Prognostic importance of mitosis quantification and PHH3 expression in oral epithelial dysplasia.

Oral epithelial dysplasia (OED) is diagnosed and graded using a range of histological features, making grading subjective and challenging. Mitotic counting and phosphohistone-H3 (PHH3) staining have been used for the prognostication of various malignancies; however, their importance in OED remains unexplored. This study conducts a quantitative analysis of mitotic activity in OED using both haematoxylin and eosin (H&E)-stained slides and immunohistochemical (IHC) staining for PHH3. Specifically, the diagnostic and prognostic importance of mitotic number, mitotic type and intra-epithelial location is evaluated. Whole slide images (WSI) of OED (n = 60) and non-dysplastic tissue (n = 8) were prepared for analysis. Five-year follow-up data was collected. The total number of mitosis (TNOM), mitosis type and intra-epithelial location was manually evaluated on H&E images and a digital mitotic count performed on PHH3-stained WSI. Statistical associations between these features and OED grade, malignant transformation and OED recurrence were determined. Mitosis count increased with grade severity (H&E: p < 0.005; IHC: p < 0.05), and grade-based differences were seen for mitosis type and location (p < 0.05). The ratio of normal-to-abnormal mitoses was higher in OED (1.61) than control (1.25) and reduced with grade severity. TNOM, type and location were better predictors when combined with histological grading, with the most prognostic models demonstrating an AUROC of 0.81 for transformation and 0.78 for recurrence, exceeding conventional grading. Mitosis quantification and PHH3 staining can be an adjunct to conventional H&E assessment and grading for the prediction of OED prognosis. Validation on larger multicentre cohorts is needed to establish these findings.

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.

Development and validation of a multivariable model for prediction of malignant transformation and recurrence of oral epithelial dysplasia.

BACKGROUND: Oral epithelial dysplasia (OED) is the precursor to oral squamous cell carcinoma which is amongst the top ten cancers worldwide. Prognostic significance of conventional histological features in OED is not well established. Many additional histological abnormalities are seen in OED, but are insufficiently investigated, and have not been correlated to clinical outcomes. METHODS: A digital quantitative analysis of epithelial cellularity, nuclear geometry, cytoplasm staining intensity and epithelial architecture/thickness is conducted on 75 OED whole-slide images (252 regions of interest) with feature-specific comparisons between grades and against non-dysplastic/control cases. Multivariable models were developed to evaluate prediction of OED recurrence and malignant transformation. The best performing models were externally validated on unseen cases pooled from four different centres (n = 121), of which 32% progressed to cancer, with an average transformation time of 45 months. RESULTS: Grade-based differences were seen for cytoplasmic eosin, nuclear eccentricity, and circularity in basal epithelial cells of OED (p < 0.05). Nucleus circularity was associated with OED recurrence (p = 0.018) and epithelial perimeter associated with malignant transformation (p = 0.03). The developed model demonstrated superior predictive potential for malignant transformation (AUROC 0.77) and OED recurrence (AUROC 0.74) as compared with conventional WHO grading (AUROC 0.68 and 0.71, respectively). External validation supported the prognostic strength of this model. CONCLUSIONS: This study supports a novel prognostic model which outperforms existing grading systems. Further studies are warranted to evaluate its significance for OED prognostication.

Beauty is only mucosa deep: a retrospective analysis of oral lumps and bumps caused by cosmetic fillers.

Introduction The injection of dermal fillers into orofacial tissues is becoming increasingly popular for cosmetic purposes, in particular for lip augmentation. Both natural and synthetic filler materials are available, producing a spectrum of clinical and histological appearances.Aims The aim of this study was to review the clinicopathological characteristics of dermal filler cases from 2006 to 2016, reported at a specialist oral pathology unit.Methods An archival search of the pathology database was performed to retrieve cases reported as being consistent with cosmetic fillers.Results Ten cases of orofacial cosmetic fillers were retrieved. Of these cases, 100% were from female patients and the mean age of presentation was 47.6 years (range 24-68 years). The lips were the most frequently involved site (80%, n = 8). The majority of provisional diagnoses were related to salivary gland disease, including neoplasms (30%, n = 3), cysts (20%, n = 2) or inflammatory disease (10%, n = 1). Only two cases (20%) were clinically thought to be related to previous cosmetic injections. A variety of filler materials were seen, including collagen, hydroxyapatite and silicone. However, hyaluronic acid-based materials were the most common (50%, n = 5).Conclusions Complications of cosmetic dermal fillers are becoming more common and should be considered within a differential diagnosis for unusual orofacial swellings.

Dissociation of increases in PGC-1α and its regulators from exercise intensity and muscle activation following acute exercise.

Muscle activation as well as changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) following high-intensity interval exercise (HIIE) were examined in young healthy men (n  = 8; age, 21.9±2.2 yrs; VO2peak, 53.1±6.4 ml/min/kg; peak work rate, 317±23.5 watts). On each of 3 visits HIIE was performed on a cycle ergometer at a target intensity of 73, 100, or 133% of peak work rate. Muscle biopsies were taken at rest and three hours after each exercise condition. Total work was not different between conditions (∼730 kJ) while average power output (73%, 237±21; 100%, 323±26; 133%, 384±35 watts) and EMG derived muscle activation (73%, 1262±605; 100%, 2089±737; 133%, 3029±1206 total integrated EMG per interval) increased in an intensity dependent fashion. PGC-1α mRNA was elevated after all three conditions (p<0.05), with a greater increase observed following the 100% condition (∼9 fold, p<0.05) compared to both the 73 and 133% conditions (∼4 fold). When expressed relative to muscle activation, the increase in PGC-1α mRNA for the 133% condition was less than that for the 73 and 100% conditions (p<0.05). SIRT1 mRNA was also elevated after all three conditions (∼1.4 fold, p<0.05), with no difference between conditions. These findings suggest that intensity-dependent increases in PGC-1α mRNA following submaximal exercise are largely due to increases in muscle recruitment. As well, the blunted response of PGC-1α mRNA expression following supramaximal exercise may indicate that signalling mediated activation of PGC-1α may also be blunted. We also indentify that increases in PDK4, SIRT1, and RIP140 mRNA following acute exercise are dissociated from exercise intensity and muscle activation, while increases in EGR1 are augmented with supramaximal HIIE (p<0.05).