Search

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The incidence of human papillomavirus (HPV)-positive oropharyngeal carcinomas is increasing worldwide. Due to a markedly different response to treatment compared to HPV-negative oropharyngeal carcinomas, determining the ideal therapeutic approach can be challenging. Particularly in never-smokers, HPV-positive oropharyngeal carcinomas respond well to primary radiation therapy; at the same time recent studies indicate comparable survival after primary surgery. For stage I tumors according to TNM‑8, retrospective analyses show very good oncologic outcomes after surgery alone, and no added benefit of adjuvant radio- or chemotherapy. Results of prospective treatment deintensification trials are expected in the coming years. Minimally invasive transoral surgical approaches for selected oropharyngeal cancers can improve preservation of postoperative function and quality of life. For both HPV-positive and HPV-negative oropharyngeal carcinomas, salvage surgery is the treatment of choice for resectable recurrent locoregional disease and resectable distant metastases.

Update for Diagnosis and Management of HPV-Driven Oropharyngeal Cancer Abstract. In the past decades, an increasing incidence of oropharyngeal squamous cell cancer could be observed. More than twenty years ago, a correlation between a pharyngeal Human papillomavirus high-risk type infection and the development of oropharyngeal cancer has been suspected. Especially younger patients without the former risk factors smoking and alcohol have a higher prevalence for this cancer type. HPV-associated cancer is developing in the lymphatic tissue of the tonsils and the base of the tongue. HPV-driven tumors can be defined as a clinical and morphologic distinct tumor entity with a significantly better prognosis compared to tumors based on smoking and alcohol consumption. They are demonstrating a clearly better treatment response irrespective of the treatment modality. The tumor development is assumed to be comparable to cervical cancer, probably through a step-wise process from dysplasia to invasive cancer. In the pharynx, no HPV-associated precursor lesions have been detected so far. Therefore, Screening program proven to be very successful in the cervix have not could not have been implemented so far. The reduction of HPV-associated tumor burden in the cervix is likely to be compensated by the rising number of HPV-driven oropharyngeal cancer. P16 as a surrogate marker for HPV has been implemented in the 8th edition of the TNM classification for oropharyngeal cancer. A worldwide accepted definition of an HPV-driven tumor is lacking so far. P16 immunhistochemistry or HPV-DNA detection by PCR as single markers have an insufficient sensitivity and specificity. A combination of both markers demonstrates a higher accuracy compared to the gold standard RNA. Antibodies to HPV oncoproteins are reliable diagnostic and prognostic markers that could in the future possibly serve for early tumor detection.

Background: The incidence of HPV-associated squamous cell carcinoma of the head and neck region (HNSCC) has increased dramatically in recent years. Despite a similar localization (oropharyngeal squamous cell epithelia) to smoking- and alcohol-associated cancers, HPV-associated carcinomas are considered to represent a distinct entity. Reasons for the different therapeutic responses of the two tumor entities are not yet fully understood., Methods and Objective: This review investigates the importance of tumor-infiltrating lymphocytes in HPV + and HPV - HNSCC by means of articles and publications concerning the tumor micromilieu, effects on prognosis, and patients' therapeutic responses., Results: HNSCC patients with a positive HPV status and increased frequencies of CD8 + T cells (CD, cluster of differentiation) demonstrated an improved therapeutic response and improved outcomes. Decreased expression of the EGF (epidermal growth factor) receptor correlates with increased T H 1 cytokine secretion by CD4 + T cells, which, in their role as T helper cells, can activate macrophages, dendritic cells, and cytotoxic T cells, amongst others. Regulatory T cells (T reg ) execute an immune-suppressive effect in the tumor micromilieu through different metabolic and signaling pathways (IL[interleukin]‑4, IL-10, TGF‑β ["transforming growth factor‑β"])., Conclusion: The importance of the adaptive immune response for treatment response and patients' prognosis has been supported by different investigations. Understanding the immunological processes in the tumor environment plays an important role for the development of new treatment approaches.

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.

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.

There is increasing evidence worldwide that human papillomavirus is a major risk factor for head and neck cancer. Only few studies on this association have been performed in Germany to date. For the purposes of the present study, tumor specimens from 223 patients with squamous cell cancer of the oral cavity, oropharynx, hypopharynx and larynx were analyzed for HPV DNA and p16INK4a expression. The prevalence of HPV genotype 16 (HPV16) DNA in the study population was 17.5%. Further high-risk HPV types were not detected. All HPV16-positive tumors showed intense p16INK4a expression. HPV16 prevalence was highest in tonsillar carcinoma (37.5%) and lowest in laryngeal cancer (2.8%). We observed a significantly higher incidence of cervical lymph node metastases in patients with HPV16-positive tonsillar carcinoma in comparison to HPV-negative tumors (p < 0.016). Tobacco and/or alcohol consumption was significantly lower in patients with HPV-positive tumors (p < 0.0001).

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.

Infections with human papillomaviruses (HPV) are a common occurrence in both men and women. In contrast HPV-associated neoplasias are relatively rare and occur only in certain areas of the body. The virus has obviously developed efficient mechanisms for its persistence without inducing too much damage to the host. The formation of neoplasia seems to be more an exception. Epigenetic mechanisms play an important role in the regulation of viral gene expression. Investigations have indicated that exactly the transition from the permissive infection stage to a transformation stage, where neoplastic alterations can occur due to expression of the viral oncogenes, is associated with certain methylation patterns of the viral genome which promote the expression of the oncogenes E6 and E7. The transforming stage is seen as the actual carcinogenic event and can be immunohistochemically detected by the biomarker p16(INK4a).

Non-neoplastic HPV-induced alterations of the vulva and vagina are frequent. The traditional three-tier grading system of vulvar intraepithelial neoplasia (VIN) will be replaced by the definition of usual and simplex type of VIN. The usual type is characterized by a strong association to high-risk HPV infections, the occurrence at younger age and multifocality, mostly associated with non-keratinizing squamous cell carcinoma. The differentiated (or simplex) type is rare and shows an association to older age and p53 alterations and is typically diagnosed co-incidentally with keratinizing squamous cell carcinoma. Vaginal intraepithelial neoplasia (VAIN) is still graded into VAIN 1-3 where VAIN 1 and 2 are mostly associated with low-risk HPV infections and a high spontaneous regression rate whereas VAIN 3 represents a high-risk HPV-associated lesion with capable progression into (micro-)invasive carcinoma. The differential diagnosis between a non-neoplastic condylomatous lesion and VIN common type and VAIN may be aided by p16 immunohistochemistry. The HPV-associated invasive vulvo-vaginal cancers are verrucous carcinoma (low-risk HPV) and the high-risk HPV-induced (non-keratinizing) squamous cell carcinoma (NOS), the condylomatous (warty) carcinoma and the very rare vaginal squamo-transitional carcinoma.

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.

The human papillomavirus (HPV) is now understood to be important in the development of oropharyngeal cancers, particularly when other risk factors typically associated with this disease, such as smoking and nicotine abuse, are less evident. Case series have suggested that HPV-positive status is associated with better outcomes than HPV-negative status. The HPV status of patients with oropharyngeal cancer should be established before treatment commences. The risks and potential benefits of individual treatment modalities for patients with HPV-positive disease should be carefully considered with the aim of preserving quality of life, improving outcomes, and minimizing morbidity. The new data presented at ASCO will be discussed.

Merkel cell carcinoma (MCC) is a very aggressive neuroendocrine carcinoma of the skin. The recently identified Merkel cell polyomavirus (MCPyV) is present in the majority of MCCs. MCPyV clonally integrates in the tumor DNA and tumor-specific viral mutations are detected within the large T-antigen. To elucidate a possible role of MCPyV in the pathogenesis of other non-melanoma skin cancers (NMSC), i.e. squamous cell carcinoma, Bowen's disease and basal cell carcinoma we tested a group of these tumors in immunosuppressed and immunocompetent patients. In addition we tested MCPyV-positive tumors for viral mutations within the large T-antigen. MCPyV DNA was significantly more frequently detected in the NMSC of the immunosuppressed patients (p<0.001). No tumor specific mutations were found within the large T-antigen. The presence of the virus in tumor cells was confirmed by FISH analysis. Although MCPyV is present in the tumor cells of squamous cell carcinoma, Bowen's disease and basal cell skin carcinoma, further investigations into the role of MCPyV in the pathogenesis of these tumors is needed.

Human papilloma viruses (HPVs) are the main tumor viruses in humans and have been identified in gynecological malignancies, especially carcinomas of the uterine cervix and their precursor lesions. In addition, they are frequently observed in other anogenital tumors such as vulva/vagina, anal and penis carcinoma. Furthermore, the potential association with head and neck cancer, in particular tonsillar carcinoma, is now well documented. However, there are controversial reports on the detection of HPV in various other tumors; these are summarized in the present report. Data revealed that apart from the heart and the kidney, the virus has been found in all other organs that have been analyzed so far, i.e., prostate, urinary bladder, oral cavity, larynx, esophagus, stomach, colon, liver, vagina/vulva, endometrium, ovary, breast, penis, anus, skin, and lung. Some of the detection rates are remarkable, e.g., colon cancer up to 97%, lung cancer 80%, and breast cancer 74%. They point to geographical differences in the incidence of HPV in different populations, but also highlight the need for validation of the results. HPV is nevertheless an important biomarker in molecular tumor diagnostics. Firstly, it is useful for the differentiation of a secondary squamous cell carcinoma from a metastasis. Secondly, HPV-positive carcinomas not only have a distinct etiology but also a particular morphological phenotype. Overall, they are characterized by different tumor biology, such as, for example, increased sensitivity to radiotherapy.

Virtually all cases of cervical cancer are caused by one of the 18 oncogenic types of human papillomavirus (HPV). It is estimated that 80% of all women will be infected by HPV in a lifetime, and the prevalence of HPV is highest among young, sexually active women and declines with increasing age. The risk of developing high-grade squamous intraepithelial lesions depends on the actual HPV type,the duration of infection, and the viral load. Due to the high prevalence of HPV infection, HPV testing in young women is of little value. The high negative predictive value of this test, combined with nor-mal Papanicolaou smear results, almost ensures that the patient is or will be free of a cancer precursor at the time of testing or in the immediate future. Hence, HPV testing combined with cytology is a reasonable approach in elderly women in order to increase the screening interval to 3-5 years. HPV testing is established for triage of borderline cytology findings of atypical squamous cells of undetermined significance if colposcopy is not performed immediately and if HPV-negative women are rescheduled within 12 months. HPV testing 6 months after cone biopsy allows increasing the follow-up interval due to its high negative predictive value. In atypical glandular lesions not otherwise specified, HPV testing may identify patients requiring immediate treatment. In immunocompromised patients with borderline cytology due to persistent HPV infection, HPV test-ing identifies patients with a low risk of cancer precursors not requiring treatment.

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.

Immunohistochemical examination of p53 protein accumulation, analysis of the p53 gene using amplification of the exons 5-8 followed by TGGE, and PCR based HPV typing were carried out on 40 oral squamous cell carcinomas. 28 of 40 oral carcinomas (70%) contained DNA of the oncogenic HPV types 16 and 18. A p53 accumulation was present in 20 of 37 tumors (54%). Mutations of the p53 gene were detected in 15 of 39 carcinomas (38%). 15 of 20 oral carcinomas with abnormal p53 expression and 11/15 tumors with mutations of the p53 gene were HPV positive. Our results demonstrate a frequent occurrence of p53 abnormalities in HPV positive oral squamous cell carcinomas. This pattern is divergent from HPV related genital carcinomas and could reflect differences in the etiology of squamous cell carcinomas of different sites.