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Plasmablastic lymphoma (PBL) is an aggressive B-cell non-Hodgkin lymphoma associated with immunodeficiency in the context of human immunodeficiency virus (HIV) infection or iatrogenic immunosuppression. While a rare disease in general, the incidence is dramatically increased in regions of the world with high HIV prevalence. The molecular pathogenesis of this disease is poorly characterized. Here, we defined the genomic features of PBL in a cohort of 110 patients from South Africa (15 by whole-exome sequencing and 95 by deep targeted sequencing). We identified recurrent mutations in genes of the JAK–STAT signaling pathway, including STAT3 (42%), JAK1 (14%), and SOCS1 (10%), leading to its constitutive activation. Moreover, 24% of cases harbored gain-of-function mutations in RAS family members (NRAS and KRAS). Comparative analysis with other B-cell malignancies uncovered PBL-specific somatic mutations and transcriptional programs. We also found recurrent copy number gains encompassing the CD44 gene (37%), which encodes for a cell surface receptor involved in lymphocyte activation and homing, and was found expressed at high levels in all tested cases, independent of genetic alterations. These findings have implications for the understanding of the pathogenesis of this disease and the development of personalized medicine approaches. Significance: Plasmablastic lymphoma is a poorly studied and extremely aggressive tumor. Here we define the genomic landscape of this lymphoma in HIV-positive individuals from South Africa and identify pervasive mutations in JAK–STAT3 and RAS–MAPK signaling pathways. These data offer a genomic framework for the design of improved treatment strategies targeting these circuits. See related commentary by Küppers, p. 23. This article is highlighted in the In This Issue feature, p. 5

Minor salivary gland tumours represent 9–25% of all salivary gland tumours. South African epidemiological reports on minor salivary gland tumours are lacking. This study aims to evaluate the frequency, epidemiology and histology of minor salivary gland tumours in a defined South African population from 1997 to 2016. This cross sectional retrospective review of epithelial minor salivary gland neoplasms recorded patient demographic data: prevalence, age, gender, site, histology. There were 553 benign (57%) and malignant (43%) minor salivary gland tumours, in patients between the ages of 9 and 93 years. There was no significant age (p = 0.64) or gender (p = 0.18) difference between males and females. Common histologic types of salivary gland tumours in the continually evolving spectrum were pleomorphic adenoma (52%), adenoid cystic carcinoma (12%) and mucoepidermoid carcinoma (10%). Common sites were the palate (56%), cheek (11%), lip (9%) and paranasal sinuses (7%). Minor salivary gland tumours represent 2.3% of head and neck pathology. Although this prevalence is higher than reported, there is no overall increase in number diagnosed per year. Minor salivary gland tumours were more prevalent in females. Benign tumours occurred at a younger age than malignant tumours. This study serves as a baseline for future studies, especially in South Africa.

Professor Mervyn Shear made immense contributions to the discipline of Oral Pathology and indeed was the founder of the speciality in South Africa, holding the first Chair of Oral Pathology in the country. He graduated BDS from Wits in 1964, Neil to MDS (Oral Pathology) in 1961 and to the FRC (Pathology) from the Royal College of Pathologists in 1965. His passion for the discipline motivated his determination that Oral Pathology should be affiliated to Anatomical Pathology, a relationship which has ensured maximum exposure for South African registrars in Oral Pathology.

AIMS AND OBJECTIVES: To determine the frequency and histomorphology of secondary Candida infection in oral HIV-associated Kaposi sarcoma (HIV-KS) and to describe the demographics of patients with oral HIV-KS with and without secondary Candida infection. MATERIALS AND METHODS: Haematoxylin and eosin, and periodic acid-Schiff stains of 32 oral HIV- KS were examined histologically for intensity and morphology of Candida colonisation, depth of invasion, number of organisms, epithelial reactions and inflammatory response. Depth of Candida invasion and severity of infection were correlated with CD4 T-cell counts of HIV-positive patients. RESULTS: Forty-one percent of oral HIV-KS were secondarily infected with Candida (n=13). Intensity varied from an isolated single pseudohyphus to matted colonies. Whilst in most cases, organisms did not invade beyond the parakeratin layer, pseudohyphae extended into stratum spinosum in two cases, and a single case showed a pseudohyphus within the lamina propria. Two cases showed pseudohyphae in the pyogenic membrane. Neutrophilic permeation of epithelium, commonly associated with Candida infection was frequently present even in absence of Candida infection CONCLUSION: Oral HIV-KS is commonly secondarily infected with large numbers of Candida organisms. Morphological characteristics of secondary Candida infection in surface epithelium of HIV-KS suggest an altered pathogenetic pathway. Further studies are indicated.

Objectives: The purpose of this retrospective study was to investigate differences between black and white persons with oral squamous cell carcinoma (OSCC) with regard to age, gender, oral site affected, and histopathological degree of differentiation; and to compare these clinicopathological parameters between persons younger and older than 40 years in a South African population sample from the greater Johannesburg area. Material and Methods: The histopathological reports of 510 cases of OSCC during the period 1995-2002 were retrospectively evaluated, and the data regarding age, gender, ethnicity/race, oral site affected, and degree of histopathological differentiation were recorded and statistically analyzed for differences between black and white persons, and between persons younger and older than 40 years of age. Results: Statistically significantly, black persons were diagnosed with OSCC at a younger mean age (57 years) than white persons (61 years) (P = 0.0086). The difference between male: female (M: F) ratio in black (3.74:1) and white persons (1.96:1) was statistically significant (P = 0.0041). White persons had a significantly higher proportion of SCC of the lower lip than black persons (P < 0.0001). Conclusion: OSCC was diagnosed at a younger age in black than in white persons; the proportion of black males in the black population group was greater than that of white males in the white population group; and the proportion of SCC of the lips was higher in younger than in older persons.

Our aim was to evaluate the histological association of mandibular solid and multicystic ameloblastoma with the inferior alveolar nerve, both in situ and in segments of the nerve that had been removed separately, to assess the feasibility of preserving the nerve during resection of mandibular ameloblastomas. In this prospective histological examination of 13 resected hemimandibulectomy specimens, we studied the proximity of tumour cells to the inferior alveolar nerve. In group 1 (n=8) this association was examined with the nerve still within the mandibular segment after resection, while in group 2 (n=5) the nerve was removed from the resected tumour and examined separately. Perineural and intraneural involvement of the ameloblastoma with the nerve was confirmed in 5 cases in group 1 and 2 cases in group 2. Tumour cells abutted the nerve directly in group 1. In group 2 tumour was removed with, and found within, the nerve. On this evidence we cannot recommend preservation of the inferior alveolar nerve during operation for large, advanced, mandibular ameloblastomas.

Human papillomavirus (HPV) infection, most commonly genotype 16 of the alpha-9 family, is implicated in the etiology of a subset of oropharyngeal squamous cell carcinomas (OPSC) worldwide. Data are scarce regarding OPSC in South Africans, and three prior studies suggest no significant etiologic role for HPV. We aimed to investigate for evidence of HPV etiology in OPSCs from black South Africans by polymerase chain reaction (PCR) methodologies with determination of HPV subtype by sequencing, in situ hybridization (ISH), and p16INK4a immunohistochemistry (IHC), as a surrogate marker for an HPV-driven tumor. It was hypothesized that HPV-driven tumors would be positive by PCR plus IHC and/or ISH whereas OPSCs with HPV background infections (HPV-passenger) would be positive by PCR alone. Formalin-fixed, paraffin embedded tissues from 51 OPSCs collected between 2005 and 2010 from 41 patients were analyzed for HPV by GP5?6? PCR (targeting the HPV L1 region), pU-1M/pU- 2R PCR (targeting the HPV E6/E7 region) and HPV-31 specific PCR (targeting the E5 region), chromogenic ISH, and p16INK4a IHC. All cases positive by PCR were subject to sequencing to determine HPV genotype. The patient mean age was 58.0 years and 88 % were male. Of the 51 evaluable tumors, 48 (94.1 %) were positive for HPV DNA by PCR: 25 (49.1 %) met criteria for an HPV-driven tumor, 23 (45.1 %) for HPV-passenger, and 3 (5.9 %) were HPV unrelated. Sequencing of the PCR-positive cases revealed the following genotypes: combined HPV-16 and 31 (41.7 %), HPV-31 (25.0 %), HPV-16 (22.9 %), combined HPV-16 and 18 (6.3 %), and a single case each of HPV 18 and HPV 33. Studies via ISH were negative in all cases. In accordance with worldwide trends but contrary to prior South African data, HPV likely plays an etiologic role in a significant subset (at least 49.1 %) of OPSC in black South Africans. We found that the alpha-9 HPV family, particularly HPV-16 and 31 either in combination or separately, to predominate in our sample tumors. The use of multiple PCR primers increased sensitivity of viral detection, and a HPV-31 specific primer confirmed the presence of this genotype in many samples. Further studies including HPV E6/E7 mRNA assays are needed to better elucidate the pathogenic role of HPV in black South African OPSCs.

Context: Langerhans cells (LCs) are effective antigen-presenting cells that function as “custodians” of mucosa, modifying the immune system to pathogen entry, and tolerance to self-antigen and commensal microbes. A reduction in number of LCs in human immunodeficiency virus (HIV)-positive individuals may predispose to local mucosal infections. Aims: To quantitatively determine the number of oral mucosal LCs in HIV/acquired immunodeficiency syndrome HIV/acquired immunodeficiency syndrome (AIDS) associated oral Kaposi sarcoma (KS) with/without oral candidiasis (OC) and to define in situ interrelationships between the cells, OC, and HIV infection. Materials and Methods: Thirty-two periodic acid-Schiff. (PAS) stained histologic sections of palatal HIV/AIDS associated KS with intact oral epithelium were examined for Candida and divided into two groups: . (1) KS coinfected with Candida and. (2) KS noninfected with Candida. Sections were immunohistochemically stained with CD1a. The standard length of surface epithelium was measured and number of positively stained LCs counted per unit length. Control cases included non-Candida infected palatal mucosa overlying pleomorphic adenoma. (PA) and oral mucosa infected with Candida in otherwise healthy individuals. Results: LC number per unit length of surface epithelium was statistically significantly greatest in uninfected PA mucosa and lowest in KS coinfected with Candida (P = 0.0001). A statistically significant difference was also noted between uninfected PA mucosa and non-Candida infected KS (P = 0.0014), in KS coinfected with Candida and non-infected KS (P = 0.0035), between OC and PA (P = 0.0001), and OC and KS coinfected with Candida (P = 0.0247). Conclusion: LC numbers are significantly reduced in oral tissues of HIV/AIDS infected patients by Candida infection when compared to oral tissues without.

The introduction of bisphosphonates has increased in the last decade following their indication for metastatic bone diseases, osteoporosis, hypercalcaemia of malignancy and Paget’s disease. Although bisphosphonates have been used clinically for more than three decades there have been no documented long-term complications of their effects on the jaws until recently, where there is now growing evidence of the influence of bisphosphonates on osteonecrosis of the jaws. The aim of this paper is to report a case of this newly described complication, to review this phenomenon, including the clinical implications and to reiterate current clinical guidelines for management of patients in which bisphosphonate therapy is indicated. To the best of our knowledge this is the first reported case of bisphosphonate-induced necrosis of the jaw in South Africa.

The follicular variant of the adenomatoid odontogenic tumor (AOT) is thought to originate from the reduced enamel epithelium of the dental follicle. The origin of the extra-follicular variant however, remains less clear. This paper presents a case of an extra-follicular AOT, which we believe originated from the epithelial lining of a unicystic ameloblastoma, and reviews the literature. The available evidence seems to indicate that some extra-follicular AOTs might arise as secondary phenomena within pre-existing odontogenic cysts or cystic tumors.

Background: Cystic lymphoid hyperplasia (CLH) describes benign salivary lymphoepithelial cysts with a strong link to human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). The pathogenesis is related to ductal dilatation of entrapped salivary elements due to intranodal HIV-associated atypical lymphoid hyperplasia. Very little is known about the immunophenotypic profile of this entity. Aim: This study aims to describe the immunopathological features of a series of CLH cases in HIV-positive patients to clarify the etiopathogenesis. Materials and Methods: Paraffin-embedded tissue from 25 cases of parotid CLH in HIV seropositive patients was immunohistochemically analyzed with CD3, CD20, CD4, CD8, and p24 using standard procedures. Statistical Analysis: The data are mostly descriptive and were analyzed using EpiInfo (3.5.1) (CDC, Atlanta, USA); significant differences were analyzed using the Student's t-test and the Chi-square test with a statistical significance level of P < 0.05 being used. Results: Immunostaining showed a CD8:CD4 of ~1:1 except in selected cases with decreased CD4 and increased CD8 expression in the interfollicular (IF) areas. p24 staining revealed 100% specificity in HIV-associated CLH. Conclusion: The immunohistochemical description of CD20, CD3, CD4, and CD8 provides an understanding of CLH pathogenesis. CLH of parotid lymph nodes in confirmed HIV-positive patients with 100% specificity with HIV p24 antibody validates the strong association of CLH with HIV and AIDS. The CD4:CD8 ratio was ~1:1; however, increased CD8 expression within IF areas may indicate possible HIV-related CLH as compared to other cystic parotid lesions.

Background:Oral mucosal melanoma (OMM) is relatively rare, runs an aggressive course, affects most frequently the hard palate and the maxillary gingiva, and may be multifocal. The aetiological factors and the chain of molecular events that give rise to OMM and to its growth and metastasis are largely unknown.Objectives:The purpose of this retrospective study was to characterize some clinical and histopathological features of OMM in a South African sample.Materials and Methods:The histopathological reports and histological sections of 17 cases with OMM during the period 1968–2013 were retrospectively evaluated, and the data regarding age, gender, ethnicity/race and the histopathological patterns were recorded. c-Kit immunohistochemical staining was performed.Results:OMM most frequently affected the palate and the maxillary gingiva of black persons without gender predilection. The age of the patients ranged from 20 to 78 years with the mean age at diagnosis being 56 years. Most tumours were nodular comprisi...

OBJECTIVE: This study analysed differences in clinicopathological features of oral leukoplakia in different racial groups in the greater Johannesburg area of South Africa, with emphasis on the black population. MATERIAL AND METHODS: The retrospective review included cases diagnosed clinically as oral leukoplakia and histologically as hyperkeratosis without dysplasia, hyperkeratosis with mild, moderate or severe dysplasia, and carcinoma in situ from 1990 to 2010. Age, gender, ethnicity, clinical appearance, site of lesion and tobacco smoking habit were recorded. RESULTS: Fourteen per cent of oral leukoplakia occurred in black South Africans compared with 80% in white South Africans. In contrast to whites, blacks were diagnosed with oral leukoplakia at a younger age; there were more men affected than women; and the proportion of idiopathic leukoplakia was greater. There were significantly more blacks (23%) than whites (13%) with non-homogenous leukoplakia and significantly more whites (51%) than blacks (23%) with dysplastic oral leukoplakia. CONCLUSION: This study suggests that oral leukoplakia, especially non-homogenous and idiopathic forms affects South African blacks less frequently than white South Africans; and in the former, it occurs more in men and at a younger age. These findings may provide some guidance in establishing screening policies for oral cancer, particularly suited for blacks. Oral Diseases (2012) doi:10.1111/odi.12040

Aims. To evaluate the immunohistochemical expression of bcl-2 and c-kit proteins in the salivary gland tumors, adenoid cystic carcinoma, and polymorphous low-grade adenocarcinoma with a view to tumor differentiation. Methods. Immunohistochemical studies were performed on 29 adenoid cystic carcinoma and 23 polymorphous low-grade adenocarcinoma archival cases with bcl-2 and c-kit antibodies using standard procedures, and the data were statistically analyzed. Results. The difference in bcl-2 expression in adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma was not statistically significant. Whilst the difference in c-kit expression was statistically significant (), the difference proved small so as to be of no practical or diagnostic importance. Moderate to strong immunostaining was noted in adenoid cystic carcinoma with c-kit, the pattern and intensity varying within different histological subtypes, being greater the more aggressive the tumor subtype. Conclusions. Bcl-2 and c-kit are not useful as immunohistochemical markers in differentiating adenoid cystic carcinoma from polymorphous low-grade adenocarcinoma.

Clinical PresentationA 31-year-old female patient presented with a swollen eye(Fig. 1). Intraoral examination showed a necrotic ulceratedlesion extending from the midline involving the buccalsulcus over the right central and lateral incisors (teeth 7 and8) (Fig. 2). The CT scan showed an erosive mass anteriorto the ethmoid cells and an opacified maxillary sinus. Thepatient is HIV negative.Differential DiagnosisImportant clinical features from the clinical photos (Figs. 1and 2) and history include:• an ulcerated intraoral tumor in the right anterior maxillaextending to the right buccal sulcus• an avascular, possibly necrotic socket of the rightmaxillary central incisor (tooth 8) with no evidence ofalveolar bone destruction, features suggestive ofischemic change and exfoliation of the central incisor(tooth 8)• tumor tissue in the maxillary and ethmoidal sinuses• periorbital swelling around the left eye suggestive oftumor infiltration or cavernous sinus thrombosis• skin ulceration suggestive of ischemic changesThese features are suggestive of an infective or neo-plastic process affecting a large area of the maxilla,crossing the midline, with bone and soft tissue involve-ment, and showing an affinity for blood vessels. Theclinical differential diagnosis includes mid-facial necro-tizing granulomatous diseases, deep fungal infections,primary intraoral neoplasms, maxillary sinus neoplasmsand the so-called midline tumors.Mid-facial necrotising granulomatous diseases includediseases such as Wegener’s granulomatosis, leprosy, sar-coidosis and tuberculosis. These conditions may presentwith skin lesions and oral ulceration but are seldom asso-ciated with ulcerative ‘‘tumors’’ or periorbital swelling.Deep fungal infections such as zygomycosis, aspergil-losis and histoplasmosis must be excluded. Zygomycosisremains a prime consideration as it has a known affinity forblood vessels resulting in thrombus formation and associ-ated ischemic necrosis. Oral ulceration and periorbitalswelling are common features. Patients frequently presentwith a short history of symptoms and are often uncon-trolled diabetics. Intraoral tumor formation however is nota common presentation.The clinical presentation of intraoral necrotic ulcerationaccompanied by paranasal sinus involvement and perior-bital swelling are highly indicative of malignant disease.Of the wide spectrum of primary intraoral malignancies,squamous cell carcinoma or salivary gland carcinomasshould be foremost considered. This patient is relativelyyoung and furthermore the hard palate is a relativelyuncommon site for a squamous cell carcinoma. The intra-oral site is more compatible for a salivary gland

Sclerosing polycystic adenosis (SPA) is a rare lesion of salivary glands with a striking resemblance to fibrocystic disease of the breast. Most of the 47 reported cases have occurred within the parotid gland, with only a single case being described within the buccal mucosa. We report an additional case of SPA of the buccal mucosa. The exact nature of this entity is unknown, but has up until recently believed to be a pseudoneoplastic reactive and inflammatory sclerosing process. Even though SPA has satisfied the criteria for monoclonality, the debate as to whether SPA represents a true neoplasm or a pseudoneoplastic inflammatory sclerosing process, with low-grade neoplastic potential continues. Awareness of the occurrence of this lesion in both major and minor salivary glands is important to promote its differentiation from other more sinister salivary gland pathology. Cure is effected by localized surgical excision and all reported cases of SPA show an excellent prognosis with no true recurrence or metastasis.