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.

HER2 Equivocal (Score = 2+) Breast Carcinoma Cases Identified by Immunohistochemistry at a South African Hospital. What is the Impact of Fluorescent In Situ Hybridization Testing?

The American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) guidelines are used for human epidermal growth factor receptor 2 (HER2) reporting in breast carcinoma. Cases that demonstrate weak to moderate complete membrane immunohistochemical staining in >10% of the tumor are scored as 2+ (equivocal). This study aimed to determine what proportion of HER2 immunohistochemistry (IHC) score = 2+ breast carcinomas were confirmed to be positive by HER2 fluorescent in situ hybridization (FISH). There were 241 HER2 IHC score = 2+ breast carcinomas included. Most (74.3%) carcinomas were estrogen and progesterone receptor-positive. Invasive breast carcinoma of no special type (89.2%) was the commonest histologic subtype. Most tumors were grade 2 (64.3%). As per the FISH report, at the time of diagnosis, 27 cases (11.2%) were HER2 FISH positive. All HER2 FISH equivocal cases and one FISH positive case assessed using the 2013 ASCO/CAP HER2 criteria were reclassified to HER2 FISH negative when the 2018 criteria were applied. There was a high level of agreement (κ = 0.979) between HER2 FISH results obtained using the 2013 and the 2018 criteria. This study provides insight into the frequency of HER2 FISH positivity (11.2%) among HER2 IHC score = 2+ breast carcinomas and the impact of modifications to the ASCO/CAP HER2 guidelines. Elimination of the HER2 FISH equivocal category by the 2018 guidelines has reduced the need for repeat testing and simplified clinical management. Reclassification of previous HER2 FISH positive to negative has resulted in some patients being ineligible for costly anti-HER therapy.

Ki67 Immunohistochemistry Quantification in Breast Carcinoma: A Comparison of Visual Estimation, Counting, and ImmunoRatio.

BACKGROUND: Molecular analysis has shown that breast carcinomas can be classified into several intrinsic subtypes, with implications for management and prognosis. In the majority of pathology laboratories molecular analysis of each case is not possible and immunohistochemistry is used for subtyping. This includes analysis of hormone receptors as well as HER2-neu and Ki67. The methodology for the interpretation of the proliferation index using Ki67 remains an area of uncertainty. We investigated the degree of agreement between different methods of Ki67 interpretation. MATERIALS AND METHODS: We analyzed 204 breast core biopsies diagnostic of breast carcinoma using visual estimation/eyeballing (EB), ImmunoRatio, and counting by 2 pathologists (CP1 and CP2). The correlation between the different methods and the interobserver agreement between the 2 pathologists was assessed. Specific analysis was also done with respect to classification of cases into low Ki67 groups (using Ki67 values<14% and <20%) since this is critical in classifying tumors into luminal A and luminal B subtypes. RESULTS: Correlation between the different methods was best achieved comparing ImmunoRatio and CP1, and worst comparing CP1 and EB. Correlation was better when considering interobserver variability (CP1 vs. CP2). Comparing the number of cases classified as low Ki67 (<14% and <20%) the Cohen κ statistic varied from κ=0.267 to 0.814 with different methods. When limiting the analysis to cases with a Ki67 of 10% to 25% according to any method, there was greater disagreement. CONCLUSIONS: At the higher and lower Ki67 levels, the correlation between the methods of assessment was acceptable, however, at levels close to the cut-off values for lumial A versus luminal B, several patients would be differently classified by the different methods and therefore potentially receive suboptimal management.

Endometrial sampling at an academic hospital in South Africa: Histological findings, lessons learnt and interesting surprises.

BACKGROUND: Outpatient sampling is used to investigate endometrial pathology. Little is known about practice habits and local failure rates at Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa. OBJECTIVE: This study assessed the frequency of samples that showed no or limited histological representation of endometrium, and described demographic and pathological features. METHODS: All endometrial sample histology reports from the National Health Laboratory Services at the hospital from 01 July 2013 to 31 May 2017 were retrieved by searching the laboratory's information system. Clinical variables (age, menopausal state, indication for biopsy, endometrial thickness on ultrasound) and pathological findings (macroscopic amount of tissue, histological diagnosis, microscopic presence of endometrial tissue) were extracted and statistically analysed. RESULTS: A total of 1926 samples were included, 91% of which were submitted for abnormal or postmenopausal bleeding. No endometrium was observed in 25% of samples and 13% showed limited endometrium. Benign diagnoses (86%) were most common, with proliferative or secretory changes, endometrial polyps and endometritis accounting for most of these. Associations between the amount of sample received and the presence of endometrial tissue (p ≤ 0.001) and benign versus malignant diagnoses (p ≤ 0.001) were noted. The greater the endometrial thickness, the greater the likelihood of obtaining more sample (bulky vs scant p < 0.001) and making a malignant versus benign diagnosis (p = 0.005). CONCLUSION: These findings are in keeping with literature outside Africa. Histology reports should be explicit when terms such as 'inadequate' or 'insufficient' are used, in order to facilitate clinical decision-making.

Spectrum of HIV-associated infectious diseases: A case series through the eyes of the histopathologist.

BACKGROUND: Human immunodeficiency virus (HIV) infection increases the risk of infection by a host of other opportunistic pathogens. The clinical presentations of these co-infections in immunocompromised patients are often atypical; therefore diagnosis is delayed in the absence of investigations such as tissue biopsy. Infection may involve sites that are difficult to access for biopsy and, as a consequence, there is limited diagnostic tissue available for analysis. The histopathologist, aided by ancillary tests, is relied upon to make a timeous and accurate diagnosis. OBJECTIVES: To illustrate key histological features of HIV-associated infectious diseases encountered in a histopathology laboratory and to highlight, with the aid of literature, the relevance of histopathology in diagnosis. METHOD: A retrospective descriptive case series of biopsies histologically diagnosed with HIV-associated infectious diseases over four years (2015-2019) was performed at the Chris Hani Baragwanath Academic Hospital National Health Laboratory Services Histopathology department. These cases have been photographed to illustrate microscopic aspects and will be accompanied by a literature review of opportunistic infections in the context of HIV infection. RESULTS: This article highlights aspects of fungal, parasitic, viral and selected bacterial infections of people living with HIV for whom the histopathological examination of tissue was an essential component of the clinical diagnosis. Histological features are noted on routine slides and accompanied by diagnostic features revealed with histochemical and immunohistochemical stains. CONCLUSION: Medical practitioners working in areas of high HIV endemicity should be familiar with the variety of infectious diseases that are encountered and with the diagnostic importance of the histopathologist in clinical management.

Xanthogranulomatous prostatitis: A rare mimicker of prostate adenocarcinoma.

Xanthogranulomatous prostatitis as mimicker of prostate adenocarcinoma can cause a diagnostic dilemma, as presented in this case. Therefore, alongside histopathology analysis, multiparametric magnetic resonance imaging (mpMRI) would be useful in this situation by identifying and characterizing suspicious prostatic lesions before biopsy thereby supporting current recommendations on the use of mpMRI.

First Report of Renal Cell Carcinoma Metastasizing to the Clivus in a Pediatric Patient.

BACKGROUND: The clivus is a rare site of tumor occurrence in general, and metastases to this site are especially rare. Renal cell carcinoma is an uncommon entity in the pediatric population. Although not infrequent in adults, when it does occur, metastases to the clivus are extremely uncommon, only having been reported 3 times in the literature. All of these cases involved adults in their sixth decade. CASE DESCRIPTION: We present the first report in the literature of renal cell carcinoma occurring in a pediatric patient and spreading to the clivus. This 11-year-old girl presented with headaches and diplopia based on a left-sided sixth cranial nerve palsy, in the context of a wasting disease. She was also found to have vague abdominal fullness, although it was only after biopsy of a clivus lesion identified on brain scanning that its true nature became apparent, prompting abdominal scans, which revealed a renal mass with hepatic metastases. CONCLUSIONS: This article reports for the first time in the literature the spread of a translocation renal cell carcinoma to the clivus in a young child. This serves to alert practitioners to this possibility when faced with a similar scenario.

Do Not Forget the Glycophorin A: An Unusual Case of Myeloid Sarcoma.

Acute erythroid leukemia is rare, with isolated reports on presentation as an extramedullary tumor mass (myeloid sarcoma). We describe a case of pure erythroid leukemia presenting as an orbital mass in a 1-year, 9-month-old girl. This is only the second case described in a child. Tissue biopsy of the tumor mass showed medium-sized cells that were glycophorin A positive and negative with conventional myeloid markers. Flow cytometry, bone marrow aspirate, and trephine confirmed the diagnosis of pure erythroid leukemia.

Kaposi's sarcoma, a South African perspective: Demographic and pathological features.

BACKGROUND: The incidence of Kaposi's sarcoma (KS) has increased dramatically since the onset of the AIDS epidemic. Of the estimated 66 200 cases of KS worldwide, 58 800 are considered to have occurred in sub-Saharan Africa. OBJECTIVES: To describe the epidemiology and pathological characteristics of KS at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. METHODS: A retrospective cross-sectional study design was used. Nine hundred and thirty-eight histopathology reports of KS diagnosed in 901 patients at CHBAH between 2005 and 2009 were reviewed. Age, gender, topographic site, CD4 count, HIV status, KS histological stage, findings of human herpesvirus 8 latency-associated nuclear antigen 1 immunohistochemistry and concomitant pathological findings were recorded. RESULTS: The male/female ratio was 1.2:1, the mean age 37 years and the median CD4 count 128 cells/µL. Lower limb skin biopsies accounted for 49.6% of cases. Paediatric, visceral and endemic KS accounted for only limited proportions (1.4%, 1.4% and 1.3% of biopsies, respectively). There were concomitant pathological findings in 4.6% of biopsy specimens, infections and inflammatory dermatoses being the most frequent. CONCLUSION: The findings of this study highlight the need for allocation of diagnostic and treatment resources for KS. Documentation of the various demographic aspects of KS will prove to be of historical, clinical and histopathological interest as the long-term outcomes of antiretroviral therapy begin to emerge.

Variability of HHV8 LNA-1 Immunohistochemical Staining Across the 3 Histologic Stages of HIV-Associated Mucocutaneous Kaposi Sarcoma: Is There a Relationship to Patients' CD4 Counts?

The histologic diagnosis of Kaposi sarcoma (KS) can be confirmed with human herpes virus 8 (HHV8) latency-associated nuclear antigen (LNA)-1 immunohistochemistry, which may show variability in distribution and intensity. This retrospective study was aimed at addressing the factors that may contribute to this variability. All cases of mucocutaneous KS diagnosed in a 5-year period at the histopathology department at a tertiary hospital in South Africa with available patients' CD4 counts and HHV8 LNA-1 immunohistochemically stained slides were reviewed, and the biopsy stages of KS (patch/plaque/nodular), CD4 counts, immunohistochemistry staining method (manual vs. automated), and distribution (diffuse/focal) and intensity (strong/weak) of HHV8 LNA-1 staining were recorded. A total of 127 cases were reviewed. No relationship was demonstrated between the median CD4 count and the histologic stages of KS (P = 0.701) or the intensity and distribution of HHV8 immunohistochemical staining using either staining method. Multivariate analysis showed that method of immunohistochemical staining was a significant predictor of distribution (P = 0.006) and intensity (P = 0.044) of staining, and that stage was a significant predictor of distribution of staining (P = 0.033).

Endometrial sampling at an academic hospital in South Africa: Histological findings, lessons learnt and interesting surprises

Background: Outpatient sampling is used to investigate endometrial pathology. Little is known about practice habits and local failure rates at Chris Hani Baragwanath Academic Hospital in Johannesburg, South Africa.Objective: This study assessed the frequency of samples that showed no or limited histological representation of endometrium, and described demographic and pathological features.Methods: All endometrial sample histology reports from the National Health Laboratory Services at the hospital from 01 July 2013 to 31 May 2017 were retrieved by searching the laboratory's information system. Clinical variables (age, menopausal state, indication for biopsy, endometrial thickness on ultrasound) and pathological findings (macroscopic amount of tissue, histological diagnosis, microscopic presence of endometrial tissue) were extracted and statistically analysed.Results: A total of 1926 samples were included, 91% of which were submitted for abnormal or postmenopausal bleeding. No endometrium was observed in 25% of samples and 13% showed limited endometrium. Benign diagnoses (86%) were most common, with proliferative or secretory changes, endometrial polyps and endometritis accounting for most of these. Associations between the amount of sample received and the presence of endometrial tissue (p ≤ 0.001) and benign versus malignant diagnoses (p ≤ 0.001) were noted. The greater the endometrial thickness, the greater the likelihood of obtaining more sample (bulky vs scant p < 0.001) and making a malignant versus benign diagnosis (p = 0.005).Conclusion: These findings are in keeping with literature outside Africa. Histology reports should be explicit when terms such as 'inadequate' or 'insufficient' are used, in order to facilitate clinical decision-making