Intratumor genetic heterogeneity and head and neck cancer relapse.

BACKGROUND: Head and neck squamous cell carcinomas are treated by surgery, radiotherapy (RT), chemoradiotherapy (CRT) or combinations thereof, but locoregional recurrences (LRs) occur in 30-40% of treated patients. We have previously shown that in approximately half of the LRs after CRT, cancer driver mutations are not shared with the index tumor. AIM: To investigate two possible explanations for these genetically unrelated relapses, treatment-induced genetic changes and intratumor genetic heterogeneity. METHODS: To investigate treatment-induced clonal DNA changes, we compared copy number alterations (CNAs) and mutations between primary and recurrent xenografted tumors after treatment with (C)RT. Intratumor genetic heterogeneity was studied by multi-region sequencing on DNA from 31 biopsies of 11 surgically treated tumors. RESULTS: Induction of clonal DNA changes by (C)RT was not observed in the xenograft models. Multi-region sequencing demonstrated variations in CNA profiles between paired biopsies of individual tumors, with copy number heterogeneity scores varying from 0.027 to 0.333. In total, 32 cancer driver mutations could be identified and were shared in all biopsies of each tumor. Remarkably, multi-clonal mutations in these same cancer driver genes were observed in 6 of 11 tumors. Genetically distinct heterogeneous cell cultures could also be established from single tumors, with different biomarker profiles and drug sensitivities. CONCLUSION: Intratumor genetic heterogeneity at the level of the cancer driver mutations might explain the discordant mutational profiles in LRs after CRT, while there are no indications in xenograft models that these changes are induced by CRT.

A population-based study of the epidemiology of oral squamous cell carcinoma in the Netherlands 1989-2018, with emphasis on young adults.

There has been an increasing trend in oral squamous cell carcinoma (OSCC) in patients under 45 years of age. The aim of this study was to evaluate the burden of OSCC in the Netherlands between 1989 and 2018 among young adults (age 20-34 years) when compared to adults (age 35-44 years), and to describe the burden in older groups as well, utilizing cancer registry data to characterize incidence patterns by age, sex, and risk factors. A total of 18,963 cases of OSCC were reported. The overall incidence rate, as measured by annual percentage change (APC), increased significantly from 1989 to 2010 by 1.3% per year (95% confidence interval (CI) 0.9-1.7%) but decreased thereafter by -0.9% (95% CI -2.5% to 0.7%). Annual incidence increased significantly by 2.4% (95% CI 1.1-3.8%) for patients aged 20-34 years, while it decreased for those aged 35-44 years by -0.9% (95% CI -1.7% to 0.0%). In patients older than 60 years, incidence rates increased overall (60-74 years: APC 1.8%, 95% CI 1.5-2.1%; ≥75 years: APC 1.5%, 95% CI 1.2-1.9%). Overall, 66.5% of patients were smokers and 65.3% were alcohol consumers. The marked differences in incidence within the young age subgroups warrants further investigation to elucidate any likely disparity in biological process and clinical outcomes in these populations.

Management and outcome of middle ear adenomatous neuroendocrine tumours: A systematic review.

Middle ear adenomatous neuroendocrine tumours (MEANTs) are rare, unpredictable tumours. Although most MEANTs are characterized by a benign biological behaviour and indolent growth pattern, some studies have reported locally invasive and metastastic disease. Currently, the optimal management strategy for MEANTs remains subject of debate. The aim of this study is to review the literature on MEANTs with focus on its clinical characteristics, treatment strategies and outcome. A systematic review was conducted using PubMed, Embase and Cochrane databases. A total of 111 studies comprising 198 patients with MEANT were included. Treatment modalities comprised surgery (90%), surgery with adjuvant radiotherapy (9%) and palliative (chemo)radiotherapy in (1%). Local recurrence was observed in 25% of the patients and 7% of the patients developed metastasis, over a median period of 5.7 years (range 7 months - 32 years). Twelve of 13 patients (92%) who developed metastases had a local recurrence. Four patients (2%) died of MEANT: three due to distant metastases and one due to extensive local recurrence. Reliable histopathologic predictors of outcome could not be identified. These findings indicate that the clinical presentations of MEANT vary substantially, the overall recurrence rate is considerable and initial local tumour control is paramount. Because of the unpredictable clinical course, prolonged follow-up is warranted.

Reasons for not reaching or using web-based self-management applications, and the use and evaluation of Oncokompas among cancer survivors, in the context of a randomised controlled trial.

INTRODUCTION: The web-based self-management application Oncokompas was developed to support cancer survivors to monitor health-related quality of life and symptoms (Measure) and to provide tailored information (Learn) and supportive care options (Act). In a previously reported randomised controlled trial (RCT), 68% of 655 recruited survivors were eligible, and of those 45% participated in the RCT. Among participants of the RCT that were randomised to the intervention group, 52% used Oncokompas as intended. The aim of this study was to explore reasons for not participating in the RCT, and reasons for not using Oncokompas among non-users, and the use and evaluation of Oncokompas among users. METHODS: Reasons for not participating were assessed with a study-specific questionnaire among 243 survivors who declined participation. Usage was investigated among 320 participants randomised to the intervention group of the RCT via system data and a study-specific questionnaire that was assessed during the 1 week follow-up (T1) assessment. RESULTS: Main reasons for not participating were not interested in participation in scientific research (40%) and not interested in scientific research and Oncokompas (28%). Main reasons for not being interested in Oncokompas were wanting to leave the period of being ill behind (29%), no symptom burden (23%), or lacking internet skills (18%). Out of the 320 participants in the intervention group 167 (52%) used Oncokompas as intended. Among 72 non-users, main reasons for not using Oncokompas were no symptom burden (32%) or lack of time (26%). Among 248 survivors that activated their account, satisfaction and user-friendliness were rated with a 7 (scale 0-10). Within 3 (IQR 1-4) sessions, users selected 32 (IQR 6-37) topics. Main reasons for not using healthcare options in Act were that the information in Learn was already sufficient (44%) or no supportive care needs (32%). DISCUSSION: Main reasons for not reaching or using Oncokompas were no symptom burden, no supportive care needs, or lack of time. Users selected many cancer-generic and tumour-specific topics to address, indicating added value of the wide range of available topics.

Body image distress in head and neck cancer patients: what are we looking at?

PURPOSE: The aim of the present study is to investigate the prevalence of body image distress among head and neck cancer (HNC) patients after treatment and to examine its association with sociodemographic and clinical factors, health-related quality of life (HRQOL), HNC symptoms, sexuality, self-compassion, and psychological distress. Second, we aim to explore daily life experiences of HNC patients regarding body image. METHODS: A cross-sectional survey among HNC patients investigated the prevalence of body image distress based on the Body Image Scale. Multivariable logistic regression analysis was applied to study associations with sociodemographic and clinical factors, HRQOL (EORTC QLQ-C30), HNC symptoms (QLQ-HN43), sexuality (FSFI-6; IIEF-5), self-compassion (SCS-SF), and psychological distress (HADS). Qualitative data from a body image writing intervention was used to explore experiences in daily life related to body image. RESULTS: Body image distress was prevalent in 13-20% (depending on cut-off scores) of 233 HNC patients. Symptoms of depression (p < 0.001), younger age (p < 0.001), problems with social contact (p = 0.001), problems with wound healing (p = 0.013), and larger extent of surgery (p = 0.014) were associated with having body image distress. This model explained 67% of variance. Writing interventions of 40 HNC patients showed that negative body image experiences were related to appearance and function, with social functioning problems described most often. CONCLUSION: Prevalence of body image distress in HNC patients, using different cut-off scores, is 13-20%. Younger patients, patients after extensive surgery, and patients who had wound healing problems are most at risk. There is a significant association between body image distress and depressive symptoms and social functioning.

Cost-utility of an eHealth application 'Oncokompas' that supports cancer survivors in self-management: results of a randomised controlled trial.

PURPOSE: The eHealth self-management application 'Oncokompas' was developed to support cancer survivors in monitoring health-related quality of life (HRQOL) and symptoms, and obtaining personalized feedback and options for supportive care. The aim of this study was to assess the cost-utility of Oncokompas compared with care as usual (CAU) among cancer survivors. METHODS: Survivors were randomly allocated to the intervention or control group. Direct (non-)medical, indirect non-medical costs, and HRQOL were measured at 3- and 6-month follow-up, using iMTA Medical Consumption and Productivity Costs and the EuroQol-5D questionnaires. Mean cumulative costs and quality-adjusted life-years (QALYs) were compared between both groups. RESULTS: In total, 625 survivors were randomized into intervention (n = 320) or control group (n = 305). Base case analysis showed that incremental costs from a societal perspective were - €163 (95% CI, - 665 to 326), and incremental QALYs were 0.0017 (95% CI, - 0.0121 to 0.0155) in the intervention group compared with those in the control group. The probability that, compared with CAU, Oncokompas is more effective was 60%, less costly 73%, and both more effective and less costly 47%. Sensitivity analyses showed that incremental costs vary between - €40 and €69, and incremental QALYs vary between - 0.0023 and - 0.0057. CONCLUSION: Oncokompas is likely to be equally effective on utilities, and not more expensive than CAU, and will therefore contribute to sustainable cancer survivorship care in a (cost-)effective manner. IMPLICATIONS FOR CANCER SURVIVORS: Oncokompas seems to improve HRQOL and reduces the burden of several tumour-specific symptoms, while costs from a societal perspective are similar to CAU.

Health-related quality of life and overall survival: a prospective study in patients with head and neck cancer treated with radiotherapy.

PURPOSE: We aimed to examine whether pre-treatment, post-treatment and change in health-related quality of Life (HRQoL) is associated with survival, in patients with head and neck cancer (HNC). METHODS: We included 948 newly diagnosed HNC patients treated with primary or adjuvant (chemo)radiotherapy with curative intent. The EORTC QLQ-C30 questionnaire was assessed pre-treatment and at 6 weeks, 6 months and 12 months post-treatment. Multivariable Cox regression analyses were performed to examine whether HRQoL at all time points and changes in HRQoL over time were associated with survival, after adjusting for demographic, clinical and lifestyle-related variables. RESULTS: Higher HRQoL scores were significantly associated with improved 5-year overall survival at all time points, except for the subscale global QoL at 6 weeks. Changes in HRQoL at 6 weeks post-treatment compared to pre-treatment were not significantly associated with survival. Changes in physical (HR: 0.88 95% CI: 0.82-0.96) and emotional functioning (HR: 0.90 95% CI: 0.85-0.96) from pre-treatment to 6 months post-treatment and changes in global QOL, and physical, emotional, and social functioning from pre-treatment to 12 months post-treatment were significantly associated with survival. CONCLUSION: Higher HRQoL reported pre-treatment and post-treatment (6 weeks, 6 months and 12 months) are significantly associated with improved survival, as well as changes in HRQoL at 6 and 12 months compared to pre-treatment. Our results highlight the value of monitoring HRQoL and to identify those patients that report decreased or deteriorated HRQOL. This may help to further improve cancer care in a timely and efficient manner.

The eHealth self-management application 'Oncokompas' that supports cancer survivors to improve health-related quality of life and reduce symptoms: which groups benefit most?

BACKGROUND: Oncokompas is a web-based self-management application that supports cancer survivors to monitor their health-related quality of life (HRQOL) and symptoms, and to obtain personalised feedback and tailored options for supportive care. In a large randomised controlled trial among survivors of head and neck cancer, colorectal cancer, and breast cancer and (non-)Hodgkin lymphoma, Oncokompas proved to improve HRQOL, and to reduce several tumour-specific symptoms. Effect sizes were however small, and no effect was observed on the primary outcome patient activation. Therefore, this study aims to explore which subgroups of cancer survivors may especially benefit from Oncokompas. MATERIALS AND METHODS: Cancer survivors (n = 625) were randomly assigned to the intervention group (access to Oncokompas, n = 320) or control group (6 months waiting list, n = 305). Outcome measures were HRQOL, tumour-specific symptoms, and patient activation. Potential moderators included socio-demographic (sex, age, marital status, education, employment), clinical (tumour type, stage, time since diagnosis, treatment modality, comorbidities), and personal factors (self-efficacy, personal control, health literacy, Internet use), and patient activation, mental adjustment to cancer, HRQOL, symptoms, and need for supportive care, measured at baseline. Linear mixed models were performed to investigate potential moderators. RESULTS: The intervention effect on HRQOL was the largest among cancer survivors with low to moderate self-efficacy, and among those with high personal control and those with high health literacy scores. Cancer survivors with higher baseline symptom scores benefitted more on head and neck (pain in the mouth, social eating, swallowing, coughing, trismus), and colorectal cancer (weight) specific symptoms. DISCUSSION: Oncokompas seems most effective in reducing symptoms in head and neck cancer and colorectal cancer survivors who report a higher burden of tumour-specific symptoms. Oncokompas seems most effective in improving HRQOL in cancer survivors with lower self-efficacy, and in cancer survivors with higher personal control, and higher health literacy.

The course of symptoms of anxiety and depression from time of diagnosis up to 2 years follow-up in head and neck cancer patients treated with primary (chemo)radiation.

OBJECTIVES: To identify sociodemographic and clinical factors, health-related quality of life (HRQOL) and head and neck cancer (HNC) symptoms associated with the course of symptoms of anxiety and depression from pretreatment to 24-month follow-up among HNC patients after (chemo)radiation. MATERIALS AND METHODS: Patients (n = 345) completed questionnaires on anxiety and depression (HADS), HRQOL and symptoms (EORTC QLQ-C30/QLQ-H&N35) before treatment, and 6-weeks,3-,6-12-,18-, and 24-months after treatment. Mixed model analyses were used to investigate the course of anxiety and depression from pretreatment to 24-months in relation to factors assessed at baseline, and the course of anxiety and depression from 6- to 24-months, in relation to factors assessed at 6-months. RESULTS: Increased risk for anxiety (HADS-anxiety > 7) was 28.7% among patients before treatment, which declined to 10.0% at 24-months. Increased risk for depression (HADS-depression > 7) was 15.1% before treatment, 18.2% at 3-months, 7.2% at 12-months and 16.0% at 24-months. Factors assessed at baseline which were significantly associated with the course of anxiety were age, pain, problems with social contact, and feeling ill, whereas chemotherapy, worse emotional functioning, speech problems and weight loss were significantly associated with the course of depression. Regarding factors assessed at 6-months, chemotherapy, worse cognitive and social functioning, insomnia, swallowing problems and trouble with social eating were associated with the course of anxiety. Nausea/vomiting, dyspnea, coughing, and feeling ill were associated with the course of depression (p-values < 0.05). DISCUSSION: Factors associated with a worse course of anxiety and depression are younger age, treatment with chemotherapy, worse HRQOL and higher symptom burden.

Demographic, clinical and lifestyle-related correlates of accelerometer assessed physical activity and fitness in newly diagnosed patients with head and neck cancer.

Introduction: Objective measurements of levels of physical activity and fitness in patients with head and neck cancer (HNC) are lacking. Furthermore, demographic, clinical and lifestyle-related correlates of low levels of physical activity and fitness in patients with HNC are unknown. This study aims to investigate the levels of accelerometer that assessed physical activity and fitness in patients with HNC and to identify their demographical, clinical and lifestyle-related correlates.Methods: Two hundred and fifty-four patients who were recently diagnosed with HNC and participated in the NETherlands QUality of life and Biomedical cohort studies In head and neck Cancer (NET-QUBIC) study were included. Physical activity (accelerometer), cardiorespiratory fitness (Chester Step Test), hand grip strength (hand dynamometer) and lower body muscle function (30-second chair-stand test) were assessed. Multivariable linear regression analyses with a stepwise forward selection procedure were used.Results: Patients spent 229 min/d in physical activity of which 18 min/d in moderate-to-vigorous physical activity. The mean predicted VO2max was 27.9 ml/kg/min, the mean hand grip strength was 38.1 kg and the mean number of standings was 14.3. Patients with lower educational level, more comorbidity and higher tumor stage spent significantly less time in physical activity. Older patients, females and patients with a higher tumor stage had significantly lower cardiorespiratory fitness levels. Older patients, females, patients with more comorbidity, patients with normal weight and patients who have never smoked had significantly lower hand grip strength. Older patients, patients with lower educational level, smokers and patients with more comorbidity had a significantly lower function of lower body muscle.Conclusions: Pre-treatment levels of physical activity, cardiorespiratory fitness and lower body muscle function are low in patients with HNC. Based on this study, exercise programs targeted and tailored to patients with low levels of physical activity and fitness can be developed.

Correction to: Advancing interdisciplinary research in head and neck cancer through a multicenter longitudinal prospective cohort study: the NETherlands QUality of life and BIomedical Cohort (NET-QUBIC) data warehouse and biobank.

Following publication of the original article [1], the authors reported the name of R.J. Baatenburg de Jong was incorrectly tagged in the HTML version of the article.

Advancing interdisciplinary research in head and neck cancer through a multicenter longitudinal prospective cohort study: the NETherlands QUality of life and BIomedical Cohort (NET-QUBIC) data warehouse and biobank.

BACKGROUND: Worldwide, over 500,000 people are diagnosed with head and neck cancer each year, a disease with major impact on life expectancy and quality of life. The purpose of the Netherlands Quality of life and Biomedical Cohort study (NET-QUBIC) is to advance interdisciplinary research that aims to optimize diagnosis, treatment, and supportive care for head and neck cancer patients and their informal caregivers. METHODS: Using an extensive assessment protocol (electronic clinical record form, patient reported outcome measures and fieldwork (interviews and physical tests)), clinical data and data on quality of life, demographic and personal factors, psychosocial (depression, anxiety, fatigue, pain, sleep, mental adjustment to cancer, posttraumatic stress), physical (speech, swallowing, oral function, malnutrition, physical fitness, neurocognitive function, sexual function), lifestyle (physical activity, nutrition, smoking, alcohol, drugs), and social factors (social function, social support, work, health care use, and costs) are collected and stored in the data warehouse. A longitudinal biobank is built with tumor tissue, blood and blood components, saliva samples, and oral rinses. An infrastructure for fieldwork and laboratory protocols is established at all participating centers. All patients fill out patient reported outcome measures before treatment and at 3, 6, 12, 24, 36, 48, and 60 months follow-up. The interviews, physical tests and biological sample collection are at baseline and 6, 12, and 24 months follow-up. The protocol for caregivers includes blood sampling and oral rinses at baseline and a tailored list of questionnaires, administered at the same time points as the patients. In total, 739 HNC patients and 262 informal caregivers have been included in 5 out of the 8 HNC centers in the Netherlands. DISCUSSION: By granting access to researchers to the NET-QUBIC data warehouse and biobank, we enable new research lines in clinical (e.g. treatment optimization in elderly patients), biological (e.g. liquid biopsy analysis for relapse detection), health related quality of life (e.g. the impact of toxicity on quality of life), and interrelated research (e.g. health related quality of life in relation to biomarkers and survival).

Referrals for head and neck cancer in England and The Netherlands: an international qualitative study of the views of secondary-care surgical specialists.

One-year survival after head and neck cancer in England has been reported to be worse than that in Europe, despite five-year conditional survival being similar, which implies that patients present later in England. One country with better rates is The Netherlands. There are many possible causes, one of which may be the system of referral from primary to secondary care. We have compared the views of secondary care specialists in the two countries about their systems for referral, and identified aspects that might have an impact on outcomes. We organised semistructured qualitative interviews of surgical specialists in head and neck cancer in England and The Netherlands (n=12 in each). The most common theme was communication between primary care and specialists. Surgeons in England identified this as the aspect most lacking under the English "two-week" rule, while Dutch specialists felt that the good communication in their system was one of its best points. Other themes included the educational needs of primary care practitioners, criticism of "tick box" referrals in England, and too many patients referred who do not have cancer. Overall, specialists in both countries identified good aspects of their respective referral systems, but those in England felt strongly that the "two-week" rule/NICE guidance system could be improved with better direct communication between primary and secondary care, which might improve the speed and quality of referrals, reduce unnecessary ones, and assist in educating primary care physicians. It is not clear whether such improvements would improve survival, but further research and piloting of such a system should be considered in England.

The course of sexual interest and enjoyment in head and neck cancer patients treated with primary (chemo)radiotherapy.

INTRODUCTION: The aim of this prospective study was to investigate the course of sexual interest and enjoyment in relation to sociodemographic and clinical factors, health-related quality of life (HRQOL), and symptoms of psychological distress in head and neck cancer (HNC) patients treated with primary (chemo)radiotherapy. METHODS: HNC patients (n = 354) completed patient-reported outcome measures (PROMs) on HRQOL (EORTC QLQ-C30 and QLQ-H&N35, including the sexuality subscale covering less sexual interest and enjoyment), and psychological distress (HADS) pretreatment, at 6-week follow-up and at 3-, 6-, 12-, 18-, and 24-month follow-up (i.e., after treatment). Linear mixed models were used to analyze the course of sexuality from pretreatment to 24-month follow-up, and to investigate its relation to sociodemographic and clinical factors, HRQOL, and psychological distress as measured at baseline, and to investigate the course of sexuality from 6- to 24-month follow-up in relation to these factors measured at 6-month follow-up. RESULTS: Before start of treatment, 37% of patients reported having less sexuality, which increased to 60% at 6-week follow-up, and returned to baseline level from 12-month follow-up onwards. Older age (p = 0.037) and trouble with social contact (p < 0.001), weight loss (p = 0.013), and constipation (p = 0.041) before treatment were associated with less sexuality over time. Female gender (p = 0.021) and poor social functioning (p < 0.001) at 6-month follow-up were associated with less sexuality from 6- to 24-month follow-up. DISCUSSION: Less sexuality is often reported in HNC patients treated with (chemo)radiotherapy. Using PROMs in clinical practice may help identify patients who might benefit from supportive care targeting sexuality.

Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations.

BACKGROUND: Germline mutations in the succinate dehydrogenase B (SDHB) gene predispose to hereditary paraganglioma (PGL) syndrome type 4. The aim of this study was to evaluate the clinical characteristics and outcome of treatment strategies for patients with head and neck paraganglioma (HNPGL) carrying SDHB germline mutations. METHODS: This was a retrospective evaluation of patients with HNPGL carrying SDHB germline mutations in the Netherlands. RESULTS: In a Dutch nationwide cohort study of SDHB germline mutation carriers, 54 patients with a total of 62 HNPGLs were identified. Forty-one of 54 patients (76 per cent) visited the outpatient clinic because of associated complaints. Eight patients (15 per cent) had multiple PGLs. One patient (2 per cent) developed a phaeochromocytoma and three (6 per cent) developed a malignant PGL. Twenty-seven patients (50 per cent) had an operation for their HNPGL and 15 (28 per cent) received radiotherapy. Three patients with HNPGL (6 per cent) were diagnosed with additional non-paraganglionic tumours. CONCLUSION: If an SDHB germline mutation is identified in a patient with HNPGL, the clinician should be aware of the variable manifestations of the SDHB-linked tumour syndrome, the risk of catecholamine excess, concurrent phaeochromocytoma, and association with non-paraganglionic tumours.

Highlights from the Second International Symposium on HPV infection in head and neck cancer.

The Second International Symposium on HPV Infection in Head and Neck Cancer was held on 3rd-4th November 2016 in Leipzig, Germany. The meeting brought together researchers and clinicians to share the latest knowledge on HPV infection in head and neck cancer and to join active and constructive scientific discussions. This report summarizes the major themes discussed during the symposium.

Evaluation of the eighth TNM classification on p16-positive oropharyngeal squamous cell carcinomas in the Netherlands and the importance of additional HPV DNA testing.

Background: Oropharyngeal squamous cell carcinomas (OPSCCs) are traditionally caused by smoking and excessive alcohol consumption. However, in the last decades high-risk human papillomavirus (HPV) infections play an increasingly important role in tumorigenesis. HPV-driven OPSCCs are known to have a more favorable prognosis, which has led to important and marked changes in the recently released TNM-8. In this 8th edition, OPSCCs are divided based on p16 immunostaining, with p16 overexpression as surrogate marker for the presence of HPV. The aims of this study are to evaluate TNM-8 on a Dutch consecutive cohort of patients with p16-positive OPSCC and to determine the relevance of additional HPV DNA testing. Patients and methods: All OPSCC patients without distant metastases at diagnosis and treated with curative intent at VU University Medical Center (2000-2015) and Erasmus Medical Center (2000-2006) were included (N = 1204). HPV status was determined by p16 immunostaining followed by HPV DNA PCR on the p16-immunopositive cases. We compared TNM-7 and TNM-8 using the Harrell's C index. Results: In total, 388 of 1204 (32.2%) patients were p16-immunopositive. In these patients, TNM-8 had a markedly better predictive prognostic power than TNM-7 (Harrell's C index 0.63 versus 0.53). Of the 388 p16-positive OPSCCs, 48 tumors (12.4%) were HPV DNA-negative. This subgroup had distinct demographic, clinical and morphologic characteristics and showed a significantly worse five-year overall survival compared with the HPV DNA-positive tumors (P < 0.001). Conclusions: TNM-8 has a better predictive prognostic power than TNM-7 in patients with p16-positive OPSCC. However, within p16-positive OPSCCs, there is an HPV DNA-negative subgroup with distinct features and a worse overall survival, indicating the importance to perform additional HPV DNA testing when predicting prognosis and particularly for selecting patients for de-intensified treatment regimens.

Epidemiologic associations of HPV-positive oropharyngeal cancer and (pre)cancerous cervical lesions.

Human papillomavirus (HPV)-induced oropharyngeal squamous cell carcinoma (OPSCC) remains increasing worldwide. We aimed to investigate if the HPV-prevalence of OPSCC in the Netherlands is rising as well, also in female patients. In addition, we evaluated the association between HPV-positive OPSCC and suspicious Pap results of the cervix in these female patients. Patients with OPSCC treated in the period 2000-2015 at the VU University Medical Center Amsterdam, were included (n = 926). The presence of an oncogenic HPV infection was determined by p16-immunostaining, followed by a high-risk HPV general primer 5+/6+ DNA PCR on the p16-immunopositive cases. A review of pathology reports in all female patients (n = 305) was undertaken to identify cytological signs of HPV-related (pre)cancer of the cervix. In total 281 of 926 (30.3%) OPSCCs were HPV-positive. Moreover, a significant increase in the prevalence of HPV-positive OPSCCs was observed from 14.0% in 2000 to 48.1% in 2015 (p < 0.001). Among the female patients with an HPV-positive OPSSC (n = 70), the results of cervical smears were available in 56 of 70 patients (80.0%). Of the female patients with HPV-positive OPSCC, 9 of 56 (16.1%) patients had a vaginal cuff Papanicolaou (Pap) test ≥3b in their medical history compared to 7 of 168 (4.2%) in the HPV-negative group (p = 0.003). In conclusion, a continuous increase in the HPV-attributable fraction of OPSCC was demonstrated in the period 2000-2015 in the Amsterdam region. HPV-positive OPSCC has a significant association with a history of suspicious Pap results of the cervix in female patients.