Validation of epidermal AMBRA1 and loricrin (AMBLor) as a prognostic biomarker for nonulcerated American Joint Committee on Cancer stage I/II cutaneous melanoma.

BACKGROUND: Combined expression of the autophagy-regulatory protein AMBRA1 (activating molecule in Beclin1-regulated autophagy) and the terminal differentiation marker loricrin in the peritumoral epidermis of stage I melanomas can identify tumour subsets at low risk of -metastasis. OBJECTIVES: To validate the combined expression of peritumoral AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. METHODS: Automated immunohistochemistry was used to analyse peritumoral AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of nonulcerated American Joint Committee on Cancer (AJCC) stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. RESULTS: Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low-risk group vs. 81.7% in the AMBLor at-risk group (multivariate log-rank, P < 0.001) and a negative predictive value (NPV) of 96.0%. In the validation cohort, AMBLor analysis revealed a RFS rate of 97.6% in the AMBLor low-risk group vs. 78.3% in the at-risk group (multivariate log-rank, P < 0.001) and a NPV of 97.6%. In a multivariate model considering AMBLor, Breslow thickness, age and sex, analysis of the combined discovery and validation cohorts showed that the estimated effect of AMBLor was statistically significant, with a hazard ratio of 3.469 (95% confidence interval 1.403-8.580, P = 0.007) and an overall NPV of 96.5%. CONCLUSIONS: These data provide further evidence validating AMBLor as a prognostic biomarker to identify nonulcerated AJCC stage I and II melanoma tumours at low risk of disease recurrence.

The clinical utility of contemporary oral epithelial dysplasia grading systems.

INTRODUCTION: Clinical management of oral potentially malignant disorders relies on accurate histopathological assessment of the presence and grade of oral epithelial dysplasia. While adjunctive laboratory tests have provided useful prognostic information, none are in widespread clinical use. This study was performed to assess the clinical utility of two contemporary oral epithelial dysplasia grading systems. METHODS: Patients were identified from a clinical database. Oral epithelial dysplasia grading was performed by three oral and maxillofacial pathologists blinded to clinical outcome using the WHO 2017 system and a binary classification. The primary outcome measure was the development of oral squamous cell carcinoma, termed 'malignant transformation'. RESULTS: One hundred thirty-one cases satisfied the inclusion criteria, of which 23 underwent malignant transformation. There was substantial inter-rater agreement between the study pathologists for both grading systems, measured using kappa statistics (κ = 0.753 - 0.784). However, there was only moderate agreement between the consensus WHO 2017 dysplasia grade for the study against the original grade assigned by a pool of six pathologists in the context of the clinical service (κ = 0.491). Higher grade categories correlated with an increased risk of developing cancer using both grading systems. CONCLUSION: This study demonstrates that the WHO 2017 and binary grading systems are reproducible between calibrated pathologists and that consensus reporting is likely to improve the consistency of grading. The WHO and binary systems were prognostically comparable. We recommend that institutions implement consensus oral epithelial dysplasia grading and prospectively audit the effectiveness of risk stratifying their patients with oral potentially malignant disorders. (249 words).

Predicting the clinical outcome of oral potentially malignant disorders using transcriptomic-based molecular pathology.

BACKGROUND: This study was undertaken to develop and validate a gene expression signature that characterises oral potentially malignant disorders (OPMD) with a high risk of undergoing malignant transformation. METHODS: Patients with oral epithelial dysplasia at one hospital were selected as the 'training set' (n = 56) whilst those at another hospital were selected for the 'test set' (n = 66). RNA was extracted from formalin-fixed paraffin-embedded (FFPE) diagnostic biopsies and analysed using the NanoString nCounter platform. A targeted panel of 42 genes selected on their association with oral carcinogenesis was used to develop a prognostic gene signature. Following data normalisation, uni- and multivariable analysis, as well as prognostic modelling, were employed to develop and validate the gene signature. RESULTS: A prognostic classifier composed of 11 genes was developed using the training set. The multivariable prognostic model was used to predict patient risk scores in the test set. The prognostic gene signature was an independent predictor of malignant transformation when assessed in the test set, with the high-risk group showing worse prognosis [Hazard ratio = 12.65, p = 0.0003]. CONCLUSIONS: This study demonstrates proof of principle that RNA extracted from FFPE diagnostic biopsies of OPMD, when analysed on the NanoString nCounter platform, can be used to generate a molecular classifier that stratifies the risk of malignant transformation with promising clinical utility.

Dysplasia and DNA ploidy to prognosticate clinical outcome in oral potentially malignant disorders.

BACKGROUND: Oral potentially malignant disorders are a clinical conundrum as there are no reliable methods to predict their behaviour. We combine conventional oral epithelial dysplasia grading with DNA ploidy analysis to examine the validity of this approach to risk assessment in a cohort of patients with known clinical outcomes. METHODS: Sections from diagnostic biopsies were assessed for oral epithelial dysplasia using the WHO grading system, and DNA ploidy analysis was performed using established methods. Patients reviewed for a minimum of 5 years who did not develop oral squamous cell carcinoma were classified as "non-transforming" cases. Patients that developed oral squamous cell carcinoma ≥ 6 months after the initial diagnostic biopsy were classified as having "malignant transformation." RESULTS: Ninety cases were included in the study. Seventy cases yielded informative DNA ploidy results. Of these 70 cases, 31 progressed to cancer. Oral epithelial dysplasia grading and DNA ploidy status were both significantly associated with clinical outcome (P < 0.05). Severe dysplasia had a hazard ratio of 3.50 (CI: 1.46, 8.45; P = 0.005) compared to cases with mild dysplasia. Aneuploidy had a hazard ratio of 2.09 (CI: 1.01, 4.32; P = 0.046) compared to cases with a diploid/tetraploid status. Receiver operating characteristic analysis gave an area under the curve of 0.617 for DNA ploidy status and 0.688 when DNA ploidy status was combined with dysplasia grading. CONCLUSION: Our findings suggest that combining dysplasia grading with DNA ploidy status has clinical utility which could be used to develop novel management algorithms.

Gene expression changes associated with malignant transformation of oral potentially malignant disorders.

BACKGROUND: A large number of oral squamous cell carcinomas (OSCCs) are believed to be preceded by oral potentially malignant disorders (OPMD) that have an increased likelihood of malignant transformation compared to clinically normal mucosa. This study was performed to identify differentially expressed genes between OPMDs that underwent malignant transformation (MT) and those that did not, termed "non-transforming" (NT) cases. METHODS: Total RNA was extracted from formalin-fixed paraffin-embedded tissue biopsies of 20 OPMD cases with known clinical outcomes (10 MT vs. 10 NT). Samples were assessed for quantity, quality and integrity of RNA prior to sequencing. Analysis for differential gene expression between MT and NT was performed using statistical packages in R. Genes were considered to be significantly differentially expressed if the False Discovery Rate corrected P-value was < 0.05. RESULTS: RNA yield was variable but RNA purity was good (A260/A280 > 1.90). Analysis of RNA-Sequencing outputs revealed 41 genes (34 protein-coding; 7 non-coding) that were significantly differentially expressed between MT and NT cases. The log2 fold change for the statistically significant differentially expressed genes ranged from -2.63 to 2.48, with 23 protein-coding genes being downregulated and 11 protein-coding genes being upregulated in MT cases compared to NT cases. CONCLUSION: Several candidate genes that may play a role in malignant transformation of OPMD have been identified. Experiments to validate these candidates are underway. It is anticipated that this work will contribute to better understanding of the etiopathogenesis of OPMD and development of novel biomarkers.

Oral epithelial dysplasia: Recognition, grading and clinical significance.

Histopathological grading of epithelial dysplasia remains the principal laboratory method for assessing the risk of malignant transformation in oral potentially malignant disorders (OPMDs). Current views on the molecular pathogenesis and histological interpretation of the features of epithelial dysplasia are described, and the use of grading systems for epithelial dysplasia is discussed. Changes to the current 2017 WHO criteria for diagnosis are proposed with emphasis on the architectural features of epithelial dysplasia. The predictive values of three-grade and binary systems are summarised, and categories of epithelial dysplasia are reviewed, including lichenoid and verrucous lesions, keratosis of unknown significance, HPV-associated dysplasia, differentiated and basaloid epithelial dysplasia. The implications of finding epithelial dysplasia in an oral biopsy for clinical management are discussed from the pathologists' viewpoint.

Oral potentially malignant disorders: A consensus report from an international seminar on nomenclature and classification, convened by the WHO Collaborating Centre for Oral Cancer.

Oral potentially malignant disorders (OPMDs) are associated with an increased risk of occurrence of cancers of the lip or oral cavity. This paper presents an updated report on the nomenclature and the classification of OPMDs, based predominantly on their clinical features, following discussions by an expert group at a workshop held by the World Health Organization (WHO) Collaborating Centre for Oral Cancer in the UK. The first workshop held in London in 2005 considered a wide spectrum of disorders under the term "potentially malignant disorders of the oral mucosa" (PMD) (now referred to as oral potentially malignant disorders: OPMD) including leukoplakia, erythroplakia, proliferative verrucous leukoplakia, oral lichen planus, oral submucous fibrosis, palatal lesions in reverse smokers, lupus erythematosus, epidermolysis bullosa, and dyskeratosis congenita. Any new evidence published in the intervening period was considered to make essential changes to the 2007 classification. In the current update, most entities were retained with minor changes to their definition. There is sufficient evidence for an increased risk of oral cancer among patients diagnosed with "oral lichenoid lesions" and among those diagnosed with oral manifestations of 'chronic graft-versus-host disease'. These have now been added to the list of OPMDs. There is, to date, insufficient evidence concerning the malignant potential of chronic hyperplastic candidosis and of oral exophytic verrucous hyperplasia to consider these conditions as OPMDs. Furthermore, due to lack of clear evidence of an OPMD in epidermolysis bullosa this was moved to the category with limited evidence. We recommend the establishment of a global research consortium to further study the natural history of OPMDs based on the classification and nomenclature proposed here. This will require multi-center longitudinal studies with uniform diagnostic criteria to improve the identification and cancer risk stratification of patients with OPMDs, link them to evidence-based interventions, with a goal to facilitate the prevention and management of lip and oral cavity cancer.

Developing and Validating a Multivariable Prognostic-Predictive Classifier for Treatment Escalation of Oropharyngeal Squamous Cell Carcinoma: The PREDICTR-OPC Study.

PURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.

Sinonasal Amoebiasis: An Unexpected Cause of Sinonasal Necroinflammatory Disease.

While amoebic infection is widely known as a cause of gastroenteritis, keratitis, and meningoencephalitis, amoebae are challenging to recognize at unexpected sites. Despite multiple case reports of sinonasal amoebiasis, amoebic infection is not regularly considered in the differential diagnosis of sinonasal necroinflammatory disease. Here, we aim to characterize the pathologic features of sinonasal amoebiasis to facilitate better recognition. We identified sinonasal amoebiasis in 4 men, median age of 67 years (range: 37 to 71 y). All were immunocompromised, including 2 with chronic lymphocytic leukemia, 1 with human immunodeficiency virus, and 1 with human immunodeficiency virus and kidney transplant. Patients presented with nasal mucosal necrosis or polypoid masses, with facial ulceration in 1 patient and distant dermal nodules in another. Biopsies displayed extensive necrotic debris and inflammation. Although amoebic cysts were abundant in 3 cases, they were mistaken for yeast at frozen section in 1 case; 1 case showed only rare trophozoites that were not recognized on initial biopsy. Periodic acid Schiff and Grocott Methenamine Silver stains highlighted the organisms, and polymerase chain reaction confirmed Acanthamoeba species in 3 cases tested. 2 patients responded well to antiprotozoal medications, but 2 died of disease. Overall, sinonasal amoebiasis presents as a necroinflammatory process in patients immunocompromised for various reasons. Amoebae can mimic other organisms or be incredibly scarce, requiring active consideration to recognize amoebiasis and differentiate it from overlapping conditions like invasive fungal sinusitis, granulomatosis with polyangiitis, and natural killer/T-cell lymphoma. Because sinonasal amoebiasis is highly treatable when diagnosed promptly, pathologists play a critical role in the recognition of this rare necroinflammatory disease.

A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer.

PURPOSE: Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer. PATIENTS AND METHODS: This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics. RESULTS: During dose escalation, 40 patients received AZD3965 at 5-30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity. CONCLUSIONS: AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

Oral brush biopsy using liquid-based cytology is a reliable tool for oral cancer screening: A cost-utility analysis: Oral brush biopsy for oral cancer screening.

BACKGROUND: This study aimed to assess the diagnostic utility and associated cost of oral liquid-based brush cytology (OLBC) in the diagnosis of oral cancer and oral potentially malignant disorders (OPMDs). METHODS: A total of 284 patients with oral mucosal lesions were included. OLBC samples were collected from all patients immediately before undergoing surgical biopsies. A liquid-based cytology slide was prepared from each OLBC sample for cytological evaluation using the modified 2014 Bethesda cytology system. The results and the cost were compared with the histopathological outcomes. RESULTS: The level of agreement between the two approaches was very good (weighted kappa = 0.824). The accuracy of OLBC in differentiating between the different diagnostic groups was 91.69%, whereas the associated sensitivity and specificity were 79.23% and 94.81%, respectively. The estimated cost of each OLBC sample was at least 26% less than the cost of a single biopsy and more than 42% less in cases of multiple biopsied lesions. CONCLUSIONS: The proposed modifications of the Bethesda system can be adopted as a standardized system for oral cytological assessment. Our findings support OLBC as a reliable adjunct to surgical biopsy in the diagnosis of OPMDs. This tool has potential for oral cancer-finding and surveillance programs.

Interventions for the treatment of oral and oropharyngeal cancers: surgical treatment.

BACKGROUND: Surgery is an important part of the management of oral cavity cancer with regard to both the removal of the primary tumour and removal of lymph nodes in the neck. Surgery is less frequently used in oropharyngeal cancer. Surgery alone may be treatment for early stage disease or surgery may be used in combination with radiotherapy, chemotherapy and immunotherapy/biotherapy. There is variation in the recommended timing and extent of surgery in the overall treatment regimens of people with these cancers. OBJECTIVES: To determine which surgical treatment modalities for oral cavity and oropharyngeal cancers result in increased overall survival, disease free survival, progression free survival and reduced recurrence. SEARCH STRATEGY: The following electronic databases were searched: the Cochrane Oral Health Group Trials Register (to 17 February 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), MEDLINE via OVID (1950 to 17 February 2011) and EMBASE via OVID (1980 to 17 February 2011). There were no restrictions regarding language or date of publication. SELECTION CRITERIA: Randomised controlled trials where more than 50% of participants had primary tumours of the oral cavity or oropharynx, and which compared two or more surgical treatment modalities or surgery versus other treatment modalities. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of risk of bias was undertaken independently by two or more review authors. Study authors were contacted for additional information as required. Adverse events data were collected from published trials. MAIN RESULTS: Seven trials (n = 669; 667 with cancers of the oral cavity) satisfied the inclusion criteria, but none were assessed as low risk of bias. Trials were grouped into three main comparisons. Four trials compared elective neck dissection (ND) with therapeutic neck dissection in patients with oral cavity cancer and clinically negative neck nodes, but differences in type of surgery and duration of follow-up made meta-analysis inappropriate. Three of these trials reported overall and disease free survival. One trial showed a benefit for elective supraomohyoid neck dissection compared to therapeutic ND in overall and disease free survival. Two trials found no difference between elective radical ND and therapeutic ND for the outcomes of overall survival and disease free survival. All four trials found reduced locoregional recurrence following elective ND.A further two trials compared elective radical ND with elective selective ND and found no difference in overall survival, disease free survival or recurrence. The final trial compared surgery plus radiotherapy to radiotherapy alone but data were unreliable because the trial stopped early and there were multiple protocol violations.None of the trials reported quality of life as an outcome. Two trials, evaluating different comparisons reported adverse effects of treatment. AUTHORS' CONCLUSIONS: Seven included trials evaluated neck dissection surgery in patients with oral cavity cancers. The review found weak evidence that elective neck dissection of clinically negative neck nodes at the time of removal of the primary tumour results in reduced locoregional recurrence, but there is insufficient evidence to conclude that elective neck dissection increases overall survival or disease free survival compared to therapeutic neck dissection. There is very weak evidence from one trial that elective supraomohyoid neck dissection may be associated with increased overall and disease free survival. There is no evidence that radical neck dissection increases overall survival compared to conservative neck dissection surgery. Reporting of adverse events in all trials was poor and it was not possible to compare the quality of life of patients undergoing different surgeries.

Morphological and p40 immunohistochemical analysis of squamous differentiation in endoscopic ultrasound guided fine needle biopsies of pancreatic ductal adenocarcinoma.

The basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and upregulation in TP63ΔN (p40) network. Adenosquamous histology can be observed. This study assessed immunohistochemical p40 expression in fine needle biopsy (FNB) samples with PDAC and association with cytomorphological features of squamous differentiation and clinical data. 106 EUS FNBs with PDAC were assessed for eight cytomorphological features of squamous differentiation. P40 H-score (intensity 0-3 × percentage positive nuclei) was analysed for association with morphological features, patient age, gender, operability, chemotherapy and survival. P40 H-score in 14 paired FNBs and resections was compared. P40 h-score was 1-3 in 31%, 4-30 in 16% and > 30 in 13% of FNBs. It was significantly associated with intercellular bridges, elongated cell shape, sharp cell borders, angular nuclei with homogenous chromatin (p < 0.001) and dense cytoplasm (p = 0.002). Keratinisation was not seen. Inoperable patients (n = 81) had a shorter median survival for h-score > 30 (n = 9, 1.8 months) than for h-score ≤ 30 (n = 66, 6.7 months) not quite reaching statistical significance (p = 0.08). P40 was significantly associated with squamous morphology in FNBs with PDAC. P40 H-score > 30 showed a trend towards shorter survival in inoperable patients. Squamous differentiation may be a treatment target in PDAC.

A Novel Combination of Blood Biomarkers and Clinical Stroke Scales Facilitates Detection of Large Vessel Occlusion Ischemic Strokes.

Acute ischemic stroke caused by large vessel occlusions (LVOs) is a major contributor to stroke deaths and disabilities; however, identification for emergency treatment is challenging. We recruited two separate cohorts of suspected stroke patients and screened a panel of blood-derived protein biomarkers for LVO detection. Diagnostic performance was estimated by using blood biomarkers in combination with NIHSS-derived stroke severity scales. Multivariable analysis demonstrated that D-dimer (OR 16, 95% CI 5-60; p-value < 0.001) and GFAP (OR 0.002, 95% CI 0-0.68; p-value < 0.05) comprised the optimal panel for LVO detection. Combinations of D-dimer and GFAP with a number of stroke severity scales increased the number of true positives, while reducing false positives due to hemorrhage, as compared to stroke scales alone (p-value < 0.001). A combination of the biomarkers with FAST-ED resulted in the highest accuracy at 95% (95% CI: 87-99%), with sensitivity of 91% (95% CI: 72-99%), and specificity of 96% (95% CI: 90-99%). Diagnostic accuracy was confirmed in an independent cohort, in which accuracy was again shown to be 95% (95% CI: 87-99%), with a sensitivity of 82% (95% CI: 57-96%), and specificity of 98% (95% CI: 92-100%). Accordingly, the combination of D-dimer and GFAP with stroke scales may provide a simple and highly accurate tool for identifying LVO patients, with a potential impact on time to treatment.

CD56 (NCAM) expression in ameloblastomas and other odontogenic lesions.

AIMS: Ameloblastomas recapitulate certain elements of tooth formation. CD56 is expressed by a variety of cells and is used in tumour diagnosis, but is also expressed in the enamel organ during tooth development. The aim of this study was to describe the expression of CD56 in odontogenic lesions with particular reference to the differential diagnosis of ameloblastoma and odontogenic keratocyst. METHODS: Cases were selected from the pathology archives at Glasgow Royal Infirmary, Glasgow, Royal Victoria Infirmary, Newcastle and Department of Diagnostic Sciences, Texas A&M Health Science Center Baylor College of Dentistry, Dallas. The study population included 38 ameloblastomas, 19 odontogenic keratocysts and a number of other odontogenic lesions, including nine compound odontomes. All sections were examined for CD56 immunoreactivity and the extent of staining was recorded. RESULTS: Thirty-seven of 38 (97%) ameloblastomas expressed CD56 on the cell membrane of peripheral cells in tumour nests (16 extensively, 21 focally). Immunoreactivity was lost in areas of inflammation, acanthomatous differentiation, in areas of cystic change and upon fusion with overlying surface epithelium. One odontogenic keratocyst expressed CD56 (5%, P < 0.0001). CD56 was expressed very focally in two odontomes, exclusively in stratum intermedium-like cells. CONCLUSIONS: CD56 expression in odontogenic epithelium is highly suggestive of ameloblastoma and can help in differentiating this from odontogenic keratocyst.

Screening programmes for the early detection and prevention of oral cancer.

BACKGROUND: Oral cancer is an important global healthcare problem, its incidence is increasing and late-stage presentation is common. Screening programmes have been introduced for a number of major cancers and have proved effective in their early detection. Given the high morbidity and mortality rates associated with oral cancer, there is a need to determine the effectiveness of a screening programme for this disease, either as a targeted, opportunistic or population based measure. Evidence exists from modelled data that a visual oral examination of high-risk individuals may be a cost-effective screening strategy and the development and use of adjunctive aids and biomarkers is becoming increasingly common. OBJECTIVES: To assess the effectiveness of current screening methods in decreasing oral cancer mortality. SEARCH STRATEGY: The following electronic databases were searched: the Cochrane Oral Health Group Trials Register (to 20 May 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), MEDLINE via OVID (1950 to 20 May 2010), EMBASE via OVID (1980 to 20 May 2010) and CANCERLIT via PubMed (1950 to 20 May 2010). There were no restrictions regarding language or date of publication. SELECTION CRITERIA: Randomised controlled trials (RCTs) of screening for oral cancer or potentially malignant disorders using visual examination, toluidine blue, fluorescence imaging or brush biopsy. DATA COLLECTION AND ANALYSIS: The original review identified 1389 citations and this update identified an additional 330 studies, highlighting 1719 studies for consideration. Only one study met the inclusion criteria and validity assessment, data extraction and statistics evaluation were undertaken by six independent review authors. MAIN RESULTS: One 9-year RCT has been included (n = 13 clusters: 191,873 participants). There was no statistically significant difference in the age-standardised oral cancer mortality rates for the screened group (16.4/100,000 person-years) and the control group (20.7/100,000 person-years). A 43% reduction in mortality was reported between the intervention cohort (29.9/100,000 person-years) and the control arm (45.4/100,000) for high-risk individuals who used tobacco or alcohol or both, which was statistically significant. However, this study had a number of methodological weaknesses and the associated risk of bias was high. AUTHORS' CONCLUSIONS: Although there is evidence that a visual examination as part of a population based screening programme reduced the mortality rate of oral cancer in high-risk individuals, whilst producing a stage shift and improvement in survival rates across the population as a whole, the evidence is limited to one study and is associated with a high risk of bias. This was compounded by the fact that the effect of cluster randomisation was not accounted for in the analysis. Furthermore, no robust evidence was identified to support the use of other adjunctive technologies like toluidine blue, brush biopsy or fluorescence imaging within a primary care environment. Further randomised controlled trials are recommended to assess the efficacy, effectiveness and cost-effectiveness of a visual examination as part of a population based screening programme.

Immunohistochemical expression of estrogens and progesterone receptors in carcinoma ex pleomorphic adenoma-undifferentiated and adenocarcinoma types.

UNLABELLED: Cancer of the salivary gland is one of the common cancers in the head and the neck regions. This type of cancer develops in the minor and the major salivary glands, and it sometimes metastasizes to other organs, particularly the lung. Morphologic mimicry and similarity in the expression of steroid hormone receptors between salivary gland tumours and breast tumours are well-known phenomena and are occasionally debated in the field of surgical pathology. The expression of sex hormone receptors in some tumours suggests a role for these receptors in tumor pathogenesis and therapy. Previous studies of the expression of estrogens and progesterone receptors in salivary gland tumours have reported conflicting results. OBJECTIVE: Our study aimed to characterize alteration in the immunohistochemical expression of oestrogens receptor and progesterone receptor in the tumour cells of carcinoma arising in pleomorphic adenoma. STUDY DESIGN: 27 cases of carcinoma arising in pleomorphic adenoma (undifferentiated and adenocarcinoma types) were examined. RESULTS: The results showed that 27 (100 %) of 27 cases had negative nuclear staining for either oestrogens or progesterone receptors. CONCLUSION: Our data suggest that carcinomas arising in pleomorphic adenoma were not dependent on endocrine function.

Quality Assessment Across Disciplines in Head and Neck Cancer Treatment Diagnostic Pathology in HNSCC.

Quality assured pathology services are integral to provision of optimal management for patients with head and neck cancer. Pathology services vary globally and are dependent on resources in terms of both laboratory provision and availability of a highly trained and accredited workforce. Ensuring a high-quality pathology service depends largely on close working and effective communication between the clinical team providing treatment and the pathologists providing laboratory input. Laboratory services should be quality assured by achieving external accreditation, most often by conforming to International Organization for Standardization (ISO) standards such as ISO15189 sometimes with ISO17025 or alternatively ISO17020. Quality of diagnostic reporting can be assured by the ISO but clinical teams should endeavor to work with pathologists who engage in continuing professional development, external quality assurance and audit. Research also contributes to diagnostic reporting quality. A number of initiatives in the UK such as the EPSRC/MRC funded Molecular Pathology Nodes and the National Cancer Research Institute Cellular-Molecular Pathology initiative (C-M Path), for example, have linked pathologists, industry and researchers. This has resulted in centers leading in digital innovation, artificial intelligence, translational research and clinical trials supported by pathologists. For rare tumors and contemporary molecular diagnostics, biopsy material can increasingly be shared with expert specialist pathologists working in specialist centers, particularly by using digital pathology platforms with potentially global reach. High quality services for the majority of diagnostic processes required for head and neck cancer management is best provided by local pathologists where communication with the treating team is more effective than with pathologists working in remote centers. Quality assurance is an increasingly important aspect of pathology, assuring not only effective turnaround times and accuracy for the diagnostic service but also high quality consistent reporting for clinical trials where even small pathology errors can potentially produce a significant bias and in the worst case negate the value of a completed trial. Better outcomes have been associated with centers engaged in clinical trials than in non-participating centers. Provision of a quality assured pathology service should extend to both the research and diagnostic services.