 4) To determine the significance of adequacy. Method: Sputum samples were collected prospectively from patients attending the Division of Pulmonology at Tygerberg hospital for a transbronchial fine needle aspiration biopsy (TBNA) or a transthoracic fine needle aspiration biopsy (TTNA) for the period from 2010 to 2012. A pre-bronchoscopy sputum was collected and submitted for processing. Stained slides were put through the FP for automated screening. After slides were qualified, sputum slides were put back in the routine screening pool. Correlation was done using the TBNA/TTNA result as the standard to evaluate the sputum results. Results: 108 sputum samples were included in this study. Of the 84.3% malignant (n=91) and 15.7% benign (n=17) cases confirmed with a diagnostic procedure, sputum cytology had a sensitivity of 38.5% (35/91 malignant cases), and a specificity of 100% (17/17 benign cases). Automated screening had a better sensitivity of 94.3% (33/35 positive sputum cases), while manual screening showed a sensitivity of 74.3% (26/35 positive sputum cases) when compared to the final sputum result. Individual parameters with a significant association with positive sputum included the presence of an endobronchial tumour, partial airway obstruction / stenosis, round mass, spiculated mass (negative association), loss of weight (negative association) and squamous cell carcinoma as the histological subtype. Adequacy was not as significant as hypothesised since 85.3% of true positive sputum, but also 65.5% of false negative sputum, had large numbers of alveolar macrophages present. Conclusion: Sputum cytology remains an important part of the screening programme for bronchogenic carcinoma in the public health sector of South Africa. Results confirm that sputum cytology is very specific, and automated screening improves sensitivity. Automated screening proved to be more time efficient, resulting in 83.1% reduction (p<0.0001) in the screening time spent per case by a cytotechnologist. Results confirm that the quantity of alveolar macrophages is not directly proprtional to pathology representation. Positive sputum results did however improve with sputum adequacy, but had no significant association. Recommendations from this study include adopting automated sputum screening.
- ItemChemotherapy naive breast cancer: a correlation study between BD Cytorich™ Red cell blocks and formalin- fixed paraffinembedded tissue blocks(Stellenbosch : Stellenbosch University, 2019-04) Van Rooyen, Evelyn; Schubert, Pawel T.; Schneider, Johann; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Anatomical Pathology.Background: The ever increasing burden of breast cancer, the most common cancer among women, demands a diagnostic test that is rapid, reliable, informative and cost-effective; particularly in countries with limited financial and medical resources. FNAB cytology and cell block combination has gained worldwide utility and has been described to be accurate and reliable. Aim: Henceforth the aim of this study was to retrospectively correlate the expression of prognostication markers, namely, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) performed on cell blocks (using the BD CytorichTM Red method) and formalin-fixed, paraffin-embedded cell blocks (FFPET) in chemotherapy naive breast carcinomas, by immunochemistry (immunocytochemistry and immunohistochemistry respectively) and to perform fluorescence in-situ hybridization (FISH) testing for over- expression of the HER2 gene. Methods: Between 2013 and 2016, 132 cases of primary breast carcinoma were identified that had both cytology (including Cytorich™ Red cell blocks) and histology specimens that were both chemotherapy naive. Immunostaining for ER, PR and HER2 was performed. The staining was scored according to the Allred scoring system for histology specimen and this system was slightly adapted for cytology specimens, which also took the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines into account. FISH for HER2 over-expression was performed. The grade of the carcinoma was also analysed on both the cytology specimens (using the Robertson’s grading system) and the histology specimens (using the Modified Elston & Ellis system). Results: ER and PR performed on cell blocks had good correlation with FFPET with 91% and 85% sensitivity, respectively. HER2 on cell blocks had an agreement of 88% with FFPET. 87.88% of cell blocks had more than a 100 tumour cells present on H&E sections and cytological grading had an agreement of 41.41% with histological grading. Conclusion: The cell block technique continues to play a vital role in the diagnosis of primary, recurrent and metastatic breast carcinoma, allowing assessment of prognosis and prediction of response to therapy.
- ItemComparison of Xpert® Breast cancer STRAT4 assay and immunohistochemistry for the evaluation of breast cancer biomarkers in South African patients(Stellenbosch : Stellenbosch University, 2020-12) Dube, Welile Vumile; De Jager, Louis; Kotze, Maritha J.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology: Anatomical Pathology.Background: Breast cancer is one of the most common cancers diagnosed in women and approximately 60% of breast cancer related deaths are reported in low-and middle-income countries. Breast cancer is a highly heterogeneousdisease, and molecular subtyping is paramount foreffective treatment of patients. Therefore, it is important to validate new molecular methods for assessing cancer biomarkers for cost-effective use in resource-poor settings.Aim:Aretrospective study was performed to determine the concordance between aQuantitativeReverse TranscriptionPolymerase Chain Reaction(RT-qPCR) CE-IVD assay (Xpert® Breast Cancer STRAT4*) and the current gold standard methods of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for determining estrogenreceptor (ER),progesterone receptor(PR), human epidermal growth factor receptor 2 (HER2)andproliferation index(KI-67)expression in breast carcinomas.Method: One hundred and one cases of breast carcinoma were retrieved from the archives of the Division of Anatomical Pathology, Tygerberg Academic Hospital. The original stained slides were reviewed and IHC expression of ER, PR, HER2 and KI-67 scored. Three-micron sections were cut from formalin-fixed paraffin embedded (FFPE) tissue blocks and processed according to the instructions of the manufacturer. The assay was run on the resultant lysates.Results:The overall percentageagreement between the Xpert® STRAT4 assay and IHC / FISH results were 85.15% for ESR, 89.90% for PGR,91.09% for ERBB2, 90.72% for MKI67 (when using a cut off of 10%) and 84.54% for MKI67 (when using a cut-off of 20%). The positive percentage agreement for ESR, PGR, ERBB2, MKI67 with 10% cut-off andMKI67 with 20% cut-offwere 82.76%, 94.64%, 68.97%, 91.30% and 96.05%, respectively, and the negative percentage agreement were 100%, 84.09%, 91.67%, 80.00% and 42.86%, respectively. Conclusion:The studyhas shownthattheXpert® BreastCancer STRAT4 assay shows good concordance with IHC and FISH in detecting breast cancer biomarkers, and may become a supplementary or alternativestandard of care aftervalidation studies are performed.
- ItemThe contribution of the placenta to the diagnosis of congenital tuberculosis(Stellenbosch : Stellenbosch University, 2014-04) Rabie, Ursula; Wright, Colleen Anne; Warren, Robin Mark; Hoek, Kim Gilberte Pauline; Bekker, Adrie; Schubert, Pawel T.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology.ENGLISH ABSTRACT: The aim of this pilot project was to determine whether mothers with laboratory confirmed or clinically suspected tuberculosis (TB) had evidence of TB in the placenta. A secondary objective was to correlate evidence of placental TB with neonatal outcome. A total of 56 placentas were examined to determine if there were any specific histopathological features predictive of tuberculosis together with Ziehl-Neelsen (ZN) staining. A total of 30 cases were positive for maternal TB and one case was a false positive maternal diagnosis of TB, whilst 25 cases were negative for maternal TB. Biopsies from these 56 placentas were collected for conventional PCR from the paraffin embedded tissue blocks. The performance of these two diagnostic modalities (histopathology and PCR) was assessed coll ectively and individually, and compared to the neonatal outcome (presence or absence of active clinical mycobacterial tuberculosis infection) and evidence of maternal pulmonary and extra pulmonary tuberculosis. The recognition of specific sites of lesions in the placenta (e.g. membranes vs. intervillous space) may lead to an understanding of the pathogenic mechanisms involved in matern alfetal transmission of tuberculosis, and thereby pave the way for further studies in understanding the pathogenesis of congenital TB. Invaluable knowledge was obtained in the diagnoses of M.tuberculosis in the placenta as it was found that micro abscesses and intervillositis were strong indicators of TB infection in the placenta, however, ZN staining still remains the gold standard for diagnosing M.tuberculosis infection in the placenta. PCR is found to have limitations, because only M.tuberculosis DNA is amplified and does not distinguish live from dead bacteria. The conclusion reached is that PCR is of limited value in the diagnosis of active M.tuberculosis infection in the placenta using FFPE tissue, while certain histological changes may be indicative of such infection; however confirmation of the organism by ZN staining is still essential.
- ItemCorrelating p16INK4a /Ki-67 co-expression and gene methylation with HIV infection and high-risk HPV in abnormal cervical squamous intraepithelial cells(Stellenbosch : Stellenbosch University, 2023-03) Louw, Meagan; Sanderson-November, Micheline; Neethling, Greta; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology: Anatomical Pathology.ENGLISH SUMMARY: Globally, cervical cancer is the fourth most common cancer amongst women. Persistent infection with high-risk human papillomavirus (HPV) is shown as the causal factor in cervical cancer development. Women living with HIV is six times more prone to cervical cancer development. The aim of this study was to identify the HR-HPV types, investigate the simultaneous expression of p16INK4a and Ki-67 and evaluate the methylation status of CADM1, MAL and miR124-2 genes in cytology samples from HIV-positive and HIV-negative women with LSIL, HSIL, ASC-US, and ASC-H Pap smear results. Study participants were women between the ages of 21 years to 60 years referred to the Colposcopy clinic at Tygerberg Academic Hospital. Exfoliated cervical intraepithelial cells were collected in Surepath medium and HR-HPV types were determined using the Hybrispot HPV direct flow chip kit, whereas the co- expression of p16INK4a/Ki-67 proteins was evaluated with the CINtec® Plus cytology immunocytochemistry kit. For methylation assays, DNA was isolated from the left-over exfoliated cells followed by the assessment of quantity and purity of isolated DNA using fluorometry and spectrophotometry, respectively. Isolated DNA was bisulfite converted and the methylation assays for the CADM 1, MAL and miR-124-2 genes were done using the respective EpiMelt assays. HPV DNA detection results were associated with cytological diagnosis as well as HIV status. In our study group 74 % (51/69; 95% CI: 62,1%-83%) of woman tested positive for HPV of which 70.6% (36/51) were of WLWH and 29.4% (15/51) of HIV negative women. Our results showed that p16INK4a /Ki-67 dual-staining was detected in 43.8% (25/57) of the samples with the HSIL cytology showing the highest p16INK4a /Ki-67 co-expression rate of 64% (16/25) compared to the other cytology groups. The proportion of the LSIL group with p16INK4a /Ki- 67 dual staining was 33,3% (4/12), whereas that of the ASC-US and ASC-H groups were 25% (2/8) and 23% (3/13) ASC-H, respectively. CADM1 methylation was detected in 12.3% (7/57) of samples, while MAL and the miR-124-2 genes showed methylation in 14% (8/57) and 12.3% (7/57)of the samples, respectively. HPV infection was detected in 28.1% (16/57) of the samples with methylated CADM1, MAL and miR-124-2 genes. A significant relationship was found between HR-HPV and miR-124-2 methylation. The logistic regression model analysis employing predictors such HR-HPV, p16INK4a and Ki- 67 co-expression, as well as the methylation status of the CADM1, MAL, and miR-124-2 genes, for LSIL cytology showed low sensitivity and high specificity, contrasting to that of the HSIL model with high sensitivity and low specificity. Therefore, we conclude that a larger study is warranted, with removing or adding predictors for model improvement.
- ItemDetermining the suitability of bio-specimens obtained by fine needle aspiration biopsy at a tertiary hospital in Malawi for immunocytochemical assessment(Stellenbosch : Stellenbosch University, 2022-04) Mulenga, Maurice; Schneider, Johann Werner; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology.ENGLISH SUMMARY: Fine-needle aspiration biopsy (FNAB) is a quick, economical, least invasive and easy to perform a minor surgical procedure. In resource-limited settings, FNAB is of utmost importance in providing a rapid diagnosis that facilitates timely and correct institution of treatment. The FNAB smear preparation provides an opportunity for either rapid on-site evaluation or routine diagnosis if ancillary tests are necessary to establish a specific diagnosis. Cell blocks (CB) prepared from FNAB specimens improve the diagnostic yield, increase the sensitivity and reduce false-positive interpretations of detecting a malignant neoplasm. In addition, CB allow for additional morphological evaluation with a better architectural pattern, enable the performance of numerous ancillary diagnostic studies, including immunocytochemistry and molecular studies and offer the storage of material that can be used for future research studies. Delays in fixing the cell block have been challenges in various cell block preparatory techniques. However, a special alcohol-based fixative, commercially available solution called CytoRich Red® (CRR) has been described to be comparative to liquid-based cytology due to its effectiveness in lysing red blood cells, reducing background material, and improving staining qualities of the nucleus and cytoplasm in routine preparations of non-gynaecological material in suspension or fluids. Despite this breakthrough, there is a paucity of data on the suitability of CRR cell blocks for immunocytochemical and DNA assessment from FNAB material obtained from solid tumours. This study aimed to establish and confirm the suitability of CytoRich Red® Cell Blocks and FNAB biospecimens obtained and prepared at Kamuzu Central Hospital, Lilongwe, Malawi, for cytomorphological and immunocytochemical assessment. This study analysed 144 cell blocks and 128 FNAB smears. It is one of the first within sub-Saharan Africa to describe diagnostic efficacy from FNAB specimens obtained from various superficial and deep masses fixed in CRR. It describes the advantage of using an alcohol-based fixative immediately to reduce pre-fixation time lag. This study showed that CRR-fixed cell blocks improve sensitivity and architectural preservation, and immunocytochemical staining characteristics of the aspirate compared to routine FNAB smears. It is envisioned that CRR-fixed cell blocks will be a source of extractable, stable and usable DNA that supports research in biorepositories and biobanks.
- ItemDevelopment of a novel pre-screen algorithm for cardio-metabolic risk management using a genomics database resource(Stellenbosch : Stellenbosch University, 2016-03) Luckhoff, Hilmar Klaus; Kotze, Maritha J.; Janse van Rensburg, Susan; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Anatomical Pathology.ENGLISH ABSTRACT: The timely assessment and treatment of dyslipidaemia is an important component of cardiovascular risk screening and intervention. The apolipoprotein E (APOE) ε-2/ε-3/ε-4 polymorphism associated with impaired lipid homeostasis provides a genetic link between cardiovascular disease (CVD) and late-onset Alzheimer’s disease (AD). Realization that the phenotypic expression of the risk associated APOEε-2 and ε-4 alleles may be dependent on non-genetic factors supports the inclusion of APOE genotyping in chronic disease screening programs. The lack of well-defined selection criteria for APOE genotyping, however, limits the use of this biomarker in clinical practice. The aim of the present study was to develop a pre-screen algorithm for identification of a target population most likely to benefit from APOE genotyping, performed in conjunction with a clinical and lifestyle assessment. Towards this goal, comprehensive patient data were evaluated from a total of 580 unrelated Caucasians enrolled in a chronic disease screening program over a five-year period (2010-2015), using an ethically approved study questionnaire. Biochemical tests performed according to standard laboratory protocols were extracted from the research database. All study participants were genotyped for the APOE ε- 2/ε-3/ε-4 polymorphism. APOE genotype distribution differed significantly (p<0.05) between study participants with and without a family history of AD. A positive association between dietary fat intake and lowdensity lipoprotein (LDL) cholesterol (p=0.001), as well as an inverse association with highdensity lipoprotein (HDL) cholesterol (p=0.002), were observed in patients with a family history of AD. Body mass index (BMI) was positively associated with LDL cholesterol and inversely associated with HDL cholesterol levels (p<0.001), irrespectively of an AD family history. Smoking was associated with higher triglycerides (p<0.001) and lower HDL cholesterol levels (p=0.004) in the total study group. Alcohol intake was positively associated with BMI (p=0.008) as well as triglyceride levels (p=0.021) in patients with a positive family history of AD. The clinical expression of a hypercholesterolaemic phenotype in APOE ε-4 allele carriers, as well as apparent mitigation by regular physical activity, were dependent on the interaction between a family history of AD and APOE genotype (p<0.001). APOE ε-2 carriers without an AD family history showed a significant increase in triglyceride levels (p=0.014). The modulating influence of APOE ε-4 on the relationship between alcohol intake and BMI as well as total cholesterol levels was also dependent on the presence or absence of AD family history (p<0.05). This study resulted in the addition of a family history of AD as a novel component to the prescreen algorithm developed for selection of at-risk individuals prior to APOE genotyping performed as part of a chronic disease screening program. The lifestyle questionnaire used in this study furthermore facilitated interpretation of the clinical relevance of variation detected in the APOE gene. This is important to prioritize the use of lipid-lowering medication towards patients with severe subtypes of dyslipidaemia such as familial hypercholesterolaemia (FH), which remains largely undiagnosed and untreated in the highrisk South African population. Incorporating the research findings into clinical practice would suggest that physical activity may be the most effective risk reduction strategy in carriers of the APOEε-4 allele, as supported by international studies.
- ItemEvaluating the role of long-term urine bio-banking on the stability of urine bio-markers in the diagnosis of pre-eclampsia(Stellenbosch : Stellenbosch University, 2019-04) Bell, Jody Lee; Swanepoel, Carmen; Isaacs, Shafieka; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Haematological Pathology.ENGLISH ABSTRACT: The aim of the pre-eclampsia (PE) and eclampsia monitoring, prevention and treatment consortium is to develop a rapid diagnostic test for PE in pregnant women because early identification of PE would decrease the likelihood of maternal and perinatal mortality and improve antenatal care, management and treatment. The identification of potential bio-markers is thus of great importance in PE because urine is a non-invasive bio-specimen and has the potential to help predict PE since proteinuria can be detected and quantified in urine. The purpose of this exploratory study was to evaluate the long-term stability of selected analytes within preservative-free urine in a pre-eclampsia cohort. Calcium, Creatinine and total protein in long-term, stored urine samples were measured using both manual Siemens and Life Assay dipsticks and compared with high-throughput, laboratory measurements. Additionally, the diagnostic and prognostic potential of an Enzyme-linked immunosorbent assay (ELISA) -based, Adipsin or Complement Factor D (CFD) test for pre-eclampsia was evaluated. Furthermore, fresh urine samples were collected, and different processing and intermediate storage conditions were evaluated and compared to the medical research gold standard to determine to what extent pre-analytical variables could affect sample integrity. Albumin, Creatinine, Calcium, Urea and Total Protein were measured using high-throughput measurements. The results of the study showed that the measurements for the Siemen dipstick and Life Assay dipstick were significantly similar. However, no agreement was found between the dipsticks and high-throughput laboratory measurements. Adipsin was measurable using the ELISA assay despite the assay not being validated for frozen urine samples. Our results also showed that the measurements for Creatinine, Protein, and Calcium were impacted after sample storage at room temperature for 48 hours, highlighting pre-analytical variable has a great influence on sample integrity. This exploratory pilot study provided insight into the sample collection, handling, processing and long-term storage of urine bio-specimens and how each step of the process can have an impact. These insights led to an understanding of the limitations of this pilot study and can help to establish priorities for a larger study in terms of selected analytes to be measured, that could improve final research design and determine the best methods for data collection and analysis.
- ItemEvaluation of high-throughput methodology for multi-gene screening in patients with Non-Alcoholic Fatty Liver Disease (NAFLD)(Stellenbosch : Stellenbosch University, 2011-12) Fisher, Leslie Reginald; Kotze, Maritha J.; Kruger, F. C.; Stellenbosch University. Faculty of Health Sciences. Dept. of Pathology.ENGLISH ABSTRACT: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent chronic liver disease in Western countries and is considered the hepatic manifestation of the Metabolic Syndrome (MetS). Its heterogeneous nature ranges from hepatic steatosis through steatohepatitis to advanced fibrosis and cirrhosis where the ingestion of significant amounts of alcohol has been excluded. The disease profile of NAFLD and its necro-inflammatory subset Nonalcoholic Steatohepatitis (NASH) were described in the parent study, which provided a clinically well-characterised patient cohort for the present investigation. South African patients with NASH had significantly higher mean serum cholesterol and triglyceride levels than those with fatty liver only. The objective of this study was to implement a high-throughput real-time polymerase chain reaction (PCR) method in our laboratory to enable the assessment of cardiovascular genetic risk factors in NAFLD patients. The specific aims were to determine the clinical utility and perform analytical validation of each mutation included in the multi-gene cardiovascular disease (CVD) screening assay. The Pathology Supported Genetic Testing (PSGT) concept developed at our department provides a practical approach to personalized medicine. The CVD multi-gene screen analyses key metabolic pathways relating to atherogenic dyslipidaemia, chronic inflammation, hypercoagulation and iron dysregulation implicated in insulin resistance, which is known to be a universal factor in the pathogenesis of NAFLD. Deleterious low-penetrance mutations in the APOE (APOE2 and E4 alleles), MTHFR (677C>T and 1298A>C), F2 (20210G>A), FV (1691G>A, Leiden) and HFE (C282Y and H63D) genes were included for analysis due to their important role as genetic contributors to these biological processes. A total of 178 patients diagnosed with NAFLD and 75 controls were studied using direct DNA sequencing and a RT-PCR system for mutation detection. In addition, two patients with high ferritin levels were included as case studies. A significant association was found between HFE mutations and elevated Alanine Transaminase (ALT) levels in the NAFLD population (p = 0.04). This discovery is interpreted as the identification of a subset of patients at greater risk of developing progressive liver damage who would benefit most from genetic testing to direct more aggressive therapy at an earlier stage. The necessity of an integrative, systems-based network approach was demonstrated to more accurately distinguish between Hereditary Haemochromatosis (HH) and Insulin Resistance-associated Hepatic Iron Overload (IR-HIO) syndrome in obese patients. The PSGT approach to personalized medicine facilitates diagnosis of CVD subtypes, prevention of cumulative risk and the formulation of gene-based intervention programs tailored to the needs of the patient. These findings support the clinical utility of the CVD multi-gene test to guide chronic disease risk management in patients with NAFLD. The HFE mutation detection component of this test is of particular relevance in directing an effective treatment strategy in patients with a medical history of CVD and/or high iron stores.
- ItemGenetic aspects of pre-eclampsia : mutation screening of the low-density lipoprotein receptor, methylenetetrahydrofolate reductase, prothrombin and factor V candidate genes(Stellenbosch : Stellenbosch University, 2001-03) Gebhardt, G. S.; Odendaal, H. J.; Hillermann, R.; Kotze, Maritha J.; Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Pathology. Anatomical Pathology.ENGLISH ABSTRACT: Pre-eclampsia is a condition unique to pregnancy and primarily affects the maternal and placental vascular endothelium. It has significant morbidity and mortality consequences for both mother and infant. Despite global research into the aetiology of the condition, the cause for this condition remains unknown. Several factors, including a strong family history of hypertension in pregnancy point to a familial or genetic component in the pathophysiology of this complication. The purpose of this research project was to investigate candidate genes implicated in endothelial damage. Common methylene-tetra-hydrofolate reductase (MTHFR) gene mutations C677T and A1298C, factor V Leiden mutation R506Q and prothrombin mutation A20210G were investigated in 50 patients with an uncomplicated pregnancy outcome (controls) and 350 patients with various clinical manifestations of preeclampsia, including severe, early onset forms and abruptio placentae. Fasting homocystein levels were determined biochemically on all participants. In addition, 126 consecutive pregnant patients were recruited at booking, fasting lipograms were performed on them as well as mutation screening of 7 common mutations in the low-density lipoprotein receptor gene. This was correlated with eventual pregnancy outcome, and those with an uncomplicated outcome were selected as an additional control group. A significant association between hyperhomocysteinaemia and early onset severe pre-eclampsia could be demonstrated. Mutant allele T of the C677T mutation could be associated with hyperhomocysteinaemia but not with pre-eclampsia whilst mutant allele C of mutation A1298C demonstrated a significant correlation with diastolic blood pressure. In addition, combined heterozygosity for these mutations may serve as a marker for abruptio placentae.
- ItemHepatitis b virus-related hepatocellular carcinoma in south africa: investigations into the risk profile of a previously unscreened population from the Western Cape(Stellenbosch : Stellenbosch University, 2018-12) Chotun, Bibi Nafiisah; Anderson, Monique Ingrid; Preiser, Wolfgang; Fernandez, Pedro; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Medical Virology.ENGLISH ABSTRACT: Hepatocellular carcinoma (HCC) is a neglected major public health problem worldwide. In SubSaharan Africa (SSA), most HCC cases are diagnosed with advanced disease, well past the timing of possible treatment. Most HCC cases worldwide are caused by chronic infection with hepatitis B virus (HBV). Although the bulk of the burden of HBV is in SSA, there are no screening programmes implemented in the general African population so only 0.8% of HBV-infected individuals are diagnosed. Most research on HBV-related HCC has been conducted in Asia, where HBV is also endemic, but where there are differences in disease progression and presentation. The present study investigated HBV and HCC from an African perspective and tackled these public health issues by incorporating three key components for early diagnosis of HBV-related HCC: HBV screening, HCC biomarkers, and HBV-related HCC genomics. The HBV screening study found the prevalence of HBV in a South African community-based cohort using a validated point-of-care test to be 2.2% (95% CI: 1.4%–3.3%). The test performed well in the field and had a sensitivity, specificity, negative and positive predictive values of 100%. The test was also accepted by the community (93% uptake) and health care providers. The results of the present study support the case for the implementation of HBV screening in South Africa by demonstrating the magnitude of the HBV health problem in South Africa and new evidence that the POCT test performs well in the field, is accepted by the community and health care providers, and that patients diagnosed with the test can be successfully linked to treatment and long-term follow-up. The HCC biomarker study found significant differences in methylation expression levels in CpG islands in the promoter region of the tumour suppressor gene RASSF1A between HCC cases and normal liver tissue controls as well as a significant association between HBV genotype A and HCC. Although the sample size was small, it showed that there are biomarkers that may be used to identify HCC, paving the way for future studies looking into developing HCC risk scores for early diagnosis of HCC. Using whole-exome sequencing, the HBV-related HCC genomics study identified two novel germline variants in the SMARCA1 and RAB19 genes that in the absence of other risk factors besides HBV infection, could have contributed to early-onset HBV-related HCC in their respective hosts. Overall, these data provide evidence that early diagnosis of HBV-related HCC in an African setting is possible especially if a multi-targeted approach is taken. The simplest approach to minimise the incidence of HCC in SSA would be to implement HBV screening, at the very least in pregnant women, to break the transmission cycle of HBV. Moreover, the biomarkers of interest identified in the present study should be investigated further in larger cohorts and non-invasive patient samples to determine their utility in stratifying HCC risk. Lastly, the WES study showed that there are germline variants that could predispose carriers to HCC although these results need to be further investigated in in-silico and proteomic studies.
- ItemHPV strain prevalence and HPV-related biomarker expression in vulvar carcinoma at Tygerberg academic hospital.(Stellenbosch : Stellenbosch University, 2019-12) Petersen, Nadine Samantha; Sanderson, Micheline; Razack, Rubina; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Anatomical Pathology.ENGLISH ABSTRACT: The incidence of vulvar carcinoma in younger women has increased, possibly due to augmented human papillomavirus (HPV) infection. Variable geographic prevalence of HPV that are associated with vulvar carcinoma exists. In South Africa, histological subtyping is not always specified and the HPV prevalence in invasive vulvar squamous cell carcinoma (iVSCC) is largely unknown. High HIV prevalence could also be problematic as one of the risk factors for HPV-dependent vulvar cancer is impaired immunological status (Saidu 2016). The objectives of this study are to identify HPV subtypes in vulvar intraepithelial neoplasia (VIN) and iVSCC FFPE tissue using quantitative real-time polymerase chain reaction (qPCR) and to correlate HPV strain prevalence results with HIV status, clinicopathological features and biomarker expression. The study samples comprised of FFPE vulvar tissue from patients diagnosed with VIN and iVSCC at Tygerberg Academic Hospital between January 2003 and June 2018. Altogether, 72 VIN and 68 iVSCC FFPE tissue samples were included. DNA and RNA were isolated from FFPE vulvar tissues and the quantity and purity were assessed using fluorometry and spectrophotometry, respectively. The integrity of the derived DNA was determined through amplification of a 205 bp fragment of the human β-globin gene, while that of RNA was analysed with the RIN number and DV200 score of the Agilent 2100 Bioanalyzer. The presence of HPV DNA was investigated using qPCR employing primers targeting the E6/E7 gene of HPV 16, 18, 11 and 35. The expression of the HPV 16 and 18 E7 mRNA transcripts was examined with specific primers and probes using qPCR. HPV DNA detection results were correlated with histological diagnosis and subgroup as well as HIV status. Furthermore, tissue microarrays were also constructed of p16INK4a block positive immunohistochemistry samples and the staining pattern between the TMA and full sections were compared. Results show that patients between the ages of 36 to 59 years diagnosed with VIN and iVSCC at Tygerberg Academic Hospital between January 2003 and June 2018 were the largest proportion of our study population. Additionally, a significant proportion of the patients who were younger than 59 years, irrespective of diagnosis, were found to be HIV positive, with a large portion even being between 18 and 35 years old. Total DNA and RNA were extracted from the included FFPE vulvar tissue blocks. Overall, DNA of sufficient quality and integrity was obtained as a 205 bp human β -globin gene fragment was amplified in all FFPE vulvar samples, suggesting that the DNA was fit for qPCR analysis. Similarly, RNA was extracted from all applicable samples and was of adequate quality for use in qPCR as indicated by the DV200 scores, RIN numbers and the expression of GAPDH in samples converted to cDNA. HPV DNA was detected in 77.8 % of VIN and 66.2 % of iVSCC samples with HPV 16 being the most prevalent strain detected in both diagnoses. The majority of patients for which HPV DNA were detected were found to be co-infected with HIV. When histopathological subtypes were compared with HPV DNA detection, results showed that 82 % of VIN II/III (HSIL) and 37.5 % of VIN I (LSIL) samples tested positive for HPV. Notably, a high HPV prevalence was also found in the keratinizing variants of the samples representative of iVSCC. Regarding mRNA transcript analysis, overall, the proportion of samples in which HPV 16 and HPV 18 mRNA was expressed were slightly less than for HPV DNA detected. However, a high concordance was found between the two HPV detection methods, with high sensitivity and specificity obtained. Two tissue microarrays, one with HIV positive and the other with HIV negative samples, were constructed using samples that were block positive for p16INK4a IHC staining. When comparing the specificity and sensitivity of the p16INK4a IHC staining on full sections slides to that of TMA slides, results showed good agreement between scoring. In conclusion, these findings showed that VIN and iVSCC were diagnosed in women of much younger age in our study population compared to more developed countries. A high HIV prevalence was noticeable in HPV positive samples, for which HPV 16 was the most common subtype detected. Results also indicated that iVSCC keratinizing variants were largely associated with HPV in our study population which were also in contrast to what is reported. The findings of this study provide some insight into the prevalence of vulvar carcinoma and its precursor lesions, emphasizing the strong association of HPV in disease development in our setting. Lastly, it was also concluded that TMA’s may be utilized for ancillary testing of vulvar specimens, with a view of exploiting this technology for its multitude of advantages, especially in the context of pre-invasive HPV associated research. The search for new biomarkers, to predict progression from precursor lesions to invasive disease is still ongoing and inconclusive, therefore, further studies are needed to aid the better understanding of the aetiology and pathophysiology of vulvar cancer in South Africa.
- ItemInvestigation and management of primary immunodeficiency in South African children(Health and Medical Publishing Group, 2014) Eley, B.; Esser, M.ENGLISH ABSTRACT: The primary immunodeficiency diseases (PIDs) are inherited, non-communicable diseases that cause immunological dysfunction. PIDs are seldom reported in South Africa (SA). Based on a mid-2013 population estimate of 52.98 million and assuming that the prevalence of PIDs is similar to that in well-resourced settings, the total number of individuals with PIDs in our country should range between 2 850 and 45 723. However, fewer than 500 cases of PID have been reported in SA. Between five and 15 new, fully characterised PIDs are reported annually. Our understanding of the physiology of the immune system has been substantially enhanced by these discoveries, and consequently the international classification of PIDs has been updated.
- ItemThe investigation of bronchoalveolar lavage fluid in paediatric chronic wheezers(Stellenbosch : Stellenbosch University., 2020-03) Marshall, Michelle Anthea; Schubert, Pawel T.; Goussard, Pierre; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Anatomical Pathology.ENGLISH ABSTRACT: Background: Paediatric broncho-alveolar lavage (BAL) is a minimally invasive procedure, performed during flexible bronchoscopy using isotonic saline to obtain a sample of bronchial and alveolar fluid from the distal lung. The BAL sample provides a determination of the different cell types that are present in the alveolar space as well as establishing the presence of lipid or haemosiderin in alveolar macrophages. In paediatric clinical practice, the patients that undergo BAL most frequently are children with chronic wheezing and recurrent chest infections as part of their workup to determine the possible cause. However, the interpretation of these results, in the clinical context is relatively uncertain. We therefore conducted this study in collaboration with the paediatric pulmonology unit at Tygerberg hospital in an attempt to determine if the BAL specimens can be used to categorize children with wheezing into either a gastro-eosophageal reflux or primary respiratory pathology group. We wanted to guage whether laboratory tests such as the differential cells counts; lipid-laden macrophage index, haemosiderin-laden macrophages index and number of carbon-laden macrophages can be used as a marker for pulmonary pathology. To determine if BAL can assist with sub-classification of the primary respiratory pathology group and determine if the amount of carbon-laden macrophages corresponds to the risk of increased lung disease Aim: Henceforth, we undertook this study to determine if the BAL specimens could be used to categorize these children as belonging to either the gastro-esophageal reflux or primary respiratory pathology group by grading the amounts of Oil red O lipid-laden macrophages (LLM) which is a marker for gastro-oesophageal reflux aspiration , Perl’s Prussian blue positive haemosiderin-laden macrophages(HLM) which serves to indicate the presence of pulmonary haemorrage and carbonladen macrophage (CLM) which may contribute to chronic lung disease, however has not yet been assessed in our setting. We also wanted to determine if the amount of phagocytosed carbon by alveolar macrophages had any correlation with chronic wheezing. Methods: Between march 2017 and march 2018, 68 paediatric patients presenting with a chronic wheeze underwent clinical investigations which included routine chemical pathology, microbiology and virology testing and the cytological evaluation of their BAL specimens. Once processed, the slides were stained with the Papanicolaou, Giemsa, Oil red O and Perl’s Prussian blue to quantitate the differential cell count as well as lipid-laden macrophage index, haemosiderin-laden macrophage index and number of carbon-laden macrophages present. After a full clinical work-up, these patients were placed into a broad category of recurrent wheeze and recurrent infection, and sub-category groups of gastro-eosaphageal reflux disease (GORD), alveolar proteinosis, idiopathic pulmonary haemosiderosis (IPH), recurrent wheeze, infection/inflammation and structural abnormalities. Results: There was no statistical significance when comparing the cellular differential counts; carbon; lipid and haemosiderin-macrophages; tuberculosis investigations; cystic fibrosis investigations; virology investigations; microbiology investigations and c-reactive protein in the broad categories of recurrent wheezer vs. recurrent infection as well as subcategories of infection/inflammation, GORD, structural abnormality, idiopathic wheezer, IPF and alveolar proteinosis. Conclusion: The cytological investigation of paediatric BAL specimens continues to play a role in the clinical work up of children with chronic wheezing. This study did not manage to yield statistically significant data to identify a specific underlying cause and further research is needed in this field.
- ItemThe MED-PED project : presymptomatic diagnosis in families with disease- related LDL receptor gene mutations(Stellenbosch : Stellenbosch University, 2000-03) Vergotine, Joseph Vincent; Kotze, Maritha J.; De Jong, G.; Stellenbosch University. Faculty of Medicine & Health Sciences . Dept. of Pathology.ENGLISH ABSTRACT: Familial hypercholesterolaemia (FH) contributes significantly to the high death rate from cardiovascular disease worldwide. FH is a common autosomal co-dominant disease characterised by raised cholesterol levels and premature coronary heart disease (CHD). Whilst these features usually are very prominent in homozygotes the clinical diagnosis of heterozygotes is complicated by variable phenotypic expression. Specific founder genes in the low-density lipoprotein receptor (LDLR) gene have increased the prevalence of FH in South African Afrikaners, Indians, Jews and Coloureds, and screening for these known mutations allows unequivocal diagnosis of FH-affected individuals. The systematic molecular analysis of FH resulted in the identification of at least ten founder-type LDLR gene mutations among the 56 different gene defects described to date in the diverse South African population. DNA screening of 792 at-risk family members for the FH-related mutations identified in 379 index cases, allowed accurate disease diagnosis in an additional 340 relatives and exclusion of the relevant mutation in 452 individuals. This effort forms part of the MED PED FH initiative, a collaborative project to "Make Early Diagnosis and Prevent Early Deaths in MEDical PEDigrees with FH". Evaluation of clinical criteria versus DNA diagnosis of three founder-related mutations (D154N, D206E and V408M) in the South African population demonstrated that the sensitivity and specificity of diagnoses, based on total cholesterol values measured in family members of index cases recruited for this study, were 88% and 77%, respectively. A population-directed DNA diagnosis of FH is therefore justified in South Africa on a routine basis, since expression of the defective gene measured in biochemical tests does not allow accurate diagnosis of FH in all cases. The application of mutation detection was illustrated by prenatal diagnosis of FH performed for a couple who are both heterozygous for the most common Afrikaner mutation, D206E. The mutation was absent in the foetus and a normocholesterolaemic infant was born. Prenatal diagnosis of FH, aimed at the detection of homozygous cases, is particularly applicable in populations and families with molecularly defined LDLR gene mutations. The MED-PED approach resulted in accurate diagnosis and subsequent treatment of FH in more patients, and referral to lipid clinics where they could receive the intensive care their condition justifies. Molecularly diagnosed FH patients will be the first to benefit from future treatment approaches based on mutation type.
- ItemMolecular-genetic analysis of Hirschsprung's disease in South Africa(Stellenbosch : Stellenbosch University, 2000-03) Julies, Monique G.; Moore, S. W.; Kotze, Maritha J.; Du Plessis, L.; Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Pathology.ENGLISH ABSTRACT: Hirschsprung's disease, or aganglionic megacolon, is a common cause of intestinal obstruction in neonates and is associated with the congenital absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the gastrointestinal tract. The affected area is usually restricted to the distal part of the colon (short segment disease), but total colonic or intestinal involvement occurs in some patients (long segment disease). DNA analysis was performed on samples from 53 unrelated sporadic HSCR patients to search for mutations in RET proto-oncogene, endothelin-B receptor (EDNRB) and endothelin-3 (EDN3) genes. The patients were from different ethnic groups in South Africa, including 29 coloured, 14 white (Caucasian) and 9 black individuals. The origin of 1 patient was unknown. PCR HEX-SSCP analysis of the RET protooncogene revealed one previously described (P973L) and five novel mutations (V202M, E480K, IVS10-2A1G, D771N, IVS19-9Crr), likely to cause or contribute to the HSCR phenotype. Nine polymorphisms were also identified in the RET protooncogene, of which four were novel (IVS6+56deIG, IVS13-29Crr, IVS16-38deIG, X1159) and five previously described (A45, A432, L769, S904, R982). All the mobility shifts detected in the EDNRB gene represented polymorph isms (A60T, S184, 1187, V234, L277, IVS3-6Crr, IVS4+3A1G). No sequence variants were identified in the EDN3 gene. The majority of mutations in the RET proto-oncogene (28.6%) were identified in coloured patients while no mutations were identified in black patients. A mutation in RET was identified in two of 14 patients (14%) presenting with HSCR and Down's syndrome compared to 6 mutations identified in 9 of 39 patients (23%) with only HSCR. The fact that Down's syndrome patients have a high chance of developing HSCR, implies the involvement of modifier gene(s) in a HSCR/Oown's syndrome phenotype. This study demonstrated that, within the South African HSCR patient population, the RET proto-oncogene is the major susceptibility gene, whereas EDNRB and EDN3 may contribute only to a minority of cases. In 81% of patients no disease-causing mutation could be identified, which is in keeping with the heterogeneous nature of HSCR. The identification of mutations in HSCR patients would in future lead to improved and accurate counselling of South African HSCR patients and their families.
- ItemOntogeny of the innate immune response in healthy South African infants(Stellenbosch : Stellenbosch University, 2012-12) Adams, Rozanne Charlene McChary; Esser, Monika Maria; Kollmann, Tobias; Bouic, Patrick J. D.; De Beer, Corena; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology.ENGLISH ABSTRACT: Infection is a major cause of morbidity and mortality in infants within the first few months of life. Susceptibility to infectious disease in this vulnerable population is more prevalent in resource-limited regions, with a higher disease burden. Due to certain deficiencies in their adaptive immune system, neonates rely predominantly on their innate immune system for protection against infection, a vital component in the early host defence against pathogens. Several studies have described differences in neonatal innate toll-like receptor-mediated responses compared to adult counterparts, though very little is known about these receptor responses within resource-limited settings. To address this issue, we assessed the longitudinal development of cytokine-specific responses of TLR4 and TLR7/8 in monocytes, myeloid dendritic cells and plasmacytoid dendritic cells in infants from a resource-limited setting, South Africa, within the first 12 months of life and compared it to adults. Contrary to previously published literature, we observed heightened production of TH-1 cytokines: we showed increased responsiveness to TLR4 and TLR7/8 stimulation in infants at two and six weeks of age, which may be due to vaccination administered at birth. Unexpectedly, the hyper-inflammatory response persisted at six months in response to the LPS (TLR4) stimulus. This increased response at six months may be attributed to decreased passive immunity through infant weaning as well as increased exposure to microbial pathogens in this setting. Maturation of most cytokine responses was reached at twelve months for the TLR4 receptor, and at six months for the TLR7/8 receptor. The first year of life represents a critical period for maturation of the immune response. Data from this study point towards an elevated response within the first six months of life. This heightened response reflects both an ability to mount a sufficient TH-1 response in infancy, but more likely, the increased exposure to microbial stimuli in the environment. Thus, we speculate that these age-specific inflammatory responses may influence the outcome of immune responses to various vaccines administered, which may result in altered responsiveness to immunisation in infancy.
- ItemPlacental syphilis: a comprehensive review of routine histomorphology, HIV co-infection, penicillin treatment, immunohistochemistry, and polymerase chain reaction.(Stellenbosch : Stellenbosch University, 2023-04) Marais, Yolandi Anne; Mason, Deidré; Barnard, Annelize; Saaiman, Chestley Rashaell; Els, Hester Christine; Kluge, Judith; Glass, Allison Joy; Wright, Colleen Anne; Schubert, Pawel Tomasz; Schubert, Pawel Tomasz; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Division of Anatomical Pathology.ENGLISH ABSTRACT: Introduction: Placental examination is useful to diagnose congenital syphilis. The classical histological diagnostic triad is, however, an infrequent finding. Additional morphological clues, special investigations, and knowledge of potential alterations by HIV co-infection and penicillin treatment can aid in making the diagnosis. Materials and methods: Placental specimens diagnosed with treponemal infection were reviewed. Morphological findings, IHC and qPCR results were assessed. Results: Two-hundred and twenty-two placentas were recruited. Villitis (93.2%), acute chorioamnionitis (91%) and villous immaturity (64%) were the most common abnormalities. HIV co-infection and penicillin treatment demonstrated alterations that may hamper diagnosis. Treponema IHC and q-PCR had a sensitivity of 74.4% and 25.81%, respectively and confirmed an additional 41 cases with negative or unknown serology. Conclusion: Villitis, acute chorioamnionitis and villous immaturity are the most common microscopic abnormalities in placental syphilis. HIV co-infection and penicillin treatment may alter morphology. Treponema IHC and q-PCR are useful adjuncts when serology is negative.
- ItemPrevalence of ERG overexpression in prostate cancer on prostate biopsies at a tertiary public hospital in the Western Cape, South Africa(Stellenbosch : Stellenbosch University, 2023-12) McCree, Kevin; Van Wyk, Abrie; Fernandez, Pedro; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Division of Anatomical Pathology.ENGLISH ABSTRACT: Background: Prostate cancer is the most diagnosed non-cutaneous malignancy in men in South Africa across all race groups with 10495 new cases reported in 2019. The TMPRSS2-ERG fusion gene and resultant overexpression of ERG is estimated to occur at a rate of 30-50% within prostate cancer. The fusion gene is specific to prostate cancer and high grade prostatic intraepithelial neoplasia and has not been reported in other malignant neoplasms. The TMPRSS2-ERG fusion gene, and by implication the overexpression of ERG, may serve as a diagnostic, prognostic or therapeutic biomarker. The prevalence of the TMPRSS2-ERG fusion gene in prostate carcinoma in South Africa has not been investigated previously. We sought to determine the prevalence of the TMPRSS2-ERG gene fusion among men undergoing prostate biopsies at Tygerberg Hospital, Cape Town, South Africa and to determine whether there is an association between prostate cancer grade and ethnicity/race. Methods: This is a retrospective descriptive laboratory study where we analysed 362 prostate biopsies, diagnosed with prostate cancer, between January 2010 and December 2017. All 362 cases were reviewed, and the diagnosis was confirmed. 336 cases were stained with ERG (Cell Marque, clone EP111) an adequate surrogate marker for the TMPRSS2-ERG fusion gene. The prevalence was calculated and compared with Gleason grade group and ethnicity/race to determine if there is an association. Results: ERG overexpression was detected in 34% of cases. Our study showed an association with a lower Gleason score and ERG overexpression. There is a higher prevalence of TMPRSS2-ERG amongst the coloured population in this cohort, at 34%. Conclusions: This is the first study to characterise the prevalence of ERG overexpression in prostate cancer in patients who underwent prostate biopsies in South Africa. Our results show that this gene rearrangement is common in the study population and that the prevalence of 34% is within the range reported in international literature.