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.

Low-dose aspirin use and mortality risk in patients with head and neck cancer: A nationwide cohort study of 10 770 patients.

Several recent observational studies have linked low-dose aspirin use to improved survival in patients with head and neck cancer. However, studies of patterns of aspirin use and risk of cancer-specific mortality are lacking. This nationwide cohort study included all patients in the Danish Cancer Registry with a primary diagnosis of head and neck squamous cell cancer (HNSCC) during 2000 to 2016, aged 30 to 84 years, without prior cancer (except nonmelanoma skin cancer) and alive 1 year after diagnosis. Nationwide registries provided information on filled prescriptions, mortality and potential confounding factors. For a subpopulation, a clinical database provided additional information, including human papillomavirus (HPV) tumor status. We used Cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between postdiagnostic low-dose aspirin use (≥1 prescription within first year after diagnosis) and risk of cancer-specific mortality. We identified 10 770 patients with HNSCC during a median follow-up of 3.9 years. Of these, 1799 (16.7%) were low-dose aspirin users. Postdiagnostic use of low-dose aspirin was associated with a HR of 0.97 (95% CI 0.82-1.15) for cancer-specific mortality. Similar neutral associations were found according to patterns of aspirin use. No apparent trends emerged according to age, sex, topography or stage. A tendency towards a decreased cancer-specific mortality risk with low-dose aspirin use was observed among HPV-positive patients; however, the statistical precision was low. In conclusion, we did not observe an association between postdiagnostic low-dose aspirin use and cancer-specific mortality in a nationwide cohort of patients with HNSCC.

Impact of specific high-risk human papillomavirus genotypes on survival in oropharyngeal cancer.

The increases observed in incidence and survival of oropharyngeal squamous cell carcinoma (OPSCC) have been attributed to human papillomavirus (HPV) infection, but the survival-impact of specific genotypes is poorly understood. We investigated the potential influence of HPV genotypes on survival in HPV-positive (HPV+) OPSCC. All patients with HPV+/p16+ OPSCC and available genotype data within the period 2011 to 2017 in Eastern Denmark were included. Descriptive statistics on clinical and tumor data, as well as overall survival (OS) and recurrence-free survival (RFS) with Cox hazard models and Kaplan-Meier plots were performed. Overall, 769 HPV+/p16+ OPSCC patients were included of which genotype HPV16 accounted for 86% (n = 662). Compared to high-risk non-HPV16 genotypes (HR non-HPV16), HPV16 patients were younger at diagnosis (median years, 60 vs 64), had a higher male to female ratio (3.7:1 vs 2.1:1), and lower performance scores of ≤1 (90%, n = 559, vs 81%, n = 74). Regarding 5-year OS and RFS, no difference was observed between HPV16 and HR non-HPV16 patients. Subgrouping the HR non-HPV16 group into HPV33 (n = 57), HPV35 (n = 26) and "other genotypes" (n = 24) a significantly worse OS in the "other genotypes" group (hazard rate: 2.33, P = .027) was shown. With similar survival results between HPV16 and non-HPV16 genotypes, genotyping in OPSCC is interesting from an epidemiological point of view as well as in vaccination programs, but not a necessary addition in prognostication of HPV+/p16+ OPSCC.

Second primary cancer following primary oral squamous cell carcinoma: a population-based, retrospective study.

BACKGROUND: Second primary cancer (SPC), defined as a metachronous solid cancer resulting from neither a recurrence of the primary cancer nor a metastasis, is a leading long-term cause of death for survivors of primary oral squamous cell carcinoma (OSCC). This study examined the risk of SPC following treatment of primary OSCC. MATERIALS AND METHODS: This semi-national, population-based, retrospective study included all patients with primary OSCC treated with curative intent in Eastern Denmark in 2000-2014. The presence of SPC was confirmed from medical records and the Danish Pathology Data Bank. The rate of SPC was compared to the occurrence of any cancer in the Eastern Danish population using data from the Danish Cancer Registry. RESULTS: A total of 936 patients with primary OSSC were enrolled. Of these, 219 patients (23%) were diagnosed with SPC during the follow-up (median 8.9 years, IQR: 5.4-12.6 years). The rate of SPC was four times higher than the occurrence of any cancer among the Eastern Danish population i.e., with a standardized incidence ratio (SIR) of 4.13 (95%CI: 3.55-4.80). SPCs were most frequently found in head and neck region (n = 97, SIR = 43.6), lower respiratory organs (n = 38, SIR = 5.6) and gastrointestinal organs (n = 33, SIR = 3.2) with increased SPC rates in all locations. Among patients who developed SPC within the study period the median time from OSCC to the first SPC was 4.4 years (IQR: 2.5-6.2). Significant associations were found between both smoking and excessive alcohol consumption after treatment of OSCC and the risk of SPC. CONCLUSIONS: A noteworthy increased rate of SPC following treatment of primary OSCC was found, especially in the head and neck region and in the lungs. Healthcare professionals should be aware of this increased risk.

The impact of tobacco smoking on survival of patients with oral squamous cell carcinoma: a population-based retrospective study.

BACKGROUND: This article aims to evaluate the impact of smoking status, accumulated tobacco exposure (ATE), and smoking cessation on overall- and disease-free survival (OS and DFS) of patients with oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: Patients with primary OSCC treated with curative intent between 2000 and 2019 in Copenhagen were included (n = 1808). Kaplan-Meier curves and multivariable Cox regression analyses were performed to compare the survival of patients with different smoking history. Interactions between ATE and (A) tumor subsite and (B) excessive alcohol consumption (EAC) on the survival were evaluated using multivariable Cox regression analyses with interaction terms. RESULTS: We included 1717 patients with known smoking status (62.8% males, median age: 64 years (IQR: 57-71 years)), who had a 5-year OS of 53.7% (95%CI: 49.8%-57.9%). Based on fully adjusted multivariable Cox regression analyses, significantly elevated hazard ratios (HRs) for OS and DFS were identified for current, but not former smokers, compared to never-smokers. An approximately linear relationship between continuous ATE and survival estimates was identified. ATE analyzed as a categorical variable showed significantly elevated HRs for OS of patients with all categories (060 PYs), however only for DFS of patients with >60 PYs, compared to 0 PYs. Furthermore, an unfavorable long-term prognosis was evident after >3.5 (OS) and >2.5 (DFS) years from diagnosis for patients who continued smoking compared to patients with smoking cessation at diagnosis. The survival estimates of patients with different tumor subsite and alcohol consumption differed with increasing ATE. CONCLUSION: Tobacco smoking (assessed as smoking status and ATE) was associated with inferior survival (OS and DFS) among patients with OSCC. Unfavorable long-term prognosis was significant for patients who continued smoking compared to patients with smoking cessation at diagnosis. The impact of ATE on survival of patients with OSCC may depend on the tumor subsite and/or alcohol consumption.

Days alive and out of hospital following primary surgery for oral cavity squamous cell carcinoma.

BACKGROUND: Days Alive and Out of Hospital (DAOH) is a recently introduced, readily obtainable postoperative outcome measure method that expresses procedure and disease-associated morbidity and mortality. In this study, we evaluated DAOH with 30- and 365-days follow-up periods after primary surgery (DAOH30 and DAOH365, respectively) for patients with oral cavity squamous cell carcinoma (OSCC). The aim of this study is to identify patient-, procedure- and disease-associated risk factors for patients treated with primary surgery for primary OSCC. MATERIAL AND METHODS: This retrospective cohort study from a prospective collected database represents patients from Eastern Denmark surgically treated for primary OSCC in the period 2000-2014. DAOH30 and DAOH365 were calculated and associations with patient characteristics including comorbidity, tumor characteristics, clinical outcomes such as length of stay, readmission, and mortality were evaluated. Tests for difference and significance between groups were assessed with Mann-Whitney U test and quantile linear regression. RESULTS: We included 867 patients (63% males, median age: 63 years (IQR 56-70 years)). Median DAOH30 and DAOH365 after OSCC surgery were 25 days (IQR 21-27 days) and 356 days (IQR 336-360 days), respectively. Alcohol consumption had a significant association with a lower DAOH365, p < 0.01, but not with DAOH30. Advanced T-stage, adjuvant radiotherapy (RT) and increased Charlson Comorbidity Index (CCI) score was significantly associated with a lower DAOH30 and DAOH365. CONCLUSION: In this population-based study in OSCC patients treated with primary surgery, we found that DAOH after 30 days was 25 days (83%), while DAOH after 365 days was 356 days (98%). Advanced T-stage acts as a predictor for significant DAOH30 and DAOH365 reduction while excessive alcohol consumption predicts a significant DAOH365 reduction. Readmission within 30 days following surgery was associated with further readmission within one year.

Impact of delay in diagnosis and treatment-initiation on disease stage and survival in oral cavity cancer: a systematic review.

AIM/OBJECTIVES: This study aimed to systematically review the literature on the impact of delay in diagnosis and treatment of oral cavity cancer. METHODS: PubMed and Embase were systematically searched for articles reporting impact of delay in diagnosis and treatment on cancer-stage and survival of oral cavity cancer. Studies comprising at least ten patients, and published since the year 2000, were included. RESULTS: Sixteen studies (n = 45,001, range: 62-18,677 per study, 83% men), from Australia, Asia, Europe, North America and South America, met the inclusion criteria. Eleven studies (n = 1,460) examined delay in diagnosis, while five studies (n = 43,541) reported delay in treatment. Eight of the eleven studies, examining delay in diagnosis (n = 1,220), analyzed the correlation between delay in diagnosis and tumor stage at diagnosis. Three studies found a significant correlation between patient delay and advanced stage at diagnosis (p < 0.05), whereas three other studies did not. The studies reporting a significant correlation were from Asian countries, whereas the three studies that did not find a correlation were from other continents. Studies reporting on professional delay and total diagnostic delay, generally, did not find a significant correlation with advanced cancer at diagnosis. Time to treatment (TTI), defined as time from diagnosis to treatment, was found significantly correlated with survival in three studies (p < 0.01, p < 0.001, p < 0.05), and nonsignificant in two studies. CONCLUSION: A significant correlation between patient delay and advanced stage cancer was reported in Asian studies only, while professional delay and total diagnostic delay were generally found to be non-correlated with advanced stage cancer at diagnosis. TTI was in some studies reported to be correlated with poorer outcome, while other studies did not report a correlation. One study presented that there was no clear advantage in overall survival (OS) for patients treated within 30 days, compared to patients treated between 30 and 44 days.

Impact of time to treatment initiation for patients with oral cavity squamous cell carcinoma: a population-based, retrospective study.

BACKGROUND: The increasing incidence of oral cavity squamous cell carcinoma (OSCC) is challenging the capacity to treat patients efficiently. The aim of this study was to evaluate the impact of time to treatment initiation (TTI) on overall survival (OS) and recurrence free survival (RFS) for patients with primary OSCC. MATERIAL AND METHODS: All patients with primary OSCC treated with curative intent at Rigshospitalet in the period 2000-2014 with known date of diagnosis and treatment initiation were included. Correlation analyses between TTI and Charlson comorbidity index (CCI), UICC stage, and year of diagnosis were performed in addition to uni- and multivariate Cox proportional hazard regression analyses. Further, interaction analysis of TTI and UICC stage were conducted. RESULTS: Eight hundred and sixty-two patients (64% men) with a median age at diagnosis of 62 years (range: 28-95 years) were included. The median TTI was 31 days (range: 2-137 days). Correlation analyses showed correlations between TTI and CCI, TTI and UICC stage, and TTI and year of diagnosis (rho = -0.10, p-value = <.01; rho = 0.16, p-value = <.001; rho = -0.47 p-value = <.001). Univariate analyses showed a statistically significant increase in hazard ratio for both OS and RFS with a five-day increase in TTI (HR = 1.05, 95%CI: 1.02-1.07 and HR = 1.04, 95%CI: 1.02-1.07). However, when adjusting for age, sex, smoking, UICC stage, tumor sublocation, CCI, and year of diagnosis in a multivariate analysis, the increase in HR with TTI was not statistically significant. There was no statistically significant interaction between TTI and UICC stage. CONCLUSION: Survival of OSCC patients decreased with increasing TTI, yet not statistically significant in multivariate analysis. There was no difference in the effect of TTI between patients diagnosed in low or advanced stages.

The impact of comorbidities on survival in oral cancer patients: a population-based, case-control study.

BACKGROUND: Comorbidities have shown to highly influence the outcome and risk of death of head and neck cancer patients. The purpose of this study was to examine the comorbidities among oral cavity squamous cell carcinoma (OSCC) patients, and to investigate the impact of comorbidities on overall survival (OS) and recurrence free survival (RFS). METHODS: Patients diagnosed with OSCC in Eastern Denmark in the period 2000-2014 and treated with curative intend were included. Patients data were linked to the Danish National Patients Register to identify comorbidities based on the Charlson Comorbidity Index (CCI) at the time of diagnosis and five years after diagnosis. Each patient was age-and sex-matched in a 1:10 ratio with an age and sex matched reference group. RESULTS: A total of 1,183 patients and 11,830 controls were included. Overall this study found comorbidities to be more common among OSCC compared to the reference group both at the time of diagnosis and five years after. The 5-year OS among patients with a CCI score of zero, one, two, and three or above was 60%, 44%, 41%, and 40%, respectively. Similarly, the multivariate cox-regression analysis showed that patients with increasing CCI score also had an increasing risk of death compared to patients with no comorbidities. CONCLUSION: OSCC patients had significantly higher comorbidity burden at diagnosis and risk of developing additional comorbidities after diagnosis compared to the reference population. Survival outcomes decreased significantly with higher CCI.

Circulating tumour DNA alterations as biomarkers for head and neck cancer: a systematic review.

Background: Head and neck squamous cell carcinoma (HNSCC) is a significant global burden. The development of a diagnostic or recurrence monitoring test could evolve from the exploitation of molecular markers such as tumour-specific DNA alterations in plasma. The aim of this study was to report specific genetic alterations of DNA in plasma from HNSCC patients, report the diagnostic accuracy, and discuss potentials for a diagnostic or recurrence monitoring test based on circulating tumour DNA (ctDNA).Methods: A systematic search was performed in PubMed, Embase, and Cochrane Library for articles published in English between 1 January 1980 and 24 October 2018. The search terms used were related to ctDNA methylations and mutations in HNSCC patients.Results: We identified 16 studies from four countries (p = 1156 patients, c = 601 controls) examining ctDNA alterations of HNSCC patients. CtDNA methylations were significantly increased in HNSCC patients compared to controls. Five studies investigated ctDNA mutations in HNSCC. The most frequent examined gene mutation was TP53. Eleven studies investigated ctDNA methylations in HNSCC. Nine studies calculated the diagnostic accuracy of ctDNA methylations in HNSCC compared to controls. The most frequent examined gene methylations were CDKN2A, DAPK1, RASSF1, and P15.Conclusion: We found that increasing the number of ctDNA genetic methylations resulted in an increase in diagnostic sensitivity accuracy. No studies investigating ctDNA mutations included a control group. A combination of multiple human ctDNA gene alterations with viral ctDNA are promising tools for developing a ctDNA biomarker for HNSCC.

Rate of locoregional recurrence among patients with oropharyngeal squamous cell carcinoma with known HPV status: a systematic review.

Background: We aimed to review systematically the literature on locoregional recurrence rates in patients with HPV-positive and -negative oropharyngeal squamous cell carcinoma (OPSCC).Methods: PubMed and Embase databases were systematically searched using key words such as human papillomavirus, oropharyngeal squamous cell carcinoma with local, regional, and locoregional recurrence.Results: Nine studies (2974 patients with known HPV-status, 59% HPV-positive) were included. Among the HPV-positive and -negative patients, 69% and 58% had lymph node metastasis at diagnosis. At a median time to recurrence ranging from 8.4 to 13.2 months among the included studies, we found that a weighted average of 9% and 26% for HPV-positive and -negative patients experienced locoregional recurrence. Overall, the median follow-up time ranged from 21 to 83 months among the included studies.Conclusion: Recurrence rates for HPV-positive and -negative OPSCC patients were 9% and 26%, respectively, equating to an almost three times higher rate of locoregional recurrence among HPV-negative patients compared to HPV-positive patients.

Improved Survival of Children, Adolescents, and Young Adults With Head and Neck Soft Tissue Sarcomas in Denmark.

AIM: The aim of this study was to estimate nationally the survival of children, adolescents, and young adults with head and neck soft tissue sarcomas. MATERIALS AND METHODS: The authors included patients 0 to 21 years of age and diagnosed with rhabdomyosarcoma (RMS) or nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) located in the head and neck between 1980 and 2014. Survival probabilities were estimated using the Kaplan-Meier method. The authors estimated the effect of covariates with univariate and multivariate Cox regression analyses. The cumulative recurrence in RMS was estimated when considering death as a competing risk. RESULTS: We identified 72 patients (50% male individuals, whereas 72% had RMS). Elder patients (older than 15 y) did worse compared with younger patients (log-rank test P=0.001). Patients diagnosed from 1980 to 1999 did worse than patients diagnosed from 2000 to 2014 (log-rank test P=0.02). Similarly, younger (younger than 15 y) patients did significantly better when diagnosed from 2000 to 2014 with reference to those diagnosed from 1980 to 1999 (log-rank test P=0.026). The multivariate hazard ratio was 0.46 (95% confidence interval, 0.23-0.92) for patients diagnosed from 2000 to 2014 with reference to patients diagnosed from 1980 to 1999. The 1-year cumulative recurrence for RMS was 21.2% (95% confidence interval, 12.3%-35.0%). CONCLUSION: Overall survival has improved throughout the study period, which is attributable to advancement in diagnostics, treatment, and the application of standardized guidelines from international protocols.

Survival and characteristics of pediatric salivary gland cancer: A systematic review and meta-analysis.

A systematic search of PubMed, EMBASE, and the Cochrane Library for studies from 2000 to 2017 including children aged 0-19 with salivary gland cancer was performed. In 19 studies, 749 children (median age of 14.2 years, female to male ratio of 1.4:1) were included; 72% had parotid tumors and 95% underwent surgery, of whom 65% had surgery alone and 24% with adjuvant radiotherapy. Low-grade and stage mucoepidermoid carcinoma were the most frequent cancer. The 5-year overall- and disease-free survival was 94% and 83%. Recurrence was observed in 20% at a median of 1.1 years from diagnosis.

Association between oropharyngeal cancers with known HPV and p16 status and cervical intraepithelial neoplasia: a Danish population-based study.

BACKGROUND: Persistent infection with high-risk genotypes of human papillomavirus (HPV) is the main risk factor in the development of uterine cervical precancerous lesions and cervical cancer (CC), and cases of HPV-induced oropharyngeal squamous cell carcinoma (OPSCC) is increasing in the Western world. We investigated the association between HPV and p16 status and previous results of cervical examinations, including cytological and histological tests, in females with OPSCC. MATERIAL AND METHODS: We included females diagnosed with an OPSCC in Eastern Denmark from 2000 to 2014. OPSCCs were assessed for p16-overexpression and HPV DNA PCR. History of cervical tests was obtained from the Danish Pathology Registry. The cytology and histological results were categorized in accordance with the 2014 Bethesda System (TBS) and WHO. Hence, we divide the cervical results into two groups. Group I were negative for intraepithelial lesion or malignancy and group II had epithelial cell abnormalities and subdivided after increasingly neoplastic severity from A-D. Chi2-tests and Fischer's exact tests were performed to compare the two groups. RESULTS: A total of 417 women with OPSCC were identified; 203 with HPV-positive tumors (49%) of which cervical cytology or histology were available in 172 women (85%). Among these, 22 (13%) patients had a cervical history of ≥ IIC. A total of 171 out of 214 women in the HPV-negative group (80%) were examined with cytology and 17 had a history of ≥ IIC. No significant difference in diagnoses of (pre)cancerous lesions between the OPSCC HPV-positive and negative groups were observed (χ2 test p = .28, Fischer's exact test p = .29). CONCLUSION: HPV status in oropharyngeal tumors was not correlated with a history of ≥ IIC in cervical examinations. The effect on cervical dysplasia may be masked by a higher incidence of smoking among the OPSCC HPV-negative group.

Incidence and survival of hypopharyngeal cancer: a Danish Nation-Wide Study from 1980 to 2014.

Objectives: To evaluate changes in incidence and survival of patients diagnosed with hypopharyngeal cancer (HPC) in Denmark in the period 1980-2014.Methods: All patients registered with HPC in the Danish Cancer Registry (DCR) in the period 1980-2014 were included. Age-adjusted incidence rates (AAIRs), average annual percentage change in incidence, and overall survival were calculated.Results: Two thousand and nine patients were included (79.7% men). The overall AAIR increased significantly from 0.3 per 100,000 to 1.1 per 100,000 during the study period, corresponding to an increase of 4.1% per year. The most frequent histology was squamous cell carcinoma (SCC) comprising 90.3%. The overall five-year survival increased with 13.5 percentage points from 13.4% in the period 1980-1985 to 26.9% in the period 2010-2014. Women demonstrated better survival compared to men with a hazard ratio of 0.83, and patients with SCC had better survival compared to the remaining histology groups.Conclusions: This nation-wide study, covering nearly four decades, showed a significant increase in incidence and survival of HPC in Denmark.

Incidence and survival of laryngeal cancer in Denmark: a nation-wide study from 1980 to 2014.

Background: The purpose of this registry study was to evaluate trends in incidence and survival of laryngeal cancer in the Danish population from 1980 to 2014. Methods: This study includes all patients with laryngeal cancer registered in the Danish Cancer Registry (DCR) in the period 1980-2014. The age-adjusted incidence rate (AAIR) per 100,000 and average annual percent change (AAPC) were calculated. We evaluated the relative survival at five years in relation to gender, anatomical location, year at diagnosis, and histological type. Further, an age-period-cohort (APC) model of incidence was constructed. Results: A total of 8748 patients (82% males) were included. The median age at diagnosis was 60 years, range 18-101 years. The AAIR decreased from 3.6 per 100,000 in 1980 to 2.3 per 100,000 in 2014 with an AAPC of -0.8% (p < .008). Considering the anatomic location, we found that glottic cancer had a significantly better survival at five years compared to the other locations. We observed no significant difference in survival for supraglottic, subglottic and larynx unspecified cancer during the observation period. During the period 1980-2014, we found no improvement in five year relative survival. Conclusions: This nation-wide study reports a significant decrease in the incidence of laryngeal cancer. Glottic cancer had a significantly better survival at five years compared to other locations.

Development and external validation of nomograms in oropharyngeal cancer patients with known HPV-DNA status: a European Multicentre Study (OroGrams).

BACKGROUND: The proxy marker for human papillomavirus (HPV), p16, is included in the new AJCC 8th/UICC 8th staging system, but due to incongruence between p16 status and HPV infection, single biomarker evaluation could lead to misallocation of patients. We established nomograms for overall survival (OS) and progression-free survival (PFS) in patients with oropharyngeal squamous cell carcinoma (OPSCC) and known HPV-DNA and p16 status, and validated the models in cohorts from high- and low-prevalent HPV countries. METHODS: Consecutive OPSCC patients treated in Denmark, 2000-2014 formed the development cohort. The validation cohorts were from Sweden, Germany, and the United Kingdom. We developed nomograms by applying a backward-selection procedure for selection of variables, and assessed model performance. RESULTS: In the development cohort, 1313 patients, and in the validation cohorts, 344 German, 503 Swedish and 463 British patients were included. For the OS nomogram, age, gender, combined HPV-DNA and p16 status, smoking, T-, N-, and M-status and UICC-8 staging were selected, and for the PFS nomogram the same variables except UICC-8 staging. The nomograms performed well in discrimination and calibration. CONCLUSIONS: Our nomograms are reliable prognostic methods in patients with OPSCC. Combining HPV DNA and p16 is essential for correct prognostication. The nomograms are available at www.orograms.org .

Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature.

BACKGROUND: The genetic profile for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) remains largely unknown. The purpose of this study was to sequence tissue material from a large cohort of locoregionally-advanced HPV+ OPSCCs. METHODS: We performed targeted deep sequencing of 395 cancer-associated genes in 114 matched tumor/normal loco-regionally advanced HPV+ OPSCCs. Mutations and copy number aberrations were determined. RESULTS: We identified a total of 3459 mutations with an average of 10 mutations per megabase and a median of 28 variants per sample. The most frequently mutated genes were KALRN (28%), SPTBN1 (32%), KMT2A (31%), ZNRF3 (9%), BNC2 (12%), NOTCH2 (25%), FGFR2 (12%), SMAD2 (6%), and AR (13%). Our findings were dominated by COSMIC signature 5 and 12, represented in other head and neck cancers and in hepatocellular carcinomas, respectively. CONCLUSIONS: We have identified multiple genetic aberrations in HPV+ OPSCCs, and the COSMIC signature 12 as most prevalent. The mutations harbour both therapeutic and prognostic potential.

Incidence of head and neck cancer in children: A Danish nationwide study from 1978 to 2014.

BACKGROUND: Pediatric head and neck malignancies are rare and only a few descriptive epidemiological studies have been published. Using unique nationwide registries, we report age-specific incidence rates of head and neck cancer (HNC) among children during four decades. METHODS: Data were obtained from the Danish Cancer Registry. We included children aged 0-14 years diagnosed between January 1, 1978 and December 31, 2014 with extra-orbital, nonskin and nonbone HNC. Patients were divided into nine groups in regard to tumor location: oral cavity, oropharynx, nasopharynx, hypopharynx, thyroid, major salivary glands, larynx, and middle ear. Based on the World Health Organization standard population and Danish age-specific population counts, age-adjusted incidence rates (AAIR) and average annual percentage change (AAPC) were calculated and examined for trends. RESULTS: In total, 169 children (55.6% females) were registered with a malignant tumor in the head and neck region. The AAIR increased with an AAPC of 2.2% (95% CI, 0.8-3.7%). Females showed an AAIR of 0.54 per 100,000 person years compared to that of males, with 0.41 per 100,000 person years (P < 0.01). The AAIR was higher among children aged 10-14 years compared to 0-9-year-old children (P < 0.01). Based on morphology, a significant increase in AAIR was observed for sarcomas, with an increase of 0.16-0.27 per 100,000 person years (P < 0.05). CONCLUSIONS: The incidence rate of pediatric HNC was higher among females and evidence of increasing rates was observed during 1978-2014, explained by an increase mainly in sarcomas.

Increasing incidence and survival of head and neck cancers in Denmark: a nation-wide study from 1980 to 2014.

BACKGROUND: The purpose of the study was to determine trends in age-adjusted incidence rates (AAIR) and survival probability in head and neck cancers (HNCs) in the Danish population from 1980 to 2014. MATERIAL AND METHODS: All patients registered with HNC in the nationwide Danish Cancer Registry from 1980 to 2014 were included. We evaluated the AAIR per 100,000 and the average annual percent change (AAPC). The relative survival probability at 5 years was calculated in relation to gender, anatomical location and histology, and we constructed age-period-cohort models of incidence. RESULTS: About 34,606 patients were included (64.7% men). The AAIR increased from 9.1 per 100,000 in 1980 to 17.4 per 100,000 in 2014 with an AAPC of 2.1%. The greatest incidence increase was observed in oropharyngeal cancer (AAPC: 5.4%) followed by hypopharyngeal cancer (AAPC: 4.2%). Adenocarcinomas had the highest AAPC (5.0%) followed by squamous cell carcinomas (AAPC: 2.0%). The AAPC was significantly higher in women (2.4%) compared with men (1.6%). For all HNC patients, the relative survival at 5 years rose significantly from 49.0% in 1980-1984 to 62.4% in 2010-2014. Women had a significantly higher survival than men with a relative survival of 61.7% compared to 50.0% in men. Laryngeal cancer had the best survival probability of cancers in the upper aerodigestive tract with hypopharyngeal cancer having the poorest survival. CONCLUSION: This nation-wide study showed a significant rise in incidence of HNC for men and women along with a significant increase in relative survival. Oropharyngeal cancer had the highest increase in incidence followed by hypopharyngeal cancer which showed the poorest survival of HNCs.