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Objectives: The aim of this study was to investigate the value of metabolic tumor imaging using hybrid PET for the preoperative detection of extranodal extension (ENE) in lymph node metastases of oropharyngeal squamous cell carcinoma (OPSCC)., Methods: We performed a retrospective analysis of a consecutive cohort of patients with OPSCC treated with primary surgery with or without adjuvant (chemo-) radiotherapy at the Kantonsspital Sankt-Gallen and the University Hospital Zurich, Switzerland, from 2010 until 2019. Hybrid PET was compared to conventional cross-sectional imaging with MRI and CT. Histopathological presence of ENE of neck dissection specimen served as gold standard., Results: A total number of 234 patients were included in the study, 95 (40.6%) of which had pathological ENE (pENE). CT has a good specificity with 93.7%; meanwhile, MRI was the most sensitive diagnostic method (72.0%). The nodal metabolic tumor parameters (SUV max , TLG, MTV) were significantly higher in patients with positive ENE (p < 0.001 for all three parameters) than in patients with negative ENE (p < 0.001, for all three parameters)., Conclusions: CT achieved the best specificity, while MRI had the best sensitivity to detect ENE. Nodal metabolic tumor parameters differed significantly between ENE-positive/negative and p16-positive/negative patients. Hence, quantitative data obtained by metabolic imaging might predict presence of ENE and, therefore, could be helpful in customizing therapy management., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The purpose of this study was to determine the negative predictive value (NPV) of a 12- to 14-wk posttreatment PET/CT for 2-y progression-free survival (PFS) and locoregional control (LRC) in patients with p16-positive locoregionally advanced oropharyngeal cancer (LA-OPC). Study was a secondary endpoint in NRG-HN002, a noncomparative phase II trial in p16-positive LA-OPC, stage T1-T2, N1-N2b or T3, N0-N2b, and ≤10 pack-year smoking. Patients were randomized in a 1:1 ratio to reduced-dose intensity-modulated radiotherapy (IMRT) with or without cisplatin. Methods: PET/CT scans were reviewed centrally. Tumor response evaluations for the primary site, right neck, and left neck were performed using a 5-point ordinal scale (Hopkins criteria). Overall scores were then assigned as negative, positive, or indeterminate. Patients with a negative score for all 3 evaluation sites were given an overall score of negative. The hypotheses were NPV for PFS and LRC at 2-y posttreatment ≤ 90% versus >90% (1-sided P value, 0.10). Results: A total of 316 patients were enrolled, of whom 306 were randomized and eligible. Of these, 131 (42.8%) patients consented to a posttherapy PET/CT, and 117 (89.3%) patients were eligible for PET/CT analysis. The median time from the end of treatment to PET/CT scan was 94 d (range, 52-139 d). Estimated 2-y PFS and LRC rates in the analysis subgroup were 91.3% (95% CI, 84.6, 95.8%) and 93.8% (95% CI, 87.6, 97.5%), respectively. Posttreatment scans were negative for residual tumor for 115 patients (98.3%) and positive for 2 patients (1.7%). NPV for 2-y PFS was 92.0% (90% lower confidence bound [LCB] 87.7%; P = 0.30) and for LRC was 94.5% (90% LCB 90.6%; P = 0.07). Conclusion: In the context of deintensification with reduced-dose radiation, the NPV of a 12- to 14-wk posttherapy PET/CT for 2-y LRC is estimated to be >90%, similar to that reported for patients receiving standard chemoradiation. However, there is insufficient evidence to conclude that the NPV is >90% for PFS., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: No large-scale prospective randomized study with a long-term follow-up period has evaluated the survival outcomes of preconcurrent chemoradiotherapy (CCRT) 18-fluorodeoxyglucose positron emission tomography-computed tomography ( 18 FDG PET-CT) in patients with non-human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC)., Patients and Methods: We included patients with stage I-IVA p16-negative OPSCC receiving definitive CCRT and categorized them into two groups according to pre-CCRT 18 FDG PET-CT and compared their outcomes: the case group consisted of patients who underwent pre-CCRT 18 FDG PET-CT, whereas the comparison group consisted of patients who did not receive pre-CCRT 18 FDG PET-CT., Results: The final cohort consisted of 3942 patients (1663 and 2279 in the case and comparison groups, respectively). According to multivariable Cox regression analysis, pre-CCRT 18 FDG PET-CT was not a significant prognostic factor for overall survival in patients with stages I-II of p16-negative OPSCC receiving standard CCRT. The adjusted hazard ratio (95% confidence interval) of all-cause death for the patients with advanced stages (III-IVA) of p16-negative OPSCC receiving pre-CCRT 18 FDG PET-CT was 0.75 (0.87-0.94, P = 0.0236)., Conclusions: Routine use of pre-CCRT 18 FDG PET-CT is not necessary for each patient with p16-negative OPSCC. Pre-CCRT 18 FDG PET-CT is associated with improved survival in patients with stage III-IVA p16-negative OSCC, but might be not in those with stage I-II p16-negative OPSCC. No large-scale prospective randomized study with a long-term follow-up period has evaluated the survival outcomes of preconcurrent chemoradiotherapy (CCRT) 18-fluorodeoxyglucose positron emission tomography-computed tomography ( 18 FDG PET-CT) in patients with p16-negative oropharyngeal squamous cell carcinoma (OPSCC). Our study is the first, largest, homogenous modality study on PET-CT including a long-term follow-up cohort to examine the survival outcomes of pre-CCRT 18 FDG PET-CT or non-pre-CCRT PET-CT for patients with p16-negative OPSCC receiving standard CCRT stratified by different clinical stages. Routine use of pre-CCRT 18 FDG PET-CT is not necessary for each patient with p16-negative OPSCC. Pre-CCRT 18 FDG PET-CT is associated with improved survival in patients with stage III-IVA p16-negative OPSCC, but might be not in those with stage I-II p16-negative OPSCC., (© 2023. The Author(s).)

Aim: Fluorescence imaging (FI) using indocyanine green (ICG) is a noteworthy alternative technique for sentinel lymph node (SLN) detection without radiation exposure in oral cavity and oropharynx cancer. However, conventional FI is monochrome, so the visibility is limited. This study assessed whether color FI using the HyperEye Medical System (HEMS) is feasible as an alternative for SLN detection., Methods: Patients with previously untreated cT1-2N0 oral or oropharyngeal cancer who were to undergo primary tumor resection and elective neck dissection (END) in our hospital were enrolled from November 2012 to March 2016. The patients underwent SLN detection for biopsy via the HEMS following the injection of ICG solution around the primary lesion before neck dissection. The visibility and the diagnostic accuracy of the imaging were evaluated., Results: SLNs were visualized in all eight cases; however, transcutaneous fluorescence detection was not observed in all cases. Utilizing color mode imaging simplified harvest by clearly discriminating SLNs from surrounding structures, while the monochrome mode proved to be more sensitive for detection. Two cases showed occult metastases on both sentinel and regional nodes. The identification and false negative rates were 100% and 0%, respectively. There were no complications incurred due to this method., Conclusion: Our results suggest that color FI with the HEMS allows for the accurate and safe harvest of SLNs with a preparatory skin incision. Although there is room for improvement of sensitivity, this easy-to-handle procedure might provide the potential to expand the role of the ICG method for SLN detection in head and neck cancer., (© 2022 John Wiley & Sons Australia, Ltd.)

Purpose: To evaluate the agreement between pathological and radiological staging in oropharyngeal cancer by comparing the 7th and the 8th edition of the AJCC TNM system., Methods: This retrospective cohort study included 57 cases of oropharyngeal cancer with lymph node metastases staged with the 7th and 8th editions of the AJCC TNM system. Comparison between clinical and radiological features and differences in agreement rates were calculated between radiological and pathological staging for the primary tumor (T) and lymph nodes (N) in HPVpos and HPVneg cases., Results: Comparison of HPVpos and HPVneg revealed a significantly different distribution between early and advanced stages in the 8 th edition, with a relevant number of HPVpos patients redefined from advanced stages whit the 7 th ed. to early stages with 8 th ed. (p < 0.01); no significant differences were found when comparing all diagnostic methods for T and N., Conclusions: The 8th edition of the AJCC TNM seems to lead to better pretreatment staging. For both HPVpos and HPVneg, the agreement between pretreatment radiological and pathological staging., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Purpose: Radiomics is a high-throughput approach that allows for quantitative analysis of imaging data for prognostic applications. Medical images are used in oropharyngeal cancer (OPC) diagnosis and treatment planning and these images may contain prognostic information allowing for treatment personalization. However, the lack of validated models has been a barrier to the translation of radiomic research to the clinic. We hypothesize that a previously developed radiomics model for risk stratification in OPC can be validated in a local dataset., Materials and Methods: The radiomics signature predicting overall survival incorporates features derived from the primary gross tumor volume of OPC patients treated with radiation +/- chemotherapy at a single institution (n = 343). Model fit, calibration, discrimination, and utility were evaluated. The signature was compared with a clinical model using overall stage and a model incorporating both radiomics and clinical data. A model detecting dental artifacts on computed tomography images was also validated., Results: The radiomics signature had a Concordance index (C-index) of 0.66 comparable to the clinical model's C-index of 0.65. The combined model significantly outperformed (C-index of 0.69, p = 0.024) the clinical model, suggesting that radiomics provides added value. The dental artifact model demonstrated strong ability in detecting dental artifacts with an area under the curve of 0.87., Conclusion: This work demonstrates model performance comparable to previous validation work and provides a framework for future independent and multi-center validation efforts. With sufficient validation, radiomic models have the potential to improve traditional systems of risk stratification, treatment personalization and patient outcomes., 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 © 2022 Elsevier B.V. All rights reserved.)

Introduction: This study aimed to determine if post-treatment HPV cell-free DNA (cfDNA) can assist in the decision-making process for salvage neck dissection in patients following non-surgical treatment of oropharyngeal squamous cell carcinoma (OPSCC) with a partial response in the neck on imaging at 12 weeks post-treatment., Methods: 86 patients who completed treatment were prospectively recruited through the regional multidisciplinary team (MDT). Treatment response was categorised as complete response (CR), partial response (PR) or progressive disease on 12-week post-treatment imaging. Pre- and post-treatment blood samples were assessed for HPV cfDNA through droplet digital PCR (ddPCR)., Results: Eight patients had an isolated partial response in the neck. One (12.5%) had detectable HPV cfDNA (22.96 copies/ml) at ∼12 weeks post-treatment with positive disease on subsequent neck dissection (positive predictive value; PPV = 100%). Of the seven patients with undetectable HPV cfDNA, two patients had evidence of regional disease recurrence at 23.9 and 27.4 months respectively (negative predictive value; NPV = 71%)., Conclusion: The detection of HPV cfDNA may help target salvage therapy in patients with a partial response in the neck. Follow-up studies in larger cohorts would be required to further validate the use of post-treatment HPV cfDNA in the management of OPSCC., Competing Interests: Declaration of competing interest TJA receives consultancy payments as Director of the company BioCaptiva. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objectives: Occult cervical lymph node metastasis is the most important reason for recurrence of early-stage tongue cancer and oropharyngeal cancer. Cervical sentinel lymph node (SLN) biopsy may help to identify them. Pigment dyes and radionuclide were used to label SLN. Both of them had shortage. This study aims to investigate the application and clinical value of indocyanine green fluorescence imaging in cervical SLN biopsy for patients with early-stage tongue cancer and oropharyngeal cancer., Methods: Retrospective analysis was conducted on 23 patients with early tongue cancer and oropharyngeal cancer, who received surgical treatment and used indocyanine green as a tracer to find SLN in Hunan Cancer Hospital from April to October 2021. The detection rate of SLN was calculated and the distribution of SLN in different regions of the neck was analyzed., Results: SLN was successfully identified in 22 of 23 patients, with a detection rate of 95.65%. Among these 22 patients, 3 patients were found to have cancer metastasis, and the rate of occult lymph node metastasis was 13.63%. No pathologically positive lymph nodes were detected in SLN-negative patients, and thus the positive predictive rate was 100%. For patients with primary lesions located in the anterior 2/3 of the tongue, the constituent ratios of SLN in neck area I, II, III, and IV were 15.15%, 71.72%, 13.13%, and 0, respectively. For patients with primary lesions located in base of the tongue, the constituent ratios of SLN in neck area I, II, III, and IV were 0, 44.44%, 44.44%, and 11.12%, respectively., Conclusions: Indocyanine green fluorescence imaging has a high detection rate with accurate positive prediction in the anterior cervical SLN biopsy in patients with early-stage tongue cancer and oropharyngeal cancer. Meanwhile, it can also reflect the lymphatic drainage of tumors located at different primary sites, which has high clinical value.

Background: Risk of contralateral nodal metastases in oropharyngeal squamous cell carcinoma (OPSCC) is relatively low, however, many OPSCC patients receive bilateral neck treatment. This study evaluates the oncological outcomes with management of the contralateral cN0 neck based on lymphatic mapping with single photon emission computed tomography (SPECT-CT)., Methods: Retrospective evaluation of patients with lateralized cT1-2 and contralateral cN0 OPSCC treated with primary surgery between December 2017 and October 2019. All patients underwent pre-operative lymphatic mapping using SPECT-CT. Clinical parameters including demographics, tumor characteristics and oncological outcomes were recorded., Results: Thirteen patients underwent primary site resection with transoral robotic surgery (TORS) and ipsilateral neck dissection with or without adjuvant therapy. Twelve patients (92.3%) had ipsilateral drainage on SPECT-CT, whereas 1 (7.7%) patient had bilateral neck lymphatic drainage. Four patients (30.8%) underwent post-operative radiation therapy (PORT). Three patients with unilateral drainage on SPECT-CT underwent PORT with unilateral neck irradiation, and 1 patient with bilateral drainage underwent PORT with bilateral neck irradiation. Seven (53.8%) patients were staged as pT1, 6 (46.2%) patients as pT2, 6 (46.2%) patients were pN0, 3 (23.1%) patients were pN1, 1 (7.7%) patient was pN2a for and 3 (23.1%) patients were N2b. The median distance of the tumor from midline was 1.05 cm (0.0-1.58). Primary sites included tonsil (n = 10, 76.9%) and tongue base (n = 3, 23.1%). The median follow-up time was 15.4 months. All patients were disease free at the latest follow-up with no contralateral neck failures., Conclusions: Pre-operative mapping of lymphatic drainage in early stage OPSCC with SPECT-CT is a promising tool which can reduce treatment to the contralateral neck potentially without compromising oncological outcomes., (© 2022. The Author(s).)

Sarcopenia is a known independent prognostic factor for decreased survival in patients with head and neck cancer; yet, its importance for the growing number of younger patients diagnosed with human papillomavirus (HPV)-positive oropharyngeal carcinoma (OPC+) has not been established. This systematic literature review aimed to determine the prevalence and impact of computed tomography (CT)-defined sarcopenia on survival outcomes for adult OPC+ patients (>18 y) undergoing any treatment modality. Prospective studies were searched using PubMed, Embase, CENTRAL, CINAHL, and Web of Science up until and including February 2022. Bias was assessed using the Quality In Prognosis Studies (QUIPS) tool, and certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. In total, 9 studies (total pooled OPC+ patients, n  = 744) were identified and included in this review; 2 at low, 6 at moderate, and 1 at high risk of bias. All studies varied in sarcopenia assessment methods and skeletal muscle index threshold cutoff values. These studies demonstrated the cumulative prevalence of sarcopenia for OPC+ patients to be 42.9% (95% CI: 37.8%, 47.9%). While overall survival (3 studies, n = 253) and progression-free survival (1 study, n = 117) was lower in sarcopenic OPC+ patients, this was not statistically significant. GRADE certainty of evidence for impact of pretreatment sarcopenia on overall survival was low and progression-free survival was very low. Although these studies showed there to be a high prevalence of pretreatment sarcopenia in patients with OPC+, which may decrease survival, the impact on progression-free survival is very uncertain. Further, high-quality research utilizing consistent sarcopenia definitions and assessment methods that are conducted specifically in OPC+ is required to strengthen evidence certainty and determine if sarcopenia is an independent prognostic factor for this population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objectives: Our objective was to determine the negative predictive value (NPV) of preoperative FDG PET/CTfor detecting locoregional nodal disease. The aim was to help inform the decision-making process when identifying patients with early-stage OPSCC that would be suitable for transoral robotic surgery (TORS) as a single-modality treatment., Materials and Methods: A retrospective cohort study was conducted of adults with primary stage cT1-2 OPSCC with up to one metastatic neck lymph node (cN0-1) planned for TORS. Patients with a preoperative PET/CT and who had undergone staging neck dissection (ND) were included. Clinical and pathological nodal staging was established based on PET/CT and ND, respectively. The primary outcome was the frequency of occult (not seen on PET/CT) nodal disease on ND., Results: Eighty-eight patients were included (N = 88). The rate of occult nodal disease was 28.4 % (n = 25). The NPV of PET/CT in the clinically negative neck was 79 % and 66 % in cases with a single clinical node. Following staging ND, thetreatment plan changed in 27 % of cases overall, 7 % in cN0 and 36.7 % in cN1. Among these, 18 % met criteria for radiotherapy and 9 % for CRT. This represented a decrease in the number of ideal candidates for TORS as single-modality treatment from 88 to 64 (73 %)., Conclusions: PET/CT is a useful tool in the workup of patients for primary TORS. However, about one third of patients with early-stage OPSCC might benefit from adjuvant therapy not predicted by preoperative PET/CT. A staging ND helps confirm candidates for single-modality treatment with TORS., 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 © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To assess intra- and inter-institutional concordance and identify methods to increase precision in radiologic extranodal extension (rENE) ascertainment in HPV+ oropharyngeal carcinoma., Methods: Six radiologists, blinded to clinical outcomes, from three centers assessed rENE in two phases: Phase-I (20 cases) utilized each individual's a priori appreciation of the literature. Phase-II (30 additional cases) was performed after deliberating experience and consolidating operating definitions. Intra- and inter-institutional Kappa were calculated at >50% and >75% certainty levels, respectively., Results: The Phase-I intra-institutional kappa was 0.76, 0.32, and 0.44 at >50% certainty and improved to 0.89, 0.61, and 0.66 at >75% certainty. Inter-institutional Fleiss' kappa also improved with higher certainty (from 0.40 to 0.57, p = 0.039).  The Phase-II inter-rater kappa was significantly higher than Phase-I at the same certainty level (both p < 0.001)., Conclusion: A learning curve exists for rENE assessment. Strategies to augment reliability include high certainty for declaration, consolidated operating definitions, and sharing experience among radiologists., (© 2022 Wiley Periodicals LLC.)

Background: Metabolic response assessment for oropharyngeal squamous cell carcinoma (OPSCC) aids in identifying locoregional persistence/recurrence (LRR). The Hopkins Criteria are a standardized qualitative response assessment system using posttreatment FDG-PET/CT., Methods: We conducted a retrospective cohort study of patients with node-positive OPSCC treated with definitive (chemo)radiotherapy. We assessed Hopkins Criteria performance for LRR, then developed and validated a competing-risks model., Results: Between 2004 and 2018, 259 patients were included with median follow-up of 43 months. The Hopkins Criteria sensitivity, specificity, negative predictive value, and accuracy were 68%, 88%, 95%, and 85%. The 36-month cumulative incidence of LRR was greater with positive scores (45% vs. 5%, HR 12.60, p < 0.001). PET/CTs performed ≤10 weeks after radiotherapy were associated with a four-fold increase in pathologically negative biopsies/surgeries (36% vs. 9%, p = 0.03). The AUC for LRR was 0.89 using a model integrating the Hopkins score., Conclusions: The Hopkins Criteria predict LRR with high accuracy for OPSCC response assessment., (© 2022 Wiley Periodicals LLC.)

Aim: Our study aimed to evaluate the use of positron emission tomography/computed tomography (PET/CT) in the initial staging of head and neck squamous cell carcinoma (HNSCC), including assessment of local and distant spread of the disease. We also aimed to compare the accuracy of PET/CT in the evaluation of human papillomavirus (HPV) positive and HPV-negative oropharyngeal carcinoma., Material and Methods: This single-center, prospective study was conducted between August 2016 and September 2021. A total of 198 patients with HNSCC who underwent PET/CT within the primary staging were included. We compared PET/CT results with histological findings. We calculated the accuracy, sensitivity, specificity, and positive and negative predictive values to assess the primary tumor, cervical lymph nodes, and distant metastases., Results: PET/CT showed a high success rate (32%) in revealing the primary site of carcinoma of unknown primary (CUP). The accuracy of PET/CT in displaying the primary tumor, cervical lymph node metastases, and distant metastases was 89.4%, 85.4%, and 87.4%, respectively. The method provided high sensitivity but lower specificity in all three areas. Specifically, PET/CT showed low specificity in the assessment of small tumors (75%), metastatic involvement of cervical lymph nodes (69.6%), and HPV-positive oropharyngeal carcinoma (55.6%)., Conclusions: The high accuracy of PET/CT to identify distant metastases and whole-body staging in one diagnostic step accelerated primary staging and resulted in earlier commencement of therapy. However, it also led to an overestimation of clinical findings and thus to extensive surgical treatment, especially in patients with small tumors, metastatic involvement of cervical lymph nodes, and HPV- positive oropharyngeal carcinoma. PET/CT is also useful for CUP diagnostics.

Purpose: Laborious and time-consuming tumor segmentations are one of the factors that impede adoption of radiomics in the clinical routine. This study investigates model performance using alternative tumor delineation strategies in models predictive of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC)., Methods: Of 153 OPSCC patients, HPV status was determined using p16/p53 immunohistochemistry. MR-based radiomic features were extracted within 3D delineations by an inexperienced observer, experienced radiologist or radiation oncologist, and within a 2D delineation of the largest axial tumor diameter and 3D spheres within the tumor. First, logistic regression prediction models were constructed and tested separately for each of these six delineation strategies. Secondly, the model trained on experienced delineations was tested using these delineation strategies. The latter methodology was repeated with the omission of shape features. Model performance was evaluated using area under the curve (AUC), sensitivity and specificity., Results: Models constructed and tested using single-slice delineations (AUC/Sensitivity/Specificity: 0.84/0.75/0.84) perform better compared to 3D experienced observer delineations (AUC/Sensitivity/Specificity: 0.76/0.76/0.71), where models based on 4 mm sphere delineations (AUC/Sensitivity/Specificity: 0.77/0.59/0.71) show similar performance. Similar performance was found when experienced and largest diameter delineations (AUC/Sens/Spec: 0.76/0.75/0.65 vs 0.76/0.69/0.69) was used to test the model constructed using experienced delineations without shape features., Conclusion: Alternative delineations can substitute labor and time intensive full tumor delineations in a model that predicts HPV status in OPSCC. These faster delineations may improve adoption of radiomics in the clinical setting. Future research should evaluate whether these alternative delineations are valid in other radiomics models., 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 © 2022 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

The clinical behaviour and outcomes of patients with oropharyngeal cancer (OPC) may be dichotomised according to their association with human papilloma virus (HPV) infection. Patients with HPV-associated disease (HPV+OPC) have a distinct demographic profile, clinical phenotype and demonstrate considerably better responses to chemoradiotherapy. This has led to a reappraisal of staging and treatment strategies for HPV+OPC, which are underpinned by radiological data. Structural modalities, such as CT and MRI can provide accurate staging information. These can be combined with ultrasound-guided tissue sampling and functional techniques (such as diffusion-weighted MRI and 18 F-fludeoxyglucose positron emission tomography-CT) to monitor response to treatment, derive prognostic information, and to identify individuals who might benefit from intensification or deintensification strategies. Furthermore, advanced MRI techniques, such as intravoxel incoherent motion and perfusion MRI as well as application of artificial intelligence and radiomic techniques, have shown promise in treatment response monitoring and prognostication. The following review will consider the contemporary role and knowledge on imaging in HPV+OPC.

Background: Spontaneous regression is defined as the partial or complete disappearance of a malignant tumour proven by microscopic examination in the absence of any substantial treatment. This paper presents the case of an older woman whose advanced-stage tonsillar squamous cell carcinoma was noted to have spontaneously regressed at seven months., Case Report: A 66-year-old woman presented with a 4-month history of dysphagia and odynophagia in September 2020. An exophytic tumour was seen on the right tonsil; this was diagnosed radiologically and histologically as a squamous cell carcinoma of the tonsils, with tumour-node-metastasis staging of T 4a N 0 M 0 . The patient received best supportive care. Seven months later, the oropharyngeal lesion had disappeared, with no treatment. Subsequent computed tomography imaging showed radiological resolution of the previously noted right-sided oropharyngeal lesion., Conclusion: Several mechanisms of spontaneous regression are discussed. Further studies should review this case in conjunction with other reports of spontaneous tumour regressions, to elucidate underlying mechanisms.

Objectives: To investigate the impact on local relapse rate (LRR) and disease specific survival (DSS) of intraoperative margins (FS) obtained by circumferential sampling method, corresponding to the lesion shape and marked using clock-face orientation combined with narrow band imaging (NBI) in head and neck squamous cell carcinoma Materials and Methods: 147 consecutive patients who underwent primary surgery with radical intent for oral and oropharyngeal cancer between 2011 and 2016 were prospectively enrolled. Patients were assigned to 3 groups with different sampling methods. In group A (n=44) a classical FS sampling method was used. In group B (n=73), the clock-face orientation sampling method (FS oclock) was used, whereas in group C (n=30), the FS oclock method combined with NBI. The primary outcome measure was the interdependence between FS sampling methods and oncological outcomes measured by LRR and DSS., Results: In total, 1534 FS samples were obtained with range of 3-24 FS taken per case, median 7.25 in group A, 8.15 in group B and 7.52 in group C. When compared FS histology and final histology in all groups the sensitivity, specificity and accuracy were 61.54%, 98.51% and 95.24%, respectively. The overall LRR equaled 8.8%. The lowest LRR was observed in FS oclock method combined with NBI (6.67%) followed by FS oclock (6.85%) and FS classic (13.64%). For all patients, DSS achieved 95.92% - 95.45% in FS classic, 95.89% in FS oclock and 96.67%. in FS oclock combined with NBI., Conclusion: The FS oclock sampling method combined with NBI increases the chance of achieving tumor-negative margins and in result improves the treatment outcome reflected by LRR and DSS.

Purpose: Human papillomavirus (HPV) status assessment is crucial for decision making in oropharyngeal cancer patients. In last years, several articles have been published investigating the possible role of radiomics in distinguishing HPV-positive from HPV-negative neoplasms. Aim of this review was to perform a systematic quality assessment of radiomic studies published on this topic., Methods: Radiomics studies on HPV status prediction in oropharyngeal cancer patients were selected. The Radiomic Quality Score (RQS) was assessed by three readers to evaluate their methodological quality. In addition, possible correlations between RQS% and journal type, year of publication, impact factor, and journal rank were investigated., Results: After the literature search, 19 articles were selected whose RQS median was 33% (range 0-42%). Overall, 16/19 studies included a well-documented imaging protocol, 13/19 demonstrated phenotypic differences, and all were compared with the current gold standard. No study included a public protocol, phantom study, or imaging at multiple time points. More than half (13/19) included feature selection and only 2 were comprehensive of non-radiomic features. Mean RQS was significantly higher in clinical journals., Conclusion: Radiomics has been proposed for oropharyngeal cancer HPV status assessment, with promising results. However, these are supported by low methodological quality investigations. Further studies with higher methodological quality, appropriate standardization, and greater attention to validation are necessary prior to clinical adoption., (© 2022. The Author(s).)

The clinical introduction of molecular imaging for the management of oropharyngeal squamous cell carcinoma (OPSCC) relies on the identification of relevant cancer‑specific biomarkers. The application of three membrane‑bound receptors, namely urokinase‑type plasminogen activator receptor (uPAR), tissue factor (TF) and EGFR have been previously explored for targeted imaging and therapeutic strategies in a broad range of solid cancers. The present study aimed to investigate the expression patterns of uPAR, EGFR and TF by immunohistochemistry (IHC) to evaluate their potential for targeted imaging and prognostic value in OPSCC. In a retrospective cohort of 93 patients with primary OPSCC, who were balanced into the 45 human papillomavirus (HPV)‑positive and 48 HPV‑negative groups, the IHC‑determined expression profiles of uPAR, TF and EGFR in large biopsy or tumor resection specimens were analyzed. Using the follow‑up data, overall survival (OS) and recurrence‑free survival were measured. Specifically, associations between survival outcome, biomarker expression and clinicopathological factors were examined using Cox proportional hazards model and log‑rank test following Kaplan‑Meier statistics. After comparing the expression pattern of biomarkers within the tumor compartment with that in the adjacent normal tissues, uPAR and TF exhibited a highly tumor‑specific expression pattern, whereas EGFR showed a homogeneous expression within the tumor compartment as well as a consistent expression in the normal mucosal epithelium and salivary gland tissues. The positive expression rate of uPAR, TF and EGFR in the tumors was 98.9, 76.3 and 98.9%, respectively. No statistically significant association between biomarker expression and survival outcome could be detected. Higher uPAR expression levels had a trend towards reduced OS according to results from univariate analysis (P=0.07; hazard ratio=2.01; 95% CI=0.92‑4.37). Taken together, these results suggest that uPAR, TF and EGFR may be suitable targets for molecular imaging and therapy in OPSCC. In particular, uPAR may be an attractive target owing to their high positive expression rates in tumors and a highly tumor‑specific expression pattern.

An isotropic expanded Planning Target Volume (PTV) neglects patient's off-axis rotation. This study designs a rotational PTV that is used instead of the standard 3-mm Clinical Target Volume (CTV) expanded PTV in oropharyngeal cancers with the goal to reduce pharyngeal constrictor muscle (PCM) mean dose. 10 patients were retrospectively evaluated. For off-axis rotation, the image was rotated around the longitudinal axis (cervical spinal canal) ± 5 degrees. These new CTVs were combined to form the rotational PTV. The standard and rotational treatment plans were designed with the goal to keep the superior and middle PCM-CTV70 mean dose to less than 50 Gy. There were a 355 cGy reduction in the superior PCM mean dose (form 5332 to 4977 cGy) and a 506 cGy reduction in middle PCM mean dose (from 4185 to 3679 cGy). 60% of patients may have at least a 20% reduction in dysphagia probability based on a Normal Tissue Complication Probability (NTCP) formula. The superior and middle PCM mean dose were reduced to less than 50 Gy in 40 and 20% of cases. There was an association between superior PCM mean dose and overlap volume of PTV70 and superior PCM in both standard (r = 0.92, p = 0.001) and rotational (r = 0.84, p = 0.002) plans. This association was present for middle PCM and PTV70 (r = 0.52, p = 0.02 and r = 0.62, p = 0.006). Rotational PTV can lower the mean dose to superior and middle PCMs, ultimately leading to lower dysphagia rates., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This study evaluated whether fluorescence lifetime imaging (FLIm), coupled with standard diagnostic workups, could enhance primary lesion detection in patients with p16+ head and neck squamous cell carcinoma of the unknown primary (HNSCCUP)., Methods: FLIm was integrated into transoral robotic surgery to acquire optical data on six HNSCCUP patients' oropharyngeal tissues. An additional 55-patient FLIm dataset, comprising conventional primary tumors, trained a machine learning classifier; the output predicted the presence and location of HNSCCUP for the six patients. Validation was performed using histopathology., Results: Among the six HNSCCUP patients, p16+ occult primary was surgically identified in three patients, whereas three patients ultimately had no identifiable primary site in the oropharynx. FLIm correctly detected HNSCCUP in all three patients (ROC-AUC: 0.90 ± 0.06), and correctly predicted benign oropharyngeal tissue for the remaining three patients. The mean sensitivity was 95% ± 3.5%, and specificity 89% ± 12.7%., Conclusions: FLIm may be a useful diagnostic adjunct for detecting HNSCCUP., (© 2022 Wiley Periodicals LLC.)

Purpose: Primary radiation therapy with or without chemotherapy (RT/CRT) is the most common treatment for oropharyngeal squamous cell carcinomas (OPSCC), but there has been an increase in transoral surgery (TOS) for T1-2 tumors. Because only a subset of T1-2 tumors are TOS-favorable, nonrandomized comparisons between RT/CRT and TOS could be confounded by indication. We aimed to compare outcomes of potential TOS-candidates versus non-TOS candidates, among patients who underwent RT/CRT for early T-stage OPSCC., Methods and Materials: For patients treated with RT/CRT for early-stage human papilloma virus positive OPSCC between 2014 and 2018, pretreatment imaging was reviewed by 3 head and neck surgeons, blinded to outcomes, to assess primary-site appropriateness for TOS, and extracapsular extension (ECE) was scored by a head and neck neuroradiologist. We compared outcomes based on surgical favorability pertaining to (1) the primary site tumor alone and (2) the primary site and an absence of ECE. Kaplan-Meier estimates for overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were compared using the log-rank test, with Cox regression used for multivariable modeling., Results: One hundred and forty-three patients were evaluated, of which 121 were male (84.6%), the median age was 59.4 years, and all of them were p16 positive (100%). The primary site was TOS-favorable in 115 of 143 (80.4%). Patients with TOS-favorable primary site experienced superior 5-year OS (89.8% vs 71.2%, P = .017), DSS (90.4% vs 63.4%, P = .022), and RFS (83% vs 49.4%, P = .04) compared with TOS-unfavorable patients. Similarly, patients with a TOS-favorable primary site and no ECE on imaging 101 of 143 (70.6%), had improved OS, DSS, and RFS (P < .05) compared with TOS-unfavorable patients., Conclusions: In this first study to assess surgical favorability as a prognostic factor among patients with T1/2 p16+ OPSCC, patients with TOS-favorable early-stage OPSCC have better outcomes than TOS-unfavorable patients. This provides valuable prognostic information for patients, and also suggests the risk of confounding by indication in nonrandomized comparisons of treatment modalities., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Tumor and target volume manual delineation remains a challenging task in head and neck cancer radiation therapy. The purpose of this study was to conduct a multi-institutional evaluation of manual delineations of gross tumor volume (GTV), high-risk clinical target volume (CTV), parotids, and submandibular glands on treatment simulation magnetic resonance scans of patients with oropharyngeal cancer., Methods and Materials: We retrospectively collected pretreatment T1-weighted, T1-weighted with gadolinium contrast, and T2-weighted magnetic resonance imaging scans for 4 patients with oropharyngeal cancer under an institution review board-approved protocol. We provided the scans to 26 radiation oncologists from 7 international cancer centers that participated in this delineation study. We also provide the patients' clinical history and physical examination findings, along with a medical photographic image and radiologic results. We used both the Simultaneous Truth and Performance Level Estimation algorithm and pair-wise comparisons of the contours, using overlap/distance metrics. Lastly, to assess experience and CTV delineation institutional practices, we had participants complete a brief questionnaire., Results: Large variability was measured between observers' delineations for GTVs and CTVs. The mean Dice similarity coefficient values across all physicians' delineations for GTVp, GTVn, CTVp, and CTVn were 0.77, 0.67, 0.77, and 0.69, respectively, for Simultaneous Truth and Performance Level Estimation algorithm comparison, and 0.67, 0.60, 0.67, and 0.58, respectively, for pair-wise analysis. Normal tissue contours were defined more consistently when considering overlap/distance metrics. The median radiation oncology clinical experience was 7 years. The median experience delineating on magnetic resonance imaging was 3.5 years. The GTV-to-CTV margin used was 10 mm for 6 of 7 participant institutions. One institution used 8 mm, and 3 participants (from 3 different institutions) used a margin of 5 mm., Conclusions: The data from this study suggests that appropriate guidelines, contouring quality assurance sessions, and training are still needed for the adoption of magnetic resonance-based treatment planning for head and neck cancers. Such efforts should play a critical role in reducing delineation variation and ensure standardization of target design across clinical practices., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: To investigate the predictive value of pretherapeutic metabolic tumor imaging using 18-fluorodeoxyglucose positron emission tomography (FDG-PET) for regional response in oropharyngeal cancer patients undergoing primary (chemo)radiation., Methods: Retrospective analysis of oropharyngeal cancer patients treated with primary (chemo)radiation at the University Hospital Zurich from 2010 to 2019 with available FDG-PET. The SUV max of the largest lymph node metastases was recorded. Regional response was assessed using posttherapeutic FDG-PET at 12 weeks and regional recurrence-free survival., Results: 95 patients with a mean age of 68.5 years (SD 10.3) were included. The median pretherapeutic nodal SUV max was 8.3 (interquartile range 4.4-13.3). A pretherapeutic nodal SUV max above 6 significantly predicted poorer regional recurrence-free survival (log-rank test, P = 0.009) in univariate analysis. However, in multivariate analysis SUV max above 6 was not significant in predicting regional recurrence-free survival (Cox regression P = 0.189). Clinical N category showed a trend in which a more severe stage had a poorer regional survival (Cox regression P = 0.073)., Conclusion: The SUV max of the largest lymph node metastasis seems to play a role in predicting regional response in oropharyngeal cancer patients, after stratifying for N category. More research is needed to investigate whether highly metabolically active disease is less likely to respond to chemoradiation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To perform a systematic review with meta-analysis to investigate the utility of post-treatment PET/CT specifically in HPV-associated oropharyngeal squamous cell carcinoma following curative intent treatment., Methods: Random-effects meta-analysis was used to pool data from 7 observational studies (2013-2019) obtained from a database search of PubMed, Web of Science, and EMBASE using an a priori protocol with dual independent evaluation for inclusion, risk of bias assessment for acceptable methodology, and extraction of data for analysis. PET/CT results, treatment failure, imaging and interventions subsequent to PET/CT findings, and efficacy of salvage therapy were extracted., Results: Of the 907 post-treatment scans, PET/CT results were largely negative (76.2%; 95% CI, 63.4-85.6) and least often positive (11.3%; 95% CI, 8.8-14.4). PET/CT results were equivocal for 22.5% (95% CI, 12.5-36.9) and equivocal/positive for 34.2% of patients (95% CI, 25.1-44.5). Patients with an initial positive scan had the highest treatment failure rates (43.1%; 95% CI, 21.4-67.7) and those with an initial negative scan had the lowest rates (7.4%; 95% CI, 5.7-9.7). The equivocal and equivocal/positive scans had intermediate prevalence of 16.5% (95% CI, 9.4-27.6) and 16.7% (95% CI, 9.1-28.7), respectively., Conclusion: The low treatment failure rate following a negative PET/CT scan is reassuring, but the data are consistent with treatment failure rates up to 9.7% suggesting follow-up of these patients is prudent. Additionally, the low positive predictive value for treatment failure observed alludes to use of post-treatment PET/CT in HPV-associated disease frequently leading to unnecessary subsequent imaging and intervention.

Background and Aim: The aim of this study was to evaluate the long-term safety of the omission of immediate neck dissections (IND) in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) achieving a less than complete nodal response on 12-week FDG PET-CT., Material and Methods: Patients with HPV-positive, node-positive HNSCC that were treated with radical (chemo) radiotherapy (RT) between January 2013 and September 2019 were identified. PET-CT responses were classified as complete (CR), incomplete (ICR) or equivocal (EQR) nodal responses. Clinical outcomes were obtained., Results: 347 patients were identified. Median follow-up was 43.9 (IQR, 30.8-61.2) months. 62.8% (218/347) achieved a CR, 23.4% (81/347) EQR and 13.8% (48/347) ICR nodal response. 70 of 81 (86.4%) patients with an EQR and 25 of 48 (52.1%) with an ICR had no residual disease during follow up (a pathologically negative ND if surgery undertaken or no subsequent neck or distant relapse clinically/radiologically). Median survival of the EQR and CR groups were not reached, and despite the omission of IND in 95% of the EQR group there was no statistically significant differences in overall survival (OS) between the groups, p = 1.0. Median survival of ICR was not reached. However, OS for ICR group was significantly worse than that of CR, and EQR, both p < 0.001., Conclusion: The omission of IND in those achieving an EQR nodal response does not compromise long-term survival. This supports the safety of extended surveillance in patients with HPV-positive disease and an EQR on 12-week FDG PET-CT., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Purpose: Fluorodeoxyglucose (FDG) positron emission tomography (PET) is increasingly used to diagnose and stage malignancy. The aim of this article is to investigate the significance of incidental FDG uptake in the Waldeyer's ring and to assess its value in predicting clinically occult oropharyngeal malignancy., Methods: All FDG-PET/CT scans performed in Imperial College NHS Foundation Trust, UK between January 2012 and November 2018 were included. Patients with known or suspected oropharyngeal malignancy or lymphoma were excluded. Minimum follow-up was 12 months., Results: A total of 724 scans revealed oropharyngeal uptake of FDG. Of these, 102 were included in the study. Most patients (62.1%) were scanned as part of staging for other malignancies. Oropharyngeal FDG uptake was asymmetrical in 57.3% of the cases. Uptake was more common in the tonsils (56.3%), followed by the tongue base (31.1%) and both sites (12.6%). In 41.7% of reports, appearance was described as likely physiological; however, 52.4% of reports advised direct visualisation, clinical correlation or ENT opinion. Only 24.3% (25/102) of patients were referred and seen by ENT, 14.6% (15/102) of which had an interval PET scan and 8.7% (9/102) proceeded to tissue diagnosis. There was one oropharyngeal cancer identified and one unexpected metastasis from esophageal cancer., Conclusion: Incidental uptake on PET/CT in the oropharynx is common. However, malignancy is rare (1.9%) and, when present, is associated with high SUVmax and asymmetrical uptake. Imaging results must be correlated clinically. These patients should be seen by an ENT specialist yet most may not require further investigations., (© 2021. Crown.)

Objective: The objective of this study was to examine tumor response with positron emission tomography (PET)/magnetic resonance imaging (MRI) during chemoradiotherapy as a predictor of outcome in patients with p16-positive oropharynx cancer., Materials and Methods: Patients with p16-positive oropharynx cancer were treated with chemoradiotherapy. Low-risk (LR) disease was defined as T1-T3 and N0-2b and ≤10 pack-years and intermediate-risk (IR) disease as T4 or N2c-3 or >10 pack-years. Patients underwent a PET/MRI scan pretreatment and at fraction 10. Change in value of imaging means were analyzed by analysis of variance. K-means clustering with Euclidean distance functions were used for patient clustering. Silhouette width was used to determine the optimal number of clusters. Linear regression was performed on all radiographic metrics using patient and disease characteristics., Results: Twenty-four patients were enrolled with 7 LR and 11 IR patients available for analysis. Pretreatment imaging characteristics between LR and IR patients were similar. Patients with LR disease exhibited a larger reduction in maximum standardized uptake value (SUV) compared with IR patients (P<0.05). Cluster analysis defined 2 cohorts that exhibited a similar intratreatment response. Cluster 1 contained 7 of 7 LR patients and 8 of 11 IR patients. Cluster 2 contained 3 of 11 IR patients. Cluster 2 exhibited significant differences compared with cluster 1 in the change in primary tumor peak SUV and largest lymph node median SUV., Conclusions: We identified that IR p16-positive oropharynx cancers exhibit heterogeneity in their PET/MRI response to chemoradiotherapy. These data support further study of intratreatment imaging response as a potential mechanism to identify patients with IR oropharynx cancer suitable for treatment deintensification., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Fluorine-18 fluorodeoxyglucose PET/computed tomography ( 18 F-FDG PET/CT) plays an important role in the staging, treatment planning, treatment response assessment, detecting recurrent disease, and predicting prognosis in patients with oral cavity and oropharyngeal squamous cell carcinoma. PET/CT has advantage especially in the detection of nodal, distant metastatic disease and second primary malignancy. PET/MR provides superior soft tissue contrast while decreasing radiation exposure, which is advantageous in evaluation of the primary tumor., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: Manual delineation of head and neck tumor contours for radiomics analyses is tedious and time consuming. This study investigates if fast or readily available tumor contours can substitute full tumor contours by an experienced observer for an MR-based radiomics model to predict locoregional control (LRC) in oropharyngeal squamous cell carcinoma (OPSCC) tumors., Materials and Methods: Radiomic features were extracted from postcontrast T1-weighted MRIs of 177 OPSCC primary tumors using six different manual delineation strategies. LRC prediction models based on recursive feature elimination combined with logistic regression were built. Models were trained and tested on data from each separate delineation. Additionally, the model derived from segmentations from the experienced reader was tested by each of the alternative delineations. Complementary, this was repeated with removal of size and shape features. Model performance was evaluated using area under the curve (AUC)., Results: Prediction performance of the experienced radiologist tumor delineation (AUC: 0.74) was superior compared to all other delineations when trained and tested (AUCs: 0.41-0.56) or trained on experienced delineations and tested (AUC: 0.56-0.67) on alternative segmentations. Removal of size and shape features considerably decreases prediction performance (AUC: 0.54). Applying the model based on expert delineations to spherical or single slice delineations makes prediction worthless since these models predict one class., Conclusion: Fast or readily available contours cannot substitute full expert tumor delineations in radiomics models predictive of LRC in OPSCC., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Infection with human papilloma virus (HPV) is one of the most relevant prognostic factors in advanced oropharyngeal cancer (OPC) treatment. In this study we aimed to assess the diagnostic accuracy of a deep learning-based method for HPV status prediction in computed tomography (CT) images of advanced OPC., Method: An internal dataset and three public collections were employed (internal: n = 151, HNC1: n = 451; HNC2: n = 80; HNC3: n = 110). Internal and HNC1 datasets were used for training, whereas HNC2 and HNC3 collections were used as external test cohorts. All CT scans were resampled to a 2 mm 3 resolution and a sub-volume of 72x72x72 pixels was cropped on each scan, centered around the tumor. Then, a 2.5D input of size 72x72x3 pixels was assembled by selecting the 2D slice containing the largest tumor area along the axial, sagittal and coronal planes, respectively. The convolutional neural network employed consisted of the first 5 modules of the Xception model and a small classification network. Ten-fold cross-validation was applied to evaluate training performance. At test time, soft majority voting was used to predict HPV status., Results: A final training mean [range] area under the curve (AUC) of 0.84 [0.76-0.89], accuracy of 0.76 [0.64-0.83] and F1-score of 0.74 [0.62-0.83] were achieved. AUC/accuracy/F1-score values of 0.83/0.75/0.69 and 0.88/0.79/0.68 were achieved on the HNC2 and HNC3 test sets, respectively., Conclusion: Deep learning was successfully applied and validated in two external cohorts to predict HPV status in CT images of advanced OPC, proving its potential as a support tool in cancer precision medicine., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This article reviews the various treatment options, by primary or postoperative external radiotherapy and by brachytherapy for the p16-negative oropharyngeal squamous cell carcinoma. Dose levels, fractionation and association with systemic treatments are presented. The need for neck node dissection post local treatment is discussed, as well as specificities for the management of p16-positive tumours. Guidelines for target volume selection and delineation are thoroughly elaborated. Last, the management by radiotherapy of locoregional recurrences is discussed., (Copyright © 2021. Published by Elsevier Masson SAS.)

MR imaging is the modality of choice in the evaluation of oral cavity and oropharyngeal cancer. Routine postcontrast MR imaging is important for the accurate localization and characterization of the locoregional extension of oral cavity and oropharyngeal cancers. The anatomy of the oral cavity and oropharynx is complex; accurate interpretation is vital for description of the extension of the masses. Understanding the new changes in the eighth edition of the American Joint Committee on Cancer staging system. MR imaging is the imaging modality of choice for detection of perineural spread., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study is to analyze the application value of NBI endoscopy in finding the concealed primary lesions of misdiagnosis of oropharyngeal cancer. Methods: The clinical data of patients with missed oropharyngeal cancer treated in the Department of Otolaryngology Head and neck surgery, the Second Affiliated Hospital of Xi'an Jiaotong University from May 2018 to June 2021, were retrospectively studied, and the missed diagnosis was also analyzed combined with results of NBI endoscopy. Results: In 31 cases of misdiagnosis of oropharyngeal cancer patients, including 25 males and 6 females, there was no significant difference in age, BMI index, course of disease and TNM stage （ P > 0.05）, and the pharyngeal or cervical symptoms were the first clinical manifestations of them, containing pharyngeal pain in 17 cases（54.8%） , pharyngeal foreign body sensation in 4 cases（12.9%） and unilateral cervical mass in 10 cases （32.3%）. No laryngoscopy was performed （21 cases） or no primary lesion was found by laryngoscopy （10 cases） at initial diagnosis. Among them, "inflammatory lesions" were given anti-inflammatory treatment with ineffective results or surgical resection was explored for suspicious lesions （17 cases）, or imaging examination （9 cases, including 6 cases with CT and MRI, 3 cases with PET-CT） and cervical lymph node biopsy （5 cases） were carried out for further diagnosis. According to these results, they were given ordinary laryngoscope （2 cases） or NBI endoscopy （29 cases） subsequently, finally they were confirmed as oropharyngeal squamous cellcarcinoma after localized biopsy at the suspicious lesions, indicating that the accuracy of NBI endoscopy in finding the concealed primary lesions of oropharyngeal cancer （93.55%） is significantly higher than that of ordinary electronic laryngoscope （6.45%）（ χ ²=43.613, P <0.01）. Conclusion: NBI endoscopy has unique advantages in finding oropharyngeal cancer in concealed parts such as tonsil, root of tongue, soft palate and lateral wall of oropharynx, which could reduce misdiagnosis of oropharyngeal cancer., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Objective: To determine the impact of Human Papilloma Virus (HPV) oropharyngeal cancer (OPC) status on the prediction of head and neck squamous cell cancer (HNSCC) chemoradiotherapy (CRT) outcomes with pre-treatment quantitative diffusion-weighted magnetic resonance imaging (DW-MRI)., Methods: Following ethical approval, 65 participants (53 male, age 59.9 ± 7.86) underwent pre-treatment DW-MRI in this prospective cohort observational study. There were 46 HPV OPC and 19 other HNSCC cases with Stage III/IV HNSCC. Regions of interest (ROIs) (volume, largest area, core) at the primary tumour ( n = 57) and largest pathological node ( n = 59) were placed to analyse ADC mean and ADC min . Unpaired t -test or Mann-Whitney test evaluated the impact of HPV OPC status and clinical parameters on their prediction of post-CRT 2 year locoregional and disease-free survival (LRFS and DFS). Multivariate logistic regression compared significant variables with 2 year outcomes., Results: On univariate analysis of all participants, the primary tumour area ADC mean was predictive of 2 year LRFS ( p = 0.04). However, only the HPV OPC diagnosis (LFRS p = 0.03; DFS p = 0.02) predicted outcomes on multivariate analysis. None of the pre-treatment ADC values were predictive of 2 year DFS in the HPV OPC subgroup ( p = 0.21-0.68). Amongst participants without 2 year disease-free survival, HPV-OPC was found to have much lower primary tumour ADC mean values than other HNSCC., Conclusion: Knowledge of HPV OPC status is required in order to determine the impact of the pre-treatment ADC values on post-CRT outcomes in HNSCC., Advances in Knowledge: Pre-treatment ADC mean and ADC min values acquired using different ROI methods are not predictive of 2 year survival outcomes in HPV OPC.

Background: To define the location of the initial contralateral lymph node (LN) metastasis in patients with oropharynx cancer., Methods: The location of the LN centroids from patients with oropharynx cancer and a single radiographically positive contralateral LN was defined. A clinical target volume (CTV) inclusive of all LN centroids was created, and its impact on dose to organs at risk was assessed., Results: We identified 55 patients of which 49/55 had a single contralateral LN in level IIA, 4/55 in level III, 1/55 in level IIB, and 1/55 in the retropharynx. Mean radiation dose to the contralateral parotid gland was 15.1 and 21.0 Gy, (p <0.001) using the modeled high-risk elective CTV and a consensus CTV, respectively., Conclusions: We present a systematic approach for identifying the contralateral nodal regions at highest risk of harboring subclinical disease in patients with oropharynx cancer that warrants prospective clinical study., (© 2021 Wiley Periodicals LLC.)

Purpose: In locally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC), (i) to investigate kinetics of human papillomavirus (HPV) circulating tumor DNA (ctDNA) and association with tumor progression after chemoradiation, and (ii) to compare the predictive value of ctDNA to imaging biomarkers of MRI and FDG-PET., Experimental Design: Serial blood samples were collected from patients with AJCC8 stage III OPSCC ( n = 34) enrolled on a randomized trial: pretreatment; during chemoradiation at weeks 2, 4, and 7; and posttreatment. All patients also had dynamic-contrast-enhanced and diffusion-weighted MRI, as well as FDG-PET scans pre-chemoradiation and week 2 during chemoradiation. ctDNA values were analyzed for prediction of freedom from progression (FFP), and correlations with aggressive tumor subvolumes with low blood volume (TV LBV ) and low apparent diffusion coefficient (TV LADC ), and metabolic tumor volume (MTV) using Cox proportional hazards model and Spearman rank correlation., Results: Low pretreatment ctDNA and an early increase in ctDNA at week 2 compared with baseline were significantly associated with superior FFP ( P < 0.02 and P < 0.05, respectively). At week 4 or 7, neither ctDNA counts nor clearance were significantly predictive of progression ( P = 0.8). Pretreatment ctDNA values were significantly correlated with nodal TV LBV , TV LADC , and MTV pre-chemoradiation ( P < 0.03), while the ctDNA values at week 2 were correlated with these imaging metrics in primary tumor. Multivariate analysis showed that ctDNA and the imaging metrics performed comparably to predict FFP., Conclusions: Early ctDNA kinetics during definitive chemoradiation may predict therapy response in stage III OPSCC., (©2021 American Association for Cancer Research.)

In head and neck cancer, early detection of recurrence after treatment is important. The contemporary development of therapeutic agents have improved the prognosis after recurrence; however, no biomarker has been established for evaluating therapeutic effects or detecting recurrence. Recently, circulating tumor DNA (ctDNA), which comprises DNA derived from tumor cells and exists in the form of cell-free DNA in the blood, has attracted attention as a minimally invasive and repeatable biomarker for detecting cancer. We validated the usefulness of ctDNA of human papilloma virus (HPV)-derived sequences as a biomarker in HPV-related p16-positive oropharyngeal cancer by assessing 25 patients with p16-positive oropharyngeal cancer. Blood samples were collected from each patient at multiple time points during the treatment, and the plasma was preserved. The ctDNA was extracted from the plasma and analyzed using digital polymerase chain reaction. HPV-derived ctDNA was detected in 14 (56%) of the 25 patients. In all the patients, the samples were found to be ctDNA-negative after initial treatment. Cancer recurrence was observed in 2 of the 14 patients; HPV-derived ctDNA was detected at the time of recurrence. Our results indicate that HPV-derived ctDNA can be a prospective biomarker for predicting the recurrence of p16-positive oropharyngeal cancer., (© 2022. The Author(s).)

Objectives: In this study, we aimed to analyze preoperative MRI images of oropharyngeal cancer patients who underwent surgical treatment, extracted radiomics features, and constructed a disease recurrence and death prediction model using radiomics features and machine-learning techniques., Materials and Methods: A total of 157 patients participated in this study, and 107 stable radiomics features were selected and used for constructing a predictive model., Results: The performance of the combined model (clinical and radiomics) yielded the following results: AUC of 0.786, accuracy of 0.854, precision of 0.429, recall of 0.500, and f1 score of 0.462. The combined model showed better performance than either the clinical and radiomics only models for predicting disease recurrence. For predicting death, the combined model performance has an AUC of 0.841, accuracy of 0.771, precision of 0.308, recall of 0.667, and f1 score of 0.421. The combined model showed superior performance over the predictive model using only clinical variables. A Cox proportional hazard model using the combined variables for predicting patient death yielded a c-index value that was significantly better than that of the model including only clinical variables., Conclusions: A predictive model using clinical variables and MRI radiomics features showed excellent performance in predicting disease recurrence and death in oropharyngeal cancer patients. In the future, a multicenter study is necessary to verify the model's performance and confirm its clinical usefulness., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Indocyanine green (ICG) fluorescence-based sentinel lymph node (SLN) biopsy has been promoted to detect early metastasis of oral/oropharyngeal carcinoma, but its diagnostic value still remains unclear. In this letter, we identified 6 studies on ICG fluorescence based SLN in the detection of lymph node metastasis in oral/oropharyngeal carcinoma. For detection of metastatic lymph node, the overall sensitivity and specificity of the studies were 0.86 and 0.91, respectively. SROC curve was determined according to the combined sensitivity and specificity, and the overall area under the curve AUC was 0.93. On the whole, ICG fluorescence-based SLN biopsy showed promising effect for earlier detection and staging., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

While there has been an overall decline of tobacco and alcohol-related head and neck cancer in recent decades, there has been an increased incidence of HPV-associated oropharyngeal cancer (OPC). Recent research studies and clinical trials have revealed that the cancer biology and clinical progression of HPV-positive OPC is unique relative to its HPV-negative counterparts. HPV-positive OPC is associated with higher rates of disease control following definitive treatment when compared to HPV-negative OPC. Thus, these conditions should be considered unique diseases with regards to treatment strategies and survival. In order to sufficiently characterize HPV-positive OPC and guide treatment strategies, there has been a considerable effort to diagnose, prognose, and track the treatment response of HPV-associated OPC through advanced imaging research. Furthermore, HPV-positive OPC patients are prime candidates for radiation de-escalation protocols, which will ideally reduce toxicities associated with radiation therapy and has prompted additional imaging research to detect radiation-induced changes in organs at risk. This manuscript reviews the various imaging modalities and current strategies for tackling these challenges as well as provides commentary on the potential successes and suggested improvements for the optimal treatment of these tumors., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To develop and validate a risk scoring system based on clinical and imaging findings to predict lymph node metastasis from HPV-related oropharyngeal squamous cell carcinomas., Methods: This study population who had undergone neck dissections or lymph node biopsies in patients with HPV+ OPSCC was obtained from a historical cohort from two tertiary referral hospitals. The training set from one hospital included 455 lymph nodes from 82 patients, and the test set from the other hospital included 150 lymph nodes from 42 patients. The baseline clinical and imaging findings on pretreatment CT or MR were investigated and the reference standards were the histopathologic results. A risk scoring system was constructed based on logistic regression and validated both internally and externally., Results: A 7-point risk scoring system was developed based on the following variables: central necrosis, infiltration of adjacent planes, lymph node level, and the maximal axial diameter of the lymph node. This risk scoring system showed good discriminative ability for metastasis in the training set (C-statistic 0.952; 95% CI, 0.931-0.972) and test set (C-statistic 0.968, 95% CI, 0.936-0.999) and good calibration ability in the training set (p = 0.723) and test set (p = 0.253)., Conclusions: We developed and validated a reliable risk scoring system that predicts lymph node metastasis from HPV+ OPSCCs based on the clinical data and pretreatment imaging findings. We expect this risk scoring system to be a useful guide for better decision-making in practice., Key Points: • It is important to diagnose lymph node metastasis from HPV+ OPSCC for treatment planning; however, there has been little research on that. • We developed and externally validated a new scoring system for stratifying the risk of lymph node metastasis from HPV+ OPSCC based on clinical and imaging data. • A predictive model combining both clinical and imaging data showed high diagnostic accuracy and efficiency for lymph node metastasis from HPV+ OPSCC., (© 2021. European Society of Radiology.)

Background: The cost utility of image-guided surveillance using computed tomography (CT) and positron emission tomography (PET)-CT to planned postradiation neck dissection (PRND) was compared for the management of advanced nodal human papillomavirus-positive oropharyngeal cancer following chemoradiation., Methods: A universal payer perspective was adopted. A Markov model was designed to simulate four treatment approaches with 3-month cycles over a lifetime horizon: 1) CT surveillance, 2) standard PET-CT surveillance, 3) a novel PET-CT approach with repeat PET at 6 months postchemoradiation for equivocal responders, and 4) PRND. Parameters including probabilities of CT nodal progression/resolution, PET avidity, recurrence, and survival were obtained from the literature. Costs were reported in 2019 Canadian dollars and utilities were expressed in quality-adjusted life years (QALYs). Deterministic and probabilistic sensitivity analyses were performed to evaluate model uncertainty., Results: PET-CT surveillance dominated CT surveillance and PRND in the base case scenario, and the novel PET-CT approach was the most cost-effective strategy across a wide range of variables tested in one-way sensitivity analysis. On probabilistic sensitivity analysis, novel PET-CT surveillance was the most cost-effective strategy in 78.1% of model iterations at a willingness-to-pay of $50,000/QALYs. Novel PET-CT surveillance resulted in a 49% lower rate of neck dissection compared with traditional PET-CT, and yielded an incremental benefit of 0.14 QALYs with average cost savings of $1309., Conclusions: Image-guided surveillance including PET-CT and CT are more cost effective than PRND. The novel PET-CT approach with repeat PET for equivocal responders was the dominant strategy and yielded both higher benefit and lower costs compared with standard PET-CT surveillance., (© 2021 American Cancer Society.)

Objectives: Cervical lymph nodes with internal cystic changes are seen with several pathologies, including papillary thyroid carcinoma (PTC), tuberculosis (TB), and HPV-positive oropharyngeal squamous cell carcinoma (HPV+OPSCC). Differentiating these lymph nodes is difficult in the absence of a known primary tumor or reliable medical history. In this study, we assessed the utility of deep learning in differentiating the pathologic lymph nodes of PTC, TB, and HPV+OPSCC on CT., Methods: A total of 173 lymph nodes (55 PTC, 58 TB, and 60 HPV+OPSCC) were selected based on pathology records and suspicious morphological features. These lymph nodes were divided into the training set (n = 131) and the test set (n = 42). In deep learning analysis, JPEG lymph node images were extracted from the CT slice that included the largest area of each node and fed into a deep learning training session to create a diagnostic model. Transfer learning was used with the deep learning model architecture of ResNet-101. Using the test set, the diagnostic performance of the deep learning model was compared against the histopathological diagnosis and to the diagnostic performances of two board-certified neuroradiologists., Results: Diagnostic accuracy of the deep learning model was 0.76 (=32/42), whereas those of Radiologist 1 and Radiologist 2 were 0.48 (=20/42) and 0.41 (=17/42), respectively. Deep learning derived diagnostic accuracy was significantly higher than both of the two neuroradiologists (P < 0.01, respectively)., Conclusion: Deep learning algorithm holds promise to become a useful diagnostic support tool in interpreting cervical lymphadenopathy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Image guidance in radiation oncology has resulted in significant improvements in the accuracy and precision of radiation therapy (RT). Recently, the resolution and quality of cone beam computed tomography (CBCT) for image guidance has increased so that tumor masses and lymph nodes are readily detectable and measurable. During treatment of head and neck squamous cell carcinoma (HNSCC), on-board CBCT setup imaging is routinely obtained; however, this CBCT imaging data is not utilized to predict patient outcomes. Here, we analyzed whether changes in CBCT measurements obtained during a course of radiation therapy correlate with responses on routine 3-month follow-up diagnostic imaging and overall survival (OS)., Materials/methods: Patients with oropharyngeal primary tumors who received radiation therapy between 2015 and 2018 were included. Anatomical measurements were collected of largest nodal conglomerate (LNC) at CT simulation, end of radiation treatment (EOT CBCT), and routine 3-month post-RT imaging. At each timepoint anteroposterior (AP), mediolateral (ML) and craniocaudal (CC) measurements were obtained and used to create a 2-dimensional (2D) maximum., Results: CBCT data from 64 node positive patients were analyzed. The largest nodal 2D maximum and CC measurements on EOT CBCT showed a statistically significant correlation with complete response on 3-month post-RT imaging (r = 0.313, p = 0.02 and r = 0.318, p = 0.02, respectively). Furthermore, patients who experienced a 30% or greater reduction in the CC dimension had improved OS (Binary Chi-Square HR 4.85, p = 0.028)., Conclusion: Decreased size of pathologic lymph nodes measured using CBCT setup imaging during a radiation course correlates with long term therapeutic response and overall survival of HNSCC patients. These results indicate that CBCT setup imaging may have utility as an early predictor of treatment response in oropharyngeal HNSCC., (© 2021. The Author(s).)

Human papillomavirus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC) are known to have differential phenotypes, including the incidence and location of metastases. HPV positive (HPV+) HNSCC are more likely to metastasize to distant sites, such as the lung, brain, and skin. Among these locations, metastasis to the brain is a rare event, and little is known about specific risk factors for this phenotype. In this report, we describe two patients who developed brain metastases from HNSCC. Both patient tumors had p16 INK4a overexpression, suggesting these tumors were HPV+. This was confirmed after PCR, in situ hybridization, and mass spectrometry detected the presence of HPV type 16 (HPV16) DNA, RNA and protein. To further characterize the presence of HPV16, we used a target enrichment strategy on tumor DNA and RNA to isolate the viral sequences from the brain metastases. Analysis by targeted next generation sequencing revealed that both tumors had the HPV genome integrated into the host genome at known hotspots, 8q24.21 and 14q24.1. Applying a similar target enrichment strategy to a larger cohort of HPV+ HNSCC brain metastases could help to identify biomarkers that can predict metastasis and/or identify novel therapeutic options.

Purpose: Accurate prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is crucial. We developed an objective and robust deep learning-based fully-automated tool called the DeepPET-OPSCC biomarker for predicting overall survival (OS) in OPSCC using [ 18 F]fluorodeoxyglucose (FDG)-PET imaging., Experimental Design: The DeepPET-OPSCC prediction model was built and tested internally on a discovery cohort ( n = 268) by integrating five convolutional neural network models for volumetric segmentation and ten models for OS prognostication. Two external test cohorts were enrolled-the first based on the Cancer Imaging Archive (TCIA) database ( n = 353) and the second being a clinical deployment cohort ( n = 31)-to assess the DeepPET-OPSCC performance and goodness of fit., Results: After adjustment for potential confounders, DeepPET-OPSCC was found to be an independent predictor of OS in both discovery and TCIA test cohorts [HR = 2.07; 95% confidence interval (CI), 1.31-3.28 and HR = 2.39; 95% CI, 1.38-4.16; both P = 0.002]. The tool also revealed good predictive performance, with a c-index of 0.707 (95% CI, 0.658-0.757) in the discovery cohort, 0.689 (95% CI, 0.621-0.757) in the TCIA test cohort, and 0.787 (95% CI, 0.675-0.899) in the clinical deployment test cohort; the average time taken was 2 minutes for calculation per exam. The integrated nomogram of DeepPET-OPSCC and clinical risk factors significantly outperformed the clinical model [AUC at 5 years: 0.801 (95% CI, 0.727-0.874) vs. 0.749 (95% CI, 0.649-0.842); P = 0.031] in the TCIA test cohort., Conclusions: DeepPET-OPSCC achieved an accurate OS prediction in patients with OPSCC and enabled an objective, unbiased, and rapid assessment for OPSCC prognostication., (©2021 American Association for Cancer Research.)

To improve risk prediction for oropharyngeal cancer (OPC) patients using cluster analysis on the radiomic features extracted from pre-treatment Computed Tomography (CT) scans. 553 OPC Patients randomly split into training (80%) and validation (20%), were classified into 2 or 3 risk groups by applying hierarchical clustering over the co-occurrence matrix obtained from a random survival forest (RSF) trained over 301 radiomic features. The cluster label was included together with other clinical data to train an ensemble model using five predictive models (Cox, random forest, RSF, logistic regression, and logistic-elastic net). Ensemble performance was evaluated over the independent test set for both recurrence free survival (RFS) and overall survival (OS). The Kaplan-Meier curves for OS stratified by cluster label show significant differences for both training and testing (p val < 0.0001). When compared to the models trained using clinical data only, the inclusion of the cluster label improves AUC test performance from .62 to .79 and from .66 to .80 for OS and RFS, respectively. The extraction of a single feature, namely a cluster label, to represent the high-dimensional radiomic feature space reduces the dimensionality and sparsity of the data. Moreover, inclusion of the cluster label improves model performance compared to clinical data only and offers comparable performance to the models including raw radiomic features.

Purpose: This study investigated the prognostic potential of intra-treatment PET radiomics data in patients undergoing definitive (chemo) radiation therapy for oropharyngeal cancer (OPC) on a prospective clinical trial. We hypothesized that the radiomic expression of OPC tumors after 20 Gy is associated with recurrence-free survival (RFS)., Materials and Methods: Sixty-four patients undergoing definitive (chemo)radiation for OPC were prospectively enrolled on an IRB-approved study. Investigational 18 F-FDG-PET/CT images were acquired prior to treatment and 2 weeks (20 Gy) into a seven-week course of therapy. Fifty-five quantitative radiomic features were extracted from the primary tumor as potential biomarkers of early metabolic response. An unsupervised data clustering algorithm was used to partition patients into clusters based only on their radiomic expression. Clustering results were naïvely compared to residual disease and/or subsequent recurrence and used to derive Kaplan-Meier estimators of RFS. To test whether radiomic expression provides prognostic value beyond conventional clinical features associated with head and neck cancer, multivariable Cox proportional hazards modeling was used to adjust radiomic clusters for T and N stage, HPV status, and change in tumor volume., Results: While pre-treatment radiomics were not prognostic, intra-treatment radiomic expression was intrinsically associated with both residual/recurrent disease (P = 0.0256, χ 2 test) and RFS (HR = 7.53, 95% CI = 2.54-22.3; P = 0.0201). On univariate Cox analysis, radiomic cluster was associated with RFS (unadjusted HR = 2.70; 95% CI = 1.26-5.76; P = 0.0104) and maintained significance after adjustment for T, N staging, HPV status, and change in tumor volume after 20 Gy (adjusted HR = 2.69; 95% CI = 1.03-7.04; P = 0.0442). The particular radiomic characteristics associated with outcomes suggest that metabolic spatial heterogeneity after 20 Gy portends complete and durable therapeutic response. This finding is independent of baseline metabolic imaging characteristics and clinical features of head and neck cancer, thus providing prognostic advantages over existing approaches., Conclusions: Our data illustrate the prognostic value of intra-treatment metabolic image interrogation, which may potentially guide adaptive therapy strategies for OPC patients and serve as a blueprint for other disease sites. The quality of our study was strengthened by its prospective image acquisition protocol, homogenous patient cohort, relatively long patient follow-up times, and unsupervised clustering formalism that is less prone to hyper-parameter tuning and over-fitting compared to supervised learning., (© 2021 American Association of Physicists in Medicine.)