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ORATOR2 was a randomized phase II trial aiming to assess an optimal approach for therapy de-escalation in early (T1-T2, N0-N2) human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC). Radiotherapy (RT) (consisting of a reduced dose of 60 Gy with concurrent weekly cisplatin in N+ patients) was compared to trans-oral surgery (TOS) and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings) in 61 patients. The primary endpoint, overall survival, favored the radiotherapy approach. This was mainly due to 3 mortality events in the surgery arm (2 surgery-related) which resulted in an early trial termination. The authors, who speak on behalf of the German Society of Otorhinolaryngology, Head & Neck Surgery (working group for oncology) warn to draw conclusions for clinical practice pointing out the main shortages/weaknesses of this trial especially in the surgery arm (at least 1 cm margins, recommending re-operation if not achieved, prohibition of regional or free flaps, high rates of tracheotomy, low rate of TLM). Small patient numbers, a highly selected patient cohort and a short follow-up time further limit this study's relevance. Therefore, patients with HPV-related OPSCC should not receive de-escalating (radiation) therapy outside of clinical trials. When deciding between a surgical or a radio-therapeutical approach, patients should be informed about the pros and cons of both modalities after interdisciplinary consent in a tumor board, as long as clinical trial results` (e. g. EORTC 1420) are pending., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

The incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is steadily increasing worldwide and has already exceeded cervical cancer rates in the USA. Due to their tumor biology, HPV-positive tumors of the oropharynx, which have been included in the eighth edition of the AJCC/UICC (American Joint Committee on Cancer/Union Internationale Contre le Cancer) Staging Manual since 2018, represent a separate entity. Following biopsy, diagnostic confirmation is performed by immunohistochemical detection of p16 expression, with p16 acting as a surrogate marker. Therapeutically, surgical and radiotherapeutic approaches are considered equivalent in terms of efficacy. With a 5-year overall survival of up to 80%, patients with HPV-positive OPSCC have a better prognosis compared to patients with HPV-negative OPSCC, where survival rates are between 40 and 50%.

At this year's Annual Meeting of the American Society for Clinical Oncology (ASCO), the keyword search "HPV-associated head and neck cancer" resulted in 920 hits-74% of the hits on human papillomavirus (HPV). This underlines the relevance of the topic. The spectrum ranged from validation and separation of the prognostic groups of patients with HPV-associated oropharyngeal carcinoma (OPSCC) according to TNM 8, to the characterization of new tumor markers and tumor mutational burden for possible de-escalation strategies to avoid toxicity of standard multimodal treatments. It has been shown that the separation of p16-positive OPSCC into Union for International Cancer Control (UICC) stages I and II with the current TNM 8 classification without further markers is not sufficiently successful to justify de-escalation strategies. Following publication of the results of the De-ESCALaTE- and RTOG-1016 trials in 2018, which confirm the current standard of care for p16-positive OPSCC, no further phase III studies on de-escalation were presented. In a presented prospective phase II study (NCT02281955), the radiotherapy dose was reduced to cumulative 60 Gy, whereby the simultaneous chemotherapy regimen with cisplatin 30 mg/m 2 weekly is not standard of care and could be administered as an alternative to cisplatin cetuximab. Some work dealt with the oral and intestinal microbiota as prognostic markers or their treatment-related changes, particularly under immunotherapy. Modification seems to have a positive impact on the success of therapy. However, robust data are still lacking for the various modified treatments for HPV-associated OPSCC, which are needed before their implementation in daily practice.

Background: In the era of precision medicine and HPV-related oropharyngeal squamous cell carcinoma (OPSCC), it is relevant to assess the risk of not only survival, but also the risk of local, regional, or distant treatment failure. The UICC 8th edition uses the surrogate marker p16 to stratify for HPV association but discordance between p16 status and HPV association has been shown. The purpose of this study was to develop a prognostic model to predict the risk of local, regional, and distant metastases and non-cancer-related death for patients with OPSCC, test the prognostic relevance of adding HPV DNA and p16 status, and validate the findings in an independent external dataset., Patients and Methods: Consecutive patients diagnosed with OPSCC and treated with curative radiotherapy with or without cisplatin in eastern Denmark from 2000 to 2014 were included. Characteristics included age, gender, TNM stage, smoking habits, performance status, and HPV status assessed with p16 and HPV DNA. The information was used to develop a prognostic model for first site of failure with four competing events: recurrence in T-, N-, and M-site, and death with no evidence of disease., Results: Overall 1243 patients were eligible for the analysis. A prognostic model with the four events was developed and externally validated in an independent dataset with a heterogeneously treated patient population from another institution. The individual prognostication from the competing risk analysis is displayed in a user friendly online tool (https://rasmussen.shinyapps.io/OPSCCmodelHPV_p16/). Replacing p16 status with the combined variable HPV/p16 status influenced the HR and patients with HPV-/p16+ had significantly higher HR of M-site recurrence than HPV+/p16+ with a HR = 2.56; CI [1.30; 5.02]; P = 0.006 (P = 0.013 in the validation cohort)., Conclusion: Patients with HPV-/p16+ have significantly higher risk of M-site recurrence and could potentially be relevant candidates for clinical trials testing systemic treatments in combination with conventional treatments., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) is reported by many countries worldwide and OPSCC associated with human papillomavirus (HPV) has been recently defined as a new class of head and neck cancers. Besides tobacco and alcohol consumption, HPV is an accepted risk and prognostic factor for OPSCC. Although the incidence increase of HPV-associated OPSCC is convincing, cancer registry studies and studies based on cohorts often have drawbacks regarding data linkage to comparable experimental data, comparable anatomical definitions or HPV diagnostics. Patients with HPV-associated OPSCC have remarkably better prognosis and the tumors differ from HPV-negative OPSCC with respect to molecular and genetic aspects. Nevertheless, choice of therapy is independent of HPV, and rather is subject to the individual patient's condition, local preference and anatomic characteristics. New concepts emerge in immune-checkpoint oncology, which might be a valuable add-on to established concepts. Also, treatment de-escalation (e.g., by reduction of radiation dosage) might be suitable for patients with certain risk profiles. Prophylactic vaccination can contribute to reducing HPV-induced disease, likewise OPSCC. Prerequisite is a high rate of vaccination, which is currently not sufficient in Germany. Because of currently low vaccination rates and the rather long time between initial infection and HPV-induced carcinogenesis, reduction of incidence increase or prevalence of HPV-associated OPSCC is not expected in the near future.

Rising incidence rates in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and a significantly improved prognosis have brought this entity into scientific focus. At this year's American Society of Clinical Oncology (ASCO) Annual Meeting, 291 studies with the keyword "HPV" were presented, the majority of which were in head and neck cancer. Due to high rates of late toxicities after conventional therapy, de-intensified treatment concepts are being increasingly discussed, although data from prospective phase III studies were not presented. Retrospective data on the latest TNM staging (downstaging in many HPV-associated patients) and other risk stratification systems were presented. HPV diagnostics based solely on p16 immunohistochemistry were discussed. Many groups presented work on the HPV association and its prognostic relevance not only in oropharyngeal carcinoma, but also in oral cavity, hypopharyngeal, and locally advanced laryngeal squamous cell carcinoma. New prognostic biomarkers such as methylation signatures appear to be promising. New data suggest equal survival rates in HPV-associated stage I OPSCC treated with surgery alone in comparison to patients who received adjuvant therapy after surgery. A possible negative effect on overall survival in stage III HPV-associated OPSCC with a cisplatin dose ≤200 mg/m 2 was discussed. Results of de-escalation studies are urgently awaited, in order to be able to treat HPV-associated OPSCC patients as precisely and as specifically as possible and ensure long-term quality of life.

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.

Based on clinical and experimental data, oropharyngeal squamous cell carcinomas (OPSCC) associated with human papillomavirus (HPV) have been recognized as a distinct entity of head and neck cancers. However, outside of clinical trials, HPV status currently has no impact on treatment. The natural replication cycle of HPV takes place in epithelial cells, and is thus spatially separated from cytotoxic immune cells in the epidermis. Dendritic cells (Langerhans cells, LC), however, are frequent in this upper dermal layer. The ability of LC to process antigens, migrate, and, ultimately activate T cells is inhibited by the activity of the viral oncoproteins (E5-E7). Downregulation of functional human leukocyte antigen I (HLA-I) epithelial cell surface expression contributes to LC inhibition. However, due to their absence in upper skin layers, corresponding activation of natural killer (NK) cells via missing-self recognition is not relevant. Genome-wide analyses have revealed specific expression signatures for HPV-associated OPSCC that are distinct from HPV-negative cancers. Interestingly, aberrations in HLA-I genes were common in HPV-associated OPSCC. Our own findings indicate more frequent infiltration of HPV-associated OPSCC by CD56-positive (CD56 + ) NK cells, which might be related to HLA-I downregulation during HPV-associated carcinogenesis. In patients with OPSCC, CD56 positivity correlates with improved prognosis after conventional therapy. This could be evidence for HPV-associated OPSCC being especially eligible for novel immune-based therapies and an indication that immunological data should be included in the design of clinical trials.

Human papilloma viruses (HPV) are responsible for approximately half of all oropharyngeal squamous cell carcinomas (OPSCC) and incidence rates of HPV-associated OPSCC continue to increase substantially. The defined viral carcinogenesis permits development of specific diagnostic, therapeutic, and prophylactic approaches. Laboratory identification of HPV-associated OPSCC may be achieved by p16(INK4a) immunohistochemistry combined with HPV DNA detection by polymerase chain reaction (PCR) using tumor tissue. Patients with HPV-associated OPSCC have a relatively good prognosis; therefore, the HPV status plays an important role in patient guidance. Due to the relatively favorable prognosis, ongoing studies are evaluating whether less rigorous therapy for HPV-positive patients results in equally good cure rates. The criteria for patient selection are, however, still uncertain. Particularly markers for detection of HPV-positive patients with a high risk of treatment failure are lacking. Besides tumor stage and comorbidities, distinct genomic, epigenetic, and immunologic alterations are prognostically relevant for HPV-associated OPSCC, and might be of predictive value. Furthermore, the characteristic molecular alterations suggest the possibility of novel vigilant and specific therapy approaches. These may be inhibitors of the phosphatidylinositol 3‑kinase (PI3K) pathway, which is frequently activated in HPV-associated OPSCC, and immunotherapeutic methods, e. g., therapeutic vaccination. Although prophylactic HPV vaccinations may also prevent development of HPV-associated OPSCC, foreseeable effects on OPSCC incidence will be low, given the low vaccination rates in Germany. This highlights the fact that interdisciplinary research networks should enhance the necessary activities related to HPV-associated OPSCC.

A significantly increasing proportion of oropharyngeal head and neck carcinomas (OSCC) in North America and Europe are associated with human papillomavirus (HPV) infections. HPV-related OSCC is regarded as a distinct tumor type with regard to its cellular, biologic, and clinical characteristics. Patients with HPV-related OSCC have significantly better local control, but higher rates of regional lymph node and distant metastases as compared to patients with HPV-negative OSCC. Classical molecular genetic investigations demonstrated specific chromosomal aberration signatures in HPV-related OSCC, and recent developments in next generation sequencing (NGS) technology have rendered possible the sequencing of entire genomes, and thus detection of specific mutations, in just a few days. Initial data from The Cancer Genome Atlas (TCGA) project obtained by using genome-wide high throughput methods have confirmed that HPV-related OSCC contain fewer, albeit more specific mutations than HPV-negative tumors. Additionally, these data revealed the presence of specific-potentially therapeutically targetable-activating driver mutations in subgroups of HPV-positive OSCC, some of which have a prognostic impact. Specific targeted NGS technologies provide new possibilities for identification of diagnostic, prognostic, and predictive biomarkers and the development of personalized cancer treatment. Patients with HPV-positive tumors are likely to profit from these developments in the future, since the genetic alterations are relatively homogenous and frequently lead to signal pathway activation. There is an urgent need for network research activities to carry out the necessary basic research in prospective cohort studies.

Cidofovir is an antiviral agent used in the therapy of recurrent respiratory papillomatosis (RRP). In this study, we hypothesized that cidofovir is effective in decreasing the viral load of human papillomavirus (HPV). We established a type specific real-time PCR and measured HPV DNA loads. The course of viral load of HPV types 6 and 11 after repeated applications of cidofovir intralesionally was compared to the clinical outcome using a modified Derkay score. In 6 of the 8 (75 %) patients, we detected HPV 6. In 2 (25 %) patients, we detected HPV 11. In all of the patients, the viral load and the modified Derkay score decreased significantly during the treatment. We conclude that viral load of HPV can be monitored using the technique described here. Cidofovir in combination with surgical debulking reduces the viral load in patients with RRP. Relapses of the symptoms cannot be avoided but might be delayed.

Head and Neck Squamous Cell Carcinoma (HNSCC) are the 6th most common cancers worldwide. While the incidence of larynx-hypopharynx carcinoma decreases, actually an increase in oropharyngeal squamous cell carcinoma (OSCC) is observed. Classical risk factors for HNSCC are smoking and alcohol. Though, it was shown recently for 25 to 60% of OSCC, to be associated with an infection by oncogenic human papilloma virus (HPV). The development of "common" head-neck-tumors is substantially enhanced by an accumulation of genetic changes, which lead to an inactivation of tumor suppressor genes or to an activation of proto-oncogenes. A more or less uniform sequence of different DNA-damages leads to genetic instability. In this context, an early and frequent event is deletion on the short arm of chromosome 9, which results in inactivation of the p16-gene. On the contrary, for HPV-induced carcinogenesis, expression of the viral proteins E6 and E7 is most important, since E6 and E7 lead to inactivation of the cellular tumor-suppressor-proteins p53 and Rb. The process of natural transoral infection is not yet clear. However, as a matter of fact peroral HPV-infection is not seldom and in most cases such an infection heals completely and uneventfully. Smoking seems to increases the probability for developing an HPV-associated tumor. The association of HNSCC with HPV can be proven with established methods in clinical diagnostics. In addition to classical prognostic factors, diagnosis of an HPV-association may become important for future therapies. Prognostic relevance of HPV probably surmounts many known risk-factors, for instance regional metastasis. Until now, no other molecular markers are established in clinical routine. Future therapy concepts may vary for the two subgroups of patients, especially patients with HPV-associated OSCC may take advantage of a less aggressive postoperative treatment. Finally an outlook will be given on possible target-aimed therapies, of which so far only antibodies against EGF-receptors are established in clinical practice., (© Georg Thieme Verlag KG Stuttgart · New York.)

Squamous cell carcinomas of the head and neck belong to the most common cancers worldwide. Although they are in general on the decline, rising incidence rates have been reported for certain specific sites. In developed countries the impact of classical risk factors like tobacco and alcohol seems to decline, while the association with oncogenic papillomavirus infections, in particular in cancers of the oropharynx, is increasing markedly. The accumulation of genetic and epigenetic changes due to toxin exposure leads to inactivation of tumor suppressors or activation of proto-oncogenes, resulting in genetic instability and malignant transformation in non-papillomavirus-related cancer. Papillomavirus-related cancers infrequently contain genetic alterations and are caused by deregulation of the cell cycle, senescence and apoptosis induced by viral oncoproteins. Detection of oncogenic papillomavirus infections may be basis for further classification of head and neck squamous cell carcinoma and could be a key in differential treatment modalities for subsets of head and neck cancer in the near future.

Oropharyngeal squamous cell carcinoma (OSCC) is associated with oncogenic human papillomavirus (HPV) infection in 30-40% of all cases in Germany. The use of PCR and / or in situ hybridisation to detect HPV in tumour tissue is used in combination with p16 immunohistochemistry to reliably distinguish HPV-related and HPV-unrelated OSCC. The distinct biological behaviour of the HPV-related subset of OSCC results in a more favourable prognosis. This might be the result of a greater response to chemotherapy and radiotherapy as seen in recent studies. Ongoing and future clinical trials will stratify for HPV status. If the results of these prospective, randomized trials are consistent with the preliminary results of recent studies, HPV status will be of enormous clinical relevance in the future.

Translational research refers to the interfaces between preclinical research and targeted short- and medium-term developments through to clinical standards. There are two distinct groups of oropharyngeal malignancies: those caused by tobacco and alcohol abuse and those caused by HPV infection. Although the prognosis of patients in the latter group is significantly better, this is not taken into consideration in the choice of treatment. However, less intensive use of radiotherapy, chemotherapy, or surgery, as well as targeted multimodal therapeutic approaches, is under research. This article summarizes the main events in the HPV life cycle, with emphasis on carcinogenic mechanisms and potential new molecular targets. Identifying distinct tumor entities of the oropharynx enables the design and development of new preventive and therapeutic strategies to reduce the incidence and mortality of HPV-associated oropharyngeal cancers in the near future.

One-third of the cases of oropharyngeal squamous cell carcinoma (OSCC) contain oncogenic human papillomavirus (HR-HPV). Epidemiologic and molecular evidence underlines the causal role of HR-HPV in these tumors, which can be defined as HPV-related OSCC. These tumors differ from chemical/toxin-induced OSCC in several biological aspects, including specific molecular and genetic alterations. This leads to a characteristic clinical profile of HPV-related OSCC. Sexual risk factors play a role; however, the knowledge about natural infection and the rate of persistence of HR-HPV in the oropharynx is marginal. It is shown that the distinct biological behavior of the HPV-related subset of oropharyngeal tumors results in a more favorable prognosis. This might be the result of a better response to chemotherapy and radiotherapy. However, further studies are needed to show whether it will be possible to reliably select patients for individualized therapy depended on the HPV status of their tumors. Therefore, we think it will be mandatory to consider and stratify HPV status in the design of prospective clinical trials in the future.

The major risk factors for head and neck squamous cell carcinomas (HNSCC) are considered to be tobacco and alcohol. A link between oncogenic types of the human papilloma virus (HPV) and the risk of HNSCC has been suggested in the literature. However, the causal link is now becoming more firmly established on the basis of recent analyses. About 20% of all HNSCC and more than 50% of tonsillar cancers contain HR-HPV. The causal role of HPV-infection in carcinogenesis and the molecular mechanisms involved could thus far be best elucidated in the case of cervical carcinomas. New insights and increasing evidence for the analogy of HPV-positive HNSCC with cervical cancer are discussed. The definition of HPV-positive HNSCC has become more important due to the implications for risk factors and prognosis.

Background: Oncogenic human papillomaviruses (HPV) DNA have repeatedly been observed in many head and neck carcinomas (HNSCCs), and HPV infections are currently considered a possible factor in the etiology of these tumors. However, the reported prevalences of HPV-DNA in HNSCC are variable. In the current study the authors used highly sensitive polymerase chain reactions (PCRs) to analyze the occurrence of viral sequences in 98 carefully stratified HNSCCs. The authors determined the load and localization of HPV DNA in a subset of tonsillar carcinomas and their metastases., Methods: Nested PCR and an HPV16 specific single step PCR were used to screen 98 HNSCCs for HPV DNA for genital- and Epidermodysplasia verruciformis (EV)-associated HPVs. Typing was performed by direct sequencing and/or sequencing of cloned amplimers. In two patients HPV16 subtypes in tonsillar carcinomas and their metastases were compared by amplification and sequencing of the long control region of the virus. In a subset of HPV16 positive tonsillar carcinomas and their metastases, localization and viral load were determined using laser assisted microdissection and real time fluorescent PCR, respectively., Results: Altogether 25 HNSCCs (26%) were found to be HPV positive. Stratified according to the tumor localization, the frequency of HPV positive lesions was 18% in the oral cavity, 45% for oropharynx, 25% for hypopharynx, 8% for nasopharynx, and 7% for larynx. The highest HPV DNA prevalence (58%) was found in tonsillar carcinomas. The high risk HPV type 16 was found in 84% of positive HNSCCs, in 14% of which EV-associated HPVs were detected. Human papillomavirus sequences were detected in 64% of biopsies with normal mucosa from 11 patients with positive carcinomas. As a control group, 14 tumor free tonsils were analyzed. In none of these specimens were HPV sequences detected. Viral long transcriptional control region sequences in homologous metastases were identical with those in primary tumors and the load values in both locations were roughly comparable. Viral loads differed substantially in different areas of one tumor. Statistical evaluation of data related to clinicopathologic parameters showed a significant linkage of HPV with tonsillar carcinomas compared to other locations. Furthermore, a significant correlation of HPV status of tonsillar carcinomas with tumor grading and alcohol consumption was found., Conclusions: Our study shows a preferential association of HPV-DNA with tonsillar carcinomas. The data support the view of HPV negative and positive tonsillar carcinomas being different tumor entities and conventional cancer risk factors being of less importance in HPV-infected individuals. The HPV genome is located in the cancer cells, whereas the infection of normal mucosa is a rare event. Data on quantification of HPV16 in tonsillar tumors and their metastases showed mean viral loads comparable to other HPV associated malignancies., (Copyright 2001 American Cancer Society.)

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