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Simple Summary Patients with head and neck squamous cell carcinoma (HNSCC) might present with different clinical behaviors, even when classified at the same stage. This perspective highlights the recent findings on prognostic biomarkers that can aid in improving the staging of HNSCC. This was conducted with an aim of subsequently improving prognostic stratification and, hence, treatment planning. Abstract Tumor-node-metastasis (TNM) staging system is the cornerstone for treatment planning of head and neck squamous cell carcinoma (HNSCC). Many prognostic biomarkers have been introduced as modifiers to further improve the TNM classification of HNSCC. Here, we provide an overview on the use of the recent prognostic biomarkers, with a focus on histopathologic parameters, in improving the risk stratification of HNSCC and their application in the next generation of HNSCC staging systems.

While the relevance of the World Health Organization histopathological grading system as a prognostic tool for oral squamous cell carcinoma has received many critics, other histopathological features such as tumor-stroma ratio, tumor-infiltrating lymphocytes, and tumor budding are displaying promising results. Here, we evaluated the prognostic impact of the incorporation of tumor-stroma ratio, tumor-infiltrating lymphocytes, and tumor budding into World Health Organization histopathological grading for patients with oral squamous cell carcinoma.A total of 95 patients with early-stage oral squamous cell carcinoma were enrolled in the study, and World Health Organization tumor grading, tumor-stroma ratio, tumor-infiltrating lymphocytes, and tumor budding were evaluated in surgical slides stained with hematoxylin and eosin. Survival analyses for cancer-specific survival and disease-free survival were performed using Cox regression models, and receiver operating characteristic curves were applied for assessment of the performance of the combinations.Tumor-stroma ratio (stroma-rich) was significantly and independently associated with both shortened cancer-specific survival and poor disease-free survival, individually and in combination with World Health Organization histopathological grading. The combination of tumor-stroma ratio with World Health Organization grading did not improve the discriminatory ability compared to tumor-stroma ratio alone. Although low tumor-infiltrating lymphocytes were associated with shortened cancer-specific survival, the association did not withstand multivariate analysis. However, in combination with World Health Organization grading, low tumor-infiltrating lymphocytes were independently associated with poor cancer-specific survival. The combination of tumor-infiltrating lymphocytes and World Health Organization histopathological grading displayed a better discrimination of poor cancer-specific survival than tumor-infiltrating lymphocytes alone, but not at a significant level.Our findings support tumor-stroma ratio as a potential prognostic marker for patients with oral squamous cell carcinoma, and the incorporation of tumor-infiltrating lymphocytes into the World Health Organization grading system improves the prognostic ability of the tumor grading alone.

Objectives: Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines. Materials and methods: 176 surgically resected stage I-IV lung adenocarcinomas were histologically reclassified according to WHO 2015 guidelines. A modified classification subdividing the acinar subtype into classic acinar, complex glandular and cribriform subtypes was further applied and potentially prognostic histopathological characteristics such as tumor-infiltrating lymphocytes were evaluated. 148 patients with stage I-III tumors and complete follow-up data were included in the survival analyses. TMB was determined by a commercial next generation sequencing panel from 131 tumors, out of which 105 had survival data available. Results: Predominant micropapillary, solid and complex glandular as well as nonpredominant cribriform histological subtypes were associated with significantly shorter survival. High TMB concentrated in micropapillary, solid and acinar predominant subtypes. Interestingly, TMB >= 14 mutations/MB conferred a stage- and histology-independent survival benefit compared to TMB

Background: Archived formalin-fixed paraffin-embedded (FFPE) specimens from nonmalignant tissues derived from cancer patients are a vast and potentially valuable resource for high-quality genotyping analyses and could have a role in establishing inherited cancer risk. Methods: We systematically searched PubMed, Ovid MEDLINE, and Scopus databases for all articles that compared genotyping performance of DNA from nonmalignant FFPE tissue with blood DNA derived from cancer patients irrespective of tumor type. Two independent researchers screened the retrieved studies, removed duplicates, excluded irrelevant studies, and extracted genotyping data from the eligible studies. These studies included, but were not limited to, genotyping technique, reported call rate, and concordance. Results: Thirteen studies were reviewed, in which DNA from nonmalignant FFPE tissues derived from cancer patients was successfully purified and genotyped. All these studies used different approaches for genotyping of DNA from nonmalignant FFPE tissues to amplify single nucleotide polymorphisms (SNPs) and to estimate of loss of heterozygosity. The concordance between genotypes from nonmalignant FFPE tissues and blood derived from cancer patients was observed to be high, whereas the call rate of the tested SNPs was not reported in all included studies. Conclusion: This review illustrates that DNA from nonmalignant FFPE tissues derived from cancer patients can serve as an alternative and reliable source for assessment of germline DNA for various purposes, including assessment of cancer predisposition.

Laryngeal sarcomas constitute an extremely rare entity among head and neck malignancies. Furthermore, most of them are chondrosarcomas, and the osteogenic form remains a true rarity. In general, there is a lack of information on the characteristics of laryngeal osteosarcoma. Thus, we sought to critically review the existing world literature on laryngeal osteosarcoma in order to develop a more accurate clinicopathological profile of this malignancy. Laryngeal osteosarcoma has a predilection for elderly male patients, as 87% were male in the present series and the mean age was 62 years (range 32–80), and without a direct association with tobacco exposure. Osteosarcoma of the larynx is typically a highly malignant neoplasm that metastasizes early, has a propensity for hematogenous spread and also has a marked tendency to recur. Twelve (41%) out of the 29 cases in the present review with follow-up data had metastatic disease. The aspects that distinguish osteosarcoma from its differential diagnostic alternatives are discussed in this review.

Although there are many histopathologic prognosticators, grading of early oral tongue squamous cell carcinoma (OTSCC) is still based on morphological cell differentiation which has low prognostic value. Here we summarize the emerging histopathological markers showing powerful prognostic value, but are not included in pathology reports. Using PubMed, Scopus, Ovid Medline, and Web of Science databases, a systematic literature search was preformed to identify early OTSCC studies that investigated the prognostic significance of hematoxylin-eosin-based histopathologic markers. Our meta-analysis showed that tumor budding was associated with overall survival (hazard ratio [HR] 2.32; 95% CI 1.40-3.84; p 0.01) and disease-specific survival (DSS) (1.89; 95% CI 1.13-3.15; p = 0.02). Worst pattern of invasion was associated with disease-free survival (DFS) (1.95; 95% CI 1.04-3.64; p = 0.04). Tumor-stroma ratio was also associated with DFS (1.75, 95% CI 1.24-2.48; p 0.01) and DSS (1.69; 95% CI 1.19-2.42; p 0.01). Tumor budding, worst pattern of invasion, and tumor-stroma ratio have a promising prognostic value in early OTSCC. The evaluation and reporting of these markers is cost-effective and can be incorporated in daily practice.

Contains fulltext : 251733.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Patients with head and neck cancer (HNC) are usually confronted with functional changes due to the malignancy itself or its treatment. These factors typically affect important structures involved in speech, breathing, chewing, swallowing, and saliva production. Consequently, the intake of food will be limited, which further contributes to loss of body weight and muscle mass, anorexia, malnutrition, fatigue, and anemia. This multifactorial condition can ultimately lead to cancer cachexia syndrome. This study aims to examine the treatment of cachexia in HNC patients. METHODS: We systematically searched OvidMedline, PubMed, Scopus, and Web of Science for articles examining the treatment of cachexia in HNC. RESULTS: A total of nine studies were found, and these suggested interventions including nutritional, pharmacologic, therapeutic exercise, and multimodal approaches. The nutritional intervention includes essential components such as dietary counseling, oral nutritional supplements, and medical nutritional support. Individualized nutritional interventions include oral, enteral (feeding tubes i.e., percutaneous endoscopic gastrostomy [PEG], nasogastric tube [NGT]) and parenteral nutrition. The pharmacologic interventions aim at increasing the appetite and weight of cachectic patients. Therapeutic exercise and increased physical activity can help to enhance the synthesis of muscle protein, reducing inflammation and the catabolic effects of cachexia syndrome. CONCLUSION: Owing to the multifactorial nature of this syndrome, it is expected that the management approach should be multi-interventional. Early implementation of these interventions may help to improve survival and quality of health and life of cachectic HNC patients.

Simple Summary The immune response has been shown to be a promising indicator to predict the clinical behavior of many cancers, including head and neck cancer. Tumor-infiltrating lymphocytes (TILs) were widely introduced as an important tool to reveal the status of the immune response. This review discusses the significance of TILs in head and neck cancers. The evaluation of tumor-infiltrating lymphocytes (TILs) has received global attention as a promising prognostic cancer biomarker that can aid in clinical decision making. Proof of their significance was first shown in breast cancer, where TILs are now recommended in the classification of breast tumors. Emerging evidence indicates that the significance of TILs extends to other cancer types, including head and neck cancer. In the era of immunotherapy as a treatment choice for head and neck cancer, assessment of TILs and immune checkpoints is of high clinical relevance. The availability of the standardized method from the International Immuno-oncology Biomarker Working Group (IIBWG) is an important cornerstone toward standardized assessment. The aim of the current article is to summarize the accumulated evidence and to establish a clear premise for future research toward the implementation of TILs in the personalized management of head and neck squamous cell carcinoma patients.

Background: The immune response has an important role in cancer progression. At the same time, anti-tumor effect of the immune response has been speculated to cause destruction of cancer cells. Rec...

The World Health Organization (WHO) grading system has a low prognostic value for early-stage oral tongue squamous cell carcinoma; greater prognostic power has been shown with tumor budding analysis. In this study, we combined tumor budding analysis with histopathologic grading according to WHO 2017. In our proposal, a revised grade I tumor is defined as a "well differentiated cohesive tumor"; revised grade II as a "moderately differentiated and/or slightly dissociated tumor"; and revised grade III as a "poorly differentiated and/or dissociated tumor." We evaluated the prognostic value of this proposed grading system in a multicenter cohort of 311 cases of early oral tongue squamous cell carcinoma. The proposed grading system showed significant prognostic value in multivariable analysis for disease-specific survival with a hazard ratio of 3.86 and a 95% confidence interval of 1.36-10.9 (P=0.001). For disease-free survival, the proposed grading system showed good predictive power in multivariable analysis (hazard ratio, 2.07; 95% confidence interval, 1.00-4.27; P=0.009). The conventional WHO grading system showed a low prognostic value for disease-specific survival and disease-free survival (P>0.05). In conclusion, the prognostic power of the WHO histopathologic grading improved significantly with incorporation of tumor budding. Our proposed grading system can be easily included in pathology reports.

Oral squamous cell carcinoma (OSCC) forms a major health problem in many countries. For several decades the management of OSCC consisted of surgery with or without radiotherapy or chemoradiotherapy. Aiming to increase survival rate, recent research has underlined the significance of harnessing the immune response in treatment of many cancers. The promising finding of checkpoint inhibitors as a weapon for targeting metastatic melanoma was a key event in the development of immunotherapy. Furthermore, clinical trials have recently proven inhibitor of PD-1 for treatment of recurrent/metastatic head and neck cancer. However, some challenges (including patient selection) are presented in the era of immunotherapy. In this mini-review we discuss the emergence of immunotherapy for OSCC and the recently introduced biomarkers of this therapeutic strategy. Immune biomarkers and their prognostic perspectives for selecting patients who may benefit from immunotherapy are addressed. In addition, possible use of such biomarkers to assess the response to this new treatment modality of OSCC will also be discussed.

Background Tumour budding (B) and depth of invasion (D) have both been reported as promising prognostic markers in oral squamous cell carcinoma (OSCC). This meta-analysis assessed the prognostic value of the tumour budding and depth of invasion combination (BD model) in OSCC. Methods Databases including Ovid MEDLINE, PubMed, Scopus and Web of Science were searched for articles that studied the BD model as a prognosticator in OSCC. PICO search strategy was "In OSCC patients, does BD model have a prognostic power?" We used the reporting recommendations for tumour marker prognostic studies (REMARK) criteria to evaluate the quality of studies eligible for systematic review and meta-analysis. Results Nine studies were relevant as they analysed the BD model for prognostication of OSCC. These studies used either haematoxylin and eosin (HE) or pan-cytokeratin (PCK)-stained resected sections of OSCC. Our meta-analysis showed a significant association of BD model with OSCC disease-free survival (hazard ratio = 2.02; 95% confidence interval = 1.44-2.85). Conclusions The BD model is a simple and reliable prognostic indicator for OSCC. Evaluation of the BD model from HE- or PCK-stained sections could facilitate individualized treatment planning for OSCC patients.

Astroprincin (APCN, FAM171A1) is a recently characterized transmembrane glycoprotein that is abundant in brain astrocytes and is overexpressed in some tumors. However, the expression and role of APCN is unknown in oral tongue squamous cell carcinoma (OTSCC). Aim of this study was to investigate the expression of APCN in OTSCC tissue samples and to analyze possible association of APCN with clinicopathological features and survival rates. This study included 76 patients treated for OTSCC. Expression of APCN in OTSCC tissue sections was examined by immunohistochemistry with a rabbit polyclonal antibody (MAP346) against APCN. All tumors were scored for intensity and percentage of APCN staining at the superficial, middle, and invasive front areas. High expression of APCN was significantly associated with increased tumor size (P = 0.013) and with OTSCC recurrence (P = 0.026). In this pilot study, we observed that the amount of APCN is associated with the size and recurrence of OTSCC. This finding suggests a role of APCN during OTSCC progression.

Background: A role for incisional biopsy in preoperative prognostication is increasingly being advocated in oral tongue squamous cell carcinomas (OTSCC). Biopsies at two locations were compared and prognostic factors in biopsies and their corresponding resections were evaluated. Methods: A total of 138 OTSCC biopsy slides from Finland and Saudi-Arabia were compared for size (horizontal and vertical) and invasive front. The Finnish cases were assessed for tumor stroma ratio (TSR) and tumor-infiltrating lymphocytes (TILs) using light microscopy and digital image analysis assessment and compared. Furthermore, TSR, TILs, and previously analyzed budding and depth of invasion (BD) score in biopsies were compared with their evaluation in the corresponding resections. Results: Finnish biopsies were deeper than Saudi-Arabian biopsies (59% versus 42%) while Saudi-Arabian biopsies were wider (98% versus 76%). Invasion fronts were more readily assessable in Finnish biopsies (72% versus 40%). There was 86.8% agreement between TSR and 75% agreement between TIL evaluation using light microscopy and digital assessment. Significant agreement was obtained on comparing the TSR (P=0.04) and BD (P Conclusions: Biopsies of ≥5 mm depth from representative OTSCC areas are essential for prognostic information. Clinical pathologists are advised to assess BD score and TSR for prognostic features in such biopsies.

Background The prediction of overall survival in tongue cancer is important for planning of personalized care and patient counselling. Objectives This study compares the performance of a nomogram with a machine learning model to predict overall survival in tongue cancer. The nomogram and machine learning model were built using a large data set from the Surveillance, Epidemiology, and End Results (SEER) program database. The comparison is necessary to provide the clinicians with a comprehensive, practical, and most accurate assistive system to predict overall survival of this patient population. Methods The data set used included the records of 7596 tongue cancer patients. The considered machine learning algorithms were logistic regression, support vector machine, Bayes point machine, boosted decision tree, decision forest, and decision jungle. These algorithms were mainly evaluated in terms of the areas under the receiver-operating characteristic (ROC) curve (AUC) and accuracy values. The performance of the algorithm that produced the best result was compared with a nomogram to predict overall survival in tongue cancer patients. Results The boosted decision-tree algorithm outperformed other algorithms. When compared with a nomogram using external validation data, the boosted decision tree produced an accuracy of 88.7% while the nomogram showed an accuracy of 60.4%. In addition, it was found that age of patient, T stage, radiotherapy, and the surgical resection were the most prominent features with significant influence on the machine learning model’s performance to predict overall survival. Conclusion The machine learning model provides more personalized and reliable prognostic information of tongue cancer than the nomogram. However, the level of transparency offered by the nomogram in estimating patients’ outcomes seems more confident and strengthened the principle of shared decision making between the patient and clinician. Therefore, a combination of a nomogram – machine learning (NomoML) predictive model may help to improve care, provides information to patients, and facilitates the clinicians in making tongue cancer management-related decisions.

Background: Cell-in-cell structures (caused by cell cannibalistic activity) have been related to prognosis of many cancers. This is the first multi-institutional study to assess the prognostic impact of cell-in-cell structures in a large cohort of early oral tongue squamous cell carcinomas (OTSCC). Methods: A total of 308 cases from five Finnish University Hospitals and from the A.C. Camargo Cancer Center, São Paulo, Brazil, were included in this study. Cell-in-cell structures were evaluated on surgical postoperative sections that stained with hematoxylin and eosin staining. Results: We found that cell-in-cell structures associated with cancer-related mortality in univariable analysis with a hazard ratio (HR) of 2.99 (95%CI 1.52–5.88; P = 0.001). This association was confirmed in multivariable analysis (HR 2.22, 95%CI 1.12–4.44; P = 0.024). In addition, statistically significant associations were observed between the cell-in-cell structures and other adverse histopathologic characteristics including deep invasion (P

Tumour budding has emerged as a promising prognostic marker in many cancers. We systematically reviewed all studies that evaluated tumour budding in diagnostic biopsies. We conducted a systematic review of PubMed, MEDLINE, Scopus, Web of Science and Cochrane library for all articles that have assessed tumour budding in diagnostic (i.e. pretreatment or pre-operative) biopsies of any tumour type. Two independent researchers screened the retrieved studies, removed duplicates, excluded irrelevant studies and extracted data from the eligible studies. A total of 13 reports comprising 11 cohorts were found to have studied tumour budding in diagnostic biopsies. All these reports showed that evaluation of tumour budding in diagnostic biopsies was easily applicable. A strong association was observed between tumour budding score in diagnostic biopsies and corresponding surgical samples. Evaluation of tumour budding in diagnostic biopsies had a significant prognostic value for lymph node metastasis and patient survival. In all studies, tumour budding was a valuable marker of tumour aggressiveness and can be evaluated in technically satisfactory diagnostic biopsies. Thus, the assessment of tumour budding seems to identify the behaviour of cancer, and therefore to facilitate treatment planning.

Background Recent research has proposed modifications for the TNM staging and the World Health Organization (WHO) histopathologic grading system of oral cancer. Objective (1) To study the significance of different cutoff points of depth of invasion (DOI) in T classification. (2) To study the incorporation of tumor budding to modify the WHO grading system. Methods In this multi-institutional study, we included 311 cases treated for early (cT1-2N0M0) oral tongue squamous cell carcinoma at the 5 university hospitals in Finland or at the A.C. Camargo Cancer Centre, Sao Paulo, Brazil. We suggest using 2 mm DOI to upstage to T2 and 4 mm DOI to upstage to T3. For histopathologic grading, our proposal incorporates tumor budding and defines Grade I as a “well-differentiated cohesive tumor”; grade II as a “moderately differentiated and/or slightly dissociated tumor”; and grade III as a “poorly differentiated and/or dissociated tumor.” Results There was a significantly improved performance in identification of the high-risk cases for recurrence (hazard ratio [HR] = 2.08; 95% confidence interval [CI], 1.07-4.01; P = .03) and cancer-related mortality (HR = 2.21; 95% CI, 1.05-4.64; P = .036) based on our proposed adjustment of the T stage. Similarly, the proposed histopathologic grade showed worse survival (HR = 3.42; 95% CI, 1.23-9.56; P = .001) and a high rate of recurrence (HR = 1.85; 95% CI, 0.91-3.76; P = .024) for cases having poorly differentiated and/or dissociated tumors. Conclusions Our proposed adjustments for staging and grading criteria could improve the risk stratification in early oral tongue squamous cell carcinoma.

It is of great clinical importance to identify simple prognostic markers from preoperative biopsies that could guide treatment planning. Here, we compared tumor budding (B), depth of invasion (D), and the combined scores (i.e., budding and depth of invasion (BD) histopathologic model) in preoperative biopsies and the corresponding postoperative specimens of oral tongue squamous cell carcinoma (OTSCC). Tumor budding and depth of invasion were evaluated in the pre- and postoperative samples from 100 patients treated for OTSCC. Sensitivity and specificity statistics were used. Our results showed statistically significant (P < 0.001) relationship between pre- and postoperative BD scores. There was an agreement between the pre- and postoperative BD model scores in 83 cases (83%) with 57.1% sensitivity (95% CI 39.4 to 73.7%) and 96.9% specificity (95% CI 89.3 to 99.6%). Our findings suggest that the BD model, analyzed from representative biopsies, could be used for the treatment planning of OTSCC.

Background Incidence rates for oral tongue squamous cell carcinoma (SCC) are steadily rising worldwide. Methods All patients diagnosed with primary oral tongue SCC at the 5 university hospitals in Finland from 2005 to 2009 were studied. The mean follow-up time was 43 months (median, 54 months; range, 0–111 months). Results Three hundred sixty patients with primary oral tongue SCC were identified. Treatment with curative intent was provided for 328 patients (91%). The 5-year disease-specific survival (DSS) rates were as follows: stage I 87%; stage II 73%; stage III 69%; and stage IV 51%. The 5-year recurrence-free survival in general has improved from 47% in our previous published series (1995–1999) to 65% in the current series (p < .001). Conclusion The outcome of oral tongue SCC has significantly improved in Finland. However, the relatively high number of disease recurrences in patients with stage I and II disease, when compared with patients with stage III and IV disease, calls for an investigation of new treatment approaches. © 2017 Wiley Periodicals, Inc. Head Neck, 2017

Oral squamous cell carcinoma (OSCC) is a common malignancy of the head and neck region. OSCC has a relatively low survival rate and the incidence of the disease is increasing in some geographic areas. Staging and grading of OSCC are established prerequisites for management, as they influence risk stratification and are the first step toward personalized treatment. The current AJCC/UICC TNM staging (8th edition, 2017) of OSCC has included significant modifications through the incorporation of depth of invasion in the T stage and extracapsular spread/extranodal extension in the N stage. Further modifications for AJCC 8 have been suggested. On the other hand, the World Health Organization (WHO) classification (4th edition, 2017) still endorses a simple, differentiation-based histopathologic grading system of OSCC (despite its low prognostic value) and ignores factors such as tumor growth pattern and dissociation, stromal reactions (desmoplasia, local immune response), and tumor-stroma ratio. The various controversies and possible developments of the current staging and grading criteria of OSCC are briefly discussed in this update together with possible applications of artificial intelligence in the context of screening and risk stratification.

Little is known about the histopathological characteristics that may differentiate early oral tongue cancer (OTSCC) between young and older patients. From a total of 311 cases diagnosed with clinically early-stage OTSCC at 6 institutions, only 42 patients were young patients were aged ≤45 years. For comparison, 42 patients >60 years old were matched for center of management, clinical stage and gender. We compared epithelial and stromal histopathologic parameters between the two groups. Most of the parameters were similar between the two groups, although the young patients appeared to have marginally higher intensity of tumor budding, histologic risk score, infiltrative pattern of invasion and tumor-stroma ratio. However, none of the factors showed significant difference when comparing the two groups. The histological parameters reflect mechanisms of invasive growth and tissue response to invasive growth, but not the etiological difference in OTSCC between young and older patients. Further investigations are necessary to compare the genetic background of early OTSCC in the two groups.

Aims Previous studies have demonstrated that the tumour-stroma ratio (TSR) and tumour budding are of prognostic value for oral squamous cell carcinomas (OSCCs). The aim of this study was to evaluate the prognostic significance of those histological parameters, individually and in combination, for OSCC. Methods and results The TSR and tumour budding (the presence of five or more buds at the invasive front) were estimated in 254 patients with OSCC. The clinicopathological association was investigated with a chi-square test, and the prognostic significance (cancer-specific survival and disease-free survival) was verified with Kaplan-Meier analysis and the Cox proportional hazard model. The TSR (>= 50%, stroma-rich) was significantly and independently associated with both shortened cancer-specific survival and poor disease-free survival, whereas tumour budding was significantly associated with reduced cancer-specific survival. The TSR/tumour budding model was independently associated with a high risk of cancer mortality and recurrence (disease-free survival). In patients with early-stage tumours (clinical stage I and II, n = 103), the TSR, tumour budding and the TSR/tumour budding model were significantly associated with both cancer-related death and recurrence, whereas, in advanced-stage tumours (clinical stage III and IV, n = 144), only the TSR and the TSR/tumour budding model were significantly associated with cancer-specific survival. Conclusions The TSR, tumour budding and their combination provide significant information on OSCC outcome, suggesting that their incorporation in the routine evaluation of histopathological specimens might be useful in prognostication for OSCC patients.

IntroductionHNCs constitute a heterogenous group of neoplasms. A recent report based on GLOBOCAN database estimated diagnosis of more than half million new cases of HNC during 2018 45, and the incidence is expected to continue increasing according to estimate for 2030 46. HNC is associated with high mortality 45, and one of the main reasons for the low survival can be explained by late diagnosis. For example, human papilloma virus associated oropharyngeal squamous cell cancer has one of the most rapidly increasing incidences among all cancer types in high-income countries and supporting the development of effective early detection strategies is seen as an important approach to improve curative treatment (Lechner M, Breeze CE, O'Mahony JF, Masterson L. Early detection of HPV-associated oropharyngeal cancer. Lancet. 2019;393:2123.) (Timbang MR, Sim MW, Bewley AF, Farwell DG, Mantravadi A, Moore MG. HPV-related oropharyngeal cancer: a review on burden of the disease and opportunities for prevention and early detection. Hum Vaccin Immunother. 2019 May 3:1-9. doi: 10.1080/21645515.2019.1600985. [Epub ahead of print])The current methods to detect HNCs include visual inspection of the upper aerodigestive mucous membranes and pathological examination of tissue biopsy of a suspicious lesion. Serological and salivary biomarkers are under evaluation to aid in the early primary diagnosis or follow-up surveillance of this patient population but none of them has yet been proved useful in clinical practice (refs). Therefore, more reliable and noninvasive methods are warranted for early diagnosis of HNC.Exhaled breath analysisNon-invasive approaches to the early diagnosis of cancer is a crucial topic of research. Available methods include, for example, surface brushing and blood sampling. The main idea of these non-invasive approaches is to identify cancer biomarkers or signatures that would allow early detection of cancer before any clinical symptoms or signs develop. Such early diagnosis will lead to treatment planning at an early-stage and that, indeed, could improve the clinical outcome 1. However, daily diagnosis of many cancers (including those of head and neck) is still based on evaluation of changes in macroscopic appearance, radiological features and histopathological characteristics. The tools that are used in this traditional evaluation are not easily applicable in population screening as these diagnostic examinations either are invasive, expensive, and/or time-consuming, and involve exposure to radiation. On the other hand, analysis of exhaled breath would represent a non-invasive, fast and inexpensive screening tool that has shown promising results in many cancers 2-8. Easy access to sample supply is one of main advantages of breath analysis. The main gas phase constituents of exhaled breath are carbon dioxide, nitrogen, oxygen, water vapour and argon. In addition to these compounds, many volatile organic compounds (VOCs) are present at trace amounts, from part-per-million (ppm, 10-6) down to part-per-trillion (ppt, 10-12) levels. VOCs can be transferred to blood either in the lungs via gas exchange between alveoli and blood or they can be released in the lower or upper airways (including the oral and nasal cavity) 9. These volatile species can be analyzed in the gas phase using various mass spectrometry techniques, optical spectroscopy or sensors based on, for example, nanoparticles or semiconductive metal oxides. In addition to sampling the exhaled gas, breath samples can also be collected by condensing the breath on a cooled surface. The so-called exhaled breath condensate (EBC) is composed mostly of condensed water vapour but will also include small amounts of respiratory droplets containing nonvolatile molecules and water-soluble volatile compounds 10. The content of the EBC can be analyzed, for example, using enzyme immunoassay kits or chromatography – mass spectrometry techniques. The theory of exhaled breath analysis for cancer diagnosis is based on the concept that cancer initiation is associated with increase in oxidative stress that can cause alteration in the profile of DNA, proteins and other components 11. Such alterations can be detected in exhaled breath as increased or decreased concentrations of biomarkers connected with a specific disease that is associated with specific pathologic changes 12. 13. The history of research on breath analysis is strongly associated with Linus Pauling, the Nobel Prize winner in 1971, who explained that human breath is a complex gas containing more than 200 VOCs 14. To date, almost 900 different VOCs have been detected in exhaled breath 15. Methodological aspects in exhaled breath analysisCollection procedure: The collection procedure for a breath sample depends on whether the aim is to collect the gas phase portion of breath or the EBC. For gas phase samples, breath is either collected to sorbent materials or sample bags (offline analysis) or it can be analyzed immediately after the sample collection (online analysis). Storage in sorbent tubes or bags introduces risks related to sample stability during handling and storage 16. Exhalations can be divided into three phases. The initial brief phase contains gas from the oral cavity and trachea, this is often called “dead space phase”. The next phase is the mixed expiratory phase in which gas from the lungs and lower airways mixes with the dead space sample. The final phase is the end-tidal, which most closely reflects alveolar gas in the lungs. In most applications of breath analysis, the focus is on collecting the end-tidal phase and the first two phases are discarded. This can be done by real-time monitoring of the carbon dioxide content during sampling. Carbon dioxide originates fully from the alveolar gas-exchange and can be used as a marker for the end-tidal phase 16. However, in the case of HNC, the first two phases should not be discarded as they should contain the most relevant biomarkers for cancers in the upper aerodigestive tract.Condensation of exhaled breath occurs below the temperature of 4oC. Collecting devices for EBC use several different types of cooling maneuvers such as dry ice, wet ice with salt, and liquid nitrogen, and accordingly the condensate can be either liquid, solid or mix of both 17,18. EBC analysis is always performed offline. Importantly, it has been reported that the condensation temperature could affect different biomarkers’ concentration and therefore, reporting the condensation temperature is essential for process standardization and registration 18. There is a wide variety of exhaled breath collection devices such as EcoScreen Turbo 19, TURBO-DECCS 20, RTube TM 21, and devices for specific patient groups e.g. infants and children 22-24, and mechanically ventilated patients 25. Duration of sample collection: For gas phase sampling, the sampling time can be as short as the duration of a single exhalation (few seconds). When collecting the breath on a sorbent material, the concentrations of the analyte gases can be enriched by using longer sampling times (few minutes). In bag or online sampling, several samples can be acquired in succession to reduce the inter-individual variation of breath levels. Various physiological factors, such as breath holding, increased tidal volume and hyperventilation can have an influence on the retrieved breath concentrations but no universal breath gas sampling procedure currently exists. Some specific breath tests which are already in clinical use have been standardized, an example is the fractional nitric oxide (FeNO) test for measuring airway inflammation 26.Although the majority of published studies recommend EBC sample collection of 10 to 30 minutes, some studies reported short collection time of 3 minutes and others prolonged the time up to 60 minutes 27. The approximate volume of exhaled breath condensate after 10 to 15 minutes breathing is 1-3 ml 28. The length of sample collection time has a direct effect on the final volume 27. Increased tidal volume and/or minute ventilation, hyperventilation and mechanical ventilation are all associated with an increase in the volume of exhaled breath condensate 29-31.Sample storage: When using offline gas phase samples, the storage temperature and time depend on whether the sample is stored in a bag or a sorbent material. The optimal temperature for bag storage is 37 °C to avoid water condensation on bag surfaces. Storage losses depend heavily on the specific biomarkers and the used bag material. Bags manufactured from Tedlar have been shown to be stable for many compounds for up to 6 hours of storage 32. For samples that were collected onto a sorbent tube, a stable storage time of 1.5 months was achieved at – 80 °C. Out of the almost 600 compounds that were studied, a significant amount showed discernible levels of change in concentration after six months of storage 33.The optimum temperature for an EBC sample storage is below -70oC. However, some biomarkers require assessment of their stability at the storage temperature. Furthermore, division of the exhaled breath samples into aliquots is recommended as repetitive freezing and thawing may result in breakdown of certain compounds such as nucleic acids and prostaglandins 34.Potential contamination by saliva and oral bacterial activity: Salivary contamination can occur during collection of EBC and it is important confounding factor especially when analyzing volatile biomarkers. A clear example of salivary contamination is that exhaled breath nitrite levels are mostly attributable to oropharyngeal bacterial flora, as their levels decrease drastically rinsing the mouth with a chlorhexidine solution 35. Exclusion of saliva contamination can be done by testing salivary amylase in the EBC sample 36,37. Additionally, the ATS/ERS Task Force on EBC recommend using nasal clip to minimise the entry of nasal airway lining fluid into the sampled air and to ensure that all exhaled air will pass through the mouth 10. Oral bacteria and oral enzymatic activity also influence the exhaled breath gas levels. For example, exhaled ammonia is mainly produced by enzymatic hydrolysis of urea in the oral cavity 38.Potential breath biomarkers of HNC: In many neoplasms, exhaled breath has been a rich source of potential cancers biomarkers 11,39,40. These biomarkers can be divided into three categories. The first category includes the small volatile compounds. These can be measured in the gas phase and, in the case of water-soluble compounds also in the breath condensate (e.g. ammonia and formic acid). The second category includes biomolecules of low-molecular weight (e.g. isoprostanes, polypeptides and nucleic acids). The third category is miscellaneous including many compounds such as lipid mediators, chemokines and cytokines. The second and third category are mainly present in the breath condensate. DNA from exhaled breath condensate of healthy people has been used to identify mutations (e.g. TP53 gene mutations) that are associated with early neoplastic changes 41. A recent study has recognized several volatile organic compounds as breath gas biomarkers of thyroid cancer 39. Reported potential breath gas biomarkers for oral squamous cell carcinoma are aldehydes including undecane, dodecane, decanal, benzaldehyde, 3,7-dimethyl undecane, 4,5-dimethyl nonane, 1-octene, and hexadecane when analyzed by solid-phase microextraction with gas chromatography-mass spectrometry 42. By using linear discriminant analysis classification of these compounds, well-defined clusters for patients and controls were revealed 42. In addition, dimethyl disulfide, decamethylcyclopentasiloxane (D5) and p-xylene (PX) were reported as gas phase biomarkers that decrease after surgery 43. Ethanol, 2-propenenitrile and undecane were identified as exhaled gas biomarkers that could distinguish laryngeal and pharyngeal head and neck squamous cell carcinoma from benign tumors and from healthy subjects 44.Exhaled breath analysis as a diagnostic tool in head and neck cancerRecent research has analyzed exhaled breath to aid in early detection of HNC. An early attempt to analyze exhaled breath for diagnosis of HNC had been conducted by Hakim et al. (2011) 13 who used breath gas testing with nanoscale artificial nose. They were able to recognize patients with HNC from healthy people and from patients with lung cancer 13. The artificial nose based on nanoparticle sensors did not provide identification of the biomarkers responsible for the sensor response. A few years later, Gruber et al. 44 in their analysis of exhaled breath from patients with laryngeal and pharyngeal cancers found that ethanol, 2-propenenitrile and undecane can be used as potential biomarkers for these two cancers. Using artificially intelligent nanoarrays, Nakhleh et al. 47 have identified a set of many diseases including HNC from exhaled breath. In oral squamous cell carcinoma, a recent study has used exhaled breath analysis and found three compounds (benzaldehyde, 3,7-dimethylundecane, and butyl acetate) that have a relationship with pathological parameters of these cancers 42. Exhaled breath analysis as a predictive tool to monitor the treatment outcomeAssessment of treatment outcome is of great importance during the follow-up to ensure high survival rate and to early recognize any failure. Exhaled breath analysis has been recently introduced as an effective tool for monitoring response to treatment in lung cancer 48. In HNC, Hakim et al 13 suggested that breath analysis using artificial nose could be utilized as a test to follow-up after treatment of HNC especially for those cases at high-risk of developing a second primary tumor. Moreover, breath analysis from cured patients who underwent resection of HNC was similar to breath analysis of healthy control which indicates a successful surgery 49. Interestingly, Hartwig et al. 43 collected breath samples before and after surgical treatment of oral squamous cell carcinoma and compared the breath analysis for each case. They reported disappearance of cancer-associated volatile organic compounds in the breath after treatment 43. However, using breath analysis in monitoring the treatment of HNC is still a new field of research that requires more scientific efforts. Conclusion and FutureIn recent years, exhaled breath analysis has received increasing research interest in the early detection of many cancers. 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The eighth edition of the American Joint Committee on Cancer (AJCC8) staging manual has major changes in oral squamous cell carcinoma (OSCC). We searched PubMed, OvidMedline, Scopus, and Web of Science for studies that examined the performance of AJCC8 in OSCC. A total of 40 808 patients were included in the studies of our meta-analysis. A hazard ratio (HR) of 1.87 (95%CI 1.78-1.96) was seen for stage II, 2.65 (95%CI 2.51-2.80) for stage III, 3.46 (95%CI 3.31-3.61) for stage IVa, and 7.09 (95%CI 4.85-10.36) for stage IVb. A similar gradual increase in risk was noted for the N classification. For the T classification, however, there was a less clear variation in risk between T3 and T4. AJCC8 provides a good risk stratification for OSCC. Future research should examine the proposals introduced in the published studies to further improve the performance of AJCC8.

Invasion and metastasis are hallmarks of cancer. The concept of tumor budding at tumor-host interface has been documented in many carcinomas. A growing body of evidence indicates that tumor budding is a sign of invasion and early step for metastasis of many epithelial cancers including head and neck squamous cell carcinoma (HNSCC). In addition, recent research has underlined the importance of tumor budding as a promising prognosticator in HNSCC. This review summarizes the findings regarding tumor budding in HNSCC and focuses on the role of tumor budding in invasion and metastasis. Also, we highlight the prognostic significance of tumor budding in HNSCC and its potential for improving clinical decision making in terms of recommending optimal individualized treatment for this patient population.

Background Oral cancer can show heterogenous patterns of behavior. For proper and effective management of oral cancer, early diagnosis and accurate prediction of prognosis are important. To achieve this, artificial intelligence (AI) or its subfield, machine learning, has been touted for its potential to revolutionize cancer management through improved diagnostic precision and prediction of outcomes. Yet, to date, it has made only few contributions to actual medical practice or patient care. Objectives This study provides a systematic review of diagnostic and prognostic application of machine learning in oral squamous cell carcinoma (OSCC) and also highlights some of the limitations and concerns of clinicians towards the implementation of machine learning-based models for daily clinical practice. Data sources We searched OvidMedline, PubMed, Scopus, Web of Science, and Institute of Electrical and Electronics Engineers (IEEE) databases from inception until February 2020 for articles that used machine learning for diagnostic or prognostic purposes of OSCC. Eligibility criteria Only original studies that examined the application of machine learning models for prognostic and/or diagnostic purposes were considered. Data extraction Independent extraction of articles was done by two researchers (A.R. & O.Y) using predefine study selection criteria. We used the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) in the searching and screening processes. We also used Prediction model Risk of Bias Assessment Tool (PROBAST) for assessing the risk of bias (ROB) and quality of included studies. Results A total of 41 studies were published to have used machine learning to aid in the diagnosis/or prognosis of OSCC. The majority of these studies used the support vector machine (SVM) and artificial neural network (ANN) algorithms as machine learning techniques. Their specificity ranged from 0.57 to 1.00, sensitivity from 0.70 to 1.00, and accuracy from 63.4 % to 100.0 % in these studies. The main limitations and concerns can be grouped as either the challenges inherent to the science of machine learning or relating to the clinical implementations. Conclusion Machine learning models have been reported to show promising performances for diagnostic and prognostic analyses in studies of oral cancer. These models should be developed to further enhance explainability, interpretability, and externally validated for generalizability in order to be safely integrated into daily clinical practices. Also, regulatory frameworks for the adoption of these models in clinical practices are necessary.

The proliferation marker, securin, is involved in the progression of many carcinomas. However, its expression in oral tongue squamous cell carcinoma (OTSCC) has not been previously studied. We examined securin expression by immunohistochemistry in OTSCC. A total of 93 cases treated for OTSCC were included in this study. Expression of securin in OTSCC was studied by immunohistochemistry of tissue microarrays (52 cases) and routine tumor sections (41 cases). Securin overexpression is significantly associated with higher tumor grade (P = 0.03). Overexpression of securin was observed more frequently in advanced stages of OTSCC than in earlier stages but the difference was not statistically significant. These findings suggest that overexpression of securin in OTSCC may be important during progression of this cancer. No significant association was found between securin expression and the prognosis of OTSCC.

Background Colorectal carcinoma development progresses through a sequence of normal mucosa-polyp-carcinoma. Early detection of premalignancy is crucial for improved outcomes. We evaluated the diagnostic performance of plasma miRNA-221 and its feasibility in discriminating premalignant from malignant neoplasms and correlating it with immunohistochemical p53 expression. Methods A total of 109 plasma samples were collected (76 carcinoma, 14 premalignant, and 19 controls). MiRNA221 was quantified by qPCR for calculation of ∆Ct using RNU6B as endogenous control. p53 immunohistochemical staining was performed on corresponding tissue. Results Plasma miRNA-221 and p53 in tissues were significantly overexpressed in the malignant group when compared with the premalignant and control groups. Plasma miRNA-221 was increased in late-stage tumors with nodal or distant metastasis. ROC curve construction for distinguishing between malignant and premalignant tumors revealed a cutoff value of 2.97 with 74% sensitivity, 79% specificity, 73.7% positive predictive value and 78.6% negative predictive value (AUC = 0.824; p = 0.001). Plasma miRNA-221 significantly correlated with p53 in cancer samples (r = 0.507). Conclusions MiRNA-221 could have a diagnostic role in differentiating malignant from premalignant neoplasms and could also serve as a predictive marker indicating tumor progression.

Background Despite the importance of immune checkpoints in immunotherapy, the prognostic value of these molecules remains controversial in oral squamous cell carcinoma (OSCC). We performed a systematic review to investigate the prognostic significance of the immune checkpoints in OSCC. Materials A systematic search was conducted in Ovid Medline, Scopus and Cochrane libraries, and all studies that evaluated the prognostic significance of immune checkpoints in OSCC were systematically retrieved. Results Twelve immune checkpoints/modulators were studied for their prognostic values in OSCC patients between 1985 and 2017. Seven immune checkpoints (FKBP51, B7-H4, B7-H6, ALHD1, PD-L1, B7-H3 and IDO1) were reported to be associated with poor patients' survival in at least one study, and five (CTLA-4, TLT-2, VISTA, PD-L2 and PD-1) did not have a significant prognostic value. PD-L1 results were controversial as it was reported to be associated with both better and worse patients' survival. Conclusions Even though immune checkpoint markers had high expectation for OSCC prognostication, our systematic review revealed that the majority of them had been studied only once. The other molecules, which had been studied more than once, had controversial findings, except B7-H3.

One of the main changes in the 8th edition of the American Joint Committee on Cancer (AJCC) for staging of oral cancer is the inclusion of depth of invasion (DOI) in the T category. However, cancers in different oral subsites have variable behavior, with oral tongue squamous cell carcinoma (OTSCC) being the most aggressive one even at early stage. Thus, it is necessary to evaluate the performance of this new T category in homogenous cohort of early OTSCC. Therefore, we analyzed a large cohort of patients with a small (ae4 cm) OTSCC to demonstrate the differences in T stage between the AJCC 7th and 8th editions. A total of 311 early-stage cases (AJCC 7th) of OTSCC were analyzed. We used 5 mm and 10 mm DOI for upstaging from T1 to T2 and from T2 to T3 respectively, as in the AJCC 8th. We further reclassified the cases according to our own proposal suggesting 2 mm to upstage to T2 and 4 mm to upstage to T3. According to AJCC 7th, there were no significant differences in the survival analysis. When we applied the 8th edition, many cases were upstaged to T3 and thus associated with worse disease-specific survival (HR 2.37, 95% CI 1.12-4.99) and disease-free survival (HR 2.12, 95% CI 1.09-4.08). Based on our proposal, T3 cases were associated with even worse disease-specific survival (HR 4.19, 95% CI 2.27-7.74). The 8th edition provides better survival prediction for OTSCC than the 7th and can be further optimized by lowering the DOI cutoffs.

The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been studied recently in many cancers. For the first time in a nonendemic region, we have evaluated the prognostic value of TILs in a whole population based nationwide cohort of nasopharyngeal carcinoma (NPC) in Finland. A total of 115 cases from Finnish hospitals were included. TILs were analyzed using hematoxylin and eosin stained slides according to the criteria of the International Immuno-Oncology Biomarker Working Group. TILs were evaluated separately in stromal and tumor compartments. The log-rank test and univariable and multivariable analyses were used to compare survival in patients with tumors with low and high TILs. A significant positive correlation was observed between the occurrence of intratumoral and stromal TILs (P

Background: Identifying informative prognostic biomarkers for oral tongue squamous cell carcinoma (OTSCC) is of great importance in order to better predict tumour behaviour and to guide treatment planning. Here, we summarise existing evidence regarding immunohistochemical prognostic biomarkers for OTSCC. Methods: A systematic search of the literature was performed using the databases of Scopus, Ovid Medline, Web of Science and Cochrane Library. All studies which had investigated the prognostic significance of immunohistochemical biomarkers in OTSCC during the period from 1985 to 2015 were retrieved. For the five most often evaluated biomarkers a random-effects meta-analysis on overall survival was performed, including those studies that provided the necessary statistical results. Results: A total of 174 studies conducted during the last three decades were found, and in these 184 biomarkers were evaluated for the prognostication of OTSCC. The five biomarkers most frequently assessed were p53, Ki-67, p16, VEGFs and cyclin D1. In the meta-analyses, the most promising results of the prognostic power for OTSCC were obtained for cyclin D1. For studies of VEGF A and C the results were equivocal, but the pooled analysis of VEGF A separately showed it to be a useful prognosticator for OTSCC. There was no sufficient evidence to support p53, Ki-67 and p16 as prognostic biomarkers for OTSCC. Limitations in the quality of the published studies (e.g., small cohorts, lack of compliance with REMARK guidelines) are widespread. Conclusions: Numerous biomarkers have been presented as useful prognosticators for OTSCC, but the quality of the conduct and reporting of original studies is overall unsatisfactory which does not allow reliable conclusions. The value of two biomarkers (VEGF-A and cyclin D1) should be validated in a multicentre study setting following REMARK guidelines.

Objective This study evaluated the association of four histopathological grading systems (WHO grading system, malignancy grading of the deep invasive margins (MG), histological risk (HR) model, and tumor budding and depth of invasion (BD) model) with clinicopathological parameters and outcome of 113 oral squamous cell carcinomas to identify their roles in prognosis. Methods Demographic and clinical features were obtained from patients' records. Sections from all paraffin-embedded blocks were evaluated according to the four grading systems. Demographic and clinical associations were analyzed using chi-square test, and correlations between the grading systems were established with the Spearman's rank correlation test. Survival curves were performed with Kaplan–Meier method, and multivariate analysis based on Cox proportional hazard model was calculated. Results Significant associations with survival were observed for WHO grading system and BD model in the univariate analysis, but only the BD model was significantly associated with disease outcome as an independent prognostic marker. Age, tumor size, and presence of regional metastasis were also independent markers of reduced survival. Conclusion A significant association between the BD model and outcome of OSCC patients was observed, indicating this new histopathological grading system as a possible prognostic tool.

Despite early diagnosis and treatment, almost 20 % of patients with early-stage (cT1-cT2N0) oral tongue squamous cell carcinoma (OTSCC) still die of their disease. The prognosis of OTSCC patients is influenced by several demographic, clinical, and histopathologic factors. The aim of this multicenter international study was to find which of the factors age, gender, stage, grade, lymphocytic host re- sponse, perineural invasion, worst pattern of invasion, or depth of invasion has the strongest prognostic power in early-stage OTSCC. Patient data of 479 patients with early-stage (cT1-2N0) OTSCC in Finland, Brazil, and the USA were retrieved and analyzed using Cox proportional hazards regression models. Our results indicate that depth of invasion (DOI) and worst pattern of invasion (WPOI) are the strongest pathological predictors for locoregional recurrence, with a hazard ratio (HR) for 4 mm DOI of 1.67 (95 % confidence interval (CI) 1.07-2.60) and HR for WPOI of 1.46 (95 %C I 0.95-2.25). In addition, mor- tality from early OTSCC was also predicted by DOI (HR 2.44, 95 % CI 1.34-4.47) and by WPOI (HR 2.34, 95 % CI 1.26-4.32). We suggest that clinically early-stage oral tongue carcinomas 4 mm or deeper, or with a growth pat- tern of small cell islands or satellites, should be considered as high-risk tumors which require multimodality treatment.

The prognostication of patient outcome is one of the greatest challenges in the management of early stage oral tongue squamous cell carcinoma (OTSCC). This study introduces a simple histopathological model for the prognostication of survival in patients with early OTSCC. A total of 311 cases (from Finland and Brazil) with clinically evaluated early stage OTSCC (cT1-T2cN0cM0) were included in this multicentre retrospective study. Tumour budding (B) and depth of invasion (D) were scored on haematoxylin-eosin-stained cancer slides. The cut-off point for tumour budding was set at 5 buds (low

Background: To determine the prevalence, types, and risk factors of oral potentially malignant disorders (OPMDs) among a group of Arab Jordanian dental patients, and to evaluate their awareness and attitudes toward early diagnosis and treatment. Materials and Methods: A total of 1,041 patients attending a University Hospital for dental care were examined for the presence of OPMDs. Histopathological examination was performed on all cases clinically diagnosed and patients were directly interviewed to evaluate their knowledge and attitudes toward early detection and treatment of oral cancer. Results: The prevalence of OPMDs overall was 2.8%. Lichen planus/lichenoid lesions were the most common lesions (1.8%) followed by leukoplakias (0.48%), chronic hyperplastic candidiosis (0.38%), and erythroplakia (0.096%). Smoking, alcohol, and age (>40 years) were the main identifiable risk factors. Patients with OPMDs displayed a general lack of awareness and negative attitudes towards early diagnosis and treatment. Conclusions: OPMDs among Arab dental patients are relatively uncommon and awareness about oral cancer among Jordanian dental patients is low. Interventions to improve public knowledge about oral cancer and attitudes toward early diagnosis and treatment are urgently indicated.