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The Programmed Death-1(PD-1)/Programmed Death Ligand 1 (PD-L1) pathway is the focus of numerous clinical trials on various tumours using immunotherapy. Endometrial tumours with Polymerase E gene mutations and microsatellite unstable neoplasms have demonstrated strong immune responses against mutationally associated neoantigens, with favourable results using immune checkpoint inhibitors. We assessed PD-L1 on endometrioid endometrial carcinomas (EECs) in South Africa’s state hospital sector, which, to the best of our knowledge, has not been investigated. We performed PD-L1 immunohistochemistry on 145 EECs and compared PD-L1 status to our data on cases that had previously undergone mismatch repair (MMR) immunohistochemistry, microsatellite instability assessment by polymerase chain reaction (PCR) and methylation analysis. PD-L1 was expressed in 13.1% (19/145) of EECs, of which, 7 (36.8%) showed MMR deficiency. There was MMR deficiency in 26.9% (34/126) of PD-L1 negative cases (p = 0.37). There were 47.4% (9/19) microsatellite unstable PD-L1 positive cases whereas 52.6% (10/19) of PD-L1 positive cases were microsatellite stable by PCR (p = 0.23). From the PD-L1 positive cases that underwent methylation testing, 80% (8/10) were methylated and 20% (2/10) were unmethylated (p = 0.54). Compared to a Jordanian study and a Chinese study, on populations also not extensively investigated, our study demonstrated lower PDL1 expression (p = 0.0170; p-value < 0.001 respectively). Our study showed that approximately two-thirds of cases were MMR proficient, which is more than twice the accepted published number of PD-L1 positive cases with MMR staining. This suggests that in our population PD-L1 staining should be considered in all EECs to identify cases that may derive benefit from immune checkpoint inhibitors. It is envisioned that this study may provide the impetus for future possible immune therapies for endometrial cancer patients in the state sector of South Africa. Our study provides data from a developing country which adds to current global data. [ABSTRACT FROM AUTHOR]

This study aimed to compare the degree of epigenetic modifications between a TB-HIV co-infected cohort and uninfected subjects. Formalin-fixed paraffin-embedded (FFPE) tissues were retrieved from 45 TB-HIV co-infected and 45 control individuals. Real-time PCR was applied to compare the level of expression of genes involved in epigenetic regulation. The protein multiplex assay was used to assess the degree of protein modification. DNA sequencing was used to determine the evolutionary relationships between the infecting HIV and Mtb strains. Our results indicated a significant increase in the expression of the five candidate genes in the patients with TB-HIV relative to the control cohort. A sharp increase in the degree of histone methylation, acetylation and phosphorylation was observed in TB-HIV co-infected patients. The phylogenetic analysis classified the strains into three distinct HIV clusters and five Mtb clusters. The disparities in the expression profiles of our candidate genes between the TB-HIV cohort and non-TB-HIV group highlights the important role played by various TB and HIV strains in regulating the host gene expression landscape. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is a global burden with the most severe subtype being triple negative breast cancer (TNBC). Despite advances in conventional therapies, treatment for TNBC is currently lacking. Interestingly, cholesterol has gained interest as a potential therapeutic target due to cancer cells' increased reliance on this macromolecule. In this study we aimed to assess the effects of cholesterol depletion as a therapeutic target in TNBC. We show that treatment with the cholesterol-depletory agent 2-hydroxypropyl-β-cyclodextrin (HPβCD) impeded the growth of cancer cells and further led to cancer cell death, which could be attributed to an altered cellular cholesterol profile following treatment. Furthermore, mice xenograft studies indicated complete eradication of early-stage tumours with no relapse, followed by a remarkable reduction in intermediate- and late-stage tumours, respectively. We have also identified SFRP1 as a possible molecular target facilitating the therapeutic action of HPβCD. These findings consequently potentiate cholesterol depletion as a novel anticancer strategy to be pursued. Cholesterol accumulation is documented in various malignancies including breast cancer. Consequently, depleting cholesterol in cancer cells can serve as a viable treatment strategy. We identified the potency of 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol-depletor in vitro against two breast cancer cell lines: MCF-7 (Oestrogen-receptor positive, ER+) and MDA-MB-231 (Triple negative breast cancer (TNBC)). The results were then compared against two non-cancerous cell lines using cytotoxic-, apoptosis-, and cholesterol-based assays. Treatment with HPβCD showed preferential and significant cytotoxic potential in cancer cells, inducing apoptosis in both cancer cell lines (p < 0.001). This was mediated due to significant depletion of cholesterol (p < 0.001). We further tested HPβCD in a MF-1 mice (n = 14) xenograft model and obtained 73.9%, 94% and 100% reduction in tumour size for late-, intermediate-, and early-stage TNBC, respectively. We also detected molecular-level perturbations in the expression patterns of several genes linked to breast cancer and cholesterol signalling pathways using RT2-PCR arrays and have identified SFRP1 as a direct binding partner to HPβCD through SPR drug interaction analysis. This work unravels mechanistic insights into HPβCD-induced cholesterol depletion, which leads to intrinsic apoptosis induction. Results from this study potentiate employing cholesterol depletion as a promising unconventional anticancer therapeutic strategy, which warrants future clinical investigations. [ABSTRACT FROM AUTHOR]

Epithelial ovarian neoplasms constitute the majority of ovarian tumours and are the most common malignant ovarian neoplasm. They are the eighth leading cause of cancer deaths worldwide. This study evaluated the epidemiology and histological subtypes of epithelial ovarian neoplasms at a single institution. This retrospective, quantitative analysis evaluated 123 epithelial ovarian neoplasms between 2013 and 2017 and classified them according to age, biological behaviour and histological subtype. Of 123 cases, 64 (52.0%), tumours were benign, 30 (24.4%) were borderline and 29 (23.6%) tumours were malignant. Serous cystadenoma was the most common benign tumour (42.2%). Mucinous borderline tumours were the most common borderline neoplasm (50.0%). High-grade serous carcinoma was the most common carcinoma (58.6%). Patients presented at an older age with borderline tumours and malignant tumours, compared with patients with benign tumours. The current study demonstrated that serous tumours were the most common type of benign and malignant tumours whilst mucinous neoplasms were the commonest subtype of borderline tumours. These findings are congruent with multiple similar studies. A higher number of borderline tumours were seen in this cohort in comparison with previous studies. This suggests a need for additional sampling of borderline tumours, over and above the international standard, in our population, to definitively exclude invasive malignancy. This study also demonstrated the histological progression of benign serous and mucinous tumours to borderline tumours and low-grade serous carcinoma and mucinous carcinoma, respectively, which supports the stepwise tumour progression model of these tumours. [ABSTRACT FROM AUTHOR]

Endometrial carcinomas are common female genital tract malignancies. Western countries identified BRAF mutations in very few endometrial carcinomas, whilst an Eastern study documented mutations in one-fifth of endometrial carcinomas. We aimed to assess BRAF mutations in an ethnically mixed South African patient population using immunohistochemistry (IHC), polymerase chain reaction (PCR) and Sanger sequencing in relation to MLH1 methylation. A total of 145 endometrioid endometrial carcinoma cases were retrieved from departmental archives and underwent MLH1, MSH2, MSH6 and PMS2 IHC testing. The 37 cases that showed MLH1 loss underwent BRAF IHC, PCR and Sanger sequencing. Six out of 37 cases demonstrated BRAF mutations: 4 were identified by PCR, whilst IHC and Sanger sequencing identified one mutation each. Three PCR mutations were at the V600E codon, whilst 1 case had a V600D mutation. Agreement between IHC versus overall BRAF mutational status, and sequencing versus overall mutational status, was 86.49% (p-value < 0.005). There was agreement of 94.59% between PCR and overall mutational status with statistically significant, moderate non-random concordance (kappa = 0.77, p = 0.0001). BRAF mutations were identified in 16.21% of cases, which is higher than frequencies noted in Western studies, but less than in an Eastern study. There was no association between MLH1 methylation and BRAF status in endometrial carcinomas from our patient population (kappa = −0.0223, p = 0.6649). Our results in endometrial carcinomas, similar to findings from Western studies, indicate that BRAF mutations are not beneficial in distinguishing which patients have spontaneously occurring tumours from those who may harbour germline mutations and are suspected of having Lynch syndrome. [ABSTRACT FROM AUTHOR]

Primary ovarian neuroendocrine tumours are very uncommon tumours. Herein, we describe a case of 27-year-old female who presented with abdominal pain and an ovarian mass, for which she underwent a right salpingo-oophorectomy. Histopathological evaluation confirmed a right-sided primary ovarian neuroendocrine tumour occurring in a benign mature cystic teratoma. The patient has not undergone any additional therapy and is currently well. This case illustrates the need for thorough clinicopathological correlation together with adequate sampling to ensure accurate diagnosis and timeous management of the patient. [ABSTRACT FROM AUTHOR]

Neuroendocrine carcinomas (Merkel cell carcinomas) of the vulva are extremely rare tumours, with very few cases reported to date. Herein, a primary neuroendocrine carcinoma (Merkel cell carcinoma) of the vulva is reported. A 34-year-old HIV-positive female on antiretroviral therapy presented with a four-month history of a right-sided vulval mass. She underwent surgical excision of a histologically confirmed neuroendocrine carcinoma. Twenty-four weeks after surgery, she died. This case illustrates the importance of a broad differential diagnosis for neoplasms in the usual sites, and the aggressive nature of this tumour, which to date has had limited effective treatment options. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is a leading male neoplasm in South Africa. Objective: The aim of our study was to describe PCa using Systemized Nomenclature of Medicine (SNOMED) clinical terms codes, which have the potential to generate more timely data. Methods: The retrospective study design was used to analyse prostate biopsy data from our laboratories using SNOMED morphology (M) and topography (T) codes where the term 'prostate' was captured in the narrative report. Using M code descriptions, the diagnosis, sub-diagnosis, sub-result and International Classification of Diseases for Oncology (ICD-O-3) codes were assigned using a lookup table. Topography code descriptions identified biopsies of prostatic origin. Lookup tables were prepared using Microsoft Excel and combined with the data extracts using Access. Contingency tables reported M and T codes, diagnosis and sub-diagnosis frequencies. Results: An M and T code was reported for 88% (n = 22 009) of biopsies. Of these, 20 551 (93.37%) were of prostatic origin. A benign diagnosis (ICD-O-3:8000/0) was reported for 10 441 biopsies (50.81%) and 45.26% had a malignant diagnosis (n = 9302). An adenocarcinoma (8140/3) sub-diagnosis was reported for 88.16% of malignant biopsies (n = 8201). An atypia diagnosis was reported for 760 biopsies (3.7%). Inflammation (39.03%) and hyperplasia (20.82%) were the predominant benign sub-diagnoses. Conclusion: Our study demonstrated the feasibility of generating PCa data using SNOMED codes from national laboratory data. This highlights the need for extending the results of our study to a national level to deliver timeous monitoring of PCa trends. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphomas are fairly common adult haematolymphoid malignancies. Approximately 40% of such tumours may present in an extranodal site. These lymphomas are, however, infrequently identified in the female genital tract and even more rarely, identified in the endometrium. The histopathological features and molecular findings of endometrial diffuse large B-cell lymphoma are discussed herein. A 36-year old female presented with per vaginal bleeding. She underwent an endometrial curettage, which demonstrated morphological and immunophenotypical features of a diffuse large B-cell lymphoma. Amplification of the immunoglobulin heavy chain (IgH) gene by polymerase chain reaction (PCR) confirmed B-cell clonality. Epstein–Barr encoding region (EBER) in-situ hybridisation was positive in tumour cells. Fluorescent in-situ hybridisation (FISH) for the detection of BCL6 and MYC gene rearrangement as well as for the detection of the t(14;18) (q32;q21) translocation was performed, all of which yielded negative results. Unfortunately, the patient was lost to follow-up. Whilst diffuse large B-cell lymphoma is not a commonly identified tumour within the uterine cavity, it should be included in the differential diagnosis of endometrial neoplastic infiltrates so as not to misdiagnose this tumour. This facilitates rapid commencement of further management for the patient. [ABSTRACT FROM AUTHOR]

Giant congenital melanocytic naevi (GCN) are rare, disfiguring lesions which carry a significant risk of malignant transformation. Melanoma is the most common malignancy documented in association with these lesions. Although exceedingly rare, other malignant neoplasms, including mesenchymal tumours such as rhabdomyosarcoma (RMS), may complicate GCN. This report documents a fatal embryonal RMS arising in a GCN on the distal left lower limb of a 4-month-old female infant, who had ipsilateral inguinal lymph node metastases at the time of presentation. To date there have been only 7 prior reports in the English literature of RMS complicating GCN. Differential diagnoses include small cell melanoma, rhabdoid melanoma, and melanoma with divergent RMS differentiation. A distinction between the latter and de novo RMS arising in GCN may have potential prognostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Urothelial bladder tumours in childhood are extremely rare, with most cases being low grade, superficial disease of the papillary subtype with favourable outcomes. Urothelial (clear cell variant) carcinoma of bladder (UCCVCB) is an exceptional histological finding in both the adult and paediatric population. Herein we describe the first case of UCCVCB diagnosed in childhood. With this case being only the fourth report of confirmed muscle invasion in childhood, we discuss the entity of UCCVCB, and furthermore review all previously reported confirmed cases of childhood muscle invasive urothelial bladder cancer, in general. [ABSTRACT FROM AUTHOR]

The paucity of animal models that simulate the replication of the hepatitis B virus (HBV) is an impediment to advancing new anti-viral treatments. The work reported here employed recombinant adeno-associated viruses (AAVs) to model HBV subgenotype A1 and subgenotype D3 replication in vitro and in vivo. Infection with subgenotype A1 is endemic to parts of sub-Saharan Africa, and it is associated with a high risk of hepatocellular carcinoma. Recombinant AAV serotype 2 (AAV2) and 8 (AAV8) vectors bearing greater-than-genome-length sequences of HBV DNA from subgenotype A1 and D3, were produced. Transduced liver-derived cultured cells produced HBV surface antigen and core antigen. Administration of AAV8 carrying HBV subgenotype A1 genome (AAV8-A1) to mice resulted in the sustained production of HBV replication markers over a six-month period, without elevated inflammatory cytokines, expression of interferon response genes or alanine transaminase activity. Markers of replication were generally higher in animals treated with subgenotype D3 genome-bearing AAVs than in those receiving the subgenotype A1-genome-bearing vectors. To validate the use of the AAV8-A1 murine model for anti-HBV drug development, the efficacy of anti-HBV artificial primary-microRNAs was assessed. Significant silencing of HBV markers was observed over a 6-month period after administering AAVs. These data indicate that AAVs conveniently and safely recapitulate the replication of different HBV subgenotypes, and the vectors may be used to assess antivirals' potency.