Search

Background: Human papillomavirus (HPV) status is the most important predictor of survival in oropharyngeal squamous cell carcinoma (OPSCC). In patients with cervical lymph node metastases of squamous cell carcinoma of unknown origin (CUPHNSCC), much less is known. Methods: We assessed a consecutive cohort of CUPHNSCC diagnosed from 2000–2018 for HPV DNA, mRNA, p16INK4a (p16) expression, and risk factors to identify prognostic classification markers. Results: In 32/103 (31%) CUPHNSCC, p16 was overexpressed, and high-risk HPV DNA was detected in 18/32 (56.3%). This was mostly consistent with mRNA detection. In recursive partitioning analysis, CUPHNSCC patients were classified into three risk groups according to performance status (ECOG) and p16. Principal component analysis suggests a negative correlation of p16, HPV DNA, and gender in relation to ECOG, as well as a correlation between N stage, extranodal extension, and tobacco/alcohol consumption. Conclusions: Despite obvious differences, CUPHNSCC shares similarities in risk profile with OPSCC. However, the detection of p16 alone appears to be more suitable for the classification of CUPHNSCC than for OPSCC and, in combination with ECOG, allows stratification into three risk groups. In the future, additional factors besides p16 and ECOG may become important in larger studies or cases with special risk profiles.

Patient characteristics OPSCC Giessen cohort

Purpose:Human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is tumorigenic and has been associated with a favorable prognosis compared with OPSCC caused by tobacco, alcohol, and other carcinogens. Meanwhile, machine learning has evolved as a powerful tool to predict molecular and cellular alterations of medical images of various sources.Experimental Design:We generated a deep learning–based HPV prediction score (HPV-ps) on regular hematoxylin and eosin (H&E) stains and assessed its performance to predict HPV association using 273 patients from two different sites (OPSCC; Giessen, n = 163; Cologne, n = 110). Then, the prognostic relevance in a total of 594 patients (Giessen, Cologne, HNSCC TCGA) was evaluated. In addition, we investigated whether four board-certified pathologists could identify HPV association (n = 152) and compared the results to the classifier.Results:Although pathologists were able to diagnose HPV association from H&E-stained slides (AUC = 0.74, median of four observers), the interrater reliability was minimal (Light Kappa = 0.37; P = 0.129), as compared with AUC = 0.8 using the HPV-ps within two independent cohorts (n = 273). The HPV-ps identified individuals with a favorable prognosis in a total of 594 patients from three cohorts (Giessen, OPSCC, HR = 0.55, P < 0.0001; Cologne, OPSCC, HR = 0.44, P = 0.0027; TCGA, non-OPSCC head and neck, HR = 0.69, P = 0.0073). Interestingly, the HPV-ps further stratified patients when combined with p16 status (Giessen, HR = 0.06, P < 0.0001; Cologne, HR = 0.3, P = 0.046).Conclusions:Detection of HPV association in OPSCC using deep learning with help of regular H&E stains may either be used as a single biomarker, or in combination with p16 status, to identify patients with OPSCC with a favorable prognosis, potentially outperforming combined HPV-DNA/p16 status as a biomarker for patient stratification.

Introduction: The oncogenic human papillomaviruses (HPV) types 16 and 18 contribute to more than 73% cases of all HPV-related cancers and commonly affect the anogenital and head and neck region, with rapidly rising incidence rates of HPV-related oropharyngeal squamous cell carcinomas (OPSCC). HPV vaccination has the potential to decrease the burden of HPV-related disease, but vaccination rates remain low in many countries. We investigated the level of awareness of HPV, and HPV-OPSCC in particular, in a representative sample of the German population. Materials and Methods: As part of an online, population-based survey, an electronic questionnaire was administered to a representative sample of 1,095 adult individuals with a specific emphasis on awareness of HPV, transmission, and indicator symptoms of oropharyngeal cancer. Statistical analysis of levels of awareness and relation of these to age, gender, and socioeconomic background were conducted using the IBM SPSS Statistics Version 25.0. Results: 699/1,095 (63.8%) subjects had never heard of HPV. Of the subjects with awareness for HPV, 210 knew that HPV could be transmitted during sex (58.3%) and 138 recognized HPV as a risk factor for OPSCC (14.2%), unrelated to gender (p = 0.357), educational status (p = 0.581), or family status (p = 0.719). 416 subjects knew that a preventive vaccine against HPV existed (44.9%). Women were significantly more aware of HPV (34.2% vs. 22.8%, p < 0.001) and the vaccination (56.4% vs. 32.7%, p < 0.001) as were men. Younger individuals (age group 25–34) were significantly more aware of HPV (p < 0.001), likely as they were offered and/or had received the HPV vaccination. There was no regional variation of HPV awareness within the German state (p = 0.051). Conclusion: Here we demonstrate a significant lack of awareness of HPV and HPV vaccination in a representative sample of the German population. Levels of awareness of the link of HPV and oropharyngeal cancer are particularly low, bearing in mind that this cancer is commonly affecting men and incidence rates are rapidly rising in many European countries and the USA. Awareness programs and further education are required to tackle the low awareness rates and increase the uptake of the vaccination program not only in Germany, but also worldwide.

Die Inzidenzen des fur humanes Papillomavirus (HPV-)positiven Oropharynxkarzinoms (OPSCC) steigen weltweit stetig an und haben in den USA die Raten des Zervixkarzinoms bereits uberschritten. Hierfur ursachlich ist im Oropharynx v. a. die Infektion mit dem Hochrisikotyp HPV-16. Aufgrund der Tumorbiologie stellen HPV-positive Tumoren des Oropharynx eine eigene Entitat dar, welche seit 2018 in der 8. Edition des AJCC/UICC Staging Manual (American Joint Committee on Cancer/Union Internationale Contre le Cancer) berucksichtigt wird. Nach Biopsie erfolgt die diagnostische Sicherung mittels des immunhistochemischen Nachweises einer p16-Expression, wobei p16 als Surrogatmarker fungiert. Therapeutisch gelten chirurgische als auch primar strahlentherapeutische Ansatze als gleichwertig in Bezug auf ihre Wirksamkeit. Mit einem 5‑Jahres-Gesamtuberleben von bis zu 80 % weisen Patienten mit HPV-positivem OPSCC gegenuber Patienten mit HPV-negativem OPSCC mit Uberlebensraten von 40–50 % eine deutlich bessere Prognose auf.

This review focuses on the importance of oral and laryngeal HPV infection which is present in majority of sexually active individuals at least once in their lifetime. Despite testing, still little is known about prevalence rates, determinants and, especially, the concurrent HPV infection in head and neck, and genitals. The purpose of this review is to clarify some issues of oral HPV incidence, prevalence, and to demonstrate the difficulties in identification of asymptomatic oral HPV carriers. The main premise to take up this topic is the high and still increasing risk for development of oropharyngeal cancer, and potential benefit from screening strategies, education programs and HPV vaccination. Transmission of HPV to the oral cavity and oropharynx is hypothesized to occur mainly through sexual contact. The exposure of oropharyngeal mucosa to HPV infection with consequence of increased risk for oropharyngeal carcinoma depends on specific sexual behavior. Male gender, older age, race or ethnicity, oral hygiene and current cigarette smoking are independently associated with any prevalent oral HPV infection. (C) 2021 The Author(s). Published by Elsevier Ltd.

Persistent human papillomavirus (HPV) infection is associated with the development of oropharyngeal squamous cell carcinoma (OPSCC), and increasing incidences of OPSCC are reported. The generally favorable treatment outcome in patients with HPV-driven OPSCC has brought de-escalation of treatment into discussion. Nevertheless, 13% to 25% develop a relapse within two years after current standard treatment. New biomarkers are urgently required to monitor therapy response, tumor burden, and minimal residual disease during follow-up. This observational study examined 50 patients with OPSCC to investigate plasma cell-free (cf) HPV-DNA derived from tumor cells before therapy and during follow-up. Real-time quantitative PCR was applied to quantify the DNA concentration of HPV oncogenes E6 and E7. A total of 85.7% of pretreatment samples from patients with HPV-driven OPSCC (n = 28) were positive for at least one marker, and cfHPV-DNA concentration increased with tumor size. Virtually no signals were detected in HPV-negative OPSCC patients (n = 20; P ≤ 0.001). Patients without clinical evidence of recurrence had significantly reduced cfHPV-DNA concentrations after therapy (P ≤ 0.001). Conversely, cfHPV-DNA levels increased or remained above threshold in five patients who had residual disease or developed recurrence. In conclusion, plasma cfHPV-DNA detection correlates with the clinical course of disease in patients with HPV-driven OPSCC. Consequently, extensive clinical investigation should be considered if cfHPV-DNA is detected during follow-up of patients with HPV-driven OPSCC.

Background A remarkably better prognosis is associated with oropharyngeal squamous cell carcinomas (OPSCC) driven by human papillomaviruses (HPV) compared with HPV-negative OPSCC. Consequently, de-escalation of standard treatment has been suggested. Due to modest specificity rates, debates are ongoing, whether p16INK4a, a surrogate marker for HPV-driven OPSCC, is sufficient to correctly identify those tumours and avoid substantial HPV misattribution and thus undertreatment of patients by de-escalation. Robust data estimating the proportion of potentially undertreated patients are missing. Methods We assessed a large-scale cohort of consecutively included OPSCC diagnosed between 2000 and 2017 for HPV–DNA, HPV genotypes, p16INK4a expression and multiple tumour- and patient-related risk factors, and investigated their impact on patients’ survival in comprehensive uni- and multivariate analyses. Results Aetiological relevance of HPV (p16INK4a- and high-risk HPV–DNA-positivity) was detected in 27.1% (n = 192) of OPSCC, with HPV16 being the most abundant HPV type (94.6%). In 5.5% patients (n = 39), p16INK4a overexpression but no HPV–DNA was detected. Principal component and survival analyses revealed that 60.6% of these p16INK4a-positive OPSCC lacking HPV–DNA did not resemble HPV16-driven but HPV-negative OPSCC regarding risk-factor profile and overall survival. Notably, this group represented 10.6% of all p16INK4a-overexpressing OPSCC. Conclusions p16INK4a as a single marker appears insufficient to indicate OPSCC patients suitable for treatment de-escalation.

Objectives Despite improved survival rates of patients with HPV-associated OPSCC, a subset has distant metastasis or develops local recurrence during follow-up. To investigate potential underlying genetic alterations, we analyzed patients with HPV-driven OPSCC who suffered from recurrence in comparison to matching pairs with successful tumor control. Materials and methods We performed chromosomal copy number analyses and targeted next generation sequencing using a custom panel comprising genes that are frequently mutated in HPV-associated OPSCC. Results Specific differences regarding chromosomal aberrations were not observed between both groups. In HPV-driven OPSCC from patients with recurrence we found higher mutation rates compared to patients with successful tumor control. Especially mutation rates of HRAS (p ≤ 0.05) PIK3R1, STK11 and TP63 (p ≤ 0.1 each) were statistically significant or trending towards significance. The respective genes can be linked to transcription factors and signaling pathways involved in cell cycle regulation, proliferation and survival. Additionally, combinations of alterations were observed on chromosomes 16 and 19, which might also influence outcome. Conclusion Patients with HPV-driven OPSCC who develop recurrence or have metastasis may be defined by genetic alterations that might be responsible for poor outcome after standard therapy. This might be of importance for stratification in future de-escalation and targeted therapy.

Background: Human papillomavirus (HPV) infections are the principal cause of cervical cancers, subsets of anogenital and head and neck cancers (HNC). During persistent infection, viral DNA integration into the host genome may occur, which is suggested to affect carcinogenesis. One of the most critical limitations of currently used HPV integration detection techniques (PCR-based or NGS-based) is their application to FFPE material, because of DNA fragmentation. The aim of this study was to assess HPV integration in HPV-positive HNSCC cell lines and FFPE tissue comparing the new Targeted Locus Amplification (TLA) technology with previously used PCR technology (APOT/DIPS). Methods: Seven HPV-positive cell lines and FFPE material of 10 HPV-positive HNSCC were used for HPV integration detection by TLA, a proximity ligation-based next-generation sequencing technique. Crosslinked DNA is digested with restriction enzymes, and re-ligated into chimeric DNA molecules. For cell lines, a PCR based HPV16 target enrichment is performed, and for FFPE material a capture-based target enrichment is performed for HPV16 and HPV18 sequences, both followed by Illumina sequencing. Results: TLA was able to sequence up to 100 kb around the target, detecting exact HPV integration loci, structural variants, and chromosomal rearrangements. In all cell lines, one or more integration sites were identified, in accordance with APOT/DIPS PCR data and the literature. In the FFPE tissue samples, TLA identified integrated HPV in 6 out of 10 tumors, with simple and complex integration patterns. In general, TLA confirmed PCR data and detected additional integration sites. Conclusion: TLA provides the opportunity for reliable and robust detection of HPV integration in HNSCC cell lines and FFPE tissue. This new sequencing technology could be a useful tool for further research on HPV integration in disease and patient outcome and eventually in clinical diagnostics. Citation Format: Imke Demers, Harini Balaji, Harma Feitsma, Irinia Sergeeva, Joost Swennenhuis, Nora Wuerdemann, Steffen Wagner, Bernd Kremer, Christian Huebbers, Jens Peter Klussmann, Ernst-Jan Speel. Targeted locus amplification based sequencing for mapping viral integration sites in human papillomavirus positive head and neck squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2229.

VEGF signaling regulated by the vascular endothelial growth factor receptor 2 (VEGFR2) plays a decisive role in tumor angiogenesis, initiation and progression in several tumors including HNSCC. However, the impact of HPV-status on the expression of VEGFR2 in OPSCC has not yet been investigated, although HPV oncoproteins E6 and E7 induce VEGF-expression. In a series of 56 OPSCC with known HPV-status, VEGFR2 expression patterns were analyzed both in blood vessels from tumor-free and tumor-containing regions and within tumor cells by immunohistochemistry using densitometry. Differences in subcellular colocalization of VEGFR2 with endothelial, tumor and stem cell markers were determined by double-immunofluorescence imaging. Immunohistochemical results were correlated with clinicopathological data. HPV-infection induces significant downregulation of VEGFR2 in cancer cells compared to HPV-negative tumor cells (p = 0.012). However, with respect to blood vessel supply, the intensity of VEGFR2 staining differed only in HPV-positive OPSCC and was upregulated in the blood vessels of tumor-containing regions (p &lt, 0.0001). These results may suggest different routes of VEGFR2 signaling depending on the HPV-status of the OPSCC. While in HPV-positive OPSCC, VEGFR2 might be associated with increased angiogenesis, in HPV-negative tumors, an autocrine loop might regulate tumor cell survival and invasion.

Tumor growth and survival requires a particularly effective immunosuppressant tumor microenvironment (TME) to escape destruction by the immune system. While immunosuppressive checkpoint markers like programmed cell death 1 ligand (PD-L1) are already being targeted in clinical practice, lymphocyte-activation-protein 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and V-domain Ig suppressor of T cell activation (VISTA) inhibitors are currently under investigation in clinical trials. Reliable findings on the expression status of those immune checkpoint inhibitors on tumor-infiltrating lymphocytes (TILs) in the TME of oropharyngeal squamous cell carcinoma (OPSCC) are lacking. This work aims to describe the expression of LAG-3, TIM-3, and VISTA expression in the TME of OPSCC. We created a tissue microarray of paraffin-embedded tumor tissue of 241 OPSCC. Expression of the immune checkpoint protein LAG-3, TIM-3, and VISTA in OPSCC was evaluated using immunohistochemistry and results were correlated with CD8+ T-cell inflammation and human papillomavirus (HPV)-status. 73 OPSCC stained positive for LAG-3 (31%, HPV+:44%, HPV-:26%, p = 0.006), 122 OPSCC stained positive for TIM-3 (51%, HPV+:70%, HPV-:44%, p &lt, 0.001) and 168 OPSCC (70%, HPV+:75%, HPV-:68%, p = 0.313) for VISTA. CD8+ T-cells were significantly associated with LAG-3, TIM-3 and VISTA expression (p &lt, 0.001, p &lt, 0.001, p = 0.007). Immune checkpoint therapy targeting LAG-3, TIM-3, and/or VISTA could be a promising treatment strategy especially in HPV-related OPSCC. Future clinical trials investigating the efficacy of a checkpoint blockade in consideration of LAG-3, TIM-3, and VISTA expression are required.

Global incidences of oropharyngeal squamous cell carcinoma (OPSCC) are rising due to an association with high-risk human papillomavirus (HPV). Although there is an improved overall survival of HPV-related OPSCC, up to 25% of the patients develop recurrent or distant metastatic disease with a fatal outcomes. Biomarkers to monitor this disease are not established. This meta-analysis reviews the role of cell-free HPV DNA in liquid biopsy (LB) as a biomarker for HPV-related OPSCC. Pubmed, Livivo, and Cochrane Library databases were searched from inception to August, 2020. All studies were analyzed by Meta-DiSc 1.4 and Stata 16.0 statistical software. In total, 16 studies were considered for systematic review, whereas 11 studies met inclusion criteria for meta-analysis, respectively. Pooled sensitivity of cfHPV-DNA at first diagnosis and during follow-up was 0.81 (95% CI, 0.78&ndash, 0.84) and 0.73 (95% CI, 0.57&ndash, 0.86), while pooled specificity was 0.98 (95% CI, 0.96&ndash, 0.99) and 1 (95% CI, 0.99&ndash, 1). The diagnostic odds ratio (DOR) at first diagnosis was 200.60 (95% CI, 93.31&ndash, 431.22) and 300.31 (95% CI, 60.94&ndash, 1479.88) during follow-up. The area under the curve (AUC) of summary receiver operating characteristic (SROC) was 0.99 at first diagnosis and 1.00 during follow-up, respectively. In conclusion, cfHPV-DNA presents a potential biomarker with high specificity in patients with HPV-related OPSCC.

Purpose: Human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is tumorigenic and has been associated with a favorable prognosis compared with OPSCC caused by tobacco, alcohol, and other carcinogens. Meanwhile, machine learning has evolved as a powerful tool to predict molecular and cellular alterations of medical images of various sources. Experimental Design: We generated a deep learning–based HPV prediction score (HPV-ps) on regular hematoxylin and eosin (H&E) stains and assessed its performance to predict HPV association using 273 patients from two different sites (OPSCC; Giessen, n = 163; Cologne, n = 110). Then, the prognostic relevance in a total of 594 patients (Giessen, Cologne, HNSCC TCGA) was evaluated. In addition, we investigated whether four board-certified pathologists could identify HPV association (n = 152) and compared the results to the classifier. Results: Although pathologists were able to diagnose HPV association from H&E-stained slides (AUC = 0.74, median of four observers), the interrater reliability was minimal (Light Kappa = 0.37; P = 0.129), as compared with AUC = 0.8 using the HPV-ps within two independent cohorts (n = 273). The HPV-ps identified individuals with a favorable prognosis in a total of 594 patients from three cohorts (Giessen, OPSCC, HR = 0.55, P < 0.0001; Cologne, OPSCC, HR = 0.44, P = 0.0027; TCGA, non-OPSCC head and neck, HR = 0.69, P = 0.0073). Interestingly, the HPV-ps further stratified patients when combined with p16 status (Giessen, HR = 0.06, P < 0.0001; Cologne, HR = 0.3, P = 0.046). Conclusions: Detection of HPV association in OPSCC using deep learning with help of regular H&E stains may either be used as a single biomarker, or in combination with p16 status, to identify patients with OPSCC with a favorable prognosis, potentially outperforming combined HPV-DNA/p16 status as a biomarker for patient stratification.

The 8th edition of the AJCC/UICC TNM-staging system for p16[HPV]-positive OPSCC manages to improve prediction of prognosis and will essentially influence choice of therapy in future. Nonetheless, adjustments of the current version are needed. The surrogate marker p16 alone is inadequate for HPV detection, the role of ECS in HPV-positive OPSCC is not fully understood, and the patient's characteristics as well as molecular signatures and genetics have not been taken into consideration yet.

Background: Correct pre-therapeutic staging of the first primary carcinoma (FPC) and detection of simultaneous second primary carcinomas (SSPCs) decisively influence therapy and prognosis of head and neck squamous cell carcinomas (HNSCC). The aim of this study was to determine the benefit of pre-therapeutic triple endoscopy for detection of SSPC and pre-therapeutic T category. Methods: A cohort of 234 HNSCC patients with completed triple endoscopy was reviewed, focusing on pre-therapeutic T category and SSPC. Risk stratification for different subsites was evaluated. Results: The risk for SSPC was 5.56%. FPC of the oral cavity and oropharynx had the highest prevalence of SSPC (46.15%, 38.46%); most SSPCs were found in the hypopharynx. No SSPCs were found in the oral cavity, nasopharynx and oesophagus. Significant results in correct pre-therapeutic T staging have been achieved for the larynx (p = 0.021) and the oropharynx (p = 0.001). Conclusions: Triple endoscopies seem to be inadequate for SSPC detection in HNSCC patients. Endoscopies of the trachea and oesophagus should be reconsidered. Alternatively, risk-directed endoscopies of the hypopharynx might be performed in patients with oral cancer. For evaluation of resectability, conducting triple endoscopy could be reduced to a single endoscopy because the complication rate is low and pre-therapeutic T staging can be improved.

Simple Summary:& nbsp;Oropharyngeal squamous cell carcinoma (OPSCC) is a common malignancy of the upper aerodigestive tract with rising incidence. While surgical and non-surgical approaches are applied in curative treatment, none of these has proven superior to date. In this study, we investigated overall survival in an unselected, bicentric cohort of patients with OPSCC and compared upfront surgery vs. primary chemoradiation treatments. A matched-pair analysis was performed to exclude confounding factors and reduce bias. Our results suggest that regardless of the treatment modality chosen, overall survival rates are comparable in both cohorts. As a consequence, future studies on functional outcome of patients with OPSCC are mandatory to identify the treatment modality most likely resulting in improved quality of life in patients with OPSCC.The two pillars of therapy for oropharyngeal squamous cell carcinoma (OPSCC) are upfront surgery and primary chemoradiotherapy. Substantial regional preferences exist with regard to the selection of treatment. Despite new therapeutic approaches, patient survival remains poor, with an approximate overall survival (OS) rate of 50% at five years. This study was conducted to investigate a potential survival benefit depending on the treatment modality in OPSCC patients. We retrospectively collected data of 853 patients with histologically confirmed OPSCC from the Giessen and Maastricht cancer databases. To identify risk factors affecting survival, a Cox-proportional hazard model was applied to 442 patients with complete data sets. Based on this cohort a matched-pair analysis with 158 patients was performed to compare OS rates of patients treated either with upfront surgery or primary chemoradiation. For the collective cohort, patients treated with upfront surgery had significantly improved OS rates compared to patients treated with primary chemoradiation. In the matched-pair analysis adjusted for patients' T-, N- and HPV-status as well as risk profile, we observed that both treatment approaches offered equivalent OS rates. Our study emphasizes that treatment recommendations should be made whenever possible on the basis of side-effect profiles caused by the therapeutic approach used. To draw further conclusions, results of the ongoing "best of" (NCT2984410) study are eagerly awaited, investigating the functional outcome after treatment of OPSCC patients.

Objectives 18 F-FDG PET/CT is widely used in clinical oncology. Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) represents an emerging disease that differs from HPV-negative OPSCC in clinical behavior and tumour biology. In these tumours, HPV-oncogenes might lead to distinct alterations in metabolic pathways. Therefore, we compared metabolic parameters using 18 F-FDG PET/CT in HPV-positive and HPV-negative OPSCC in relation to histopathological findings. Materials Eighty-six patients with OPSCC received pre-therapeutic 18 F-FDG PET/CT. Standardised uptake volume (SUV), total lesion glycolysis (TLG) and metabolic tumour volume (MTV) were analysed for the primary tumour. SUVmax was determined for neck lymph nodes. HPV-status was determined; overall survival rates (OS) were estimated. Results 32/86 patients (37.2%) had HPV-related OPSCC. Overall, PET-parameters in primary tumours of both groups did not differ significantly. Comparing early with locally advanced primary tumours, there was a significant increase in 18 F-FDG uptake in HPV-negative patients (p 18 F-FDG uptake between primary and respective positive nodes in HPV-related primary OPSCC (p = 0.001). SUV-max and –mean values did not correlate with OS in HPV-related OPSCC. Conclusion The intraindividual homogeneity of 18 F-FDG uptake in HPV-related OPSCC could reflect the more homogenously, HPV-triggered carcinogenesis compared to the mutation-driven carcinogenesis in the HPV-negative OPSCC with heterogenic 18 F-FDG uptake.

The contribution of human papillomavirus (HPV) to the development and clinical outcome of oropharyngeal cancers has been well documented. The association of HPV in laryngeal squamous cell carcinoma (LSCC) has been examined in several studies, but controversy exists regarding its role in carcinogenesis, the outcome of the patients and thus, clinical significance of HPV testing in LSCC. In this review, we give an update of known associations between HPV-positive testing and carcinogenesis in laryngeal cancer. In an early study, the HPV-DNA detection rate in LSCC was documented being 24.0% with significant regional differences. Non-HPV-16 types were more often detected in LSCC when compared to the oropharynx. Later, single institution case series revealed markedly fewer amounts (

Background: Upfront surgery is a valuable treatment option for oropharyngeal squamous cell carcinoma (OPSCC) and risk stratification is emerging for treatment de-escalation in human papillomavirus (HPV)-related OPSCC. Available prognostic models are either based on selected, mainly non-surgically treated cohorts. Therefore, we investigated unselected OPSCC treated with predominantly upfront surgery. Methods: All patients diagnosed with OPSCC and treated with curative intent between 2000 and 2009 (n=359) were included. HPV association was determined by HPV-DNA detection and p16INK4a immunohistochemistry. Predictors with significant impact on overall survival (OS) in univariate analysis were included in recursive partitioning analysis. Results: Risk models generated from non-surgically treated patients showed low discrimination in our cohort. A new model developed for unselected patients predominantly treated with upfront surgery separates low-, intermediate- and high-risk patients with significant differences in 5-year OS (86%, 53% and 19%, P

Salivary gland carcinomas (SGCs) are rare and can be subdivided into distinct entities, some of which confer a poor prognosis. As targets for effective systemic therapy are warranted, some studies investigated the role of immune-checkpoint proteins PD-L1 and CTLA-4 in SGC. Our study depicts the expression of lymphocyte activation gene 3 (LAG3) in a test cohort and a larger validation cohort, totaling 139 SGCs. LAG3 is expressed on tumor-infiltrating lymphocytes (TILs), mediates T cell exhaustion and is subject to numerous currently recruiting clinical studies. Overall, one-third of SGCs were infiltrated by LAG3-expressing TILs with a strikingly high concordance between the test cohort and the validation cohort (30% and 28.2%, respectively). In the validation cohort, entity-wise LAG3 expression frequencies were highly variable. The highest rates were observed in salivary duct carcinoma (SDC; 66.7%) and adenocarcinoma not otherwise specified (ANOS; 50.0%). We observed LAG3 expression on effector T cells and in smaller frequencies also on FOXP3− T helper cells and FOXP3+ Tregs. LAG3 expression significantly correlated with advanced nodal metastases, cytotoxic T cell infiltrate and TP53 mutations. In the group of adenoid cystic carcinomas, LAG3 expression was also associated with a shorter event-free survival (EFS). Tumors with TP53 nonsense mutations (TP53 null type) exhibited higher LAG3 frequencies and a shorter EFS compared to TP53 wild type. This is the first report of LAG3 expression in SGC, a promising target for immunotherapy. LAG3 blockage could be distinctly applicable for SDC and ANOS, two SGC types with a particularly poor outcome.

A remarkably better prognosis is associated with oropharyngeal squamous cell carcinomas (OPSCC) driven by human papillomaviruses (HPV) compared with HPV-negative OPSCC. Consequently, de-escalation of standard treatment has been suggested. Due to modest specificity rates, debates are ongoing, whether p16We assessed a large-scale cohort of consecutively included OPSCC diagnosed between 2000 and 2017 for HPV-DNA, HPV genotypes, p16Aetiological relevance of HPV (p16p16

Introduction: This study reports the oncological outcome of a non-selected series of patients with human papillomavirus(HPV)-positive and -negative oropharyngeal squamous cell carcinoma (OSCC) preferentially managed with upfront surgery. Methods: Consecutive OSCC cases (n = 378) diagnosed from 2000 to 2010 in our department were evaluated for risk factors, HPV association, therapy and overall survival (OS). HPV status was determined by combined DNA and p16 testing, and treatment was defined as the first course of treatment with any kind of surgery (upfront surgery) or primary chemoradiotherapy. OS of HPV-associated and HPV-negative patients was compared using Kaplan-Meier and multivariable Cox regression analyses. Results: The majority of OSCC patients (215 of 361; 69.5%) received upfront surgery as first-line treatment in curative intent. The 5-year OS rate in patients with HPV-positive and HPV-negative tumors were 81.1 and 39.7%, respectively. Upfront surgery in HPV-negative (p < 0.001) and HPV-positive patients (p = 0.05) resulted in improved OS only in advanced stages. Multivariate analysis for patients revealed age in HPV-associated OSCC as an independent predictor for improved survival, and age, performance, N status and therapy as independent predictors in HPV-negative OSCC. Conclusions: Non-selected OSCC patients amenable to curative therapy show poor 5-year OS. The benefit of upfront surgery remains unclear. A younger patient age was the main factor for a better outcome in patients with HPV-associated OSCC.

Das humane Papillomavirus (HPV) gehort zur Familie der Papillomaviren. Basierend auf dem karzinogenen Potenzial der Viren erfolgt die Einteilung in Niedrig- und Hochrisikotypen. Niedrigrisikotypen sind verantwortlich fur genitale Papillome und die rekurrierende respiratorische Papillomatose, wahrend HPV-Hochrisikotypen weltweit 5 % der Karzinome induzieren. HPV gilt als sexuell ubertragbare Erkrankung und ist, neben der Entstehung anogenitaler Karzinome, im Kopf-Hals-Bereich fur die Pathogenese des HPV-assoziierten Oropharynxkarzinoms (OPSCC) verantwortlich. Diese Arbeit basiert auf einer selektiven Literaturrecherche in der Datenbank PubMed zum Thema HPV-assoziierte OPSCC. Die Inzidenz dieser vorrangig in der Tonsille sowie im Zugengrund lokalisierten HPV-assoziierten Kopf-Hals-Karzinome steigt. Aufgrund der virusgetriebenen Karzinogenese unterscheiden sich HPV-assoziierte OPSCC hinsichtlich genetischer und molekularbiologischer Aspekte von den noxenassoziierten OPSCC und weisen im Vergleich eine signifikant verbesserte Prognose auf. Der Nachweis einer HPV-Assoziation erfolgt u. a. uber den immunhistochemischen Nachweis einer Uberexpression des Surrogatmarkers p16, welcher seit 2017 in der 8. Auflage der TNM-Klassifikation maligner Tumoren berucksichtigt wird. Bisher wird bei der Wahl der Therapie nicht aufgrund des HPV-Status unterschieden, welches in beiden Entitaten zu einer hohen Nebenwirkungsrate fuhrt. Um zukunftig eine Therapiedeeskalation bestimmter Patientengruppen zu ermoglichen, wurden prognostische Modelle zur Risikostratifizierung entwickelt. Zur Uberwachung des Krankheitsverlaufs sowie der fruhzeitigen Detektion eines Therapieversagens werden aktuell Screeningmethoden wie die Flussigbiopsie auf ihre Validitat gepruft. Die HPV-Impfung, welche der primaren Prophylaxe einer Tumorentstehung dient, wird fur Madchen sowie seit kurzem auch fur Jungen im Alter von 9 bis 14 Jahren von der Standigen Impfkommission (STIKO) empfohlen.

Eighty-six patients with OPSCC received pre-therapeutic32/86 patients (37.2%) had HPV-related OPSCC. Overall, PET-parameters in primary tumours of both groups did not differ significantly. Comparing early with locally advanced primary tumours, there was a significant increase inThe intraindividual homogeneity of 18F-FDG uptake in HPV-related OPSCC could reflect the more homogenously, HPV-triggered carcinogenesis compared to the mutation-driven carcinogenesis in the HPV-negative OPSCC with heterogenic

Human papillomavirus(HPV)-related head and neck cancer is recognized as a distinct tumor entity with rising incidence reported for several countries. These tumors arise from squamous cells, typically in the oropharynx. In contrast to cancer associated with other risk factors, HPV-related cancer is driven by viral oncoprotein activity and has individual profiles regarding protein expression, and genetic and epigenetic alterations. Molecular characteristics are p16IN4A overexpression, absence of p53 inactivating mutations, and PI3K/AKT and Wnt pathway modulation. Patients with HPV-related head and neck cancer have improved survival compared to those with HPV-negative tumors, and p16INK4A staining has been introduced into tumor staging recently. However, no specific or toxicity-reduced treatment modalities have been established for this entity so far. Although the still incomplete and partially inconsistent data in this field needs further study, particular features of HPV-related cancers such as specific microRNA expression, immunology, or gene methylation patterns certainly have the potential to be implemented in future diagnostic and therapeutic concepts.

Reply to ‘Comment on ‘Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer”