Tanapox, South Africa, 2022.

Tanapox is a rarely diagnosed zoonosis known to be endemic to equatorial Africa. All previously reported human cases were acquired within 10° north or south of the Equator, most recently 19 years ago. We describe a human case of tanapox in South Africa (24° south of the Equator). Expanded surveillance for this pathogen is warranted.

A presumptive case of cutaneous emergomycosis in a female patient with HIV - Maseru, Lesotho.

Emergomycosis is a recently described emerging opportunistic fungal infection among individuals living with HIV, in whom it is a cause of significant mortality and morbidity. This article retrospectively reports on a presumptive case of extensive cutaneous emergomycosis in a young immunocompromised patient from Lesotho. The histopathological features on skin biopsy were in keeping with emergomyces infection. The lesions responded to treatment with amphotericin B and oral fluconazole. Contribution: This case contributes to the existing evidence that as an emergent opportunistic infection, emergomycosis is possibly widespread in Africa but the true extend of the disease is not fully defined. This is further aggravated by the diagnostic difficulty as a result of limited resources in some areas in the region.

Endemic mycoses in South Africa, 2010-2020: A decade-long description of laboratory-diagnosed cases and prospects for the future.

BACKGROUND: Emergomycosis, histoplasmosis, sporotrichosis and blastomycosis are endemic to southern Africa; the first two are AIDS-related mycoses. We described laboratory-diagnosed cases of endemic and imported mycoses in South Africa over a decade and discuss available diagnostic tools, reasons for the current under-estimation of cases and future strategies to improve case ascertainment. MATERIALS AND METHODS: We analysed electronic pathology laboratory data from all public laboratories and one large private laboratory in South Africa from 2010-2020. Diagnostic specimens processed at the national mycology reference laboratory were also included. We classified cases as proven, probable and possible based on the method of identification. RESULTS: We identified 682 cases, of which 307 were proven, 279 were probable and 96 were possible. Of 307 culture-confirmed cases, 168 were identified by phenotypic methods plus sequencing, 128 by phenotypic methods alone and 11 by direct PCR. Of 279 probable cases, 176 had yeasts observed on histology, 100 had a positive Histoplasma antigen test and 3 a positive pan-dimorphic PCR test. All 96 possible cases had compatible clinical syndrome with inflammatory infiltrates on skin tissue histology. A majority of cases had an unspecified endemic mycosis (207/682, 30.4%), followed by sporotrichosis (170/682, 24.9%), emergomycosis (154/682, 22.6%), histoplasmosis (133/682, 19.5%), blastomycosis (14/682, 2.1%) and talaromycosis (4/682, 0.6%). CONCLUSIONS: This study reports a relatively low number of cases over a decade considering an estimated large population at risk, suggesting that a substantial fraction of cases may remain undiagnosed. There is a need to increase awareness among healthcare workers and to develop rapid point-of-care diagnostic tools and make these widely accessible.

Clinical Improvement of Disseminated Acanthamoeba Infection in a Patient with Advanced HIV Using a Non-Miltefosine-Based Treatment Regimen in a Low-Resource Setting.

Disseminated Acanthamoeba species infection is likely an underrecognized and underdiagnosed opportunistic infection in patients with advanced human immunodeficiency virus (HIV) disease in South Africa. It presents a unique clinical challenge in that the diagnosis can be difficult to establish and management options are limited in low-resource settings. To our knowledge, there is a paucity of literature to date on the successful use of combination treatment options for patients in low-resource settings without access to miltefosine. We present a case describing the clinical improvement of disseminated Acanthamoeba infection in a patient with advanced HIV using a non-miltefosine-based treatment regimen. The case serves to highlight that Acanthamoeba sp. infection should be considered as a differential diagnosis for nodular and ulcerative cutaneous lesions in patients with advanced HIV in South Africa, and that although there are alternative options for combination treatment in countries without access to miltefosine, efforts should be made to advocate for better access to miltefosine for the treatment of acanthamoebiasis in South Africa.

Emergomycosis (Emergomyces africanus) in Advanced HIV Disease.

In 2013, a novel thermally dimorphic fungal pathogen was described to cause disseminated disease among persons living with advanced HIV/AIDS in South Africa. Although the organism was initially described as an Emmonsia-like fungus, it is now known to belong to a new genus of thermally dimorphic fungi and was recently named Emergomyces africanus. There is considerable clinical and histopathological overlap between emergomycosis and histoplasmosis. This review addresses taxonomic, clinical, diagnostic, and therapeutic aspects of Es. africanus disease, a condition which has, to date, only been reported from southern Africa.

South African Tick Bite Fever: An Overview.

The rickettsiae are a diverse group of vector-borne zoonotic bacterial pathogens. The two common spotted fever diseases in existence in southern Africa are boutonneuse fever-like tick bite fever (TBF), caused by Rickettsia conorii, and African TBF, caused by R. africae. This review addresses demographic, epidemiological, clinical, diagnostic, therapeutic, and preventive aspects of TBF in the southern African context, including a discussion of the dermatopathological findings and potential diagnostic pitfalls.

Malignant Chondroid Syringoma: A Report of Two Cases with a Sarcomatous Mesenchymal Component.

Malignant chondroid syringoma (MCS; malignant mixed tumour) is a rare neoplasm typically arising on the extremities and trunk. We are report 2 unique cases of MCS, one occurring on the scalp of a 78-year-old man and the other on the trunk of a 72-year-old woman. Both tumours harboured malignant epithelial and malignant mesenchymal components. The latter was represented by liposarcoma in the first case. The malignant components of the second tumour comprised spindle cell squamous cell carcinoma (SCC) and osteosarcoma. Origin from a pre-existing benign chondroid syringoma was clearly evident in both neoplasms. The presence of heterologous malignant mesenchymal components, however, is hitherto unreported in the context of MCS, while a spindle cell SCC component is exceptionally rare. The 2 cases presented herein highlight an expanded morphological spectrum of MCS, with resultant blurring of the boundaries between MCS and cutaneous carcinosarcoma.

Rhabdomyosarcoma Arising in a Giant Congenital Melanocytic Naevus: Case Report and Literature Review.

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.

An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS.

BACKGROUND: The global mortality from HIV and the cutaneous burden of infective, inflammatory and malignant diseases in the setting of AIDS have significantly declined following the advent of highly active antiretroviral therapy. Regrettably, there has been a contemporaneous escalation in the incidence of adverse cutaneous drug reactions (ACDR), with studies attesting that HIV-positive individuals are a hundred times more susceptible to drug reactions than the general population, and advanced immunodeficiency portending an even greater risk. Several variables are accountable for this amplified risk in HIV. SUMMARY: Adverse reactions to trimethoprim-sulfamethoxazole are the most common, increasing from approximately 2-8% in the general population over to 43% amongst HIV-positive individuals to approximately 69% in subjects with AIDS. Antituberculosis drugs and antiretrovirals are also well-known instigators of ACDR. Cutaneous reactions range from mild morbilliform eruptions to severe, life-threatening manifestations in the form of Stevens-Johnson syndrome/toxic epidermal necrolysis. Histological features vary from vacuolar interface changes to full-thickness epidermal necrosis with subepidermal blister formation. A precipitous diagnosis of the ACDR, clinically and histologically if necessary, together with the isolation of the causative drug is critical. The identification process, however, is often complex and multifaceted due to polypharmacy and inconclusive data on which drugs are the most likely offending agents, especially against the background of tuberculosis co-infection. KEY MESSAGES: Whilst milder cutaneous reactions are treated symptomatically, severe reactions mandate immediate treatment discontinuation without rechallenge. Further studies are required to establish safe rechallenge guidelines in resource-limited settings with a high HIV and tuberculosis prevalence.

Keratolytic Winter Erythema: An Update.

Keratolytic winter erythema (KWE) is a rare autosomal dominant keratoderma affecting primarily the palms and soles, manifesting with recurrent waves of erythema followed by epidermal peeling. The condition is so named in view of its anecdotal worsening during the winter months. It is highly penetrant but shows considerable individual clinical variability, waning and reappearing throughout the life course. Histologically, early established lesions of KWE manifest with degenerative changes involving the Malpighian layer, with associated absence of the stratum granulosum. The damaged zone undergoes parakeratotic transformation and subsequent centrifugal ejection. Thick peeling occurs when the stratum corneum eventually separates off as a result of a keratolytic split occurring above, through or below the parakeratotic zone. Reconstitution of the stratum granulosum ensues. KWE is caused by a duplication of an intergenic enhancer element upstream of the cathepsin B gene on chromosome 8. This leads to the upregulation of cathepsin B in the stratum granulosum and subsequent peeling of the epidermis as the end result. With elucidation of the molecular pathology of KWE, new therapeutic approaches to KWE may be considered.

Epstein-Barr Virus-Associated Smooth Muscle Tumour: A Case Series with a Significant Proportion of Tumours Showing Proclivity for Cutaneous Soft Tissues.

BACKGROUND: Epstein-Barr virus-associated smooth muscle tumours (EBV-SMTs) are rare neoplasms of uncertain biological potential. They are seen in the setting of immune suppression from a variety of causes, including HIV infection and post-transplant immunosuppression. Most of the literature pertaining to these neoplasms comprises case reports and small case series, with a dearth of documented cases from South Africa. OBJECTIVE: To expand on the literature of these rare neoplasms in the South African context, with an emphasis on a subset showing a predilection for the cutaneous soft tissues. METHOD: Twenty-one EBV-SMTs from 19 consecutive patients were retrieved from the archives of the Division of Anatomical Pathology in the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and the National Health Laboratory Service. Clinical and pathological characteristics of each case were recorded, including patient age, tumour site, H&E morphology, immunophenotypic features and the tumoural EBV status. RESULTS: The patients' ages ranged from 12 to 63 years, with a mean of 36 years. Thirteen (68%) of the patients in whom the HIV status was known were HIV-positive. Two of the 19 patients each had 2 tumours, thus accounting for the total of 21 neoplasms studied. Although 12 of the 21 tumours (57.1%) were from a variety of visceral organs, 9 (42.9%) originated in the dermis and superficial subcutaneous tissues, making the cutaneous soft tissues the most commonly affected site. Morphologically, all of the neoplasms were characterised by fascicles of myoid cells, admixed rounder tumour cells, scattered intratumoural lymphocytes and variable immunohistochemical staining with markers of smooth muscle differentiation. All 21 neoplasms were proven to harbour EBV DNA. CONCLUSION: A significant proportion of EBV-SMTs may present in the cutaneous soft tissues. This neoplasm should, therefore, be included in the histopathological differential diagnosis of any cutaneous or superficial subcutaneous spindle cell tumour, especially in patients with a history of underlying immune suppression. Accurate diagnosis thereof and its distinction from other spindle cell neoplasms is important in view of management implications and the potential for multicentricity in some patients.

Carcinoid Syndrome-Induced Scleroderma-Like Disease.

Scleroderma is a rare complication of carcinoid syndrome and is usually encountered in the setting of a metastatic primary neuroendocrine tumour of the distal ileum. Associated endocardial fibrosis is a frequent finding and the condition carries a poor prognosis. We report a case of scleroderma occurring in a 72-year-old female with metastatic neuroendocrine carcinoma and associated pericardial fibrosis. The use of an alternative nomenclature such as "scleroderma-like" or "sclerodermoid" disease is proposed in order to emphasise its distinction from true idiopathic scleroderma, despite the histopathological similarities on skin biopsy.

A potpourri of pathogenetic pathways in endometrial carcinoma with a focus on Lynch Syndrome.

Endometrial carcinoma is the most frequently occurring female genital tract malignancy in developed nations, with a rising annual incidence. Endometrioid endometrial carcinoma (EEC), the most common histological variant, differs in morphologic and molecular characteristics from serous carcinomas but morphological distinction of high-grade EECs from serous carcinomas may prove difficult. Thus, molecular categorization of tumors may allow for better tumor classification with greater insight into the underlying biology of endometrial carcinomas with new therapeutic options. Microsatellite instability (MSI) is a commonly occurring molecular aberration in EECs and has been identified in most Lynch Syndrome (LS) associated tumors. This tumor syndrome predisposes afflicted individuals to a myriad of tumors including endometrial carcinoma. Herein, the molecular signature of endometrial tumors as well as LS, and its clinical manifestations are reviewed. Understanding of the pathogenetic pathways allows for greater comprehension of occurrences at a molecular level which are then appreciated at a cellular and tissue level, by the histopathologist. The molecular classification of endometrial tumors allows for further targeted therapeutic options for affected patients. Screening tests for patients with suspected LS enables surveillance of other tumors in the affected patient and her family with the potential to decrease morbidity and mortality. It is envisioned that this overview will allow for enhanced comprehension of genetic pathways by practicing pathologists, oncologists, gynecologists and other members of the multidisciplinary team, all of whom are involved in the management of the patient with an endometrial malignancy.

Sustained Inhibition of HBV Replication In Vivo after Systemic Injection of AAVs Encoding Artificial Antiviral Primary MicroRNAs.

Chronic infection with hepatitis B virus (HBV) remains a problem of global significance and improving available treatment is important to prevent life-threatening complications arising in persistently infected individuals. HBV is susceptible to silencing by exogenous artificial intermediates of the RNA interference (RNAi) pathway. However, toxicity of Pol III cassettes and short duration of silencing by effectors of the RNAi pathway may limit anti-HBV therapeutic utility. To advance RNAi-based HBV gene silencing, mono- and trimeric artificial primary microRNAs (pri-miRs) derived from pri-miR-31 were placed under control of the liver-specific modified murine transthyretin promoter. The sequences, which target the X sequence of HBV, were incorporated into recombinant hepatotropic self-complementary adeno-associated viruses (scAAVs). Systemic intravenous injection of the vectors into HBV transgenic mice at a dose of 1 × 1011 per animal effected significant suppression of markers of HBV replication for at least 32 weeks. The pri-miRs were processed according to the intended design, and intrahepatic antiviral guide sequences were detectable for 40 weeks after the injection. There was no evidence of toxicity, and innate immunostimulation was not detectable following the injections. This efficacy is an improvement on previously reported RNAi-based inhibition of HBV replication and is important to clinical translation of the technology.

Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families.

Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1-p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals.

Adult-onset acral peeling skin syndrome in a non-identical twin: a case report in South Africa.

BACKGROUND: Acral peeling skin syndrome is a rare autosomal recessive disorder in which skin exfoliation is limited to the hands and feet. While it typically manifests from early childhood, in this first reported case from South Africa, the patient did not manifest clinically until the fourth decade of life. CASE REPORT: A 44-year-old woman of African descent, 1 of a set of non-identical twins, presented with recurrent episodes of skin peeling of the upper and lower limbs. The first episode occurred 4 years prior, followed by perennial skin peeling during the spring seasons. She was not on treatment for any chronic disease and reported no exposure to chemicals or other irritants. The family, including the non-identical twin sister, has no history of skin disorders and the patient's HIV antibody test was negative. At presentation, physical examination revealed ongoing exfoliation with new skin formation on the palms and soles. The mucous membranes and nails were spared. Other systems were normal. Skin biopsy taken from the palms confirmed peeling skin syndrome. The patient was managed with topical aqueous cream and analgesics. She was briefly counseled on the nature and prognosis of the disease, and referred for genetic testing and counseling. On follow-up, she continues to have skin peeling once or twice a year. CONCLUSIONS: This first reported case of this rare disease in South Africa contributes to the growing body of literature on the disease and highlights the need for clinicians to be aware of its variable clinical onset.

Recognition of Dual or Multiple Pathology in Skin Biopsies from Patients with HIV/AIDS.

A large percentage of patients with HIV/AIDS will develop dermatological complications. Consequently, all practising clinicians and pathologists in regions with a high prevalence of HIV/AIDS must be familiar with the diverse cutaneous manifestations of the disease. This paper highlights the fact that biopsy material in this clinical context may occasionally reveal more than one pathological process. The potential spectrum includes two or more infections in a single skin biopsy (e.g., herpes simplex and cytomegalovirus infection), neoplastic lesions containing infective organisms (Kaposi sarcoma (KS) and cryptococcosis), dermatoses in association with neoplastic lesions (e.g., KS and interface dermatitis), or more than one dermatosis in a given specimen (e.g., papulopruritic eruption and nodular prurigo). Rare biopsies may even demonstrate triple pathology. The importance of careful examination of skin biopsies in this clinical context is emphasised. Failure to recognise an undiagnosed concomitant opportunistic infective pathogen could have potentially disastrous consequences for the patient.

Cutaneous mixed tumor, eccrine variant: a clinicopathologic and immunohistochemical study of 50 cases, with emphasis on unusual histopathologic features.

Mixed tumor, eccrine type, is a rare cutaneous adnexal neoplasm, mostly reported as isolated case reports. A systematic analysis of its histopathologic and immunohistochemical features has not previously been performed on a large series. The purpose of our investigation was to study a large number of cutaneous eccrine mixed tumors so as to fully characterize the entire spectrum of changes in the epithelial and stromal components, with an emphasis on unusual histopathologic features that may represent a diagnostic pitfall. This article reports a light microscopic and immunohistochemical study of 50 cases of eccrine mixed tumor, complemented by a literature review. Our study identified some unusual histopathologic features, thus extending the morphologic spectrum of this neoplasm. These included prominent cribriform areas, clear cell change, pseudorosette structures, prominent osseous metaplasia, and physaliphorous-like cells. Most of these features have not been previously recorded in eccrine mixed tumors and may represent a potential diagnostic pitfall.