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Introduction: Squamous cell carcinoma of unknown primary in the head and neck (HNSCCUP) remains a diagnostic challenge. Tongue base mucosectomy by transoral robotic surgery (TORS-TBM) can increase the diagnostic yield and de-intensify treatment. However, the added value of TORS-TBM as an adjunct to work-up programs for HNSCCUP is unclear. Furthermore, the optimal extent of the procedure and selection criteria remain to be established., Aim: The primary aim of the present study was to assess the diagnostic yield of TORS-TBM as a supplement to a standardized work-up program, using the Danish national guidelines as an example. Secondary aims include predictive values of HPV-testing and PET/CT., Methods: This was a national multicenter observational cohort study including all patients diagnosed with HNSCCUP from January 2013 to December 2019, who subsequently underwent TORS-TBM. In most cases HPV status was based on dual testing (p16 and HPV-DNA). Predictive values of PET/CT and HPV status were calculated., Results: A total of 100 consecutive patients underwent TORS-TBM; 93 total TBMs and 7 unilateral TBMs. The primary tumor was detected in 49 % (49/100) of patients. The detection rate was 58 % (47/81) in patients with HPV-associated disease (PPV of HPV status) and 11 % (2/19) in patients with HPV-independent disease. The NPV of HPV status was 89 %. The PPV and NPV of PET/CT was 53 % and 52 %, respectively., Conclusion: Adding total TORS-TBM to the current Danish guideline-based work-up program on HNCCCUP patients with HPV-associated disease significantly improved the diagnostic yield., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Squamous cell carcinomas of unknown primary (SCCUP) are often Human Papillomavirus (HPV)-positive. Due to their small size, extensive surgical workup is required to locate the primary tumors. High-frequency transoral ultrasound (US) may provide improved visualization of these small tumors. Our study aimed to explore whether surgeon-performed intraoperative transoral US for patients with HPV-positiveSCCUP could improve primary tumor detection during panendoscopy., Methods: This was a single-center, prospective diagnostic study including patients undergoing panendoscopy under general anesthesia with HPV-positive SCCUP. Preoperative MRIs, PET/CTs, and HPV DNA-testing of lymph node metastases were performed in all patients. Intraoperative transoral US was performed prior to panendoscopy. Frozen section biopsies were performed unblinded to US results, and transoral US-guided biopsies were attempted if initial biopsies were negative. Final histopathology was obtained with palatine- and/or lingual tonsillectomy if frozen section was negative. The main outcome was the primary tumor detection rate with intraoperative transoral US and panendoscopy., Results: Thirty patients were included: 24 (80 %) were men, and the median age was 60 years [range 35-79 years]. Twenty-nine primary tumors (97 %) were confirmed; 18 (62 %) and 10 (34 %) in the lingual- and palatine tonsils, respectively, and one (3 %) in the posterior oropharynx. Transoral US had a significantly higher sensitivity than panendoscopy to locate the primary tumor (93 % vs 76 %, p = 0.02), and significantly higher than pre-operative PET/CT (62 %, p = 0.002), CT (45 %, p < 0.001), and MRI (28 %, p < 0.001)., Conclusions: Intraoperative transoral US during panendoscopy is a promising diagnostic tool that may improve the detection of HPV-positive SCCUP., Competing Interests: Declaration of competing interest None of the authors declare any competing financial interests or personal relationships that could have appeared to incluence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased in recent decades, driven by infection with human papillomavirus (HPV). Transoral robotic surgery (TORS) and neck dissection (ND) has been employed as an alternative to radiotherapy/chemoradiotherapy. The current literature is lacking studies providing an exhaustive overview of recurrence characteristics and long-term outcomes in TORS-treated OPSCC-patients., Methods: All patients treated for OPSCC with primary TORS + ND in Eastern Denmark between 2013 and 2020 were included in the study. The aim was to explore overall survival (OS), recurrence-free survival (RFS), recurrence patterns, and ultimate failure rate (UFR). OS and RFS were examined using the Kaplan-Meier method. Cox proportional regression analyses were employed to examine effect of different variables on risk of death and recurrence., Results: The study included 153 patients of which 88.9 % (n = 136) were treated with TORS alone while 11.1 % (n = 17) received adjuvant therapy. The 1-, 3-, and 5-year OS were 97.4 %, 94.1 %, and 87.6 % while 1-, 3-, and 5-year RFS were 96.6 %, 87.8 %, and 84.9 %. The UFR was 6.5 % in the cohort. Patients with HPV+/p16 + OPSCC had a significantly better 5-year OS of 92.3 % than patients with discordant or double-negative HPV/p16 status (OS = 73.3 %). No differences in outcomes between patients treated with or without adjuvant therapy were found in regression analysis., Conclusion: Excellent survival and disease control was obtained with TORS + ND in this cohort, despite lesser application of adjuvant therapy than other TORS-centers, implying that TORS without adjuvant therapy can be successfully applied in treatment of early-stage OPSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Oral squamous cell carcinoma (OSCC) is responsible for high morbidity and mortality worldwide. Although the oral cavity encompasses different anatomical subsites, it is unclear whether subsite localization of carcinoma influences outcome., Methods: This retrospective cohort study examined overall survival (OS), recurrence-free survival (RFS) and local recurrence-free survival (L-RFS) at different subsites by Kaplan-Meier survival curves. Cox proportional hazards regression analysis was performed to investigate the impact of subsite on overall death, locoregional recurrence, and local recurrence., Results: The cohort included 1702 patients treated with curative intent for OSCC according to standardized national guidelines. The 5-year OS was superior in oral tongue to retromolar trigone as well as in both oral tongue and floor-of-mouth (FOM) compared to tumors involving multiple locations. The 3-year RFS in oral tongue and FOM was superior to tumors involving multiple locations, and in FOM compared to retromolar trigone. The 3-year L-RFS in oral tongue and FOM was higher than gingiva, retromolar trigone and tumors involving multiple locations. Adjusting for relevant covariables using oral tongue as reference, tumors involving multiple locations was the only category presenting higher risk for locoregional recurrence, while risk of local recurrence was higher in gingiva, retromolar trigone, hard palate and to tumors involving multiple locations. The study found no difference in risk of death between subsites., Conclusion: The study found differences in survival outcomes between subsites. After adjusting for covariables, subsite mainly had significant impact on local recurrence, with no distinct pattern of influence on overall death or locoregional recurrence., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Comorbid conditions impact outcome for patients treated for oropharyngeal squamous cell carcinoma (OPSCC) and serve as competing risk factors for death. The purpose of this study was to examine differences in comorbidities in patients with OPSCC and known HPV-DNA., Material and Methods: We included patients diagnosed with OPSCC in Eastern Denmark in 2000-2014. Patients were linked to the Danish National Patient Register to identify comorbidities based on the Charlson Comorbidity Index (CCI) at time of diagnosis and following cancer treatment. Patients were age-and sex-matched in a 1:10 ratio with a reference group and stratified according to HPV-status., Results: In total 1,499 patients (55.0% HPV+) and 14,990 controls were included. Significantly more HPV+ patients had no comorbidities compared to HPV- patients at time of diagnosis (RR: 1.5 (1.3;1.6), n = HPV+: 522, HPV-: 302) and following treatment (RR 1.5 (1.4;1.6), n = HPV+: 342, HPV-: 142). Most prevalent comorbidity was malignancy not including OPSCCs. HPV+ patients had an increased risk of having AIDS before their OPSCC diagnosis compared to the reference population (OR: 4.8 (1.8;12.9)). HPV- patients had increased risk of multiple comorbidities including cerebrovascular disease (OR: 1.9 (1.4;2.5)), peripheral vascular disease (OR: 1.7 (1.9;3.7)), dementia (OR: 2.9 (1.4;5.8)), ulcer disease (OR: 2.6 (1.9;3.5)), liver disease, mild (OR: 9.5 (7.0;13.0)) and severe (OR: 13.9 (5.8;22.8))., Conclusion: This study showed that HPV- patients had more comorbidities than HPV+ patients at the diagnosis time and following treatment. Irrespective of HPV-status, OPSCC patients had a significant increased risk of (secondary) malignancy compared to the reference population., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent malignancy worldwide. Immunotherapy with checkpoint inhibitors such as anti-CTLA-4 anti-PD-l and anti-PD-L1 has shown promising results in treating patients with recurrent/metastatic HNSCC. We aimed to systematically review the literature on immunotherapy with checkpoint inhibitors as treatment for advanced HNSCC., Methods: PubMed, EMBASE, Google Scholar, and the Cochrane Library were systematically searched with the purpose of identifying all studies addressing the effects of checkpoint inhibitors as treatment for HNSCC in human clinical trials. We assessed effects of the treatment with checkpoint inhibitors on overall survival (OS), progression-free survival (PFS), HPV-status, PD-L1-status, and adverse events., Results: We identified eight studies (n = 1431 patients) with an OS ranging from 7.5 to 14.9 months in PD-1 checkpoint inhibition. Two studies (n = 541 patients) observed a significantly (p = 0.01) and (p = 0.007) longer OS with checkpoint inhibition compared to standard-treatment, platinum-based chemotherapy (7.5 versus 5.1 months and 14.9 months versus 10.7 months). Two studies (n = 411 patients) found an increased OS associated with PD-L1-postive patients compared to PD-L1-negative patients. The eight studies have heterogenous design with only three being randomized., Conclusion: Few clinical trials have investigated the treatment with checkpoint inhibition for HNSCC. Solely, two randomized studies comprising 240 patients treated with nivolumab (anti-PD-L) and 301 patients treated with pembrolizumab (anti-PD-L) showed a significantly prolonged survival in patients with recurrent/metastatic HNSCC compared with standard-treatment. There is a further need for randomized clinical trials investigating a putative role of checkpoint inhibition in the treatment of advanced HNSCC., (Copyright © 2019. Published by Elsevier Ltd.)

Background: MicroRNAs (miRNAs) hold promise as diagnostic cancer biomarkers. Here we aimed to define the miRNome in oral squamous cell carcinoma (OSCC) and normal oral mucosa (NOM), and to identify and validate new diagnostic miRNAs and miRNA combinations in formalin-fixed paraffin-embedded (FFPE) tissue samples and plasma samples., Methods: We performed next-generation miRNA sequencing in FFPE tissue samples of OSCC (n = 80) and NOM (n = 8). Our findings were validated by quantitative polymerase chain reaction (qPCR) analysis of OSCC (n = 195) and NOM (n = 103) FFPE tissue samples, and plasma samples from OSCC patients (n = 55) and healthy persons (n = 18)., Results: The OSCC miRNome included 567 miRNAs, 66 of which were differentially expressed between OSCC and NOM. Using qPCR data, we constructed receiver operating curves to classify patients as NOM or OSCC based on miRNA combinations. The area under the curve was of 0.92 from FFPE tissue (miR-204-5p, miR-370, miR-1307, miR-193b-3p, and miR-144-5p), and 1.0 from plasma samples (miR-30a-5p and miR-769-5p). Model calibration and discrimination were evaluated using 10-fold cross-validation., Conclusions: Analysis of the miRNome from many OSCC cases improves our knowledge of the importance of individual miRNAs and their predictive potential in OSCC. We successfully identified miRNA classifiers in FFPE OSCC tissue and plasma with a high discriminatory ability between OSCC and NOM. The proposed combination of miR-30a-5p and miR-769-5p in plasma from OSCC patients could serve as a minimal invasive biomarker for diagnosis and control of T-site recurrences., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: The incidence of human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) is increasing. Currently, data is sparse on the pattern and timing of recurrence. This long-term study concerning both HPV- and p16-status aimed to report predictive factors, pattern, timing of loco-regional recurrence (LRR) and distant recurrence (DR), and survival following recurrence in patients diagnosed with OPSCC., Material and Methods: We included patients diagnosed with OPSCC from 2000 to 2014 in Eastern Denmark, who were treated with curative intent. Tumors were defined as HPV-positive when they were both HPV-DNA and p16-positive. Time-to-failure and -death were estimated by the Kaplan-Meier method. Cox proportional hazards models were used to evaluate predictors of failure., Results: The cohort consisted of 1244 consecutive patients with OPSCC of which 288 patients (23%) experienced recurrence. Of these patients, the majority (n = 197/1244; 16%) experienced LRR and the remaining (n = 91/1244; 7%) DR. Significantly more HPV-negative patients experienced recurrence (n = 170/486; 35%) compared to HPV-positive patient (n = 112/726; 15%). DR occurred for both groups predominantly to the lung (n = 63/91; 69.2%) followed by the liver and bone. Factors influencing risk of LRR included gender, T-classification, and HPV-status. The same variables influenced risk of DR in addition to the UICC-8 classification, N-classification, pack years of smoking, and performance status. HPV-status was the strongest risk factor for LRR and DR., Conclusion: LRR and DR occur significantly less often in HPV-positive patients compared with HPV-negative patients. HPV-status is an independent and strong predictor of recurrence. DR most commonly occurs to the lungs, irrespective of HPV-status., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) represents a distinct tumour entity in comparison to HPV-negative OPSCC. The clinical, radiological, morphological features and distribution of HPV E6/E7 mRNA were investigated in resected specimens of OPSCC., Methods: We retrieved formalin-fixed, paraffin-embedded whole section slides from 24 p16/HPV-DNA positive and 18 p16/HPV-DNA negative primary tumours and 16 corresponding metastases in patients with early-stage OPSCC who underwent planned curative or diagnostic primary transoral robotic surgery. A detailed clinicoradiological and histopathological investigation of the tumours was performed along with detection of HPV E6/E7 mRNA by in situ hybridisation., Results: HPV-driven OPSCC was characterised by non-keratinising morphology and was dominated by a cohesive invasion pattern at the leading edge of the tumour. Dysplastic zones of the squamous epithelium were strictly located in the tonsillar crypts in contrast to HPV-negative OPSCC which predominantly arised from the dysplastic surface epithelium. Thirteen HPV-driven OPSCC invaded through the tonsillar lymphoid compartment and into soft tissue, causing a stromal desmoplastic reaction. HPV mRNA was consistently but inhomogenously expressed in the entire tumour area and in the dysplastic squamous epithelium. There was no HPV expression in the adjacent normal epithelium and in the non-neoplastic tissues., Conclusions: This study enhances the current understanding of HPV-driven OPSCC. Only tumours that invade through the lymphoid compartment induce a stromal desmoplastic reaction. A consistent but inhomogenous expression of E6 and E7 mRNA was found in tumour and dysplastic areas, emphasizing that the E6/E7 oncogenes are the driving factors in HPV-driven OPSCC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing, but data on the incidence of synchronous, bilateral tonsillar squamous cell carcinomas (BiTSCCs) is sparse. In this study, we report the incidence and tumour characteristics of BiTSCCs in a population-based, consecutive cohort of OPSCCs., Methods: We identified all patients diagnosed with tonsillar squamous cell carcinoma (TSCC) in eastern Denmark during a 15-year period to detect the incidence of synchronous BiTSCCs. The tumours were assessed for p16 Ink4a expression, the presence of HPV DNA and HPV genotypes. Furthermore, we systematically reviewed the literature examining BiTSCCs., Results: Of the total of 1119 TSCCs diagnosed in eastern Denmark from 2000 to 2014, we identified 12 BiTSCCs, nine of which initially presented as a cancer of unknown primary (CUP) in the neck. Nine cases were bilaterally HPV16 positive (HPV16+), while two cases were HPV16+ in one tonsil and respectively, HPV33 and HPV35 positive in the contralateral tonsil. One case was bilaterally HPV-negative. We also identified an increase in the incidence of BiTSCCs after 2012 when histological examination of the entire tonsil tissue became routine, suggesting that BiTSCCs might be underdiagnosed. In the literature, we identified 15 studies from six countries, encompassing 25 cases in total., Conclusions: BiTSCCs were primarily HPV16+ and were most often diagnosed as part of the diagnostic work-up for CUP. We found an incidence of 9% BiTSCCs in patients with TSCC after 2012 and we therefore recommend focusing on putative BiTSCC with total embedding and histological examination of tonsils harvested by bilateral tonsillectomies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Currently, oropharyngeal squamous cell carcinomas (OPSCC) are treated based on the traditional TNM-classification, although this scheme might be inadequate for the subgroup of human papillomavirus (HPV)-associated OPSCCs. It remains debatable whether this subgroup of patients with favorable prognosis should be offered altered treatment. Besides the well-known biomarkers of HPV and p16, new promising immune cells and markers might nuance the prognosis and treatment for patients with HPV+ OPSCC. We systematically reviewed the literature on immunological features of HPV-associated OPSCCs, and report that a high number of cytotoxic T cells (CD8s) and a low number of CD98 positive cells is associated with better outcome, while an increased CD4/CD8 ratio and a high human leukocyte antigen 1 (HLA1) intensity is most likely associated with worse outcome. These findings might contribute to future OPSCC staging and treatment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)