A meta-analysis of cases of Rosai Dorfman disease reported on the African continent and a description of two cases from a tertiary academic hospital in Johannesburg, South Africa.

Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by the accumulation of activated histiocytes within affected tissues. The original haematopathological description of RDD has links to the late South African born haematopathologist, Ronald Dorfman, with a descriptive account of two cases of the disease treated at Chris Hani Baragwanath Academic Hospital are described herein. Alongside the two case descriptions is a meta-analysis of 149 published cases from the African continent. Sequential literature searches were performed on Google Scholar and PubMed with the search terms "sinus histiocytosis with massive lymphadenopathy", "Rosai-Dorfman disease", "Rosai-Dorfman Destombes" and "lymphadenopathy" together with the name of each individual country on the African continent, from Algeria to Zimbabwe. All possible cases of RDD reported in published literature from Africa were captured on a Microsoft Excel spreadsheet recording details, where available, of demographics, nodal (nodal groups) or extra-nodal disease as well as treatment. Of the 54 African countries on the continent, published data was available from half of these countries (n=27). Nigeria (35), Tunisia (25) and South Africa (23) contributed the majority of cases for data collection with a clear paucity of reportable information available from Central Africa. Of the 149 cases from the African continent, the majority were from patients aged ten years and younger with a decrease in reported cases in patients with increasing age. The mean age at diagnosis was 25.66 years [95% CI: 21.81-29.51] with a median age of diagnosis of 24.5 years. The youngest patient in the series was 3 months old and the oldest patient aged 72 (range 71.75 years, IQR 31). The cases reported were fairly split between males and females with a male-to-female ratio of 1.07: 1. HIV seropositivity was reported in seven patients (4.8%) and no HIV results were available in 104 patients (71.2%). Disease presentation was split between nodal disease in 43% of patients (n=64), Extra nodal (EN) disease in 32.9% (n=32), mixed (nodal/EN) disease in 11.4% (n=17) and unknown in 12.8% (n=19). Fever was present in 18.1% (n=27) of cases. Hepatic enlargement was noted in nine patients (6%) and splenic enlargement in four patients (2.7%). Commonly ascribed sites of EN disease, in descending order, were skin and soft tissue, ocular, ear/nose/throat (ENT), abdominal organ(s), bone, lung/pleura, brain parenchyma (including dura), endocrine glands, spine, breast, pericardium, pseudotumour formation (unspecified site), joint(s), peripheral nerves and genitourinary tract disease. The upfront administration of glucocorticosteroids was seen in the majority of cases. Rosai-Dorfman-Destombes, although a rare disorder, should be considered as a differential diagnosis in patients with massive bilateral cervical lymphadenopathy and is confirmed with accompanying pathological changes on microscopic and immunohistochemical examination of biopsy specimens. The role of infection, particularly HIV infection, is considered to be a possible contributor to the pathogenesis of RDD and HIV testing in patients from areas of high HIV endemicity with co-existing RDD should be undertaken. Consideration for mycobacterium tuberculosis infection in patients with generalized significant lymphadenopathy still remains an important differential for massive lymphadenopathy and requires confirmation by appropriate microbiological investigations. The treatment landscape in RDD is limited in many resource-poor settings, with the upfront use of glucocorticosteroids employed routinely in the majority of cases.

Feasibility of Cell-Free DNA Collection and Clonal Immunoglobulin Sequencing in South African Patients With HIV-Associated Lymphoma.

PURPOSE: Diagnosis of AIDS lymphoma in low-resource settings, like South Africa, is often delayed, leaving patients with limited treatment options. In tuberculosis (TB) endemic regions, overlapping signs and symptoms often lead to diagnostic delays. Assessment of plasma cell-free DNA (cfDNA) by next-generation sequencing (NGS) may expedite the diagnosis of lymphoma but requires high-quality cfDNA. METHODS: People living with HIV with newly diagnosed aggressive B-cell lymphoma and those with newly diagnosed TB seeking care at Chris Hani Baragwanath Academic Hospital and its surrounding clinics, in Soweto, South Africa, were enrolled in this study. Each participant provided a whole blood specimen collected in cell-stabilizing tubes. Quantity and quality of plasma cfDNA were assessed. NGS of the immunoglobulin heavy chain was performed. RESULTS: Nine HIV+ patients with untreated lymphoma and eight HIV+ patients with TB, but without lymphoma, were enrolled. All cfDNA quantity and quality metrics were similar between the two groups, except that cfDNA accounted for a larger fraction of recovered plasma DNA in patients with lymphoma. The concentration of cfDNA in plasma also trended higher in patients with lymphoma. NGS of immunoglobulin heavy chain showed robust amplification of DNA, with large amplicons (> 250 bp) being more readily detected in patients with lymphoma. Clonal sequences were detected in five of nine patients with lymphoma, and none of the patients with TB. CONCLUSION: This proof-of-principle study demonstrates that whole blood collected for cfDNA in a low-resource setting is suitable for sophisticated sequencing analyses, including clonal immunoglobulin NGS. The detection of clonal sequences in more than half of patients with lymphoma shows promise as a diagnostic marker that may be explored in future studies.

MYC status in HIV-associated plasmablastic lymphoma: dual-colour CISH, FISH and immunohistochemistry.

AIMS: We utilised chromogenic and fluorescence in-situ hybridisation (CISH and FISH) to evaluate MYC gene copy numbers and rearrangements within HIV-associated plasmablastic lymphomas (PBLs). Thereafter, clinicopathological features were explored retrospectively. METHODS AND RESULTS: Sixty-seven (n = 67) patients were included and the HIV seropositive status was confirmed in 98% (63 of 64) with a median viral load of 55 587 (IQR 273 582) copies/ml and median CD4 count of 170 (IQR 249) cells/µl. The mean age was 41 ± 10.1 years and females comprised 54%. PBL was documented predominantly at extra-oronasal topographic regions. Starry-sky (SS) appearance was evident in 33% in association with monomorphic morphology (P-value 0.02). c-MYC protein was expressed in 81% and latent EBV infection was detected in 90%. EBER ISH-positive status and MYC rearrangement occurred in 67% of HIV PBL. MYC aberrations included MYC rearrangement (70%), low-level increase in MYC gene copy numbers (43%), concurrent MYC rearrangement and increased MYC gene copy numbers (49%) as well as low-level chromosome 8 polysomy (6%). MYC aberrations in HIV PBLs were significantly associated with SS appearance (P -0.01), monomorphic morphology (P - 0.03), c-MYC protein expression ≥40% (P - 0.03) and mortality (P - 0.03). There was advanced stage (Ann Arbor III/IV) at presentation (77%) and the median overall survival for HIV PBL was 75 days (95% CI 14-136). CONCLUSION: Majority of the HIV-associated PBL tumours harbour MYC aberrations. Due to the persistently inferior survival outcome of HIV-associated PBL in the era of antiviral treatment, targeted and/or intensified therapy of oncogenic MYC may need to be explored in future.

An Expanded Spectrum of High-Grade B-Cell Non-Hodgkin Lymphomas Involving the Cervicovaginal Region.

The uterine cervix and vaginal regions are infrequently infiltrated by lymphoma. Involvement of these topographic regions may constitute primary disease or more commonly represent a manifestation of systemic lymphomatous disease. Herein, we report an expanded spectrum of high-grade B-cell non-Hodgkin lymphomas comprising plasmablastic lymphoma (with and without plasmacytic differentiation), ALK-positive large B-cell lymphoma, and diffuse large B-cell lymphoma which involved the uterine cervix and/or vagina of 6 patients at initial diagnosis. These tumors clinically mimicked carcinoma and developed predominantly, but not exclusively, in the setting of human immunodeficiency virus infection.

Hepatosplenic T-cell lymphoma: A case series.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare type of Non-Hodgkin Lymphoma (NHL), grouped under the mature or peripheral T-cell lymphomas. It is characterised by extranodal infiltration and proliferation of malignant T-cells within the sinusoids of the liver, sinuses and red pulp of the spleen, and the bone marrow. The tumour cells express CD2 and CD3, but are CD4, CD5 and CD8 negative and express a clonally restricted gamma-delta (or less commonly alpha-beta) T-cell receptor. The disease has an aggressive clinical course associated with a poor prognosis. We highlight and report three patients from South Africa with HSTCL, all of whom had hepatosplenomegaly and cytopaenias, and despite being HIV seronegative and immunocompetent, had a poor outcome, with a mean survival of 7.5 months in the two evaluable patients. This rare entity has not previously been reported from South Africa and as yet needs to be adequately characterised in a population where lymphoma is the most common haematological malignancy in adults, and where approximately two thirds of the adult lymphoma population are HIV seropositive.

Classical Hodgkin Lymphoma involving the central nervous system (brain) - an unusual presentation.

KEY CLINICAL MESSAGE: Intracranial Hodgkin lymphoma (HL) is considered so atypical that an intracranial space-occupying lesion in a patient with known HL should be thoroughly investigated to rule out a second disease process.

Human immunodeficiency virus infection and chronic myeloid leukemia.

CML (chronic myeloid leukaemia) in association with HIV (human immunodeficiency virus) infection (HIV-CML) is rarely described and is likely to be coincidental. The natural history and behaviour of HIV-CML is different, being more atypical and aggressive. Both conditions, and their respective treatments may cause myelosuppression. Concurrent treatment with cART (combination antiretroviral therapy) and the tyrosine kinase inhibitors (TKI's) can result in appropriate control of CML and HIV infection, as well as long term survival. However, drug interactions between ARV's and TKI's may require adjustment of treatment.