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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (4 June 2021) | Viewed by 56447

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Prof. Dr. Christian von Buchwald

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Department of Otorhinolaryngology— Head and Neck Surgery and Audiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Interests: human papillomavirus and head and neck cancer; biomarkers: circulating tumor DNA including circulating HPV DNA; reduction of treatment morbidity (trans-oral robotic surgery); sinonasal pathology; stem cells
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Prof. Dr. Tina Dalianis

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Guest Editor

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Interests: human papillomaviruses and cancer; especially in head and neck cancer; targeted therapy in head and neck cancer and pediatric cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Anders Näsman

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Guest Editor

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Interests: head and neck cancer; tonsillar; base of tongue cancer; salivary gland cancer; clinical pathology; diagnostics and biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There are more than 100 human papillomaviruses (HPVs), 13 of which are considered to be carcinogenic. Of those types, HPV 16 is associated with roughly 90% of HPV+ head and neck cancers, and the incidences of HPV+ tonsillar and base of tongue cancer have been increasing in many Western countries. Notably, HPV+ tonsillar and base of tongue cancer also have a considerably better prognosis than corresponding HPV- tonsillar and base of tongue cancer. In addition, other HPV members cause benign tumors of the head and neck region.

In this Special Issue, we wish to explore current research in HPV in the head and neck region. Topics of interest include, but are not limited to, the following:

The role of human papillomaviruses in cancer, benign tumors and lesions in the head and neck region;
Diagnosis of human papillomavirus in cancer of the head and neck region;
Epidemics of human-papillomavirus-induced cancer in the head and neck region;
Therapeutic approaches including immune responses and biomarkers in human-papillomavirus-positive cancer of the head and neck region;
HPV vaccination of boys.

Prof. Dr. Christian von Buchwald
Prof. Dr. Tina Dalianis
Dr. Anders Näsman
Guest Editors

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Keywords

HPV head and neck cancer
HPV head and neck cancer diagnosis
HPV head and neck cancer epidemiology
HPV head and neck cancer therapy
HPV head and neck cancer vaccination

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Published Papers (13 papers)

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Editorial

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2 pages, 175 KiB

Open AccessEditorial

Special Issue “HPV in the Head and Neck Region”

by Tina Dalianis, Christian von Buchwald and Anders Näsman

Viruses 2021, 13(12), 2452; https://doi.org/10.3390/v13122452 - 6 Dec 2021

Viewed by 2193

Abstract

Previously, human papillomaviruses were best known for causing diseases in the genital tract, where high-risk types may cause, e.g., cancer of the cervix uteri, while low risk types could cause condylomas [...] Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

8 pages, 29374 KiB

Open AccessEditorial

Focal Epithelial Hyperplasia

by Simone Kloch Bendtsen, Kathrine Kronberg Jakobsen, Amanda-Louise Fenger Carlander, Christian Grønhøj and Christian von Buchwald

Viruses 2021, 13(8), 1529; https://doi.org/10.3390/v13081529 - 2 Aug 2021

Cited by 14 | Viewed by 4847

Abstract

Focal epithelial hyperplasia (FEH) or Heck’s disease is a rare, benign, oral condition that is associated with infection by human papillomavirus type 13, 32 or both. The whiteish to mucosal-colored, soft, papular or nodular elevated lesions in the oral cavity are normally asymptomatic but can grow to a size or at a location where treatment is needed. The diagnosis is often based on clinical presentation and histopathology, and the HPV genotype can be determined using PCR utilizing specific primers or DNA sequencing. While FEH was reported to often affect several members of the same family and exist primarily among indigenous populations around the world, the number of reported cases within the European region is increasing. This contemporary review summarizes the main findings in relation to HPV genotypes, impact of superinfection exclusion and vaccination, transmission, diagnosis, geographical and ethnical distribution, comorbidities and treatment of FEH with an emphasis on including the most recent case reports within the field. Furthermore, we describe for the first time a FEH lesion infected with the low-risk HPV90. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

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Review

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12 pages, 330 KiB

Open AccessReview

Barriers towards HPV Vaccinations for Boys and Young Men: A Narrative Review

by Maria Grandahl and Tryggve Nevéus

Viruses 2021, 13(8), 1644; https://doi.org/10.3390/v13081644 - 19 Aug 2021

Cited by 46 | Viewed by 8261

Abstract

Background: HPV vaccination of both girls and boys can protect against infection and eliminate the risk for HPV-associated cancer. Due to a common misconception that the virus only poses risks to women, vaccine coverage is suboptimal among men in many countries. It is urgent to identify barriers to vaccination of boys and men. Methods: We conducted a narrative review of publications examining attitudes and beliefs regarding HPV vaccination for boys and young men. The electronic databases searched were PubMed, PsychInfo and Scopus (December 2020; last update July 2021). A total of 103 original articles were included in the final analysis. Results: The central barriers against vaccination of boys and men are: (1) lack of knowledge, (2) vaccine hesitancy in general, (3) lack of recommendation from and/or discussions with healthcare providers, (4) cost and logistics, and (5) the idea that HPV vaccination may promote promiscuity. Men who have sex with men and families belonging to ethnic minorities express a need for information tailored to their situation. Conclusions: Boys should be included in national immunization programs and men should also be offered catch-up vaccinations. Future studies should focus on addressing vaccine hesitancy and developing interventions to promote pan-gender HPV vaccination. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

26 pages, 1336 KiB

Open AccessReview

HPV-Associated Benign Squamous Cell Papillomas in the Upper Aero-Digestive Tract and Their Malignant Potential

by Stina Syrjänen and Kari Syrjänen

Viruses 2021, 13(8), 1624; https://doi.org/10.3390/v13081624 - 17 Aug 2021

Cited by 35 | Viewed by 9239

Abstract

Squamous cell papilloma (SCP) in the upper aero-digestive tract is a rare disease entity with bimodal age presentation both at childhood and in adults. It originates from stratified squamous and/or respiratory epithelium. Traditionally, SCPs have been linked to chemical or mechanical irritation but, since the 1980s, they have also been associated with human papillomavirus (HPV) infection. Approximately 30% of the head and neck SCPs are associated with HPV infection, with this association being highest for laryngeal papillomas (76–94%), followed by oral (27–48%), sinonasal (25–40%), and oropharyngeal papillomas (6–7%). There is, however, a wide variation in HPV prevalence, the highest being in esophageal SCPs (11–57%). HPV6 and HPV11 are the two main HPV genotypes present, but these are also high-risk HPVs as they are infrequently detected. Some 20% of the oral and oropharyngeal papillomas also contain cutaneous HPV genotypes. Despite their benign morphology, some SCPs tend to recur and even undergo malignant transformation. The highest malignant potential is associated with sinonasal inverted papillomas (7–11%). This review discusses the evidence regarding HPV etiology of benign SCPs in the upper aero-digestive tract and their HPV-related malignant transformation. In addition, studies on HPV exposure at an early age are discussed, as are the animal models shedding light on HPV transmission, viral latency, and its reactivation. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

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14 pages, 2373 KiB

Open AccessReview

Human Papillomavirus Related Neoplasia of the Ocular Adnexa

by Ingvild Ramberg and Steffen Heegaard

Viruses 2021, 13(8), 1522; https://doi.org/10.3390/v13081522 - 2 Aug 2021

Cited by 12 | Viewed by 3462

Abstract

Human papillomaviruses (HPV) are a large group of DNA viruses that infect the basal cells of the stratified epithelium at different anatomic locations. In the ocular adnexal region, the mucosa of the conjunctiva and the lacrimal drainage system, as well as the eyelid skin, are potential locations for HPV-related neoplasia. The role of HPV in squamous cell neoplasia of the ocular adnexa has been debated for several decades. Due to the rarity of all these tumors, large studies are not available in the scientific literature, thereby hampering the precision of the HPV prevalence estimates and the ability to conclude. Nevertheless, increasing evidence supports that defined subsets of conjunctival papillomas, intraepithelial neoplasia, and carcinomas develop in an HPV-dependent pathway. The role of HPV in squamous cell tumors arising in the lacrimal drainage system and the eyelid is still uncertain. Further, the potential of HPV status as a diagnostic, prognostic, or predictive biomarker in these diseases is a topic for future research. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

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9 pages, 624 KiB

Open AccessReview

The Effect of Prophylactic HPV Vaccines on Oral and Oropharyngeal HPV Infection—A Systematic Review

by Kristoffer Juul Nielsen, Kathrine Kronberg Jakobsen, Jakob Schmidt Jensen, Christian Grønhøj and Christian Von Buchwald

Viruses 2021, 13(7), 1339; https://doi.org/10.3390/v13071339 - 11 Jul 2021

Cited by 46 | Viewed by 5057

Abstract

Human papillomavirus (HPV) imposes an increased risk of developing cervical, anal and oropharyngeal cancer. In the Western world, HPV infection is currently the major cause of oropharyngeal cancer. The effectiveness of HPV vaccines for oral or oropharyngeal HPV infection is yet to be determined. This study conducted a systematic literature search in Pubmed and Embase. Studies investigating the impact of HPV vaccines on oral or oropharyngeal HPV infection were enrolled. This review reports the relative prevention percentage (RPP), including a risk of bias assessment as well as a quality assessment study. Nine studies were included (48,777 participants): five cross-sectional studies; one randomized community trial study (RCT); one longitudinal cohort study; and two case-control studies. A significant mean RPP of 83.9% (66.6–97.8%) was calculated from the cross-sectional studies, 82.4% in the included RCT and 83% in the longitudinal cohort study. Further, two case-control studies that measured antibody response in participants immunized with HPV vaccines were included. Respectively, 100% and 93.2% of participants developed HPV-16 Immunoglobulin G (IgG) antibodies in oral fluids post-vaccination. Analysis of the studies identified a significant decrease in vaccine-type oral or oropharyngeal HPV infections in study participants immunized with HPV vaccines across study designs and heterogenous populations. Further, a significant percentage of participants developed IgG antibodies in oral fluid post-vaccination. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

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12 pages, 323 KiB

Open AccessReview

Human Papillomavirus and Squamous Cell Carcinoma of Unknown Primary in the Head and Neck Region: A Comprehensive Review on Clinical Implications

by Mikkel Hjordt Holm Larsen, Hani Ibrahim Channir and Christian von Buchwald

Viruses 2021, 13(7), 1297; https://doi.org/10.3390/v13071297 - 2 Jul 2021

Cited by 13 | Viewed by 2986

Abstract

Squamous cell carcinoma of unknown primary (SCCUP) is a challenging diagnostic subgroup of oropharyngeal squamous cell carcinoma (OPSCC). The incidence of SCCUP is increasing in parallel with the well-documented increase in OPSCC and is likewise driven by the increase in human papillomavirus (HPV). The SCCUP patient often presents with a cystic lymph node metastasis and undergoes an aggressive diagnostic and treatment program. Detection of HPV in cytologic specimens indicates an oropharyngeal primary tumor origin and can guide the further diagnostic strategy. Advances in diagnostic modalities, e.g., transoral robotic surgery and transoral laser microsurgery, have increased the successful identification of the primary tumor site in HPV-induced SCCUP, and this harbors a potential for de-escalation treatment and increased survival. This review provides an overview of HPV-induced SCCUP, diagnostic modalities, and treatment options. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

27 pages, 376 KiB

Open AccessReview

Oropharyngeal Squamous Cell Carcinoma Treatment in the Era of Immune Checkpoint Inhibitors

by Peter L. Stern and Tina Dalianis

Viruses 2021, 13(7), 1234; https://doi.org/10.3390/v13071234 - 25 Jun 2021

Cited by 13 | Viewed by 3439

Abstract

While head and neck squamous cell carcinomas (HNSCC) are marginally decreasing due to the reduction in exposure to the major risk factors, tobacco and alcohol, the incidence of high-risk human papillomavirus (HPV)-positive oropharynx squamous cell carcinomas (OPSCC), especially those in the tonsil and base of tongue subsites, are increasing. Patients with the latter are younger, display a longer overall survival, and show a lower recurrence rate after standard-of-care treatment than those with HPV-negative OPSCC. This may reflect an important role for immune surveillance and control during the natural history of the virally driven tumour development. Immune deviation through acquisition of immune-suppressive factors in the tumour microenvironment (TME) is discussed in relation to treatment response. Understanding how the different immune factors are integrated in the TME battleground offers opportunities for identifying prognostic biomarkers as well as novel therapeutic strategies. OPSCC generally receive surgery or radiotherapy for early-stage tumour treatment, but many patients present with locoregionally advanced disease requiring multimodality therapies which can involve considerable complications. This review focuses on the utilization of newly emerged immune checkpoint inhibitors (PD-1/PD-L1 pathway) for treatment of HNSCC, in particular HPV-positive OPSCC, since they could be less toxic and more efficacious. PD-1/PD-L1 expression in the TME has been extensively investigated as a biomarker of patient response but is yet to provide a really effective means for stratification of treatment. Extensive testing of combinations of therapeutic approaches by types and sequencing will fuel the next evolution of treatment for OPSCC. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

17 pages, 331 KiB

Open AccessReview

Relevance of Human Papillomaviruses in Head and Neck Cancer—What Remains in 2021 from a Clinician’s Point of View?

by Markus Hoffmann and Elgar Susanne Quabius

Viruses 2021, 13(6), 1173; https://doi.org/10.3390/v13061173 - 18 Jun 2021

Cited by 12 | Viewed by 2587

Abstract

Human papillomaviruses (HPV) cause a subset of head and neck cancers (HNSCC). HPV16 predominantly signs responsible for approximately 10% of all HNSCC and over 50% of tonsillar (T)SCCs. Prevalence rates depend on several factors, such as the geographical region where patients live, possibly due to different social and sexual habits. Smoking plays an important role, with non-smoking patients being mostly HPV-positive and smokers being mostly HPV-negative. This is of unparalleled clinical relevance, as the outcome of (non-smoking) HPV-positive patients is significantly better, albeit with standard and not with de-escalated therapies. The results of the first prospective de-escalation studies have dampened hopes that similar superior survival can be achieved with de-escalated therapy. In this context, it is important to note that the inclusion of p16^INK4A (a surrogate marker for HPV-positivity) in the 8th TMN-classification has only prognostic, not therapeutic, intent. To avoid misclassification, highest precision in determining HPV-status is of utmost importance. Whenever possible, PCR-based methods, still referred to as the "gold standard”, should be used. New diagnostic antibodies represent some hope, e.g., to detect primaries and recurrences early. Prophylactic HPV vaccination should lead to a decline in HPV-driven HNSCC as well. This review discusses the above aspects in detail. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

18 pages, 281 KiB

Open AccessReview

Prognostic Markers and Driver Genes and Options for Targeted Therapy in Human-Papillomavirus-Positive Tonsillar and Base-of-Tongue Squamous Cell Carcinoma

by Anders Näsman, Stefan Holzhauser, Ourania N. Kostopoulou, Mark Zupancic, Andreas Ährlund-Richter, Juan Du and Tina Dalianis

Viruses 2021, 13(5), 910; https://doi.org/10.3390/v13050910 - 14 May 2021

Cited by 16 | Viewed by 3144

Abstract

The incidence of Human-papillomavirus-positive (HPV⁺) tonsillar and base-of-tongue squamous cell carcinoma (TSCC and BOTSCC, respectively) is increasing epidemically, but they have better prognosis than equivalent HPV-negative (HPV⁻) cancers, with roughly 80% vs. 50% 3-year disease-free survival, respectively. The majority of HPV⁺ TSCC and BOTSCC patients therefore most likely do not require the intensified chemoradiotherapy given today to head and neck cancer patients and would with de-escalated therapy avoid several severe side effects. Moreover, for those with poor prognosis, survival has not improved, so better-tailored alternatives are urgently needed. In line with refined personalized medicine, recent studies have focused on identifying predictive markers and driver cancer genes useful for better stratifying patient treatment as well as for targeted therapy. This review presents some of these endeavors and briefly describes some recent experimental progress and some clinical trials with targeted therapy. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

Other

Jump to: Editorial, Review

9 pages, 380 KiB

Open AccessBrief Report

Human Papillomavirus-Related Multiphenotypic Sinonasal Carcinoma—An Even Broader Tumor Entity?

by Mark Zupancic and Anders Näsman

Viruses 2021, 13(9), 1861; https://doi.org/10.3390/v13091861 - 17 Sep 2021

Cited by 12 | Viewed by 2522

Abstract

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is a recently defined tumor subtype with apparent favorable clinical outcome despite aggressive histomorphology. However, in recent years, additional numbers of cases, with more variable features and at locations outside the sinonasal region, have complicated the definition of HMSC. Here, we have performed a systematic review of all cases described so far in order to accumulate more knowledge. We identified 127 articles published between 2013 and 2021, of which 21 presented unique cases. In total, 79 unique patient cases were identified and their clinical and micromorphological nature are herein summarized. In our opinion, better clinical follow-up data and a more detailed tumor characterization are preferably needed before HMSC can finally be justified as its own tumor entity. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

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18 pages, 3925 KiB

Open AccessSystematic Review

Diagnostic Accuracy of HPV Detection in Patients with Oropharyngeal Squamous Cell Carcinomas: A Systematic Review and Meta-Analysis

by Kathrine Kronberg Jakobsen, Amanda-Louise Fenger Carlander, Simone Kloch Bendtsen, Martin Garset-Zamani, Charlotte Duch Lynggaard, Christian Grønhøj and Christian von Buchwald

Viruses 2021, 13(9), 1692; https://doi.org/10.3390/v13091692 - 26 Aug 2021

Cited by 11 | Viewed by 2604

Abstract

The aim of the study was to evaluate the diagnostic accuracy of Human Papillomavirus (HPV) techniques in oropharyngeal cancer. PubMed, EMBASE, the Cochrane Library and clinicaltrials.org were systematically searched for studies reporting methods of HPV detection. Primary outcomes were sensitivity and specificity of HPV detection. In this case, 27 studies were included (n = 5488, 41.6% HPV+). In this case, 13 studies evaluated HPV detection in tumour tissue, nine studies examined HPV detection in blood samples and five studies evaluated HPV detection in oral samples. Accuracy of HPV detection in tumour tissue was high for all detection methods, with pooled sensitivity ranging from 81.1% (95% CI 71.9–87.8) to 93.1% (95% CI 87.4–96.4) and specificity ranging from 81.1% (95% CI 71.9–87.8) to 94.9% (95% CI 79.1–98.9) depending on detection methods. Overall accuracy of HPV detection in blood samples revealed a sensitivity of 81.4% (95% CI 62.9–91.9) and a specificity of 94.8% (95% CI 91.4–96.9). In oral samples pooled sensitivity and specificity were lower (77.0% (95% CI 68.8–83.6) and 74.0% (95% CI 58.0–85.4)). In conclusion, we found an overall high accuracy for HPV detection in tumour tissue regardless of the HPV detection method used. HPV detection in blood samples may provide a promising new way of HPV detection. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

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12 pages, 989 KiB

Open AccessSystematic Review

A Contemporary Systematic Review on Repartition of HPV-Positivity in Oropharyngeal Cancer Worldwide

by Amanda F. Carlander, Kathrine K. Jakobsen, Simone K. Bendtsen, Martin Garset-Zamani, Charlotte D. Lynggaard, Jakob Schmidt Jensen, Christian Grønhøj and Christian von Buchwald

Viruses 2021, 13(7), 1326; https://doi.org/10.3390/v13071326 - 9 Jul 2021

Cited by 67 | Viewed by 4214

Abstract

Significant variation in human papillomavirus (HPV) prevalence in oropharyngeal squamous cell carcinoma (OPSCC) across countries ranging from 11% in Brazil to 74% in New Zealand has been reported earlier. The aim of this study was to systematically review the most recently published studies on the occurrence of HPV in OPSCC globally. PubMed and Embase were systematically searched for articles assessing the occurrence of HPV+ OPSCC published between January 2016 and May 2021. Studies with a study period including 2015 and the following years were included. Both HPV DNA and/or p16 were accepted as indicators of HPV+ OPSCC. 31 studies were enrolled comprising 49,564 patients with OPSCC (range 12–42,024 patients per study) from 26 different countries covering all continents. The lowest occurrences of HPV+ OPSCC were observed in India (0%) and Spain (10%) and the highest occurrences were observed in Lebanon (85%) and Sweden (70%). We observed great variation in HPV prevalence in OPSCC worldwide varying from 0% to 85%. The highest occurrences of HPV+ OPSCC were found in general in Northern European countries, USA, Lebanon, China, and South Korea. We observed a trend of increase in HPV-positivity, indicating a mounting burden of HPV+ OPSCC. Full article

(This article belongs to the Special Issue HPV in the Head and Neck Region)

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