Browsing by Author "Ikumi, Nadia"

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    Open Access
    Electron microscopic morphometry of podocyte foot process effacement as a tool to distinguish primary from secondary focal segmental glomerulosclerosis (FSGS)
    (2024) da Costa, Nelson; Price, Brendon; Singh Shivani; Davidson, Bianca; Ikumi, Nadia
    Background: Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular injury and one of the most common causes of end-stage renal disease in adult patients. Two major subtypes of FSGS (primary oand secondary) have been identified, with differences in clinical presentation, electron microscopy (EM) foot process width (FPW) and effacement (FPE), and treatment options. Primary FSGS commonly presents as nephrotic syndrome (NS), shows diffuse FPE with a FPW >1500nm, and is generally responsive to steroid therapy. Secondary FSGS does not present with NS (non-nephrotic), shows focal FPE and a FPW <1500nm, and does not respond to steroids. Sometimes, it may be clinically very difficult to differentiate between the two. In these scenarios, EM becomes of paramount importance. In this study, we evaluated podocyte FPW and FPE in FSGS patients to investigate whether a significant difference exists between primary and secondary FSGS. Methods: Cases histologically diagnosed as FSGS in adult native renal biopsies over a 5-year period at Groote Schuur Hospital and Livingstone Hospital were reviewed. Using the 2021 KDIGO guidelines, cases were classified as nephrotic syndrome (NS) or non-nephrotic syndrome (NNS). Using EM and imaging software, podocyte FPWs were calculated and the extent of FPE determined for each case. The results were analysed and correlated with multiple variables. Results: Of a total sample size of 35, 32 cases of FSGS and 3 controls were reviewed. 23 patients presented with NS while 9 patients did not meet the criteria for NS. The NS group had a calculated median FPW of 3076nm, while the NNS group had a median FPW of 1322nm (p=0.003). 83% of the NS group had diffuse FPE, whereas 78% of the NNS group had focal FPE (p=0.003). Logistic regression revealed a FPW threshold value of 2550nm correlated with an 80% probability of a NS diagnosis. A strong correlation between primary FSGS and oedema (p=0.006), proteinuria (p=0.0005), cholesterol (p=0.003) and albumin (p=0.0002) were found. A strong correlation existed between FPW and proteinuria (p=0.0021), eGFR (p=0.017), and albumin (p=0.012). No differences were identified with regards to age, gender, and HIV status. Unsupervised hierarchical cluster analysis with no a priori assumptions identified three clusters, one NNS cluster and two NS clusters, the latter demonstrating 2 separate populations differing with respect to uPCR, creatinine, and FPW. The significance of this finding will be investigated in follow up studies. Conclusion: This is the first study, to our knowledge, in the sub-Saharan African setting to use EM to calculate FPW and determine FPE in FSGS patients. The current study results align with those of previously published international studies. In this study, primary FSGS is generally associated with diffuse FPE and FPW>3000nm, whereas secondary FSGS is associated with focal FPE and FPW <1500nm. In clinically difficult scenarios, EM FPW calculation and FPE determination remains an important adjunct to histopathology and clinical parameters in the differentiation of primary from secondary FSGS in the South African population. The significance of making this distinction lies in completely different patient management regimens between the two groups.
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    Histological outcome of atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (asc-h) papanicolaou smears diagnosed at Groote Schuur hospital
    (2025) Wessels, Raisa; Chokoe Maluleke, Mmaphuti Jackie; Ikumi, Nadia
    Background - Cervical cancer imparts a huge burden on South African women and the healthcare system, making up 17.33% of all cancers in females. Cervical cytology screening, assessed under the Bethesda system, forms an integral part of this effort. Within this system, the Atypical Squamous Cells, cannot exclude High grade squamous intraepithelial lesion (ASC-H) category is said to carry a positive predictive value for High grade Squamous Intraepithelial neoplasia (HSIL) that lies between Atypical Squamous Cells of Uncertain Significance (ASC-US) and HSIL. Aim: The aim of this study was to assess the histological outcome of the ASC-H Papanicolaou smears diagnosed between January 2009 and December 2019 and to compare the yield of high grade histology with the literature. Methods: A computerized search of the Laboratory Information Systems (LIS) at Groote Schuur Hospital yielded 1694 ASC-H cases. Results: Of the 1694 cases identified, 699 cases had data on histology. Of the 699 cases with histology data, the majority of cases showed High Grade Squamous Intraepithelial Lesion (HSIL) on histology (n=271, 38.8%). There were 225 (32.1%) cases of Low grade Squamous Intraepithelial Lesion (LSIL), 75 (10.7%) showed normal histology, 40 (5.7%) cases showed cervicitis, 26 (3.7%) cases showed squamous cell carcinoma, 25 (3.6%) cases were suboptimal for assessment, 21(3.1%) cases showed squamous metaplasia and 16(2.3%) cases reflected diagnoses falling into an “other” category (which includes entities such as benign polyps and glandular lesions). Conclusion: With the larger proportion of cases showing HSIL, the intention of the ASC-H category to identify likely high risk cervical changes and expedite follow-up colposcopy, biopsy and management has been proven.
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    Renal allograft biopsies at Groote Schuur Hospital: a histopathologic descriptive study with molecular insights
    (2025) Lunn, Jarryd; Price, Brendon; Chetty, Dharshnee; Ikumi, Nadia
    Background: Kidney transplantation is the definitive treatment for end-stage kidney disease. Immune-mediated rejection remains a barrier to success. It is diagnosed through the Banff classification, which incorporates histopathology and biomarkers (C4d/donor specific antibodies (DSA)). In resource-limited settings, DSA testing can be challenging, necessitating reliable alternatives. Aim: This study evaluated: (1) rejection patterns at our hospital; (2) the impact of the Banff 2022 criteria with a computer-assisted tool; and (3) the utility of C4d as a predictor of DSA status. Methods: We analysed 197 for-cause historic biopsy reports between 2015-2022 for details of rejection- and non-rejection pathologies, Banff lesion scores and DSA status. A computer- based tool was used on historic data to re-calculate Banff 2022 classification diagnoses, which were compared to historic diagnoses. Logistic regression assessed C4d as a predictor of DSA. Results: The cohort showed a male predominance (59.3%). Sixty-three percent of cases showed non-rejection pathology, with acute tubular injury and pyelonephritis being the most frequent. TCMR was the most common form of rejection (17.3%), with AMR being the least common (7.6%). The computer-based tool demonstrated agreement of 92.4% for AMR/TCMR and 84.6% of borderline TCMR, but was confounded by non-rejection pathologies. C4d predicted DSA-positivity with 95% specificity but only 29.5% sensitivity. Conclusion: The Banff 2022 criteria were additive in rejection diagnosis, with a computer-based tool acting as a guide but not a pure diagnostic tool. The high specificity of C4d makes it valuable where DSA testing is limited. Contribution: This study validates the role of the Banff 2022 in our setting, aided by a computer-based tool that aims to decrease logical- and transcription errors when using the complex Banff classification. It also demonstrates C4d's role as a practical DSA proxy, offering actionable solutions in resource-limited settings.
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    The prevalence of different human papillomavirus genotypes in lesions of the uterine cervix as a method in risk assessment of cervical cancer
    (2025) Dittrich, Corneli; Pillay, Komala; Ikumi, Nadia
    Cervical cancer carries significant morbidity and mortality worldwide and presents a global health challenge. Despite longstanding screening programmes for precursor lesions, there remains a high incidence and prevalence of disease. Cervical cancer is caused by persistent infection with Human Papillomavirus (HPV), a sexually transmitted, oncogenic virus. There are more than 100 different HPV genotypes. Of these, studies have largely shown that the high- risk types 16 and 18 account for most cancers. However, with improved screening methods, other genotypes in particular HPV 31, are also emerging as significant. It is therefore important that there is an increase in National health education drives, opportunistic cervical screening and management programmes, particularly in low-income and middle-income countries (LMICs) where the bulk of cervical cancer cases and cancer-related deaths occur. The South African health system is disparate in that most women do not have access to adequate screening and that a small percentage of women with access to private healthcare are prone to over-screening. There is access to prophylactic vaccination, however, the only formal program available exists in the public setting, with vaccination against two oncogenic HPV genotypes, types 16 and 18. Given that other genotypes are emerging as significant causes of cancer across other settings globally, there is need for data on the prevalence of the different high-risk HPV genotypes in the South African population. Adequate data regarding prevalence of specific High-risk genotypes will also guide vaccination choices. Aim: To establish the prevalence of the different high-risk Human Papillomavirus genotypes in precursor and malignant lesions of the uterine cervix within a South African cohort. To compare our results to published data on prevalence of different HPV genotypes to South African statistics, Sub-Saharan African statistics and global statistics. Method: This was a cross-sectional, retrospective study using data from a pre-existing anonymised database that was created during the validation of the BD Viper as a new platform. There are two main arms to the study: Cytopathology and Histopathology. In both, the prevalence of the different high risk HPV genotypes will be established in different cohorts. The former in different screening groups and the latter on confirmed cases of malignancy. HPV genotyping is available on different platforms with different assays. For this study the focus is on PCR-based tests. Other methodologies such as linear array will be included in the literature review. Available PCR tests include the Cepheid Test on the GeneXpert platform, the Roche assay on the Cobas® platform and the BD OnclarityTM assay on the Viper system. The former two tests report HPV 16, 18 and a pool of ‘other' high risk genotypes on LBC samples. The latter offers extended genotyping, beyond 16 and 18 on LBC and formalin fixed paraffin embedded tissue samples (FFPE). This study therefore aims to report on the results from screening of the routine LBC samples for diagnostic co-tests performed on Roche Cobas® 6000 HPV Test used as a validation benchmark for the BD OnclarityTM HPV Assay. In addition, the study will include the analysis of the findings on the performance of the BD OnclarityTM HPV Assay on the genotyping of formalin fixed paraffin embedded tissue samples of proven cervical squamous cell carcinoma and adenocarcinoma for validation purposes of FFPE testing. Results: In the first group in the cytology arm of the study (NILM, ASCUS and LSIL) the three most prevalent high-risk genotypes for all LBC samples were HPV P2 (HPV types 56, 59 and 66) at 23%, P3 (HPV types 35, 39 and 68) accounting for 18% and type 31 at 14%. Among high-grade precursor lesions (HSIL and AGC) on cytology HPV 16 was the most frequently detected genotype, accounting for 33% of the total genotypes identified, followed by HPV P3 (HPV types 35/39/68) [17%], HPV 52 (11%), and HPV P1 (HPV types 33/58) [9%]. V The other high-risk genotypes in precursor lesions are HPV P3 (HPV types 35/39/68), HPV 52 and HPV P1 (HPV types 33/58), and in invasive carcinoma are HPV 18, HPV P3 (HPV types 35/39/68) and HPV 45. There were neither squamous cell carcinomas nor adenocarcinomas diagnosed on LBC and therefore no genotype analysis was performed. On the histopathology samples of squamous cell carcinoma HPV 16 was the most frequently detected genotype, accounting for approximately half (49%) of the genotypes identified, followed by HPV 18 (13%), HPV P3 (HPV types 35/39/68) [9%], and HPV 45 (9%). In cervical adenocarcinoma HPV 18 was the most frequently detected genotype, accounting for 50% of the total genotypes identified, followed by HPV 16 (23%), HPV 45 (14%), and HPV P3 (9%). An interesting finding was that of multiple HPV oncotypes detected in single cases. Conclusion: HPV 16 is the most common genotype in high-grade precursor lesions and invasive squamous cell carcinoma. HPV 18 is the most common genotype in invasive adenocarcinoma of the uterine cervix. The other high-risk genotypes in high-grade precursor lesions are HPV P3 (35/39/68), HPV 52 and HPV P1 (33/58), and in invasive carcinoma are HPV 18, HPV P3 (35/39/68) and HPV 45. For better comparison assays should match, as our pooled group results does not distinguish between individual oncotypes. Further studies and a South African meta-analysis are needed. We recommend that for adequate vaccine prevention of carcinoma of the cervix, in addition to HPV 16 and HPV 18 more genotypes should be included i.e. vaccination with the nano valent vaccine which offers protection against high-risk HPV types 16, 18, 31, 33, 45, 52, and 58. As an added benefit vaccination with this vaccine also protects against genital warts (condyloma acuminata) caused by HPV types 6 and 11.
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    The relationship between BRAF genetic alterations and the risk of tumour recurrence in Pilocytic Astrocytomas in children diagnosed at Red Cross Children's Hospital over a 33-year period
    (2024) Viljoen, Nandi; Pillay, Komala; Ramburan Amsha; Singh, Shivhani; Ikumi, Nadia
    Introduction: Pilocytic astrocytomas (PAs), glial-derived neoplasms, are the most common central nervous system (CNS) tumours reported in the paediatric population. 1 PAs are circumscribed astrocytic gliomas associated with a favourable overall survival and thus regarded as low grade by the World Health Organisation (WHO), with a reported five-year survival rate between 75% to 100%. 2,3 Optimal treatment of partially resected, deep anatomic location and recurrent tumours are challenging. Over the past decades, PAs have been the object of an increasing number of molecular studies which tried to identify favourable and unfavourable prognostic factors. Essentially all PAs harbour genetic aberrations resulting in the deregulation of the MAPK signalling pathway, with BRAF gene mutations being the most frequent. 4 However, reports on the impact of specific mutations on patient prognosis are controversial. 5–8 Advances in molecular techniques have opened the door for further studies to determine the relationship between these BRAF alterations (point mutations and gene fusions) and the risk of tumour recurrence. Purpose: The overall aim of this study was to determine if BRAF genetic alterations impact patient prognosis. This was done by evaluating the expression of BRAF using immunohistochemistry (IHC), fluorescence-in-situ hybridisation (FISH) and polymerase chain reaction (PCR) and comparing it to tumour recurrence. The results will also be compared to clinicopathological findings. Methods: Study design: A retrospective cohort laboratory-based study included all cases diagnosed with PAs that presented to Red Cross Children's Hospital (RCC) from January 1984 to December 2016. Patient selection and data collection: Convenient sampling was done by searching the electronic laboratory information database (Disa and NHLS TrakCare) of the Division of Anatomical Pathology for all cases diagnosed with PAs. Data collection included: age at diagnosis, tumour site, management and recurrence. Laboratory methods: Archived stained slides of all the cases were reviewed, the diagnosis was confirmed on histology, and tissue blocks were retrieved. The presence of BRAF genetic aberrations were examined using immunohistochemistry, FISH and PCR. Results: Sixty-nine paediatric patients with PAs were identified over the study period with a median age of 6 years. This included 33 females and 21 males (in 15 cases the gender was not documented). Most tumours (62.32%) were located in the cerebellum, followed by the cerebral hemisphere (18.84%). The tumour recurred in 21 individuals, of which 3 had incomplete surgical resections. 46.16% of supratentorial tumours recurred compared to a recurrence risk of only 20.93% in infratentorial tumours. BRAF immunohistochemistry was negative in all the cases, and FISH studies did not show BRAF rearrangements. Conclusion: The findings of this study were broadly consistent with published literature in terms of age at presentation, location of the tumour and tumour location concerning the risk of recurrence. While most studies revealed an equal or slight male predominance, this study showed that the tumour developed slightly more frequently in females. Our study did not find a correlation between the risk of recurrence and BRAF genetic aberrations.