Clinicopathological analysis and survival outcomes of primary salivary gland tumors in pediatric patients: A systematic review.

BACKGROUND: Salivary gland tumors are a diverse group of uncommon neoplasms that are rare in pediatric patients. The aim of this study was to evaluate the clinicopathological profile and survival outcomes of pediatric patients affected by salivary gland tumors. MATERIALS AND METHODS: An extensive search was carried out using the MEDLINE/PubMed, EMBASE, Scopus databases, and grey literature. The risk of bias was available in all papers included. RESULTS: A total of 2,830 articles were initially retrieved with 54 remaining for data extraction, resulting in 2,937 cases. This comprised forty-five case series' and nine cohort studies. These tumors were slightly more prevalent in females (57.4%). The patients' age ranged from 0.3 to 19 years old, with a mean age of 13.3 years. Parotid was the most affected site (81.9%), and 99.2% of cases clinically exhibited a swelling. Presence of pain/tenderness was reported in 13.5% of the cases, with an average duration of 12.6 months for the appearance of symptoms. Most of the reported cases were malignant tumors (75.4%), with mucoepidermoid carcinoma the most common tumor of all tumors (44.8%), followed by pleomorphic adenoma (24.1%). Surgery alone was the leading treatment choice in 74.9% cases, and the 5-year overall survival rate of patients was 93.1%. Patients with symptoms (P = .001), local recurrence (P < .001), metastasis (P < .001), and those not undergoing surgery or surgery combined with radiotherapy (P < .001) showed lower survival rates. CONCLUSION: The pediatric patients present a high frequency of malignant salivary neoplasms and a high overall survival rate.

Burkitt lymphoma of the head and neck: An international collaborative study.

BACKGROUND: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma with three variants (endemic, sporadic, and immunodeficiency-associated), presenting with specific epidemiological and clinical features. Burkitt lymphoma affects the head and neck region (BLHN) in approximately 10% of cases. The aim of this study was to undertake a comparative analysis of the clinicopathologic and immunohistochemical (IHC) features of BLHN diagnosed in patients from Africa, Guatemala, and Brazil. METHODS: Cases diagnosed as BLHN were collected from the files of six oral pathology laboratory services (Brazil, South Africa, and Guatemala) and one Brazilian pediatric oncology hospital from 1986 to 2020. Clinicopathological and IHC data, and Epstein-Barr virus (EBV) status by in situ hybridization data for each case were reviewed and described. RESULTS: Of the 52 cases, BLHN was predominant in pediatric patients [43 (82.69%)] and males [43 (82.69%)], with a mean age of 11.26 ± 9.68 years (range, 1-39 years). Neck and cervical lymph nodes [14 (26.92%)], and involvement of both maxilla and mandible [8 (15.38%)], were the most common anatomical sites. Clinically, tumor/swelling [40 (31.25%)], cervical lymphadenopathy [14 (10.94%)], pain [12 (9.38%)], and bone destruction [12 (9.38%)] were frequent findings. All cases showed typical morphological characteristics of BL. IHC profiles included positivity for CD20 [52 (100%)], CD10 [38 (79.17%)], Bcl6 [29 (87.88%)], and c-Myc protein [18 (81.82%)]. EBV was positive in 18 cases (62.07%). The Ki-67 index ranged from 90 to 100%. CONCLUSION: The clinicopathological and EBV profile of BLHN in South African, Guatemalan, and Brazilian patients is similar.

Human papillomavirus (HPV) can establish productive infection in dysplastic oral mucosa, but HPV status is poorly predicted by histological features and p16 expression.

AIMS: Previous studies have reported the presence of high-risk human papillomavirus (HR-HPV) in a subset of dysplastic oral epithelial lesions. Many cases show a histological spectrum of atypia similar to that seen in non-human papillomavirus (HPV) severe epithelial dysplasia, but some studies have suggested that HPV status can be inferred on the basis of histological features. We aimed to assess the utility of such histological features and p16 as surrogate markers of HPV infection in a retrospective cohort of 33 cases of severe epithelial dysplasia, with matched clinicopathological data and histological features. METHODS AND RESULTS: Tissue sections were assessed for the expression of p16, minichromosome maintenance 2, HPV E4 and HPV L1 by the use of immunohistochemistry. HPV16/18 E6 and E7 expression was assessed by the use of RNA in-situ hybridisation (RNAScope). In the cohort, 18.2% of cases (6/33) were HR-HPV-positive, with no age/gender differences between the HPV-positive and HPV-negative groups. HPV E4 and HPV L1 were expressed in surface keratinocytes in four of six (66%) HPV-positive cases, indicative of productive HPV infection. Lack of p16 expression was predictive of HPV-negative status, but sensitivity and specificity varied according to the cut-off. Histologically, the presence of karyorrhectic nuclei and abnormal mitotic figures was higher in HPV-positive lesions (P < 0.05), but the predictive specificity and sensitivity were suboptimal (sensitivity, 0.75; specificity, 0.52). CONCLUSIONS: This study demonstrates, for the first time, that a minority of severely dysplastic oral lesions harbour productive, biologically relevant HPV infection. Consideration should be given to the specific assessment of HPV status in severe epithelial dysplasia cases, as both p16 status and the presence of karyorrhectic cells are poor predictive markers of HPV status.

Malignant transformation of craniomaxillofacial fibro-osseous lesions: A systematic review.

The purpose of this study was to perform a systematic review of the literature concerning all documented cases of malignant transformation of craniomaxillofacial fibro-osseous lesions (FOLs). Three electronic databases were searched. Data were evaluated descriptively. Kaplan-Meier survival curves were constructed and compared using the log-rank test. A critical appraisal of included articles was performed through the Joanna Briggs Institute tool. A total of 19 studies including 27 patients were selected for data extraction. Twenty-six cases were initially diagnosed as fibrous dysplasia and one as ossifying fibroma. The mean age at the time of malignant transformation was 38.11 years, and the average time from initial diagnosis to malignant transformation was 18.2 years. The male:female ratio was 1:1.2, and the maxilla:mandible ratio was 1.5:1. The histological type of the malignant tumor was predominantly osteosarcoma. Follow-up was available for 21 patients. The 3-year overall survival rate was 51%. Mandible tumors and diagnoses other than osteosarcoma tended to have poor survival rates, but no significant difference was identified. We concluded that between all FOLs, only fibrous dysplasia seems to have a considerable increased risk of malignant transformation. Thus, a regular and long follow-up period is advised.

Different patterns of expression of cell cycle control and local invasion-related proteins in oral squamous cell carcinoma affecting young patients.

OBJECTIVES: Oral squamous cell carcinoma (OSCC) predominantly affects males in the fifth decade of life; nevertheless, an increased incidence in young patients has been reported worldwide, and the clinical and behavioral characteristics of tumors in this group are controversial, and the literature shows divergent results. PURPOSE: To investigate the clinicopathological features and prognostic significance of the immunoexpression of cell cycle and local invasion proteins in OSCC affecting young patients (≤40 years old). METHODS: A tissue microarray was performed with 132 OSCC samples (61 cases of young patients vs 71 cases of elderly patients) and submitted to immunohistochemical reactions with Ki67, p53, p16, Bcl-2, Cyclin D1, C-ErbB2, p21, Myc, EGFR, MMP-9, SMA, Cathepsin K and FGF-2 antibodies. RESULTS: Clinicopathological features and survival rates were similar in both groups. Although overexpression of EGFR (P=.042) and MMP-9 (P=.001) was more frequent in young patients, only C-ErbB-2 (P=.048) and SMA (P=.048) expression correlated with lower disease-free survival (DFS) in this group of patients. CONCLUSION: Clinicopathological features and survival rates are similar between younger and older patients with OSCC. The different patterns of C-ErbB2, EGFR, MMP-9, and SMA expression between the groups merits further investigation to understand their role in the early tumor onset in young patients.

Molecular signature of salivary gland tumors: potential use as diagnostic and prognostic marker.

Salivary gland tumors are a highly heterogeneous group of lesions with diverse microscopic appearances and variable clinical behavior. The use of clinical and histological parameters to predict patient prognosis and survival rates has been of limited utility, and the search for new biomarkers that could not only aid in a better understanding of their pathogenesis but also be reliable auxiliaries for prognostic determination and useful diagnostic tools has been performed in the last decades with very exciting results. Hence, gene rearrangements such as CRTC1-MAML2 in mucoepidermoid carcinomas have shown excellent specificity, and more than that, it has been strongly correlated with low-grade tumors and consequently with an increased survival rate and better prognosis of patients affected by neoplasms carrying this translocation. Moreover, MYB-NFIB and EWSR1-ATF1 gene fusions were shown to be specifically found in cases of adenoid cystic carcinomas and hyalinizing clear cell carcinomas, respectively, in the context of salivary gland tumors, becoming reliable diagnostic tools for these entities and potential therapeutic targets for future therapeutic protocols. Finally, the identification of ETV6-NTRK3 in cases previously diagnosed as uncommon acinic cell carcinomas, cystadenocarcinomas, and adenocarcinomas not otherwise specified led to the characterization of a completely new and now widely accepted entity, including, therefore, mammary analogue secretory carcinoma in the list of well-recognized salivary gland carcinomas. Thus, further molecular investigations of salivary gland tumors are warranted, and the recognition of other genetic abnormalities can lead to the acknowledgment of new entities and the acquirement of reliable biomarkers.

Immunoexpression of hoxb7 and hoxb9 in salivary gland tumours.

BACKGROUND: Salivary gland carcinomas are uncommon neoplasms and the identification of new prognostic indicators could improve their management. HOXB7 and HOXB9 are members of the class I homeobox-containing genes important for normal embryogenesis and that are dysregulated in several human neoplasms. This study investigated HOXB7 and HOXB9 expressions in salivary gland tumourigenesis, their correlation with neoplastic proliferative and angiogenic features and their importance as prognostic markers. METHODS: A hundred and fifty salivary gland tumours were organized in tissue microarray and expressions of CD105, Ki67, HOXB7 and HOXB9 were determined through immunohistochemistry. Reactions were quantified and correlated with clinicopathological parameters. RESULTS: In normal glands, HOXB7 was found in basal cells, whereas HOXB9 was seen in serous acinar and scattered ductal cells. Malignancies exhibited an increased vascular density, proliferative index, HOXB7 and HOXB9 expressions when compared with pleomorphic adenoma and Warthin's tumour. Significant correlation was found between HOXB7 and CD105 (P = 0.004) in adenoid cystic carcinomas, and HOXB7 higher expression significantly correlated with the presence of paresthesia (P = 0.02). No marker exhibited a significant association with survival rates (P > 0.05). CONCLUSION: HOXB7 and HOXB9 were expressed in normal salivary gland and were present in benign and malignant tumours derived from these structures, and HOXB7 significantly correlated with neoangiogenesis in AdCC. These findings suggest that both proteins might play a role in salivary gland tumourigenesis, but they were not significant prognostic determinants in this sample.

Semaphorins and neuropilins expression in salivary gland tumors.

BACKGROUND: Salivary gland tumors (SGT) account for 3-10% of all head and neck neoplasms, and little is known about their angiogenic properties. Despite semaphorins and neuropilins have been demonstrated to be prognostic determinants in many human cancers, they remain to be investigated in SGT. Therefore, the objective of this study was to analyze the clinical significance of the expression of class 3 semaphorins A (Sema3A) and B (Sema3B) and neuropilins-1 (Np-1) and neuropilins-2 (Np-2), in SGT. METHODS: Two hundred and forty-eight SGT were organized in tissue microarray paraffin blocks and expression of CD34, Sema3A, Sema3B, Np-1, and Np-2 was determined through immunohistochemistry. The immunoreactions were quantified using digital algorithms and the results correlated with clinicopathological parameters. RESULTS: Malignant tumors had an increased vascular density than their benign counterparts and their increased vascular area significantly correlated with recurrences (P < 0.05). Patients older than 40 years and the presence of recurrences determined an inferior survival rate (P = 0.0057 and P = 0.0303, respectively). In normal salivary glands, Np-1 and Np-2 expression was restricted to ductal cells, whereas Sema3A and Sema3B were positive in the serous acinar compartment. Tumors were positive for all markers and the co-expression of Np-1/Np-2 significantly correlated with the presence of paresthesia and advanced stages of the tumors (P = 0.01 and P = 0.04, respectively). CONCLUSION: Sema3A, Sema3B, Np-1, and Np-2 may be involved in the pathogenesis of SGT, but their expression did not present a statistically significant prognostic potential in this study.

Demystifying oral epithelial dysplasia: a histological guide.

Oral epithelial dysplasia is a histologically diagnosed potentially premalignant disorder of the oral mucosa, which carries a risk of malignant transformation to squamous cell carcinoma. The diagnosis and grading of oral epithelial dysplasia is challenging, with cases often referred to specialist oral and maxillofacial pathology centres for second opinion. Even still there is poor inter-examiner and intra-examiner agreement in a diagnosis. There are a total of 28 features of oral epithelial dysplasia listed in the 5th edition of World Health Organization classification of tumours of the head and neck. Each of these features is poorly defined and subjective in its interpretation. Moreover, how these features contribute to dysplasia grading and risk stratification is even less well defined. This article discusses each of the features of oral epithelial dysplasia with examples and provides an overview of the common mimics, including the normal histological features of the oral mucosa which may mimic atypia. This article also highlights the paucity of evidence defining these features while offering suggested definitions. Ideally, these definitions will be refined, and the most important features identified to simplify the diagnosis of oral epithelial dysplasia. Digital whole slide images of the figures in this paper can be found at: https://www.pathogenesis.co.uk/r/demystifying-dysplasia-histology-dataset.

High incidence of DNA ploidy abnormalities and increased Mcm2 expression may predict malignant change in oral proliferative verrucous leukoplakia.

AIMS: To assess the DNA content of cases of oral proliferative verrucous leukoplakia (PVL) and correlate the DNA ploidy findings with the expression of Mcm2, geminin, and Ki67, and with clinicopathological data. METHODS AND RESULTS: DNA quantification was performed by image cytometry using the ACIS III Automated Cellular Imaging System. Expression of Ki67, Mcm2 and geminin was determined by immunohistochemistry. There were 21 cases of PVL, the female/male ratio was 6:1, and the average age was 65.5 years. Seventeen patients (81.0%) did not report tobacco and alcohol consumption. Nine patients (42.9%) developed verrucous or squamous cell carcinoma. Levels of Mcm2 expression showed a positive correlation with increasingly severe epithelial changes (P = 0.03). Twenty patients had their DNA examined by ACIS III, and 19 (95%) showed aneuploidy. The frequency and severity of aneuploidy (P < 0.0001), the mean values of the DNA heterogeneity index (P < 0.0001) and the 5n-exceeding fractions (P = 0.0007) increased according to epithelial alterations. Abnormal DNA content was observed even in the more indolent lesions. CONCLUSIONS: Mcm2 expression and DNA ploidy analysis could be used to predict areas of malignant transformation. The clinicopathological findings associated with the immunohistochemical and DNA ploidy results support the distinct and aggressive profile of this entity.

A review of paediatric oral and maxillofacial pathology.

This review aims to summarise common paediatric oral and maxillofacial pathology. It will focus on lesions that have a particular predilection for children, lesions that impart significant morbidity or rare and important entities which paediatric specialists may be less familiar with. Although the vast majority of pathology encountered will be benign or require minimal intervention, there are also lesions that may require urgent referral to an appropriate specialist, multidisciplinary team care and significant surgery. Recognition and appreciation of the clinicopathological features should facilitate an appreciation that the growth, anatomy, physiology or relationship of the maxillofacial structures may have been altered by the pathological entity or treatment received.

Epithelial salivary gland tumors in pediatric patients: An international collaborative study.

OBJECTIVE: Salivary gland tumors (SGT) are a diverse group of uncommon neoplasms that are rare in pediatric patients. This study aimed to characterize the clinicopathological profile of pediatric patients affected by SGT from a large case series derived from an international group of academic centers. STUDY DESIGN: A retrospective analysis of pediatric patients with SGT (0-19 years old) diagnosed between 2000 and 2021 from Brazil, South Africa, and the United Kingdom was performed. SPSS Statistics for Windows was used for a quantitative analysis of the data, with a descriptive analysis of the clinicopathological characteristics and the association between clinical variables and diagnoses. RESULTS: A total of 203 cases of epithelial SGT were included. Females were slightly more commonly (56.5%), with a mean age of 14.1 years. The palate was the most common site (43.5%), followed by the parotid gland (29%), lip (10%), and submandibular gland (7.5%). The predominant clinical presentation was a flesh-colored, smooth, and painless nodule. Pleomorphic adenoma (PA) was the most frequently diagnosed SGT (58.6%), followed by mucoepidermoid carcinoma (MEC) (26.6%). Surgery (90.8%) was the favored treatment option. CONCLUSIONS: Benign SGT in pediatric patients are more commonly benign than malignant tumors. Clinicians should keep PA and MEC in mind when assessing nodular lesions of possible salivary gland origin in pediatric patients.

Oestrogen receptor ß in adenoid cystic carcinoma of salivary glands.

AIMS: This study aimed to describe the expression of oestrogen receptor (ER)α, ERß and aromatase in salivary gland adenoid cystic carcinoma (ACC). METHODS AND RESULTS: ERα, ERß and aromatase expression was analysed by immunohistochemistry in tissue microarray blocks from 38 cases of ACC and seven normal salivary glands. The intracellular localization and amount of total protein expression were investigated by immunofluorescence and western blotting in an ACC cell line. Western blotting analysis showed overexpression of ERα, ERß and aromatase in the ACC cell line; however, with immunofluorescence, only ERß was shown to be expressed in the nucleus. Immunohistochemistry revealed positive nuclear expression of ERß, positive cytoplasmic expression of aromatase and a lack of ERα expression as compared with normal salivary glands. CONCLUSIONS: The nuclear expression of ERß indicates that oestrogen may be active in ACC and possibly able to mediate E2-targeted gene transcription. This study strongly suggests that ERß may be involved in tumour progression, playing a role in tumour development, and thus corroborating the indication for ER antagonists in the clinical control of ACC. This study opens a new perspective on the potential use of anti-oestrogens and aromatase inhibitors as therapeutic agents against ACC.

Histopathological features that predict the recurrence of odontogenic keratocysts.

BACKGROUND: Odontogenic keratocysts (OKCs) constitute between 1.8% and 21.5% of odontogenic cysts and are associated with higher propensity to recur than other odontogenic cysts following surgical removal. Previous studies have been performed to identify clinico-pathological predictive factors in relation to such behaviour. The relationship between the presence of hyalinisation and recurrence of the OKC has not been explored. METHODS: A total of 110 OKCs were selected, comprising 53 non-recurrent cases, 50 cases known to subsequently recur and seven syndromic cases. Cases were examined blind, and histological assessment of the epithelial lining, connective tissue capsule and cyst lumen was made. Statistical analysis was completed using Pearson Chi-square, Fisher's exact test and logistic regression analysis. RESULTS: Subepithelial hyalinisation of the underlying connective tissue capsule (P = 0.006) was significantly more common in OKC that recurred. Recurring cysts demonstrating hyalinisation were seen in a younger age group (mean = 40.8 years) than the non-recurrent cysts (mean = 56.4 years). In addition, subepithelial splitting (P = 0.015) and the position of mitotic figures (P = 0.033) were more common in recurring cysts. CONCLUSION: In this case series, several differences were found in relation to histological features of recurring and non-recurring OKCs. There are many factors responsible for the high recurrence rate of OKCs, and the presence of subepithelial hyalinisation may be used as an additional histopathological feature to predict a greater tendency for recurrence.

Expression pattern of PLUNC proteins as an auxiliary tool for the diagnosis of high-grade mucoepidermoid carcinoma of the salivary gland.

BACKGROUND: Mucoepidermoid carcinomas are the most frequent malignant neoplasia of the salivary glands and are histologically classified as low, intermediate, and high grade. At present, histochemical stains such as periodic acid-Schiff or mucicarmine are useful tools in making a diagnosis. Recently, expression of the PLUNC proteins has been described in mucin-producing salivary gland tumors, with the suggestion that they could provide a powerful tool for the diagnosis of difficult cases. METHODS: This study evaluates the expression of PLUNC proteins in 30 cases of salivary gland mucoepidermoid carcinomas. Tumors were reviewed and classified according to histological grade. Periodic acid-Schiff, mucicarmine, and immunohistochemical staining for SPLUNC1, LPLUNC1, SPLUNC2, and LPLUNC2 were carried out. Immunostaining was classified as positive or negative. RESULTS: The majority of the tumors (63%) were classified as low grade, 13% were intermediate grade, and 23% were high grade. SPLUNC1 (90%) and LPLUNC1 (93%) were positive in the majority of cases, mainly in mucous cells, mucin plugs, and intermediate cells. SPLUNC2 and LPLUNC2 did not present significative expression within the tumors; however, LPLUNC2 was found to stain positively in mast cells in 83% of the samples. CONCLUSIONS: SPLUNC1 and LPLUNC1 showed a similar pattern of expression and could prove useful in the diagnosis of high-grade cases because of the differential staining in intermediate and epidermoid cells. The expression of LPLUNC2 in mast cells has not previously been reported, but further studies are necessary to validate this finding and to determine its significance.

Human papillomavirus and head and neck squamous cell carcinoma in a UK population: Is there an association?

Background: Human papillomavirus (HPV) is an evolving important risk factor for head and neck cancer (HNC), especially for individuals who do not smoke and drink alcohol. The aim of this study was to establish the prevalence of HPV infection and elucidate its association with head and neck squamous cell carcinoma (HNSCC) patients in UK population. Methods: The presence and association of HPV was investigated in HNSCC patients in this retrospective clinical study. Samples were obtained from archived biopsies and resections. HPV screening was performed by the use of polymerase chain reaction (PCR) using the GP5+/GP6+ and the SPF1/2 consensus as primers and by immunohistochemistry (IHC). Samples of viral warts that were IHC positive for HPV and fibroepethelial polyps (FEP) were used, as positive and negative controls, respectively. Results: The cohort included 124 patients with HNSCC with an age range of 27-97 years (median, 60 years) and a male to female ratio of 2:1. Among the 124 HNSCC, 43/124 (34.7%) were from the tongue, 74/124 (60%) presented with advanced stage III or IV disease, 112/124 (90%) had a conventional phenotype, 84/124 (68%) were moderately differentiated, and 89/124 (72%) had bands or cords at the invasive front. Of the 124 patients with HNSCC, 84/124 (68%) demonstrated the presence of HPV, 0/124 (0%) was for oral squamous cell carcinomas (OSCC). HPV16 was the associated virus type in all positive samples. However, no significant association was observed between HPV positivity and other clinico-pathological variables including age and gender of the patients, stage, and malignancy differentiation. Conclusion: The results we provide suggest that HPV infection is low in HNSCC, in general, and absent in OSCC, specifically, in this UK population during this time period. This implies that HPV infection may not play an important role in HNSCC carcinogenesis compared to other risk factors in UK population. This information can aid in more effective treatment approaches for treating UK cases of HNSCC.

Keratoameloblastoma: A Report of Seven New Cases and Review of Literature.

BACKGROUND: Keratoameloblastoma (KA) is an uncommon and controversial variant of ameloblastoma exhibiting central keratinisation. Due to their rarity, there is limited information in the literature on their clinical, radiologic and histologic features. This study adds seven additional cases of KA to the literature, and reviews the current published literature on this rare entity. METHODS: KAs were retrospectively reviewed over a 20-year period from three Oral and Maxillofacial Pathology Laboratories. Included cases were examined and the diagnosis confirmed under conventional microscopy. Immunohistochemistry with the use of a monoclonal antibody against calretinin was performed on included cases. The clinical, radiologic and histologic features of the seven new cases of KA were analysed and compared to existing cases in the literature. RESULTS: KAs presented at a mean age of 40 years with a nearly equal gender distribution and a mandibular predilection (65%). The majority (92%) of cases presented with localised swelling with associated pain in 32% of cases. Mixed density or internal calcifications were noted in 40% of cases. All tumours presented with bony expansion, with cortical destruction noted in 62% of cases. Histologically, all tumours consisted of solid and cystic follicles with surface parakeratinisation and lamellated accumulations of central keratin. In areas the cystic follicles had an epithelial lining suggestive of an OKC. There were focal luminal areas of loosely arranged polygonal cells reminiscent of the stellate reticulum. The basal cells consisted of columnar cells with evidence of palisading and prominent subnuclear vacuolisation. Of the cases treated via tumour resection, 27% presented with tumour recurrence. CONCLUSION: This case series reports seven additional cases of KA, taking the total to 26 reported cases. The identification of subtle histologic features, including focal stellate reticulum-like central areas, subnuclear vacuolisation and lamellated-type central keratinisation, are key in diagnosing KA. The radiologic features will often indicate signs of aggressiveness such as cortical destruction, differentiating KA from OKC. All cases were completely negative for calretinin IHC, limiting its use in distinguishing KA from OKC. Further large series are needed to expand the current understanding of this rare variant of ameloblastoma.

High incidences of DNA ploidy abnormalities in tongue squamous cell carcinoma of young patients: an international collaborative study.

AIMS: This multi-centre analysis assessed the DNA content of TSCC in 37 young patients (<40 years) and 28 old patients (>50 years) and determined the correlation of DNA ploidy findings with clinicopathological data. METHODS AND RESULTS: Image cytometry was carried out using an automated cellular imaging system on Feulgen-stained histological sections to obtain high-fidelity DNA histograms. Among young patients, 37.8% were females compared to 18.7% in the older group (P=0.002). In total, 48.6% patients were non-smokers and 40.5% were non-drinkers compared to 10.7% non-smokers and non-drinkers in the older group (P<0.0001). TNM, clinical stage of disease and histological grade of differentiation did not differ between groups. Tumour aneuploidy was detected in 86.5% and tetraploidy in 24.3% young patients; this was significantly greater than in the older group where 64.3% were aneuploid (P<0.0001) and 7.2% tetraploid (P<0.0001). The mean values of DNA index (DI) and DNA heterogeneity index as well as the percentage of cells with DI exceeding 5N were higher in young patients (P<0.0001). CONCLUSIONS: Young patients with TSCC represent a distinct clinical entity. The high incidence of DNA ploidy abnormalities suggest that they may have increased genomic instability and indicates underlying genetic differences between TSCC in young and older patients.

The role of α9ß1 integrin in modulating epithelial cell behaviour.

BACKGROUND: Integrins initiate signalling in response to the extracellular matrix (ECM), which is important in wound healing and cancer. Previous studies have shown that over-expression of the αvß6 integrin in oral squamous cell carcinoma (OSCC) cells results in enhanced motility and expression of matrix-degrading proteases, and the aim of this study was to investigate whether this is also the case for the α9ß1 integrin. METHODS: H357 OSCCcells were transfected with the α9 integrin subunit and proliferation, adhesion and migration assays were performed on these along with null vector control and wild-type cells. The effect of ligand engagement on matrix metalloproteinase expression and the plasminogen activator system was measured using ELISA and chromogenic assays. Expression of α9 integrin was examined in oral squamous cell carcinoma tissue by immunohistochemistry. RESULTS: Functionally active α9 integrin mediated specific upregulation of adhesion and migration towards the TNfn3RAA fragment of tenascin-C but reduced proliferation. Migration towards collagen I was also enhanced in transfected cells. Matrix metalloproteinase-2 and metalloproteinase-9 expression was increased upon TNfn3RAA ligand engagement. Cell surface plasmin generation was also enhanced in α9-expressing cells and was the result of enhanced expression of urokinase receptor. In normal oral mucosa, α9 integrin expression was restricted to the suprabasal and prickle cell layers, and expression was heterogeneous in tumours but present in islands infiltrating connective tissue particularly in moderately and well-differentiated lesions. CONCLUSIONS: The α9ß1 integrin may play a key role in modulation of tumour behaviour including enhanced cell migration and expression of matrix-degrading proteases.

CEOT Variants or Entities: Time for a Rethink? A Case Series with Review of the Literature.

The first detailed description of calcifying epithelial odontogenic tumor (CEOT) are ascribed to Jens Pindborg, but this tumor was described some years previously. Subsequently, CEOT was included in the 1971 WHO classification of odontogenic tumors and a since then number of variants have been described, which have added confusion to the diagnostic criteria. We aimed to survey the literature on the variants of CEOT, in parallel with a review of our single institution experience of CEOTs. Cases identified were collated, including available clinical, radiological and histological information and then reviewed, taking into account changes in the understanding and classifications of odontogenic tumors since initial diagnosis. We identified 26 cases from 1975 to 2017 for which histological material was available. Of these, only 13 (50%) showed the "classic" histological appearance, whilst two cases were identified as recognized variants. In 11 cases, other diagnoses or a differential diagnosis were preferred, with no agreed diagnosis in four of these. The proliferation fraction (Ki67) in the 10 cases tested was 2.1% ± 0.18. These findings illustrate the diagnostic challenges in this group of tumors and highlight the gaps in knowledge. Techniques, such as EWSR1 gene cytogenetic analysis, may be helpful in cases with clear cells. However, in other areas of controversy, including the non-calcifying and Langerhans cell rich variants, further investigation, perhaps utilizing sequencing technologies may be needed to refine the classification. Owing to the relative rarity of these lesions it would be beneficial if future work could be pursued as an international collaboration.