Standardised definitions and diagnostic criteria for extranodal extension detected on histopathological examination in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Detection of extranodal extension on histopathology in surgically treated head and neck squamous cell carcinoma indicates poor prognosis. However, there is no consensus on the diagnostic criteria, interpretation, and reporting of histology detected extranodal extension, which has contributed to conflicting evidence in the literature, and likely clinical inconsistency. The Head and Neck Cancer International Group conducted a three-round modified Delphi process with a group of 19 international pathology experts representing 15 national clinical research groups to generate consensus recommendations for histology detected extranodal extension diagnostic criteria. The expert panel strongly agreed on terminology and diagnostic features for histology detected extranodal extension and soft tissue metastasis. Moreover, the panel reached consensus on reporting of histology detected extranodal extension and on nodal sampling. These consensus recommendations, endorsed by 19 organisations representing 34 countries, are a crucial development towards standardised diagnosis and reporting of histology detected extranodal extension, and more accurate data collection and analysis.

Criteria for the diagnosis of extranodal extension detected on radiological imaging in head and neck cancer: Head and Neck Cancer International Group consensus recommendations.

Extranodal extension of tumour on histopathology is known to be a negative prognostic factor in head and neck cancer. Compelling evidence suggests that extranodal extension detected on radiological imaging is also a negative prognostic factor. Furthermore, if imaging detected extranodal extension could be identified reliably before the start of treatment, it could be used to guide treatment selection, as patients might be better managed with non-surgical approaches to avoid the toxicity and cost of trimodality therapy (surgery, chemotherapy, and radiotherapy together). There are many aspects of imaging detected extranodal extension that remain unresolved or are without consensus, such as the criteria to best diagnose them and the associated terminology. The Head and Neck Cancer International Group conducted a five-round modified Delphi process with a group of 18 international radiology experts, representing 14 national clinical research groups. We generated consensus recommendations on the terminology and diagnostic criteria for imaging detected extranodal extension to harmonise clinical practice and research. These recommendations have been endorsed by 19 national and international organisations, representing 34 countries. We propose a new classification system to aid diagnosis, which was supported by most of the participating experts over existing systems, and which will require validation in the future. Additionally, we have created an online educational resource for grading imaging detected extranodal extensions.

PET-CT-guided, symptom-based, patient-initiated surveillance versus clinical follow-up in head neck cancer patients (PETNECK2): study protocol for a multicentre feasibility study and non-inferiority, randomised, phase III trial.

BACKGROUND: Approximately 40% of treated head and neck cancer (HNC) patients develop recurrence. The risk of recurrence declines with time from treatment. Current guidelines recommend clinical follow-up every two months for the first two years after treatment, with reducing intensity over the next three years. However, evidence for the effectiveness of these regimes in detecting recurrence is lacking, with calls for more flexible, patient-centred follow-up strategies. METHODS: PETNECK2 is a UK-based multi-centre programme examining a new paradigm of follow-up, using positron emission tomography-computed tomography (PET-CT)-guided, symptom-based, patient-initiated surveillance. This paradigm is being tested in a unblinded, non-inferiority, phase III, randomised controlled trial (RCT). Patients with HNC, one year after completing curative intent treatment, with no clinical symptoms or signs of loco-regional or distant metastasis will be randomised using a 1:1 allocation ratio to either regular scheduled follow-up, or to PET-CT guided, patient-initiated follow-up. Patients at a low risk of recurrence (negative PET-CT) will receive a face-to-face education session along with an Information and Support (I&S) resource package to monitor symptoms and be in control of initiating an urgent appointment when required. The primary outcome of the RCT is overall survival. The RCT also has an in-built pilot, a nested QuinteT Recruitment Intervention (QRI), and a nested mixed-methods study on patient experience and fear of cancer recurrence (FCR). An initial, single-arm feasibility study has been completed which determined the acceptability of the patient-initiated surveillance intervention, the completion rates of baseline questionnaires, and optimised the I&S resource prior to implementation in the RCT. DISCUSSION: We hypothesise that combining an additional 12-month post-treatment PET-CT scan and I&S resource will both identify patients with asymptomatic recurrence and identify those at low risk of future recurrence who will be empowered to monitor their symptoms and seek early clinical follow-up when recurrence is suspected. This change to a patient-centred model of care may have effects on both quality of life and fear of cancer recurrence. TRIAL REGISTRATION: ISRCTN: 13,709,798; 15-Oct-2021.

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis.

BACKGROUND: p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. METHODS: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. FINDINGS: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0·744, p=0·0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5-82·7) for p16+/HPV+, 40·4% (38·6-42·4) for p16-/HPV-, 53·2% (46·6-60·8) for p16-/HPV+, and 54·7% (49·2-60·9) for p16+/HPV-. 5-year disease-free survival was 84·3% (95% CI 82·9-85·7) for p16+/HPV+, 60·8% (58·8-62·9) for p16-/HPV-; 71·1% (64·7-78·2) for p16-/HPV+, and 67·9% (62·5-73·7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. INTERPRETATION: Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. FUNDING: European Regional Development Fund, Generalitat de Catalunya, National Institute for Health Research (NIHR) UK, Cancer Research UK, Medical Research Council UK, and The Swedish Cancer Foundation and the Stockholm Cancer Society.

Feasibility of mass cytometry proteomic characterisation of circulating tumour cells in head and neck squamous cell carcinoma for deep phenotyping.

BACKGROUND: Circulating tumour cells (CTCs) are a potential cancer biomarker, but current methods of CTC analysis at single-cell resolution are limited. Here, we describe high-dimensional single-cell mass cytometry proteomic analysis of CTCs in HNSCC. METHODS: Parsortix microfluidic-enriched CTCs from 14 treatment-naïve HNSCC patients were analysed by mass cytometry analysis using 41 antibodies. Immune cell lineage, epithelial-mesenchymal transition (EMT), stemness, proliferation and immune checkpoint expression was assessed alongside phosphorylation status of multiple signalling proteins. Patient-matched tumour gene expression and CTC EMT profiles were compared. Standard bulk CTC RNAseq was performed as a baseline comparator to assess mass cytometry data. RESULTS: CTCs were detected in 13/14 patients with CTC counts of 2-24 CTCs/ml blood. Unsupervised clustering separated CTCs into epithelial, early EMT and advanced EMT groups that differed in signalling pathway activation state. Patient-specific CTC cluster patterns separated into immune checkpoint low and high groups. Patient tumour and CTC EMT profiles differed. Mass cytometry outperformed bulk RNAseq to detect CTCs and characterise cell phenotype. DISCUSSION: We demonstrate mass cytometry allows high-plex proteomic characterisation of CTCs at single-cell resolution and identify common CTC sub-groups with potential for novel biomarker development and immune checkpoint inhibitor treatment stratification.

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.

A digital score of tumour-associated stroma infiltrating lymphocytes predicts survival in head and neck squamous cell carcinoma.

The infiltration of T-lymphocytes in the stroma and tumour is an indication of an effective immune response against the tumour, resulting in better survival. In this study, our aim was to explore the prognostic significance of tumour-associated stroma infiltrating lymphocytes (TASILs) in head and neck squamous cell carcinoma (HNSCC) through an AI-based automated method. A deep learning-based automated method was employed to segment tumour, tumour-associated stroma, and lymphocytes in digitally scanned whole slide images of HNSCC tissue slides. The spatial patterns of lymphocytes and tumour-associated stroma were digitally quantified to compute the tumour-associated stroma infiltrating lymphocytes score (TASIL-score). Finally, the prognostic significance of the TASIL-score for disease-specific and disease-free survival was investigated using the Cox proportional hazard analysis. Three different cohorts of haematoxylin and eosin (H&E)-stained tissue slides of HNSCC cases (n = 537 in total) were studied, including publicly available TCGA head and neck cancer cases. The TASIL-score carries prognostic significance (p = 0.002) for disease-specific survival of HNSCC patients. The TASIL-score also shows a better separation between low- and high-risk patients compared with the manual tumour-infiltrating lymphocytes (TILs) scoring by pathologists for both disease-specific and disease-free survival. A positive correlation of TASIL-score with molecular estimates of CD8+ T cells was also found, which is in line with existing findings. To the best of our knowledge, this is the first study to automate the quantification of TASILs from routine H&E slides of head and neck cancer. Our TASIL-score-based findings are aligned with the clinical knowledge, with the added advantages of objectivity, reproducibility, and strong prognostic value. Although we validated our method on three different cohorts (n = 537 cases in total), a comprehensive evaluation on large multicentric cohorts is required before the proposed digital score can be adopted in clinical practice. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Exploring the views of patients' and their family about patient-initiated follow-up in head and neck cancer: A mixed methods study.

OBJECTIVE: The objective of this work was to explore head and neck cancer (HNC) patients' and their family members' views on acceptability and feasibility of patient-initiated follow-up (PIFU), including concerns and anticipated benefits. METHODS: Patients were recruited from UK HNC clinics, support groups and advocacy groups. They completed a survey (n = 144) and/or qualitative interview (n = 30), three with a family member. Qualitative data were analysed thematically, quantitative data using descriptive statistics. RESULTS: Preference for follow-up care in HNC was complex and individual. Many patients thought PIFU could beneficially reallocate health care resources and encourage self-management. Patients' main concerns with PIFU were losing the reassurance of regular clinic appointments and addressing mental well-being needs within PIFU, possibly using peer support. Patients were concerned about their ability to detect recurrence due to lack of expertise and information. They emphasised the importance of a reliable, direct and easy urgent appointment service and of feeling supported and heard by clinicians. Patients believed family and friends need support. CONCLUSION: PIFU may be feasible and acceptable for certain HNC patients, providing it addresses support for mental well-being, provides quick, reliable and direct clinician access and information on "red flag" symptoms, and ensures patients and their caregivers feel supported.

Symptom-based remote assessment in post-treatment head and neck cancer surveillance: A prospective national study.

OBJECTIVES: To report the incidence of locoregional recurrence in head and neck cancer (HNC) patients under surveillance following treatment undergoing symptom-based remote assessment. DESIGN: A 16-week multicentre prospective cohort study. SETTING: UK ENT departments. PARTICIPANTS: HNC patients under surveillance following treatment undergoing symptom-based telephone assessment. MAIN OUTCOME MEASURES: Incidence of locoregional recurrent HNC after minimum 6-month follow-up. RESULTS: Data for 1078 cases were submitted by 16 centres, with follow-up data completed in 98.9% (n = 1066). Following telephone consultation, 83.7% of referrals had their face-to-face appointments deferred (n = 897/1072). New symptoms were reported by 11.6% (n = 124/1072) at telephone assessment; 72.6% (n = 90/124) of this group were called for urgent assessments, of whom 48.9% (n = 44/90) came directly for imaging without preceding clinical review. The sensitivity and specificity for new symptoms as an indicator of cancer recurrence were 35.3% and 89.4%, respectively, with a negative predictive value of 99.7% (p = .002). Locoregional cancer identification rates after a minimum of 6 months of further monitoring, when correlated with time since treatment, were 6.0% (n = 14/233) <1 year; 2.1% (n = 16/747) between 1 and 5 years; and 4.3% (n = 4/92) for those >5 years since treatment. CONCLUSIONS: Telephone assessment, using patient-reported symptoms, to identify recurrent locoregional HNC was widely adopted during the initial peak of the COVID-19 pandemic in the United Kingdom. The majority of patients had no face-to-face reviews or investigations. New symptoms were significantly associated with the identification of locoregional recurrent cancers with a high specificity, but a low sensitivity may limit symptom assessment being used as the sole surveillance method.

Civilian penetrating neck trauma at a level I trauma centre: A five-year retrospective case note review.

OBJECTIVES: To report the experience of civilian penetrating neck trauma (PNT) at a UK level I trauma centre, propose an initial management algorithm and assess the degree of correlation between clinical signs of injury, operative findings and radiological reports. DESIGN: Retrospective case note review. SETTING: UK level I trauma centre April 2012-November 2017. PARTICIPANTS: Three hundred ten cases of PNT were drawn from electronic patient records. Data were extracted on hard and soft signs of vascular or aerodigestive tract injury, clinical management, radiological imaging and patient outcomes. MAIN OUTCOME MEASURES: Patient demographics, mechanism of injury, morbidity and mortality. The correlation between clinical signs, and radiological reports to internal injury on surgical exploration. RESULTS: Two hundred seventy-one (87.4%) male and 39 (13.6%) female patients with a mean age of 36 years (16-87) were identified. The most common causes of injury were assault 171 (55.2%) and deliberate self-harm 118 (38%). A knife was the most common instrument 240 (77.4%). Past psychiatric history was noted in 119 (38.4%), and 60 (19.4%) were intoxicated. 50% were definitively managed in theatre with a negative exploration rate of 38%, and 50% were managed in ED. Pre-operative radiological reports correlated with operative reports in 62% of cases with venous injury the most common positive and negative finding. Multivariate correlation was r = 0.89, p = 0.045, between hard signs plus positive radiology findings and internal injury on neck exploration. CONCLUSIONS: Management of PNT by clinical and radiological signs is safe and effective, and can be streamlined by a decision-making algorithm as proposed here.

Conservative management of oesophageal soft food bolus impaction.

BACKGROUND: Impaction of a soft food bolus in the oesophagus causes dysphagia and regurgitation. If the bolus does not pass spontaneously, then the patient is at risk of aspiration, dehydration, perforation, and death. Definitive management is with endoscopic intervention, recommended within 24 hours. Prior to endoscopy, many patients undergo a period of observation, awaiting spontaneous disimpaction, or may undergo enteral or parenteral treatments to attempt to dislodge the bolus. There is little consensus as to which of these conservative strategies is safe and effective to be used in this initial period, before resorting to definitive endoscopic management for persistent impaction. OBJECTIVES: To evaluate the efficacy of non-endoscopic conservative treatments in the management of soft food boluses impacted within the oesophagus. SEARCH METHODS: We searched the following databases, using relevant search terms: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL. The date of the search was 18 August 2019. We screened the reference lists of relevant studies and reviews on the topic to identify any additional studies. SELECTION CRITERIA: We included randomised controlled trials of the management of acute oesophageal soft food bolus impaction, in adults and children, reporting the incidence of disimpaction (confirmed radiologically or clinically by return to oral diet) without the need for endoscopic intervention. We did not include studies focusing on sharp or solid object impaction. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. MAIN RESULTS: We identified 890 unique records through the electronic searches. We excluded 809 clearly irrelevant records and retrieved 81 records for further assessment. We subsequently included one randomised controlled trial that met the eligibility criteria, which was conducted in four Swedish centres and randomised 43 participants to receive either intravenous diazepam followed by glucagon, or intravenous placebos. The effect of the active substances compared with placebo on rates of disimpaction without intervention is uncertain, as the numbers from this single study were small, and the rates were similar (38% versus 32%; risk ratio 1.19, 95% confidence interval 0.51 to 2.75, P = 0.69). The certainty of the evidence using GRADE for this outcome is low. Data on adverse events were lacking. AUTHORS' CONCLUSIONS: There is currently inadequate data to recommend the use of any enteral or parenteral treatments in the management of acute oesophageal soft food bolus impaction. There is also inadequate data regarding potential adverse events from the use of these treatments, or from potential delays in definitive endoscopic management. Caution should be exercised when using any conservative management strategies in these patients.

Definition of locally recurrent head and neck squamous cell carcinoma: a systematic review and proposal for the Odense-Birmingham definition.

PURPOSE: The objectives of this study were (1) to systematically review current definitions of head and neck squamous cell carcinoma (HNSCC) recurrence and (2) to propose a definition of locally recurrent HNSCC. METHODS: A systematic literature review was performed according to the 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' statement in Medline, Embase, and Cochrane databases guided by the study question "What is the definition of local recurrence for patients with HN:SCC?". All retrieved studies were reviewed and qualitatively analyzed. RESULTS: The systematic literature search resulted in 3467 publications after removal of duplicates. Forty studies were examined as full text, and a total of five were found suitable for inclusion. All five included studies dealt with definitions of second primary HNSCC and were based on the Warren and Gates Criteria; (1) each of the tumors are malignant, (2) each must be distinct, and (3) the probability of one being a metastasis of the other must be excluded. Each of the included studies added specific anatomical and/or temporal separation measures to the criteria of second primary HNSCC. We propose the definition of locally recurrent HNSCC to be: (1) Same anatomical subsite or adjacent subsite within 3 cm of the primary lesion, (2) time-interval no more than 3 years (from completed treatment of the primary lesion), and (3) same p16-status for oropharyngeal carcinomas. CONCLUSIONS: No uniform definition of locally recurrent HNSCC currently exists. We propose the Odense-Birmingham definition based on the anatomical subsite combined with a specific measurable distance and a temporal separation of three years.

Circulating Tumour Cell Expression of Immune Markers as Prognostic and Therapeutic Biomarkers in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

Rates of loco-regional recurrence and distant metastasis remain high among head and neck squamous cell carcinoma (HNSCC) patients, despite advancing cancer treatment modalities and therapeutic agents. One area that has generated considerable interest is the immune landscape of the tumour, heralding a wave of immune checkpoint inhibitors with notable efficacy in recurrent/metastatic HNSCC patients. However, HNSCC remains poorly served by biomarkers that can direct treatment in a personalised fashion to target the tumour heterogeneity seen between patients. Detection and analysis of circulating tumour cells (CTCs) in HNSCC has provided a previously unseen view of the metastasis forming cells that are potentially contributing to poor clinical outcomes. In particular, identifying CTC expression of phenotypic and druggable protein markers has allowed CTC sub-populations to be defined that hold prognostic value or are potential therapeutic targets themselves. The aim of this systematic review was to examine the role of CTC immune-marker expression as prognostic/therapeutic biomarkers in HNSCC by evaluating progress to date and discussing areas for future research. Our results highlight how few studies have been able to demonstrate prognostic significance of immune-marker expression in CTCs. As expected, the immune checkpoint PD-L1 was the most widely investigated marker. However, no studies evaluated CTC target immune marker expression in immunotherapy cohorts. Despite these findings, the data presented demonstrate promise that CTCs may be a source of future biomarkers for immunotherapy and will provide valuable information regarding the potential immune evasion of these metastasis forming cells.

Patient advocacy in head and neck cancer: Realities, challenges and the role of the multi-disciplinary team.

This paper explores the concept of advocacy in head and neck cancer. We define inherent challenges in the development and success of advocacy within this context and offer ways to embed it within clinical practice. We outline what advocacy is, ways in which it may benefit people with head and neck cancer and the engagement required from healthcare professionals to facilitate advocacy to improve outcomes.

Factors affecting prognosis in locoregional recurrence of oral squamous cell carcinoma.

BACKGROUND: Recurrence of oral squamous cell carcinoma (rOSCC) after primary treatment is associated with poor survival outcomes. Salvage treatment with further surgery, radiotherapy and chemotherapy has high morbidity, making patient selection crucial. However, in the recurrence setting, reliable stratification data are scarce. Decision-making in this context is consequently complex. We investigated factors influencing overall survival after rOSCC. METHODS: Retrospective cohort study of patients with rOSCC (n = 83) at the Queen Elizabeth Hospital Birmingham, UK between 2006 and 2016. Associations with overall survival were analysed using univariate and multivariate analyses to identify important clinical prognostic indicators. RESULTS: Overall survival at 1 year was 32.5% and at 5 years was 18.1% after a median follow-up of 7.4 months. Multivariate analysis identified four independent predictors of overall survival following rOSCC: size of primary tumour (HR 2.077; 95% CI 1.034-4.172), extent of recurrent disease (HR 3.286; 95% CI 1.545-6.991), history of moderate alcohol consumption (HR 0.351; 95% CI 0.162-0.763), and close or positive margins at primary resection (HR 1.955; 95% CI 1.063-3.595). CONCLUSIONS: We identified four key factors that help prognostication and risk stratification of rOSCC. Given the high morbidity associated with salvage treatment, we recommend that the multidisciplinary team (MDT) and the patient weigh these factors carefully when considering further treatment. Further investigation of the biology underlying these oncophenotypes may contribute to better patient stratification.

The presentation, natural history and outcome of T1 a/b thyroid cancer with regard to new grading systems.

INTRODUCTION: The seventh edition tumor, node metastasis (TNM) classifies tumors <10 mm as T1a and tumors between 10 mm and 20 mm as T1b. Previous editions of the TNM staging system did not differentiate these lesions. We compare new classification in terms of presentation and outcome. METHODS: Early thyroid cancers that were previously staged under the TNM sixth edition were re-staged using the TNM seventh edition to identify whether the new staging system differentiated lesions in terms of presentation and outcome. Differences in presentation, rates of recurrent disease and surgical complications were recorded and compared. RESULTS: Of 1,415 thyroid operations, 369 were for malignant disease and there were 220 papillary carcinomas. There were 35 T1a/b lesions accounting for 11% of malignancies with no increasing incidence. Reclassification showed 64% T1a and 36% T1b lesions. There were no differences in presentation. Outcomes in terms of persistent or recurrent disease were the same after median follow up was 6.8 years. CONCLUSION: Isolated T1a/b thyroid cancer made up only a small proportion of malignancies, the majority of which were discovered incidentally. We have not seen the increase in early lesions reported elsewhere. In our series, the seventh TNM edition did not differentiate early lesions and we ultimately feel that parameters other than size of primary lesion are likely to be of greater importance in determining prognosis.

Investigation of p16(INK4a) as a prognostic biomarker in oral epithelial dysplasia.

BACKGROUND: Human papilloma virus is a risk factor for oropharyngeal cancer. Evidence for a similar aetiological role in the development of oral dysplasia or its transformation to oral cancer is not as clear. Meta-analyses estimate the prevalence of high-risk human papilloma virus (HPV) serotypes to be three times higher in pre-malignant lesions and cancer than in normal oral mucosa. However, this does not imply a causal relationship. Conflicting results are reported from the few studies examining the prognostic significance of HPV positivity in the development of oral cancer. We aimed to examine the ability of p16(INK4a) protein expression, a surrogate marker of HPV infection, to predict malignant progression in a large cohort of oral dysplasia patients. METHODS: One hundred forty eight oral dysplasia cases underwent immunohistochemical analysis using a monoclonal antibody against p16(INK4a) . Clinical factors were also collated on each case. Slides were double scored independently by two trained observers. Univariate analyses using both logistic and Cox regression models were performed. RESULTS: Thirty nine of 148 cases progressed to cancer. Ten of 148 cases (7%) were p16(INK4a) positive. High grade of dysplasia (P = 0.0002) and lesion morphology (P = 0.03) were found to be prognostic of malignant progression. p16(INK4a) score was not prognostic in this cohort (P = 0.29). This did not change with a time to event analysis (P = 0.24). CONCLUSION: Few studies have assessed the aetiological role of HPV in cancer development from dysplastic lesions. Our study, using one of the largest cohorts of oral dysplasia, demonstrated a low rate of p16(INK4a) positivity and was unable to confirm a prognostic ability for this biomarker.

Prognostic biomarkers for malignant progression of oral epithelial dysplasia: an updated systematic review and meta-analysis.

Oral epithelial dysplasia (OED) is a premalignant condition that carries an appreciable risk of malignant progression. The current grading system for severity, as defined by the World Health Organization, is a valuable clinical tool, but further work is required to improve the accuracy of predicting OED malignant progression. This systematic review aimed to assess progress in prognostic biomarker discovery in OED over the past 16 years. The primary objective was to update the latest evidence on prognostic biomarkers that may predict malignant progression of OED, with strict inclusion criteria of studies with a longitudinal design and long-term follow-up data to enhance the robustness and translational clinical potential of the findings. Of 2829 studies identified through the searching of five databases, 20 met our inclusion criteria. These studies investigated a total of 32 biomarkers, 20 of which demonstrated significant potential to predict malignant progression of OED. Meta-analysis demonstrated the significant prognostic value of four biomarkers: podoplanin, EGFR expression, p16 methylation, and DNA aneuploidy. Our review has identified 20 reported biomarkers with prognostic potential to predict malignant progression in OED, but their translation into clinical practice remains elusive. Further research is required, and this should focus on validating the promising biomarkers identified in large cohort studies, with adherence to standardised reporting guidelines.