BACKGROUND:South Africa (SA) has the highest prevalence of people with tuberculosis (TB) and HIV coinfection globally. People living with HIV have an increased risk of TB infection, and are more likely to develop extrapulmonary TB. Approximately 10 - 20% of extrapulmonary TB accounts for skeletal TB, with spinal involvement in 50 - 60% of instances. Previous studies have shown highly heterogenic results regarding the effect of HIV status on clinical and laboratory characteristics in patients with spinal TB (STB). OBJECTIVE:To describe the clinical, laboratory, radiographical and histopathological characteristics of patients diagnosed with STB stratified by HIV status. METHODS:Data from patients who were treated for STB at the Division of Orthopaedic Surgery, Groote Schuur Hospital, SA, between 2013 and 2016 were analysed. We compared clinical, laboratory, radiographical and histopathological parameters of STB patients with HIV infection to those without HIV infection. To assess differences in means between the two groups, an independent samples t-test was used for normally distributed continuous data, and a χ2 test for categorical data. To assess correlations between continuous data groups, the Pearson correlation coefficient was used. RESULTS:We assessed 52 patients with STB (mean (standard deviation (SD) age 38 (15.2) years, range 17 - 80 years), of whom 55.8% were female, and 59.6% HIV infected. Five (9.6%) patients were identified with multidrug-resistant TB of the spine, with four (19.0%) in the HIV-infected cohort and one in the HIV-uninfected cohort (p=0.058). Significantly more STB patients without HIV infection presented with neurogenic symptoms (29%, p=0.029). The mean (SD) overall erythrocyte sedimentation rate was 69.3 (35.9) mm/h, with no significant difference between HIV-infected and HIV-uninfected patients (p=0.086). The rate of vertebral collapse was higher in the HIV-infected cohort (39% v. 67%, p=0.048). HIV-infected patients showed a higher count of involved vertebrae (mean 3.0 v. 3.85; p=0.034). There was no correlation between CD4 count and the number of involved vertebrae. The mean (SD) number of granulomata per low-power field was 10 (12.6), with no difference between the two cohorts. However, we found a positive correlation between granuloma count and CD4 cell count in HIV-infected STB patients (Pearson 0.503, p=0.02), with significantly higher formation of granulomata at a CD4 cell count >400 cells/μL (p=0.045). CONCLUSION:In our cohort, HIV-infected patients with STB were more likely to present with vertebral collapse, and more vertebrae on average were diseased compared with HIV-uninfected patients with STB. CD4 cell count may affect granuloma formation, and it seems that HIV infection has a negative effect on cellular immunoresponse in STB, which emphasises the need for early antiretroviral therapy initiation.

Background: Published information on African patients with gastrointestinal stromal tumours (GISTs) is limited. Aim: The aim of this study was to review patient and tumour characteristics, and treatment, for a cohort of African patients and compare findings to studies from other centres. Setting: Groote Schuur Hospital, South Africa. Methods: Data were collected on all patients referred to Groote Schuur Hospital (GSH) during the period October 2003 to November 2019, including demographics, tumour characteristics and treatment outcomes. Results: There were 124 patients in total. There was a slight male predominance (55.6%) and the median age was 56 years. The most common primary tumour sites were the stomach (66.2%) and small bowel (21.8%) with a median primary tumour diameter of 95.5 mm. Mutational analysis was conducted for 39 patients with 66.7% of these patients having mutations in KIT exon 11. The primary tumour was resected in 72 patients, with 48.6% having high-risk tumours according to the National Institutes of Health (NIH) risk assessment. The 10-year overall survival (OS) values for patients by risk group were 83% (very low and low risk), 73% (intermediate risk) and 66% (high risk). The disease control rate for patients treated with imatinib was 84.6%. The median progression-free survival (PFS) for patients treated with imatinib for palliation was 23 months with OS of 31 months. Conclusion: In contrast to patients from other centres, our patients were younger and had larger tumours. Contribution: The distribution of primary tumour site, mutational analysis and response to imatinib was consistent with the literature.

BACKGROUND:Colorectal cancer (CRC) in the indigenous African population of South Africa is uncommon (age standardised incidence rates of 11.29 for males and 7.27/100 000 for females) and tends to occur at a young age. Lynch syndrome (LS), an inherited mismatch repair (MMR) gene abnormality, accounts for 3-4% of newly diagnosed CRCs in high incidence areas. There is some evidence that the contribution of an MMR abnormality to the overall CRC burden may be increased in low incidence areas. We aimed to determine the prevalence of MMR deficiency in an indigenous African population.METHODS:A cohort of 66 self-declared indigenous African patients, less than 50 years of age at diagnosis with CRC was identified from clinical and pathological records. The original histopathology was reviewed to confirm the diagnosis and features suggestive of MMR abnormality determined (pushing edge, mucinous, lymphocytic infiltration, Crohn's like reaction). Where sufficient tissue was available, samples were sectioned and stained for the four MMR proteins.RESULTS:Histopathological examination confirmed adenocarcinoma in 31 individuals. At least one feature suggestive of MMR was identified in 22 of these specimens. Twenty-seven cases were stained for all four MMR proteins using standard immunohistochemistry (IHC). MMR deficiency was found in 37% (n = 10/27) of cases. Median age of diagnosis was 35 years in the MMR-proficient group and 44 years in the MMR-deficient group, p < 0.008. No other significant differences between the groups were noted.CONCLUSION:MMR deficiency was common in colorectal carcinomas in the older patients in this cohort, but very young indigenous Africans CRCs do not appear to result from mismatch repair gene mutations.

Background. Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, has been a component of first-line antiretroviral therapy (ART) in the South African HIV/AIDS programme since 2004. It is extensively used in ART programmes in other low- and middle-income countries. The natural history of the previously recognised EFV drug-induced liver injury (DILI) is not known. Objectives. To define and establish a causality assessment for EFV DILI and document its natural history by detailing a patient cohort. All relevant features characterising the patterns of clinical and histological injury, the duration of clinical and biochemical recovery and the associated mortality rate were documented. Factors associated with specific histological patterns of liver injury were analysed. Methods. Patients were prospectively included after meeting causality and inclusion criteria for EFV DILI. Clinical, demographic and liver histological features (where possible) were documented from the time of presentation and throughout follow-up. Prednisone at 0.25 - 0.5 mg/kg was initiated at the discretion of the treating hepatologist. Results. Fifty patients were prospectively included in the analysis. The median age was 34 (interquartile range (IQR) 29 - 39) years, males being older than females ( p =0.014). Most (92%) were female, and 86% were of black African ethnicity. The median duration of ART at presentation was 6 months, with half of the women having initiated ART during pregnancy, at a median gestation of 24 (IQR 11 - 36) weeks. The median CD4 nadir at ART treatment initiation was 517 cells/µL, with no significant difference in CD4 nadir between those who were pregnant and those who were not ( p =0.6). The median RUCAM (Roussel Uclaf Causality Assessment Method) score was 7, and among the 75% of patients who had liver biopsies, three histological patterns were identified: submassive necrosis (60%), nonspecific hepatitis (35%), and mixed cholestatic hepatitis (5%). On multivariate analysis, predictors for the development of submassive necrosis included younger age (<30 years; p =0.045), ART initiation in pregnancy ( p =0.02), and a baseline CD4 count >350 cells/µL ( p =0.018). For the nonspecific hepatitis group, pregnancy was also an associated factor ( p =0.04). The mortality rate was 14%, with a median time from admission to death of 15 days. The median (IQR) time to initial hospital discharge was a lengthy 33 (24 - 52) days. Biochemical recovery was prolonged, necessitating a follow-up period of more than a year at an outpatient specialist clinic, with 86% of patients initiating a protease inhibitor-based ART regimen successfully. Conclusions. EFV DILI is a severe drug complication of ART with appreciable mortality and significant inpatient morbidity, requiring prolonged hospitalisation and follow-up.

BACKGROUND:The classification of gastrointestinal (GI) neuroendocrine neoplasms (NENs) has been updated in the WHO classification of tumours of the digestive tract. Mitotic rate and Ki-67 proliferation index are central to the histopathological grading of these tumours. Assessing these variables is not standardised in local practice. This study addresses this deficit in the South African context.METHODS:This is a retrospective audit of archival material of resection specimens of GI NENs (excluding appendix) at Groote Schuur Hospital from 2004 to 2017. We performed a mitotic count and immunohistochemistry for Ki-67 to reclassify tumours according to the 2019 WHO criteria.RESULTS:Thirty-five resection specimens were examined. These represented stomach (n = 5), jejunoileum (n = 17), colon (n = 7) and rectum (n = 6). The mean age at the time of resection was 56 years (range 32-72). Twenty-one cases (60%) were women and 14 (40%) were men. The majority (24/35) of tumours were classified as grade 1 well-differentiated neuroendocrine tumours (WD NETs), 8/35 were classified as grade 2 WD NETs and 3/35 were classified as small cell poorly differentiated neuroendocrine carcinomas (PD NECs). Re-classification resulted in 7/35 (20%) changes in tumour grade (4 upgraded, 3 downgraded). In most instances (7/8), the Ki-67 proliferation index was the determining factor in assigning tumour grade.CONCLUSION:This study has increased awareness of the recently updated WHO classification system. We conclude that an objective and systematic approach to counting of mitoses and determination of the Ki-67 proliferation index is recommended in routine practice.

Abstract Background Insulinomas are rare clinical entities, but concurrent diabetes mellitus is even more uncommon, and the combination is easily missed. Recurrent hypoglycemia could be misconstrued as improved glycemic control. We present an unusual patient with type 2 diabetes and neuroglycopenia, with apparent improved glycemic control due to an insulinoma. Case presentation A 54-year-old mixed ancestry man with a positive family history of type 2 diabetes mellitus was diagnosed with type 2 diabetes mellitus and hypertension 8 years prior to admission. He presented with episodes of abnormal behavior and hypoglycemia. Inappropriately high insulin and C-peptide concentrations were identified at the time of hypoglycemia. Despite poor adherence to his diabetic treatment, he had no target organ damage relating to diabetes, and his hemoglobin A1c (HbA1c) was 5.3%. A diagnosis of insulinoma was made, and he was started on diazoxide, with endoscopic ultrasound revealing a possible lesion in the pancreatic tail measuring 12 mm × 12 mm. A fine-needle aspiration biopsy could not be performed due to overlying splenic arteries and the risk of vascular perforation. An intraoperative ultrasound confirmed a 15 mm × 10 mm tumor in the pancreatic tail, necessitating a partial pancreatectomy and splenectomy, which were curative. A well-differentiated intermediate grade 2 pancreatic neuroendocrine tumor producing insulin was confirmed on histopathology. Conclusions Recurrent, progressive hypoglycemia and improved glycemic control in a diabetic, without an alternative explanation, may suggest an insulinoma. Insulinomas that exist with type 1 diabetes mellitus, particularly malignant insulinomas, must have escaped autoimmune attack through lack of autoantigen expression. Computed tomography on its own may be insufficiently sensitive for diagnosis of insulinomas, whereas endoscopic and intraoperative ultrasonography may improve the identification of the culprit lesion.

Cutaneous lymphomas are encountered infrequently in general surgical pathology practice, and the broad array of pathological entities poses a diagnostic challenge. Integration of clinical information, results of additional laboratory investigations, and an extensive immunohistochemical panel are essential in arriving at the correct diagnosis. We present a case of blastic plasmacytoid dendritic cell neoplasm that occurred in an unusual clinical setting. This case highlights the need for a broad differential diagnosis and an extensive immunohistochemical workup when approaching a cutaneous lymphoma.

BACKGROUND Despite increasing numbers of human immunodeficiency virus (HIV)-infected South Africans receiving antiretroviral therapy (ART), tuberculosis remains the leading cause of mortality. Approximately 25% of patients treated for tuberculosis have microbiologically unconfirmed diagnoses. We assessed whether elevated Kaposi's sarcoma-associated Herpes Virus (KSHV) viral load (VL) contributes to mortality in hospitalized HIV-infected patients investigated for tuberculosis. METHODS 682 HIV-infected patients admitted to Khayelitsha Hospital, South Africa, were recruited, investigated for tuberculosis, and followed for 12-weeks. KSHV-serostatus, peripheral blood KSHV-VL, and KSHV-associated clinical correlates were evaluated. RESULTS Median CD4 count was 62 cells/μL (range: 0-526); KSHV-seropositivity was 30.7% (95%CI: 27-34%); 5.8% had detectable KSHV-VL (median 199.1; range: 13.4-2.2x106 copies/106 cells); 22% died. Elevated KSHV-VL was associated with mortality (adjusted OR=6.5 [95%CI: 1.3, 32.4]) in patients without tuberculosis or other microbiologically confirmed co-infections (n=159). Six patients had "possible KSHV-inflammatory cytokine syndrome (KICS)": five died, representing significantly worse survival (p<0.0001), and one was diagnosed with KSHV-associated multicentric Castleman disease at autopsy. CONCLUSION Given the association of mortality with elevated KSHV-VL in critically ill HIV-infected patients with suspected but not microbiologically confirmed tuberculosis, KSHV-VL and KICS criteria may guide diagnostic and therapeutic evaluation.

Renal cell carcinoma (RCC), a highly aggressive and lethal urological malignancy, has a wide variation of signs and symptoms. We report a rare case of papillary RCC (pRCC), presenting as a renal abscess. The knowledge of this association between RCC and a renal abscess is critical to prevent misdiagnosis and/or delayed treatment especially in the elderly and immunocompromised patients.

Introduction: Overlap of clinical, endoscopic and radiographic features, coupled with a poor microbiological yield makes differentiating Crohn's disease (CD) from intestinal tuberculosis (ITB) challenging. A potential histological differentiating mechanism is the use of immunohistochemical staining for the mesenchymal stem cell marker CD73, as a pilot study showed ITB but not CD granulomas stained positive for this marker. The aim of this study was to assess the value of CD73 in differentiating ITB from CD granulomas in a South African cohort. Methods: Patients with confirmed CD or ITB were identified from a pathology database. Tissue sections were reviewed by a pathologist to confirm the presence of granulomas. These were then stained with a mouse monoclonal anti-CD73 antibody. The slides were examined together by a pathologist and gastroenterologist in a blinded manner for anti-CD73 staining around granulomas. Results: Ninety six cases were available for analysis; 50 cases of ITB and 46 cases of CD. Thirty percent of CD granulomas (14/46) stained positive for CD73, whereas CD73 positivity was seen in 52% (26/50) of cases of ITB. This was statistically significant (OR 2.48, 95% CI 1.1-5.72, p = .03). The area under the curve (AUC) was 0.61. Sensitivity of CD73 in predicting ITB was 52% and specificity was 70%. Overall CD73 staining of granulomas correctly classified only 60% of cases. Conclusions: In our study we have shown that significantly more patients with ITB express CD73 in their granulomas than those with CD. However the relatively poor sensitivity, specificity and AUC make this test unlikely to be of value in our clinical practice.

Introduction: About 20% of renal angiomyolipomas (RAML) are associated with tuberous sclerosis complex (TS). About 34-80% of patients with TS present with RAML. RAMLs associated with TS are at higher risk of potentially life-threatening hemorrhage and hypovolemic shock. Only a few case reports of giant RAML, defined as larger than 10 cm in diameter, and its management, have been reported. Observation: We present a 21 year old woman with abdominal distension over the last 2 years. A contrast-enhanced CT scan revealed a giant RAML on the left side. Based on the presence of at least 3 major features of the clinical diagnostic criteria of tuberous sclerosis complex, the diagnosis was made. An open nephrectomy was performed. Therapeutic options described in literature are conservative management, medical treatment with mTOR inhibitors, arterial embolization, radioablation and partial or total nephrectomy. Conclusion: In giant TS-associated RAML total nephrectomy, rather than conservative treatment, is the treatment of choice in order to reduce the risk of potentially life-threatening bleeding. (c) 2018 Pan African Urological Surgeons Association. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.

1 Department of Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 2 Department of Dermatology, University of Cape Town, Cape Town, Western Cape, South Africa, 3 Department of Anatomical Pathology, National Health Laboratory Service Groote Schuur Hospital Branch, Cape Town, Western Cape, South Africa, 4 Division of Infectious Diseases & HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 5 Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, Western Cape, South Africa, 6 National Institute for Communicable Diseases-Centre for Healthcare-Associated Infections, Antimicrobial Resistance and Mycoses, National Health Laboratory Service, Sandringham, Gauteng, South Africa, 7 Sexually Transmitted Infectious Unit, Institute of Tropical Medicine, Antwerp, Belgium, 8 Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada, 9 Global Health Institute, University of Antwerp, Antwerp, Belgium

Aims The study was conducted to assess the expression levels of epithelial mesenchymal transition (EMT) proteins (E-cadherin, N-cadherin, snail-1 and vimentin) and miRNA-21. In addition, we correlated these data with clinicopathological features in Colorectal cancer. Methods H&E slides from a total of 59 formalin fixed paraffin embedded tissue blocks were examined by a pathologist to demarcate normal and tumour regions. Immunohistochemical analysis of mismatch repair proteins (MLH1, MSH2 and MSH6) and EMT markers (E-cadherin, N-cadherin, snail-1 and vimentin) was performed. The miRNA-21 expression levels were determined using qRT-PCR and the data was analysed using the relative quantification method. The Fisher's exact and Pearson's χ 2 tests were used to correlate snail-1, E-cadherin, miRNA-21 and clinicopathological data. Results Our results showed a statistically significant correlation between high miRNA-21 expression levels and E-cadherin positive cases. There was also an association between high miRNA-21 expression levels and negative snail-1 expression. No significant correlation was seen between miRNA-21 expression levels and clinicopathological features. Moreover, high expression levels of miRNA-21 were significantly associated with the sporadic cases. Conclusions Our data suggest that miRNA-21 in association with E-cadherin and snail-1 does not play a significant role in the development and progression of this disease.

A 72-year-old woman presented with a slow growing mass on the left side of the abdomen, which was found to originate from the mesentery of the descending colon. Histopathology revealed a seromucinous cystadenocarcinoma of the mesentery, a rare clinical entity occurring most often in females. There are only 20 cases reported in the literature. It is postulated that these tumours develop as a result of serous or mucinous metaplasia of pre-existing coelomic mesothelium. Surgical excision remains the mainstay of successful management.

Introduction: Retroperitoneal fibrosis (RPF) is a rare inflammatory disease resulting in the development of a retroperitoneal mass, which may encase the aorta and its branches, as well as the ureters.Observation: The systemic inflammatory response causes constitutional symptoms. The mass itself leads to symptoms of non-specific back pain and abdominal pain, as well as ureteric obstruction and subsequent renal insufficiency. Immunoglobulin 4 (IgG4) has recently been found to be involved in the pathogenesis of multiple autoimmune and inflammatory disorders, including RPF. Blood work-up, imaging and biopsy of the mass remain the mainstay of diagnosis.Conclusion: RPF remains a diagnosis of exclusion. Treatment hinges on corticosteroids, but other immunosuppressants and disease-modifying agents are also being used more commonly. Surgical intervention is only carried out when conservative measures have failed or are contraindicated, and in order to preserve renal function. (C) 2016 Pan African Urological Surgeons' Association. Production and hosting by Elsevier B.V. All rights reserved.

Background: Gastric resections for carcinoma are common, but gastric carcinoma in South Africa, and particularly within the Western Cape province, has not been well documented. Method: The objective of the study was to immunohistochemically evaluate HER2/neu overexpression, determine aberrations in β-catenin and epithelial-cadherin (E-cadherin) expression, and correlate these findings with gastric carcinoma subtypes. Results: Ninety-seven gastric adenocarcinoma resections were morphologically categorised as intestinal-, diffuse- or mixed-type adenocarcinomas, and immunohistochemically stained for β-catenin, E-cadherin (extracellular and cytoplasmic domains) and HER2/neu. The results of staining were compared between the subtypes for statistically significant differences. All 97 cases were confirmed as gastric adenocarcinomas, with 39 (40%) intestinal-type, 51 (53%) diffuse-type, and 7 (7%) mixed-type tumours identified. Patient ages ranged from 18-84 years. HER2/neu was overexpressed in 12 (12%) cases, with intestinal-type morphology (p = 0.017) reported in nine. Fourteen cases (14%) demonstrated abnormal β-catenin localisation. Aberrant E-cadherin (extracellular domain) localisation occurred in 36 (37%) cases. Diffuse-type morphology was associated with a significantly high proportion (p = ≤ 0.001). Aberrant E-cadherin (cytoplasmic domain) localisation occurred in 7 (7%) cases. A significantly high proportion (six of these cases) (p = 0.023) of these was diffuse-type morphology. Eleven (11%) adenocarcinomas occurred in patients aged ≤ 40 years, with intestinal morphology reported in nine of these 11. Aberrant E-cadherin (extracellular domain) localisation was noted in seven of the 11, a significantly high proportion when compared to that in the older patients (p = 0.025). Conclusion: Distinct immunomorphological correlations are apparent in tumours demonstrating HER2/neu overexpression or abnormal E-cadherin localisation. Intestinal morphology, poor differentiation and E-cadherin abnormalities are frequently demonstrated in tumours occurring in younger individuals.

The differential diagnoses in patients with advanced HIV/AIDS presenting with fever and systemic illness is wide and warrants both infectious and non-infectious considerations. The need to make an early and accurate diagnosis is important to effect correct therapy and thus improve outcome. We describe a patient with several co-morbidities and an unusual disseminated fungal infection.