Advances in testing for human papillomavirus -mediated head and neck cancer.

PURPOSE OF REVIEW: New evidence has recently emerged regarding the utility and benefits of dual p16 INKa (p16) and Human papillomavirus (HPV) status testing when determining the diagnosis and prognosis of patients with oropharyngeal cancer. RECENT FINDINGS: HPV RNA polymerase chain reaction (PCR) is the most accurate diagnostic test. The other assays (HPV DNA PCR, HPV DNA/RNA in-situ hybridization (ISH) and p16) applied to formalin fixed tumour tissue have varying but high sensitivities and specificities. Dual p16 and HPV testing identifies discordant (p16+/HPV- or p16-/HPV+) results in 9.2% of cases, who have significantly poorer prognoses than p16+/HPV+, particularly in smokers. The proportion of discordant cases varies by region, and appears to be highest in regions with lowest attributable (p16+/HPV+) fractions. Dual testing improves prognostication for oropharyngeal cancer cases by identifying discordant cases and improving the prognostic power of the Tumour Node Metastasis (TNM) classification, especially in regions with high discordant rates. SUMMARY: Dual testing is essential when considering patients for clinical trials of treatment de-escalation, and may be important when counselling patients on prognosis, especially in regions with high discordant rates and in smokers.

Clinical and molecular characteristics of Jordanian oropharyngeal cancer patients according to P16 expression: a retrospective study and a report of a novel biomarker.

The purpose of this study was to assess the clinicopathological features of oropharyngeal cancer patients in Jordan based on their HPV status. Sixty-nine biopsies from two hospitals were included. Tissue microarrays were prepared from formalin-fixed paraffin-embedded (FFPE) specimens and stained with antibodies for CDKN2A/P16, EGFR, PI3K, PTEN, AKT, pS473AKT, PS2mTOR, and TIMAP. The cohort was divided according to P16 expression. Chi-square test and survival analyses were employed to evaluate the variations among the study variables and determine the prognostic factors, respectively. P16 expression was found in 55.1% of patients; however, there was no significant association between P16 expression and the patients' clinicopathological features. The Kaplan-Meier test revealed that smoking in P16-positive group and younger age (< 58 years) negatively impacted disease-free survival (DFS) (P = 0.04 and P = 0.003, respectively). Multivariate Cox regression test indicated that smoking, age, PI3K, and AKT were negative predictors of DFS (P = 0.021, P = 0.002, P = 0.021, and P = 0.009, respectively), while TIMAP was a positive predictor (P = 0.045). Elevated P16 expression is found in more than half of the patients' specimens. DFS is negatively affected by younger age and the combined effect of smoking and P16 overexpression. TIMAP is overexpressed in P16-positive oropharyngeal cancer, and it is a favorable predictor of DFS.

Etiology, diagnosis, treatment, and prevention of human papilloma virus-associated oropharyngeal squamous cell carcinoma.

Classical oropharyngeal squamous cell carcinoma (OPSCC) caused by alcohol consumption and smoking and HPV-associated OPSCC caused by human papillomavirus (HPV) infection have different etiologies, incidences, and prognoses. Therefore, the 8th American Joint committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM classifications propose distinguishing HPV-associated OPSCC from classical OPSCC and classifying it as an independent disease. Therefore, this review provides an overview of HPV-associated OPSCC from the perspectives of epidemiology, carcinogenesis, development, diagnosis, treatment, and prevention. The incidence of HPV-associated OPSCC is increasing. Although HPV vaccination has been shown to be effective at reducing the incidence of cervical cancer, it is still unclear how it affects the incidence of HPV-associated OPSCC. Additionally, the prognosis of patients with HPV-associated OPSCC is extremely favorable compared to that of patients with classical OPSCC. Therefore, patients with HPV-associated OPSCC may undergo reduced-dose therapy, although attempts to reduce treatment intensity should be carefully planned to ensure they do not compromise oncological outcomes, and large-scale trials aimed at reducing treatment intensity are ongoing.

Use of tongue base palpation among oral healthcare providers: Cross-sectional survey.

OBJECTIVES: To assess the use of tongue base palpation during cancer screening exams by Oral Healthcare Providers (OHPs) and explore attitudes about (1) the usefulness of oral cancer screening (OCS) in detecting early, asymptomatic lesions and (2) routine OCS of the general population. STUDY DESIGN: Survey study. SETTING: Private and hospital-based clinical practices of OHPs located in Massachusetts and Connecticut, United States. METHODS: An anonymous, online 9-item survey assessing beliefs and practice patterns about cancer screening exams was distributed to OHPs with practices in Massachusetts and Connecticut from August 2020 to June 2021. Data were analyzed using chi-square tests and Pearson correlations. Statistically significant levels were established at P < .050. RESULTS: One hundred seventy-one responses were analyzed (response rate 17 %). Tongue base palpation was performed as part of a routine cancer screening exam by 55 % of otolaryngologists, 34 % of dentists and 29 % of OMFS (P = .030). Providers who palpated the tongue base were also more likely to use palpation as an exam technique in the tonsils (r = 0.52 [95 % CI 0.40-0.62]; P < .001) among other intra-and extra-oral anatomical subsites. Almost all dentists (92 %) and OMFS (98 %) but only 58 % of otolaryngologists considered OCS useful for detection of early, asymptomatic malignant lesions in the oral cavity (P < .001). CONCLUSIONS: While tongue base palpation can detect oropharyngeal cancers in a pre-symptomatic stage, it is underutilized during routine cancer screening exams. Considering the rising incidence of oropharyngeal cancer, tongue base palpation should be established as a routine part of cancer screening by OHPs.

[ctHPV-DNA based precision oncology for patients with oropharyngeal cancer - Where are we?] / ctHPV-DNA-basierte Präzisionsonkologie für Patienten mit Oropharynxkarzinom ­ wo stehen wir?

Human papillomavirus (HPV) is an established etiologic factor for cancers in the head and neck region, specifically for Oropharyngeal Squamous Cell Carcinoma (OPSCC). The comparatively good overall survival justifies the current discussion regarding therapy de-escalation for patients with a low-risk profile. In addition to the immunohistochemistry-based biomarker p16INK4a, there is still a need for diagnostic and prognostic biomarkers that allow risk stratification and monitoring during therapy and follow-up of these patients. In recent years, liquid biopsy, especially in the form of plasma samples, has gained importance and is already used to monitor viral DNA in patients with Epstein-Barr virus-associated nasopharyngeal carcinoma. Circulating DNA (ctDNA) released by the tumor into the bloodstream is particularly suitable for a high specificity in detecting virus-associated tumors. Detection of viral E6 and E7 oncogenes in HPV-positive OPSCC is predominantly performed by droplet digital/quantitative PCR as well as next generation sequencing. Detection of circulating HPV-DNA derived from tumor cells (ctHPV-DNA) at diagnosis is associated with advanced tumor stage, locoregional and distant metastases. Longitudinal studies have further demonstrated that detectable and/or increasing ctHPV-DNA levels are associated with treatment failure and disease relapse. However, a standardization of the diagnostic procedure is necessary before introducing liquid biopsy into the clinical routine. In the future, this might allow a valid reflection of disease progression in HPV-positive OPSCC.

Performance of oral HPV DNA, oral HPV mRNA and circulating tumor HPV DNA in the detection of HPV-related oropharyngeal cancer and cancer of unknown primary.

A biomarker that is useful for the detection of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) and cancer of unknown primary (CUP) is indispensable. We evaluated the diagnostic performance of HPV DNA and mRNA in oral gargle samples and circulating tumor HPV16 DNA (ctHPV16DNA) in blood samples. Oral HPV DNA and mRNA were analyzed using commercially available HPV assays of the GENOSEARCH HPV31 and Aptima, respectively. ctHPV16DNA was analyzed using in-house droplet digital polymerase chain reaction. Seventy-four patients with OPC and eight patients with CUP were included. The sensitivity and specificity of oral HPV DNA, oral HPV mRNA, and ctHPV16DNA were 82% (95% confidence interval [CI] = 66-92) and 100% (95% CI = 88-100), 85% (95% CI = 69-94) and 94% (95% CI = 73-100), and 93% (95% CI = 81-99) and 97% (95% CI = 84-100), respectively, for HPV16-related OPC, while those were 20% (95% CI = 1-72) and 100% (95% CI = 3-100), 0% (95% CI = 0-52) and 100% (95% CI = 3-100), and 100% (95% CI = 54-100) and 100% (95% CI = 16-100), respectively, for HPV16-related CUP. The sensitivity of ctHPV16DNA for HPV16-related OPC was higher than that of oral biomarkers, though the difference was not statistically significant. ctHPV16DNA remarkably correlated with the anatomic extent of disease, total metabolic tumor volume and HPV16 copy number per tumor genome in patients with HPV16-related OPC/CUP, whereas oral biomarkers did not. In conclusion, ctHPV16DNA is a potentially promising biomarker for HPV16-related OPC, while further studies are required for HPV16-related CUP.

Lack of CD44 and Sox-2 Overexpression as Two Independent Favourable Prognostic Factors in HPV Positive Patients with Oropharyngeal Cancers.

INTRODUCTION: In our earlier publications, in the group of 63 patients with oropharyngeal cancer, we have found HPV16 infection (assessed by qPCR) in 25 tumours (39.7%), immunohistochemical overexpression of CD44, CD98, ALDH1/2 and Nanog in, respectively: 43 (68.2%), 30 (47.6%), 33 (52.4%), and 53 (84.1%) cancers. Analysing CD44, CD98, ALDH1/2, we have also shown that lack of CD44 overexpression indicates excellent prognosis in patients with HPV16 positivity. The aim of the present study was to compare prognostic potential of Nanog, Oct3/4, Sox-2 expression in relation to CD44, CD98, ALDH1/2 immunoreactivity (assessed by us earlier) and clinicopathological features in the subgroups of patients: with HPV16 positivity and HPV16 negativity. METHODS: Status of Oct3/4 and Sox-2 expression was assessed for 63 patients with oropharyngeal cancers based on immunohistochemistry. In survival analysis, two endpoints were applied: overall survival (OS) and disease-free survival (DFS). RESULTS: Overexpression of Oct3/4 and Sox-2 was found in 0 (0.0%) and 27 (42.9%) of patients. In the subgroup with HPV16 positivity, the DFS for patients with lack of Sox-2 overexpression was significantly (p = 0.003) higher than for patients with Sox-2 overexpression. In the subgroup with HPV16 negativity, Nanog and Sox-2 immunoexpression did not significantly influence OS and DFS. In multivariate analysis performed for the subgroup with HPV16 positivity, lack of CD44 overexpression (p = 0.012) and lack of Sox-2 overexpression (p = 0.027) were positive independent prognostic factors. CONCLUSION: Based on CD44 and Sox-2 immunoreactivity, it is possible to differentiate the prognosis of HPV16-positive patients with oropharyngeal cancers.

Accuracy of high-risk HPV DNA PCR, p16(INK4a) immunohistochemistry or the combination of both to diagnose HPV-driven oropharyngeal cancer.

BACKGROUND: The incidence of high-risk human papillomavirus (hrHPV)-driven head and neck squamous cell carcinoma, in particular oropharyngeal cancers (OPC), is increasing in high-resource countries. Patients with HPV-induced cancer respond better to treatment and consequently have lower case-fatality rates than patients with HPV-unrelated OPC. These considerations highlight the importance of reliable and accurate markers to diagnose truly HPV-induced OPC. METHODS: The accuracy of three possible test strategies, i.e. (a) hrHPV DNA PCR (DNA), (b) p16(INK4a) immunohistochemistry (IHC) (p16), and (c) the combination of both tests (considering joint DNA and p16 positivity as positivity criterion), was analysed in tissue samples from 99 Belgian OPC patients enrolled in the HPV-AHEAD study. Presence of HPV E6*I mRNA (mRNA) was considered as the reference, indicating HPV etiology. RESULTS: Ninety-nine OPC patients were included, for which the positivity rates were 36.4%, 34.0% and 28.9% for DNA, p16 and mRNA, respectively. Ninety-five OPC patients had valid test results for all three tests (DNA, p16 and mRNA). Using mRNA status as the reference, DNA testing showed 100% (28/28) sensitivity, and 92.5% (62/67) specificity for the detection of HPV-driven cancer. p16 was 96.4% (27/28) sensitive and equally specific (92.5%; 62/67). The sensitivity and specificity of combined p16 + DNA testing was 96.4% (27/28) and 97.0% (65/67), respectively. In this series, p16 alone and combined p16 + DNA missed 1 in 28 HPV driven cancers, but p16 alone misclassified 5 in 67 non-HPV driven as positive, whereas combined testing would misclassify only 2 in 67. CONCLUSIONS: Single hrHPV DNA PCR and p16(INK4a) IHC are highly sensitive but less specific than using combined testing to diagnose HPV-driven OPC patients. Disease prognostication can be encouraged based on this combined test result.

HPV as a Carcinomic Driver in Head and Neck Cancer: a De-escalated Future?

OPINION STATEMENT: Patients with HPV-associated oropharyngeal squamous cell carcinoma have improved prognosis relatively to those with tumors not driven by HPV. Both definitive radiotherapy (typically with concurrent chemotherapy) and transoral robotic surgery (with adjuvant therapies based on pathologic risk factors) are both acceptable treatment options for patients. The decision on which treatment is optimal depends on individual patient factors and should be made in a multi-disciplinary setting with input from a radiation oncologist, head and neck surgeon, and medical oncologist. Where appropriate, patients in this setting should be considered for enrollment on clinical studies evaluating de-escalation of treatment intensity given the very favorable outcomes and high toxicity profile associated with conventional therapies. However, caution is needed given negative data for de-escalation in the definitive chemotherapy and radiation setting. It remains unclear what the prognostic significance of HPV status is in patients with squamous cell carcinomas of the head and neck outside of the oropharynx.

Accuracy of liquid-based brush cytology and HPV detection for the diagnosis and management of patients with oropharyngeal and oral cancer.

OBJECTIVES: This study aims to evaluate the usefulness of liquid-based brush cytology for malignancy diagnosis and HPV detection in patients with suspected oropharyngeal and oral carcinomas, as well as for the diagnosis of tumoral persistence after treatment. MATERIAL AND METHODS: Seventy-five patients with suspicion of squamous cell carcinoma of the oropharynx or oral cavity were included. Two different study groups were analyzed according to the date of the sample collection: (1) during the first endoscopy exploration and (2) in the first control endoscopy after treatment for squamous cell carcinoma. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for malignancy diagnosis as well as for HPV-DNA detection on brush cytologies were assessed. RESULTS: Before treatment, the brush cytology showed a sensitivity of 88%, specificity of 100%, and accuracy of 88%. After treatment, it showed a sensitivity of 71%, specificity of 77%, and accuracy of 75%. HPV-DNA detection in cytology samples showed a sensitivity of 85%, specificity of 100%, and accuracy of 91% before treatment and an accuracy of 100% after treatment. CONCLUSIONS: Liquid-based brush cytology showed good accuracy for diagnosis of oropharyngeal and oral squamous cell carcinoma before treatment, but its value decreases after treatment. Nevertheless, it is useful for HPV-DNA detection, as well as to monitor the patients after treatment. CLINICAL RELEVANCE: Brush cytology samples are reliable for the detection of HPV-DNA before and after treatment and may be a useful method to incorporate in the HPV testing guidelines.

Machine Learning to Predict Treatment in Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVES: This study seeks to (1) demonstrate how machine learning (ML) can be used for prediction modeling by predicting the treatment patients with T1-2, N0-N1 oropharyngeal squamous cell carcinoma (OPSCC) receive and (2) assess the impact patient, socioeconomic, regional, and institutional factors have in the treatment of this population. METHODS: A retrospective cohort of adults diagnosed with T1-2, N0-N1 OPSCC from 2004 to 2013 was obtained using the National Cancer Database. The data was split into 80/20 distribution for training and testing, respectively. Various ML algorithms were explored for development. Area under the curve (AUC), accuracy, precision, and recall were calculated for the final model. RESULTS: Among the 19,111 patients in the study, the mean (standard deviation) age was 61.3 (10.8) years, 14,034 (73%) were male, and 17,292 (91%) were white. Surgery was the primary treatment in 9,533 (50%) cases and radiation in 9,578 (50%) cases. The model heavily utilized T-stage, primary site, N-stage, grade, and type of treatment facility to predict the primary treatment modality. The final model yielded an AUC of 78% (95% CI, 77-79%), accuracy of 71%, precision of 72%, and recall of 71%. CONCLUSION: This study created a ML model utilizing clinical variables to predict primary treatment modality for T1-2, N0-N1 OPSCC. This study demonstrates how ML can be used for prediction modeling while also highlighting that tumor and facility realted variables impact the decision making process on a national level.

Human Papillomavirus and Oral Lesions: What is the Best Diagnostic Method?

ABSTRACT: Oropharyngeal squamous cell carcinoma is the most common neoplasm of head and neck cancers related to the presence of human papillomavirus (HPV). in the dental, maxillofacial and ENT fields, the finding of mediated HPV lesions is quite common. The diagnostic techniques currently available are different and can be more or less invasive depending on the type of lesion and the need for the clinician. In this study, two clinical cases subjected to a double diagnostic technique were considered in order to exclude any possible risk of false negatives. The polymerase chain reaction (PCR) technique showed a lower sensitivity or in any case dictated by a limited number of HPV strains analyzed. Histological examination nowadays turns out to be the best diagnostic method despite requiring a surgical phase.

Fluid Biomarkers in HPV and Non-HPV Related Oropharyngeal Carcinomas: From Diagnosis and Monitoring to Prognostication-A Systematic Review.

Biomarkers are crucial in oncology, from detection and monitoring to guiding management and predicting treatment outcomes. Histological assessment of tissue biopsies is currently the gold standard for oropharyngeal cancers, but is technically demanding, invasive, and expensive. This systematic review aims to review current markers that are detectable in biofluids, which offer promising non-invasive alternatives in oropharyngeal carcinomas (OPCs). A total of 174 clinical trials from the PubMed search engine in the last 5 years were identified and screened by 4 independent reviewers. From these, 38 eligible clinical trials were found and subsequently reviewed. The biomarkers involved, categorized by human papillomavirus (HPV)-status, were further divided according to molecular and cellular levels. Recent trials investigating biomarkers for both HPV-positive and HPV-negative OPCs have approaches from various levels and different biofluids including plasma, oropharyngeal swabs, and oral rinse. Promising candidates have been found to aid in detection, staging, and predicting prognosis, in addition to well-established factors including HPV-status, drinking and smoking status. These studies also emphasize the possibility of enhancing prediction results and increasing statistical significance by multivariate analyses. Liquid biopsies offer promising assistance in enhancing personalized medicine for cancer treatment, from lowering barriers towards early screening, to facilitating de-escalation of treatment. However, further research is needed, and the combination of liquid biopsies with pre-existing methods, including in vivo imaging and invasive techniques such as neck dissections, could also be explored in future trials.

Robotic vs. transoral laser surgery of malignant oropharyngeal tumors-what is best for the patient? : A contemporary review.

Human papillomavirus (HPV)-associated squamous cell carcinoma of the oropharynx is a malignancy of increasing prevalence. The oncologic community is currently evaluating the safety and efficacy of de-intensifying treatment without compromising oncologic outcomes. Paramount to these treatment algorithms is primary surgery through transoral approaches. This article reviews the literature and concepts pertaining to transoral surgery and describes the two most common techniques, transoral laser microsurgery (TLM) and transoral robotic surgery (TORS).

Natural history of oral HPV infection: Longitudinal analyses in prospective cohorts from Australia.

Oral infection with human papillomavirus (HPV) is likely to underpin the rapidly rising incidence of oropharyngeal squamous cell carcinoma; however, there are few data describing the natural history of oral HPV infection. We recruited 704 participants aged 20 to 70 years from worksites, universities and primary care practices in Brisbane, Australia. Participants completed questionnaires at baseline, 12 and 24 months and donate four saliva samples at baseline, 6, 12 and 24 months for HPV polymerase chain reaction testing and typing. We estimated the prevalence of oral HPV infection at baseline, incidence of new infections among those HPV-negative at baseline, clearance rate and persistent infections. At baseline, 10.7% of participants had oral HPV infections from 26 different HPV types. Sexual behaviours were associated with oral HPV infection, including more partners for passionate kissing (29 or more; odds ratio [OR] 3.4, 95% confidence interval [CI] 1.5-8.0), and giving and receiving oral sex (16 or more; OR 5.4, 95% CI 1.6-17.7 and OR 5.6, 95% CI 1.6-18.7, respectively). Of 343 participants, HPV-free at baseline and with subsequent saliva samples, 87 (25%) acquired new infections over the 24 months. Sixty-eight of 87 people included in the clearance analysis (78%) cleared their oral HPV infections. Clearance was associated with being a nonsmoker (OR 12.7, 95% CI 1.3-122.8), and no previous diagnosis of a sexually transmitted infection (OR 6.2, 95% CI 2.0-19.9). New oral infections with HPV in this sample were not rare. Although most infections were cleared, clearance was not universal suggesting a reservoir of infection exists that might predispose to oropharyngeal carcinogenesis.

Prediction of the local treatment outcome in patients with oropharyngeal squamous cell carcinoma using deep learning analysis of pretreatment FDG-PET images.

BACKGROUND: This study aimed to assess the utility of deep learning analysis using pretreatment FDG-PET images to predict local treatment outcome in oropharyngeal squamous cell carcinoma (OPSCC) patients. METHODS: One hundred fifty-four OPSCC patients who received pretreatment FDG-PET were included and divided into training (n = 102) and test (n = 52) sets. The diagnosis of local failure and local progression-free survival (PFS) rates were obtained from patient medical records. In deep learning analyses, axial and coronal images were assessed by three different architectures (AlexNet, GoogLeNET, and ResNet). In the training set, FDG-PET images were analyzed after the data augmentation process for the diagnostic model creation. A multivariate clinical model was also created using a binomial logistic regression model from a patient's clinical characteristics. The test data set was subsequently analyzed for confirmation of diagnostic accuracy. Assessment of local PFS rates was also performed. RESULTS: Training sessions were successfully performed with an accuracy of 74-89%. ROC curve analyses revealed an AUC of 0.61-0.85 by the deep learning model in the test set, whereas it was 0.62 by T-stage, 0.59 by clinical stage, and 0.74 by a multivariate clinical model. The highest AUC (0.85) was obtained with deep learning analysis of ResNet architecture. Cox proportional hazards regression analysis revealed deep learning-based classification by a multivariate clinical model (P < .05), and ResNet (P < .001) was a significant predictor of the treatment outcome. In the Kaplan-Meier analysis, the deep learning-based classification divided the patient's local PFS rate better than the T-stage, clinical stage, and a multivariate clinical model. CONCLUSIONS: Deep learning-based diagnostic model with FDG-PET images indicated its possibility to predict local treatment outcomes in OPSCCs.

RNA in situ hybridization for human papillomavirus testing in oropharyngeal squamous cell carcinoma on a routine clinical diagnostic platform.

BACKGROUND: The current diagnostic standard for detection of high-risk human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma is via a two-stage algorithm, namely p16 immunohistochemistry followed by HPV DNA in situ hybridization in p16 positive cases. This study evaluated the feasibility of automated RNA in situ hybridization on a clinical platform as a single-step alternative to the two-stage algorithm within a routine diagnostic histopathology setting. METHODS: Thirty-eight cases positive for both p16 and DNA in situ hybridization, 42 p16 negative cases and 20 cases positive for p16 but negative for DNA in situ hybridization were randomly selected. High-risk HPV RNA in situ hybridization was undertaken on all cases on an automated clinical platform. Manufacturer-recommended and on-slide additional p16/HPV positive and negative controls were used. Test quality assurance and diagnostic RNA in situ hybridization were independently assessed by two observers. A consensus diagnosis was reached in the presence of a third observer on discordant cases. All RNA in situ hybridization results were then correlated against p16 and DNA ISH status. RESULTS: Inter-slide RNA in situ hybridization staining variation was observed in control sections. RNA in situ hybridization demonstrated a high inter-observer agreement rate (κ = .897, P < .001). Following consensus review, there was full concordance between RNA in situ hybridization and the current standard. CONCLUSION: Human papillomavirus testing by standalone automated RNA in situ hybridization on a clinical diagnostic platform currently available in routine diagnostic histopathology laboratories is a feasible alternative to the two-step algorithm of p16 and DNA in situ hybridization. Control tissue staining procedures need to be adapted to achieve the most accurate results.

Diagnostic approaches to carcinoma of unknown primary of the head and neck.

Squamous cell carcinoma in cervical lymph nodes arising from an undetected primary tumour, termed carcinoma of unknown primary (SCCUP), is a well-recognized clinical presentation within head and neck oncology. SCCUP is a common presentation for patients with human papillomavirus-mediated oropharyngeal cancer (HPV + OPSCC), as patients with HPV + OPSCC often present with smaller primary tumours and early nodal metastasis. Meticulous work-up of the SCCUP patient is central to the management of these patients as identification of the primary site improves overall survival and allows for definitive oncologic resection or more focused radiation when indicated. This review summarizes the comprehensive diagnostic approach to the SCCUP patient, including history and physical examination, methods of biopsy of the cervical lymph node, imaging modalities and intraoperative methods to localize the unknown primary. Novel techniques such as transcervical ultrasound of the oropharynx, narrow band imaging and diagnostic transoral robotic surgery are also discussed.

Prognostic impact of additional HPV diagnostics in 102 patients with p16-stratified advanced oropharyngeal squamous cell carcinoma.

PURPOSE: p16 overexpression was considered as surrogate marker to identify human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCCs). METHODS: 102 patients with advanced stage OPSCCs treated primarily by transoral lasermicrosurgery were included. Prognostic associations of p16- and HPV-status were analyzed separately and combined. RESULTS: In contrast to p16, the HPV-status resulted in no significant survival discrepancies (5-year overall survival (OS) HPV-positive 64.9%, HPV-negative 78.7%). Combining both markers, p16-positive (p16-positive/HPV-positive, p16-positive/HPV-negative) and p16-negative/HPV-negative groups demonstrated comparable high survival (OS 78.1% vs. 85.6% vs. 73.6%). Lowest survival was observed for patients with p16-negative/HPV-positive OPSCCs (OS 40.8%). Never smoking patients with p16-positive OPSCCs demonstrated the highest survival, whereas within former/current smokers with p16-positive and p16-negative disease it was comparable low (OS 90.0% vs. 63.0% vs. 57.4%). CONCLUSIONS: p16- and HPV-status should not be considered as equivalent markers for a better prognosis. Furthermore, they should not generally predominate patient associated factors like smoking.

Oral Cavity and Oropharyngeal Cancer Surveillance and Control in Alberta: A Scoping Review.

OBJECTIVES: This scoping review provides a comprehensive overview of oral cavity cancer (OCC) and oropharyngeal cancer (OPC) in Alberta. METHODS: A database search was conducted up to 2018 using Web of Science, Scopus, Medline, PubMed and Embase, along with a manual search of gray literature. Data from the Alberta Cancer Foundation's dedicated fund for research, Cancer Surveillance and Reporting and Alberta Cancer Registry were also collected. RESULTS: Our review included 8 published papers and 14 other sources, including data on 3448 OCC and OPC patients from Surveillance and Reporting and Alberta Cancer Registry. Cancer registry data (2005-2017) showed that most OCC and OPC lesions were diagnosed at an advanced clinical stage, with a significantly large number of advanced OPC lesions in stage IV (OCC 45.2%, OPC 82.4%); 47.9% of these patients died. Survival rates were lowest in rural and First Nations areas. In Alberta, 35% of HPV-associated cancers were linked to OPCs, which were more prevalent in men and younger age groups. No routine public oral cancer screening program currently exists in Alberta. General practitioners and dentists refer patients to specialists, often with long waiting times. CONCLUSION: OCC and OPC patients in Alberta continue to be diagnosed in stage IV and experience high mortality rates.