Human papillomavirus-driven head and neck cancers in Japan during 2008-2009 and 2018-2019: The BROADEN study.

There is limited understanding of epidemiology and time trends of human papilloma virus (HPV)-driven head and neck cancers (HNC) in Japan, especially outside of the oropharynx. To assess HPV-driven HNC, a non-interventional study (BROADEN) of HNC patients diagnosed in 2008-2009 and 2018-2019 was conducted in Japan. Adult patients with oropharyngeal, nasopharyngeal, laryngeal, hypopharyngeal or oral cavity cancers were included in this study. HPV was centrally tested using p16INK4a immunohistochemistry, HPV-DNA PCR and HPV E6*I mRNA. HPV attributability required positivity in at least two tests (p16INK4a immunohistochemistry, HPV-DNA PCR, HPV E6*I mRNA) in the oropharynx, and HPV-DNA and HPV E6*I mRNA positivity for non-oropharynx sites. Nineteen hospitals included a total of 1108 patients, of whom 981 had valid samples. Men accounted for 82% of HNC diagnoses. Patients in the earlier cohort were younger and included a higher percentage of smokers. There was an increasing trend of HPV-driven oropharyngeal cancer over the last decade, from 44.2% to 51.7%. HPV attribution in nasopharyngeal cancers was 3.2% in 2008-2009 and 7.5% in 2018-2019; and 4.4% and 0% for larynx respectively. In total, 95.2% of HPV-driven HNC were attributed to HPV genotypes included in the 9-valent HPV vaccine being HPV16 the most prominent genotype. These results suggest that an epidemiologic shift is happening in Japan, with a decrease in smoking and alcohol use and an increase in HPV-driven HNC. The increasing trend of HPV-driven HNC in Japan highlights the need for preventive strategies to mitigate the rise of HPV-driven HNC.

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

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

Post-therapeutic surveillance of HPV-driven oropharyngeal cancers: are we ready to change our practices?

PURPOSE: Although HPV-positive and negative oropharyngeal cancers are two distinct diseases, Post-Therapeutic Surveillance (PTS) modalities are similar. Adjusting PTS strategies to HPV status will represent a massive practice change that raises the issue of its acceptability, by both physicians and patients. METHODS: Two distinct surveys were designed and submitted, respectively, to HPV-positive patients and physicians (surgeons, radiation and medical oncologists) involved in head and neck cancer treatment. RESULTS: 133 patients and 90 physicians have participated to the study. Most patients were reluctant to embrace new PTS options (remote consultations, nurse consultations and smart phone applications). However, 84% of patients would be favorable to use HPV Circulating DNA (HPV Ct DNA) measurement to guide surveillance modalities. 57% of physicians acknowledged that our current PTS strategy is improvable and most of them would accept the use of new monitoring options from the third year of follow-up. 87% of physicians would be interested to participate to a trial comparing the current PTS strategy to a new approach, where monitoring modalities (number of visits, imaging prescription) would depend on HPV Ct DNA level. CONCLUSIONS: Patients and physicians are aware that PTS modalities should depend on HPV status. Their adhesion is a prerequisite to any potential changes. Strategies based on HPV Ct DNA measurement should be assessed within a randomized clinical trial.

Recommendations for head and neck surgical oncology practice in a setting of acute severe resource constraint during the COVID-19 pandemic: an international consensus.

The speed and scale of the global COVID-19 pandemic has resulted in unprecedented pressures on health services worldwide, requiring new methods of service delivery during the health crisis. In the setting of severe resource constraint and high risk of infection to patients and clinicians, there is an urgent need to identify consensus statements on head and neck surgical oncology practice. We completed a modified Delphi consensus process of three rounds with 40 international experts in head and neck cancer surgical, radiation, and medical oncology, representing 35 international professional societies and national clinical trial groups. Endorsed by 39 societies and professional bodies, these consensus practice recommendations aim to decrease inconsistency of practice, reduce uncertainty in care, and provide reassurance for clinicians worldwide for head and neck surgical oncology in the context of the COVID-19 pandemic and in the setting of acute severe resource constraint and high risk of infection to patients and staff.

HPV circulating tumoral DNA quantification by droplet-based digital PCR: A promising predictive and prognostic biomarker for HPV-associated oropharyngeal cancers.

We aimed to determine whether pretherapeutic assessment of HPV circulating tumoral DNA (HPV ctDNA) by droplet-based digital PCR (ddPCR) could constitute a predictive and prognostic biomarker for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). A mono-institutional prospective biomarker study on 66 patients with p16+/HPV16-positive oropharyngeal squamous cell carcinoma (OPSCC) was conducted in European Georges Pompidou Hospital, Paris, France. Blood samples were collected at the time of diagnosis before any treatment. Optimized digital PCR assays were used to quantify HPV16 ctDNA. Forty-seven (71%) patients showed a positive pretherapeutic HPV ctDNA at time of diagnosis. Interestingly, the quantity of HPV16 ctDNA at baseline, as assessed by ddPCR, was significantly correlated with the T/N/M status or OPSCC stages according to the 2018 new staging criteria for high-risk human papillomavirus (HR HPV) related OPSCC from American Joint Committee on Cancer (AJCC). Moreover, all recurrences and the majority (83%) of death reported events occurred in patients with positive HPV16 ctDNA at baseline. Finally, when posttreatment blood samples were available (n = 6), the kinetic of pretreatment/posttreatment HPV16 ctDNA was clearly associated with treatment success or failure. HPV ctDNA monitoring by ddPCR could constitute a useful and noninvasive dynamic biomarker to select HR HPV-related OPSCC patients eligible for potential treatment de-escalation and to monitor treatment response.

Correlation between the duration of locoregional control and survival in T1-T2 oropharyngeal cancer patients.

PURPOSE: To investigate the correlation between the time to locoregional recurrence and survival in T1-T2 oropharyngeal squamous-cell carcinoma (OPSCC) patients. METHODS: A retrospective, single-site study of patients with T1-T2 OPSCC treated with curative intent between 2000 and 2015 who had a locoregional recurrence without distant metastases. Patients without a disease-free interval (i.e., persistent macroscopic disease after the end of treatment and a time to locoregional recurrence of less than 3 months) were excluded. The endpoint considered was overall survival (OS). RESULTS: Out of 602 T1-T2 OPSCC patients, 121 patients had a locoregional recurrence and they were, hence, analyzed. All of the patients were heavy-smokers, with a consumption of more than 20 pack-years. The recurrence was local in 59.5%, regional in 27.3%, and both local and regional in 13.2% of the patients. The median time to locoregional recurrence and median OS was 15 months and 44 months, respectively. The time to locoregional recurrence was correlated with OS (p < 0.0001). In multivariate analyses, factors associated with survival were an initial N0-N2a versus N2b-N3 nodal staging and a 12-month threshold for the time to locoregional recurrence. CONCLUSIONS: Locoregional control in T1-T2 OPSCC is not only a qualitative prognostic factor but also a quantitative prognostic factor of survival. A time to locoregional recurrence of less than 12 months was correlated with an unfavorable prognosis.

HPV RNA CISH score identifies two prognostic groups in a p16 positive oropharyngeal squamous cell carcinoma population.

HPV-related and HPV-unrelated oropharyngeal squamous cell carcinomas are two distinct entities according to the Union for International Cancer Control, with a better prognosis conferred to HPV-related oropharyngeal squamous cell carcinomas. However, variable clinical outcomes are observed among patients with p16 positive oropharyngeal squamous cell carcinoma, which is a surrogate marker of HPV infection. We aimed to investigate the prognostic value of RNA CISH against E6 and E7 transcripts (HPV RNA CISH) to predict such variability. We retrospectively included 50 histologically confirmed p16 positive oropharyngeal squamous cell carcinomas (p16 positive immunostaining was defined by a strong staining in 70% or more of tumor cells). HPV RNA CISH staining was assessed semi-quantitatively to define two scores: RNA CISH "low" and RNA CISH "high". Negative HPV RNA CISH cases were scored as RNA CISH "low". This series contained 29 RNA CISH low cases (58%) and 21 RNA CISH high cases (42%). Clinical and pathologic baseline characteristics were similar between the two groups. RNA CISH high staining was associated with a better overall survival in both univariate and multivariate analyses (p = 0.033 and p = 0.042, respectively). Other recorded parameters had no prognostic value. In conclusion, HPV RNA CISH might be an independent prognostic marker in p16 positive oropharyngeal squamous cell carcinomas and might help guide therapeutics.

Relationship between the time to locoregional recurrence and survival in laryngeal squamous-cell carcinoma.

To assess the relationship between the locoregional disease-free interval after treatment of the primary tumor and survival after a recurrence in patients with laryngeal carcinoma. We retrospectively investigated patients treated in our Cancer Center for a laryngeal cancer who subsequently developed a locoregional recurrence and were followed up until death. Post-recurrence survival was defined as the time from the locoregional recurrence to death. One hundred and twenty-three patients were included. Median post-recurrence survival was 7 months. The locoregional disease-free interval (LRDFI) after treatment of the primary was weakly correlated with post-recurrence survival (r = 0.210, p = 0.020). A LRDFI cut-off of 12 months was a significant prognostic factor (p = 0.005; median, 5 months, 95% CI: 2.239-6.761, vs 10 months, 95% CI: 7.270-12.730). The time to locoregional recurrence in laryngeal cancer was a prognostic factor correlated with post-recurrence survival. Locoregional failure within the first year after treatment of the primary tumor was associated with an unfavorable prognosis.

Outcomes and prognostic factors for squamous cell carcinoma of the oral tongue in young adults: a single-institution case-matched analysis.

There is controversy regarding prognosis and treatment of young patients with oral cavity cancer compared to their older counterparts. We conducted a retrospective case-matched analysis of all adult patients younger than 40 years and treated at our institution for a squamous cell carcinoma of the oral cavity. Only non-metastatic adult patients (age >18) with oral tongue cancer were eventually included and matched 1:1 with patients over 40 years of age, at least 20 years older than the cases, with same T and N category and treatment period. Sixty-three patients younger than 40 had an oral cavity squamous cell cancer out of which 57 had an oral tongue primary during the period 1999-2012, and 50 could be matched with an older control. No difference could be seen between younger and older patients with regard to overall, cancer-specific, or progression-free survival. The patterns of failure were similar, although in young patients, almost all failures occurred during the first 2 years following treatment. Although overall survival shows a trend toward lower survival in older patients, cancer-specific survival and analysis of pattern failure suggest that disease prognosis is similar between young and older adults with oral tongue cancer. Further work is needed to identify the younger patients with poorer prognosis who overwhelmingly fail during the first year after treatment and could benefit from treatment intensification. Until then, young adults ought to be treated using standard guidelines.

Sinonasal squamous cell carcinoma without clinical lymph node involvement : Which neck management is best?

OBJECTIVES: The purpose of this work was to report outcomes of patients with nonmetastatic sinonasal squamous cell carcinoma (SNSCC) and to discuss the impact of elective neck irradiation (ENI) and selective neck dissection (SND) in clinically negative lymph node (N0) patients. METHODS: Data from 104 nonmetastatic SNSCC patients treated with curative intent were retrospectively analysed. Uni- and multivariate analyses were used to assess prognostic factors of overall survival (OS) and locoregional control (LRC). RESULTS: Median follow-up was 4.5 years. Eighty-five percent of tumours were stage III-IV. Treatments included induction chemotherapy (52.9 %), surgery (72 %) and radiotherapy (RT; 87 %). The 5­year OS, progression-free survival, and LRC rates were 48, 44 and 57 %, respectively. Absence of surgery predicted a decrease of OS (hazard ratio [HR] 2.6; 95 % confidence interval [CI] 1.4-4.7), and LRC (HR 3.5; 95 % CI 1.8-6.8). Regional relapse was observed in 13/104 (13 %) patients and most common sites were level II (n = 12; 70.6 %), level III (n = 5; 29.4 %) and level Ib (n = 4; 23.5 %). Management of the neck in N0 patients (n = 87) included 11 % SND alone, 32 % ENI alone, 20 % SND + ENI and 37 % no neck treatment. In this population, a better LRC was found according to the management of the neck in favour of SND (94 % vs. 47 %; p = 0.002) but not ENI. CONCLUSION: SND may detect occult cervical positive nodes, allowing selective postoperative RT. ENI (ipsilateral level II, ±Ib and III or bilateral) needs to be proposed in selected patients, especially when SND has not been performed.

Anatomic Variability of the Upper Mediastinal Lymph Node Level VII.

OBJECTIVE: Lymph node level VII, between the sternal notch and the innominate artery, is a frequent site of lymph node metastases in thyroid cancer. The objective of this study was to determine the cranial-caudal dimensions of level VII in patients undergoing central neck dissection for thyroid cancer and its accessibility through a neck incision only. PATIENTS AND METHODS: Consecutive patients undergoing central neck dissection for thyroid cancer, with no previous neck dissection, mediastinal or thoracic surgery. The innominate artery was identified and the distance between the sternal notch and the upper border of the artery was measured to the nearest .5 mm. The sizes of level VII were compared with respect to age, sex, height, body mass index, type of neck dissection (therapeutic or prophylactic), and the incidence of previous thyroidectomy. RESULTS: One-hundred-one consecutive patients (65 women, 36 men, mean age 44 years (range 15-87) underwent prophylactic (n = 55) or therapeutic (n = 46) bilateral central compartment neck dissection. Level VII was accessible via the horizontal neck incision in all cases. Sizes of level VII ranged from 6 cm above the sternal notch to 35 mm below the sternal notch, with a mean distance of 3.5 mm below the sternal notch. The innominate artery was at the level of the sternal notch in 29 patients, and cranial to the sternal notch in 20 cases. No statistical relationship with age, sex, therapeutic/prophylactic neck dissection, previous surgery, body mass index or height was found. CONCLUSIONS: The maximal distance below the sternal notch was 35 mm. Level VII did not exist in 49 % of patients, and was less than 25 mm caudal to the sternal notch in 95 % of cases. Distinguishing level VII from level VI in thyroid cancer surgery may not be pertinent, due to the ease of access via a classic horizontal neck incision and the small sizes of level VII in the majority of patients.

Intraoperative Near-infrared Imaging for Parathyroid Gland Identification by Auto-fluorescence: A Feasibility Study.

BACKGROUND: Parathyroid glands (PGs) can be particularly hard to distinguish from surrounding tissue and thus can be damaged or removed during thyroidectomy. Postoperative hypoparathyroidism is the most common complication after thyroidectomy. Very recently, it has been found that the parathyroid tissue shows near-infrared (NIR) auto-fluorescence which could be used for intraoperative detection, without any use of contrast agents. The work described here presents a histological validation ex vivo of the NIR imaging procedure and evaluates intraoperative PG detection by NIR auto-fluorescence using for the first time to our knowledge a commercially available clinical NIR imaging device. METHODS: Ex vivo study on resected operative specimens combined with a prospective in vivo study of consecutive patients who underwent total or partial thyroid, or parathyroid surgery at a comprehensive cancer center. During surgery, any tissue suspected to be a potential PG by the surgeon was imaged with the Fluobeam 800 (®) system. NIR imaging was compared to conventional histology (ex vivo) and/or visual identification by the surgeon (in vivo). RESULTS: We have validated NIR auto-fluorescence with an ex vivo study including 28 specimens. Sensitivity and specificity were 94.1 and 80 %, respectively. Intraoperative NIR imaging was performed in 35 patients and 81 parathyroids were identified. In 80/81 cases, the fluorescence signal was subjectively obvious on real-time visualization. We determined that PG fluorescence is 2.93 ± 1.59 times greater than thyroid fluorescence in vivo. CONCLUSIONS: Real-time NIR imaging based on parathyroid auto-fluorescence is fast, safe, and non-invasive and shows very encouraging results, for intraoperative parathyroid identification.

Diagnosis of HPV-driven head and neck cancer with a single test in routine clinical practice.

Accurate screening of HPV-driven head and neck squamous cell carcinoma is a critical issue. Although there are commercial direct and indirect assays for HPV-related head and neck squamous cell carcinoma, none are ideal. Recently, a novel RNA in situ hybridization test (the RNAscope HPV-test) has been developed for the detection of high-risk HPV E6/E7 mRNA in formalin-fixed paraffin-embedded tissue. However, validation of this assay against the 'gold standard' (identification of high-risk HPV E6/E7 mRNA in fresh-frozen tissue by quantitative real-time (qRT)-PCR) has only been reported by one team. Formalin-fixed paraffin-embedded samples from 50 patients with tonsil or tongue base carcinoma were tested using the RNAscope HPV-test, p16 immunohistochemistry, and chromogenic in situ hybridization for high-risk HPV-DNA. The results were compared with those of qRT-PCR on matched fresh-frozen samples. Compared with the reference test, the sensitivity, specificity, positive, and negative predictive values of the RNAscope HPV-test and of p16 immunohistochemistry were 93%, 94%, 96%, 88% and 96%, 93%, 96%, and 93%, respectively. Five cases were discrepant between the RNAscope HPV-test and p16-immunohistochemisrty. The RNAscope HPV-test demonstrated excellent analytical performance against the 'gold standard' and is easier to interpret than chromogenic in situ hybridization. p16-immunohistochemistry also performed very well, however its main weakness is that it is an indirect marker of the presence of HPV. These data suggest that the RNAscope HPV-test is a promising test that could be developed as a clinical standard for the precise identification of HPV-driven oropharyngeal squamous cell carcinoma.

Management of retropharyngeal node metastases from thyroid carcinoma.

BACKGROUND: Lymph node metastases are relatively common in thyroid carcinoma, but retropharyngeal nodes (RPN) are rare. Management may be surgical or non-surgical, according to the context of the disease. METHODS: Systematic review of cases reported in the literature and report of 5 cases. RESULTS: Most case series report surgical management, via a cervical or transoral approach. RPN was the specific object of 26 case series, with a total of 85 patients, with surgery performed in 22/26 studies. Our 5 cases illustrated various strategies in the multidisciplinary management, with surgery for three patients (also with (131)I in one case), targeted therapy for one patient with concurrent distant metastases, and watch and wait for one elderly patient. CONCLUSIONS: Management of RPN is not always surgical. Discussion of options in a multidisciplinary tumor board setting may optimize care.

Impact of prophylactic central neck dissection on oncologic outcomes of papillary thyroid carcinoma: a review.

Prophylactic neck dissection (PND) for papillary thyroid carcinoma (PTC) is controversial. Our aim was to assess current levels of evidence (LE) according to the Oxford Centre for Evidence-based Medicine ( http://www.cebm.net/?O=1025 ) regarding the oncologic benefits of PND. Data were analyzed via MEDLINE keywords: PTC, differentiated thyroid carcinoma, PND, central lymph node metastases, central compartment, recurrence-free survival. There was conflicting evidence regarding the rate of reoperation for recurrence, with some studies showing a lower rate after PND with increased recurrence-free survival and a higher rate of undetectable pre- and post-ablation thyroglobulin levels (LE 4), whereas other studies did not show a difference (LE 4). Only one study (LE 4) showed improved disease-specific survival with PND. PND may improve recurrence-free survival, although this is supported by only a low LE. Current recommendations can only be based on low-level evidence.

Prophylactic level II neck dissection guided by frozen section for clinically node-negative papillary thyroid carcinoma: is it useful?

BACKGROUND: Prophylactic lateral neck dissection (PLND) is generally not performed for papillary thyroid carcinoma(PTC). When performed, occult metastases are found in upto 50 % of patients, although the incidence of occult level II nodes seems low. Our aim was to evaluate frozen section analysis-oriented elective level II PLND in patients with clinically node-negative (cN0) PTC. METHODS: This retrospective study included patients with cN0 PTC treated with total thyroidectomy and prophylactic bilateral central and lateral neck dissection of ipsilateral levels III and IV. Frozen section analysis of PLND III and IV was performed. If positive, the PLND was extended to level II. We measured the accuracy of frozen section analysis, the incidence of occult level II metastasis, and oncologic outcomes. RESULTS: A total of 295 patients were included. For frozen section analysis, the sensitivity was 71.0 %, specificity 99.6 %, positive predictive value 97.8 %, negative predictive value 92.4 %, overall accuracy 93.2 %. Definitive analysis found lateral node metastases in 63 of the 295(21 %) patients. Extension to level II was performed in 27 of 46 cases (59 %). Level II contained metastatic nodes in 12 of 27 (44 %) patients. There was no difference in total doses of 131I administered to patients with or without level II disease. Even when extension of PLND to level II was not performed, no cases of recurrent or persistent disease in level II occurred. CONCLUSIONS: Frozen section analysis was highly accurate.The rate of occult metastases in level II was low. Detection of additional metastases in level II did not modify subsequent treatment or the rate of recurrence and is not useful for routine application.

HPV-related oropharyngeal squamous cell carcinomas: a comparison between three diagnostic approaches.

PURPOSE: HPV-related oropharyngeal squamous cell carcinomas clearly represent a growing entity in the head and neck with distinct carcinogenesis, clinico-pathological presentation and survival profile. We aimed to compare the HPV prevalence rates and clinico-pathological correlations obtained with three distinct commonly used HPV detection methods. MATERIALS AND METHODS: p16-immunohistochemistry (IHC), HPV DNA viral load by real-time PCR (qPCR), and HPV genotyping by a reverse hybridization-based line probe assay (INNO-LiPA) were performed on pretreatment formalin-fixed paraffin-embedded tumor samples from 46 patients treated for single primary oropharyngeal carcinomas. RESULTS: Twenty-eight patients (61%) had a p16 overexpression in IHC. Twenty-nine patients (63%) harbored HPV DNA on qPCR. Thirty-four patients (74%) harbored HPV DNA on INNO-LiPA. The concordance analysis revealed a good agreement between both HPV DNA detection methods (κ=0.65); when both tests were positive, the depicted HPV subtypes were always concordant (HPV16 in 27 cases, HPV18 in 1 case). Agreement was moderate between IHC and qPCR (κ=0.59) and fair between IHC and INNO-LiPA (κ=0.22). CONCLUSIONS: Certain highly sensitive methods are able to detect the mere presence of HPV without any carcinogenetic involvement while other more specific tests provide proof of viral transcriptional activity and thus evidence of clinically relevant infections. The use of a stepwise approach allows reducing false positives; p16-immunostaining seems to be an excellent screening test and in situ hybridization may overcome some of the PCR limitations.

Primary Total Laryngectomy for Endolaryngeal cT3-4M0 Squamous Cell Carcinoma: A STROBE Analysis.

OBJECTIVES: To document 10-year oncologic outcome of primary total laryngectomy (TL) for patients with cT3-4M0 endolaryngeal squamous cell carcinoma (SCC). STUDY DESIGN: Observational inception cohort of 531 patients with isolated untreated endolaryngeal cT3-4M0 SCC review over 40 years using STROBE guideline. 94% of patients were followed until death or for a minimum of 10 years. SETTING: Academic tertiary referral care center. METHODS: All patients underwent primary TL. Prior tracheotomy, induction chemotherapy, thyroid gland resection, level II-IV neck dissection, level VI dissection, and postoperative radiation therapy were associated in 6%, 40%, 43%, 89%, 47%, and 74% of cases, respectively: The main objective was to determine the 10-year actuarial local control estimate. Accessory objectives comprised screening for clinical variables increasing the risk of local recurrence, and analysis of long-term oncologic consequences of local recurrence. RESULTS: The 10-year actuarial local control estimate was 89.7%. Local recurrence was salvaged in 11% of cases, resulting in 92% overall local control. On multivariate analysis, none of the study variables correlated with local recurrence. Local recurrence resulted in significantly reduced nodal control, distant metastasis control, and survival. Postoperative complications, persistent index SCC, intercurrent disease, and metachronous second primary cancer accounted for respectively 3%, 37%, 33%, and 28% of the 334 deaths noted during the 10 years following TL. CONCLUSION: The present study underscored the long-term oncologic efficacy of primary TL, the dangers of local recurrence, the key role of local control for survival, and the importance of a long-term oncologic watch policy. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:2288-2294, 2024.

HPV-driven oropharyngeal cancer burden in Paris and its region (ILE DE FRANCE) from 1981 TO 2021.

BACKGROUND: France has the sixth highest incidence of oropharyngeal cancer (OPC) in Europe, but the epidemiological impact of high-risk HPV (HR-HPV) remains poorly documented. The objective of our study was to assess the proportion of OPCs caused by HR-HPV in Paris, and its suburbs, over the four past decades. This area accounts for almost one-fifth of the total population of France. METHODS: OPCs diagnosed in 1981, 1986, 1991, 1996, 2001, 2006, 2011, 2016 and 2020/2021 in two of the main referral cancer centers for HNCs in Paris and its suburbs were retrieved from the tumor biobanks. HPV status was determined by p16-staining and HPV-DNA detection. Samples were considered HPV-driven if both assays were positive. Results were compared to the French cancer registry data. RESULTS: Samples from 697 OPC patients were assessed (including 82 % of all samples diagnosed in 2001, 2006, 2011, 2016, 2021). The proportion of HPV-driven cases rose from 2.7 % to 53 % between 1981 and 2021. HPV16 was the dominant genotype during the study period. Of patients with HPV-driven OPC, 81 % were male and 42 % were smokers versus 80 % and 92 % in their HPV-negative counterparts. The age of OPC patients increased significantly, during the study period, independent of their HPV status CONCLUSION: The proportion of HPV-driven OPCs has significantly increased in Paris and its suburbs, during the last four decades. OPCs has become the 2nd predominant type of head and neck cancer, in France. This may be linked to the rise in HPV-driven cases and the decrease of tobacco and alcohol consumption in men.

[French national standard for the treatment of squamous cell carcinoma of upper aero-digestive tract - General principles of treatment]. / Référentiel national de traitement des carcinomes épidermoïdes des voies aérodigestives supérieures ­ Principes généraux de traitement.

OBJECTIVES: The management of upper aerodigestive tract cancers is a complex specialty. It is essential to provide an update to establish optimal care. At the initiative of the INCa and under the auspices of the SFORL, the scientific committee, led by Professor Béatrix Barry, Dr. Gilles Dolivet, and Dr. Dominique De Raucourt, decided to develop a reference framework aimed at defining, in a scientific and consensus-based manner, the general principles of treatment for upper aerodigestive tract cancers applicable to all sub-locations. METHODOLOGY: To develop this framework, a multidisciplinary team of practitioners was formed. A systematic analysis of the literature was conducted to produce recommendations classified by grades, in accordance with the standards of the French National Authority for Health (HAS). RESULTS: The grading of recommendations according to HAS standards has allowed the establishment of a reference for patient care based on several criteria. In this framework, patients benefit from differentiated care based on prognostic factors they present (age, comorbidities, TNM status, HPV status, etc.), conditions of implementation, and quality criteria for indicated surgery (operability, resectability, margin quality, mutilation, salvage surgery), as well as quality criteria for radiotherapy (target volume, implementation time, etc.). The role of medical and postoperative treatments was also evaluated based on specific criteria. Finally, supportive care must be organized from the beginning and throughout the patients' care journey. CONCLUSION: All collected data have led to the development of a comprehensive framework aimed at harmonizing practices nationally, facilitating decision-making in multidisciplinary consultation meetings, promoting equality in practices, and providing a state-of-the-art and reference practices for assessing the quality of care. This new framework is intended to be updated every 5 years to best reflect the latest advances in the field.