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The design of prophylactic and diagnostic tools specific to animal papillomaviruses is hampered by the difficulties of viral in vitro manipulation and by the scarce availability of dedicated biotechnological tools. This paper reports the production of Ovine Papillomavirus 3 (OaPV3)-based virus-like particles (OaPV3-VLPs) in the baculovirus system and their use to investigate host humoral immune response through the establishment of an indirect ELISA test., Polyclonal sera and monoclonal antibodies were generated against OaPV3-VLPs, and their isotype and reactivity were determined. Additionally, antibodies allowed OaPV3 detection in ovine squamous cell carcinoma (SCC) samples by immunohistochemistry. Results encourage the standardization of OaPV3-specific prophylactic and serological diagnostic tools, and open new perspectives for the study of host-viral interaction and SCC development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Mohs micrographic surgery is the gold standard for treating many types of skin cancer, particularly skin cancers of high-risk areas such as the face, genitalia, and digits, due to its tissue-sparing technique and low recurrence rates. The use of Mohs micrographic surgery for human papilloma virus-associated cutaneous malignancies has yet to be explored in a systematic review. The authors sought to assess outcomes including recurrence rates of Mohs micrographic surgery for human papilloma virus-associated cutaneous malignancies. PubMed was searched for the use of Mohs micrographic surgery in types of human papilloma virus-associated cutaneous malignancies. After application of exclusion and inclusion criteria, 33 articles were included. 700 cases from 33 studies were included. Overall recurrence rate following Mohs micrographic surgery was 39/478 (8.2%) at a mean follow-up time of 51.5 months. Recurrence rate for nail unit/digit squamous cell carcinoma was 10/103 (9.7%) at mean follow-up of 47.6 months. Recurrence rate for penile squamous cell carcinoma was 15/181 (8.3%) at mean follow-up of 45.9 months. Recurrence rate for Bowen's disease in extragenital areas was 11/189 (5.9%) at mean follow-up of 59.7 months. Patients overall reported satisfactory functional and cosmetic results. Mohs micrographic surgery demonstrates low recurrence rates and excellent functional and cosmetic outcomes in the treatment of human papilloma virus-associated cutaneous malignancies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Paraneoplastic pemphigus (PNP) is a rare, life-threatening autoimmune bullous disease. Among the ≈500 reported cases of PNP, only 1 case has been associated with tonsillar cancer, specifically, human papillomavirus (HPV)-positive squamous carcinoma. However, the occurrence of PNP in non-HPV-related tonsillar cancer is exceptionally rare and has not been reported to date., Methods: We present a 58-year-old male with a history of smoking, who experienced recurrent oral ulcers, right neck swelling, and hoarseness for 5 months. Diagnosis of right tonsillar squamous cell carcinoma (cT1N3bM0) was confirmed through computed tomography/magnetic resonance imaging and pathology, not associated with HPV. Histological and immunohistochemical findings indicated PNP., Results: The patient underwent primary tumor resection and ipsilateral neck dissection. Topical steroids and antifungal agents were administered to manage oral lesions and prevent secondary infections. Adjuvant concurrent chemoradiotherapy with cisplatin proceeded smoothly. Postconcurrent chemoradiotherapy follow-up at 3, 6, and 9 months, utilizing computed tomography/magnetic resonance imaging and nasopharyngoscopy, revealed no signs of recurrent cancer or PNP., Conclusion: Early indicators, such as oral mucosal ulcers and skin blisters, prompt consideration of underlying oral cancer in PNP. Comprehensive examination is crucial for diagnosing PNP and identifying concurrent internal neoplasms. Effective management includes occult malignancy treatment, postoperative steroid therapy, and infection prevention., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Several observational or retrospective studies have previously been conducted to explore the possible association between lung cancer and human papillomavirus (HPV) infection. However, there may be inconsistencies in the data and conclusions due to differences in study design and HPV testing methods. There are currently no studies that provide conclusive evidence to support the involvement of HPV in the occurrence and development of lung cancer. Therefore, the relationship between HPV and lung cancer remains controversial and uncertain. This study aimed to explore whether HPV infection is causally related to lung cancer risk by systematically performing a two-way Two-Sample Mendelian Randomization (TSMR) analysis., Methods: In the International Lung Cancer Consortium (ILCCO) genome-wide association study dataset, we included 11,348 lung cancer (LUCA) cases, including 3275 squamous cell carcinoma (LUSC) cases, 3442 adenocarcinoma (LUAD) cases, and 15,861 cases of control. Using genetic variants associated with the HPV E7 protein as instrumental variables, we summarized statistics associated with HPV infection in the MRC IEU OpenGWAS database, which included the HPV-16 E7 protein and the HPV-18 E7 protein. Two-sample Mendelian randomization (MR) results are expressed as odds ratios (OR) and 95% confidence intervals (CI)., Results: Based on a comprehensive analysis of genome-wide association study (GWAS) data from public databases, we mainly used inverse-variance weighted (IVW) to estimate causal relationships, while using MR-Egger, weighted median, simple mode, and weighted mode, and other four methods as supplements. Two-sample MR Analysis revealed no causal relationship between exposure factors (HPV-16 E7 protein and HPV-18 E7 protein) and outcome factors (lung cancer (LUCA) and its subtypes squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD)) in forward MR Analysis using the IVW approach.HPV-16 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 1.002; 95% [CI]: 0.961 - 1.045; p = 0.920; [OR] = 1.023; 95% [CI]: 0.966 - 1.084; p = 0.438; [OR] = 0.994; 95% [CI]: 0.927 - 1.066; p = 0.872); HPV-18 E7 protein and LUCA and its subtypes LUSC and LUAD by IVW method results: [OR] = 0.965; 95% [CI]: 0.914 - 1.019; p = 0.197; [OR] = 0.933; 95% [CI]: 0.834 - 1.043; p = 0.222; [OR] = 1.028; 95% [CI]: 0.945 - 1.118; p = 0.524. It was observed through reverse MR that LUCA and its subtypes LUSC and LUAD were used as exposure factors, and HPV infection (HPV-16 E7 protein and HPV-18 E7 protein) was used as the outcome factors, the results of the IVW method are also invalid.LUCA and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.036; 95% [CI]: 0.761 - 1.411; p = 0.82; [OR] = 1.318; 95% [CI]: 0.949 - 1.830; p = 0.099; LUSC and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.123; 95% [CI]0.847 - 1.489; p = 0.421; [OR] = 0.931; 95% [CI]: 0.660 - 1.313; p = 0.682; LUAD and HPV-16 E7 protein and HPV-18 E7 protein by IVW method results: [OR] = 1.182; 95% [CI] 0.983 - 1.421; p = 0.075; [OR] = 1.017; 95% [CI]: 0.817 - 1.267; p = 0.877.Our results indicate that there is no causal relationship between genetically predicted HPV infection and LUCA and its subtypes LUSC and LUAD. In addition, in the reverse MR analysis, we did not observe a significant causal relationship between LUCA and its subtypes LUSC and LUAD on HPV infection., Conclusions: Our findings do not support a genetic association between HPV infection and lung cancer., (© 2024. The Author(s).)

Purpose: Human Papilloma Virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct disease from other head and neck tumors. This guideline provides evidence-based recommendations on the critical decisions in its curative treatment, including both definitive and postoperative radiation therapy (RT) management., Methods: ASTRO convened a task force to address 5 key questions on the use of RT for management of HPV-associated OPSCC. These questions included indications for definitive and postoperative RT and chemoradiation; dose-fractionation regimens and treatment volumes; preferred RT techniques and normal tissue considerations; and posttreatment management decisions. The task force did not address indications for primary surgery versus RT. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength., Results: Concurrent cisplatin is recommended for patients receiving definitive RT with T3-4 disease and/or 1 node >3 cm, or multiple nodes. For similar patients who are ineligible for cisplatin, concurrent cetuximab, carboplatin/5-fluorouracil, or taxane-based systemic therapy are conditionally recommended. In the postoperative setting, RT with concurrent cisplatin (either schedule) is recommended for positive surgical margins or extranodal extension. Postoperative RT alone is recommended for pT3-4 disease, >2 nodes, or a single node >3 cm. Observation is conditionally recommended for pT1-2 disease and a single node ≤3 cm without other risk factors. For patients treated with definitive RT with concurrent systemic therapy, 7000 cGy in 33 to 35 fractions is recommended, and for patients receiving postoperative RT without positive surgical margins and extranodal extension, 5600 to 6000 cGy is recommended. For all patients receiving RT, intensity modulated RT over 3-dimensional techniques with reduction in dose to critical organs at risk (including salivary and swallowing structures) is recommended. Reassessment with positron emission tomography-computed tomography is recommended approximately 3 months after definitive RT/chemoradiation, and neck dissection is recommended for convincing evidence of residual disease; for equivocal positron emission tomography-computed tomography findings, either neck dissection or repeat imaging is recommended., Conclusions: The role and practice of RT continues to evolve for HPV-associated OPSCC, and these guidelines inform best clinical practice based on the available evidence., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objective: To comprehensively analyze reported cases of nasolacrimal squamous cell carcinoma (NLSCC), focusing on risk factors, treatment modalities, and outcomes. Additionally, investigate the impact of human Papillomavirus (HPV) status and histopathological subtypes' impact on prognosis., Data Sources: Pubmed, Embase., Review Methods: We conducted a systematic literature review to identify relevant studies reporting cases of NLSCC. The review methods adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The final update was performed on May 31, 2023., Results: The 72 studies included a total of 313 participants (mean age: 55; 60% male). Longer symptom duration (44.1 ± 59.2 months) correlated with recurrence (p = 0.004), and males exhibited higher mortality rates (19.6% vs. 2.4% in females, p = 0.01). The overall survival (OS) rate among all patients was 87.1%. Basaloid NLSCC had a worse death outcome (p ≤ 0.001). HPV-positive cases showed comparable OS, recurrence, and metastasis rates to the general population (p = 0.917, 0.851, 0.07, respectively). Comparing treatment approaches (surgery, surgery with adjuvant radiation, chemoradiotherapy [CRT] followed by surgery), no significant differences in 5 and 10-year OS rates or recurrence were observed (p = 0.4, 0.24, respectively), but 5-year metastasis events were significant (p = 0.024). Eye exenteration rates were 31.1%, 20%, and 0% for the respective treatments (p = 0.089). Induction chemotherapy saved four cases from potential exenteration with favorable prognosis., Conclusion: Early detection and diagnosis are of utmost importance in the management of NLSCC. Regardless of the treatment approach, HPV-related NLSCC demonstrated similar outcomes to the general population. Basaloid histology represents the worst subtype in terms of prognosis. Limited adjuvant CRT cases showed improved outcomes and induction chemotherapy's importance was emphasized in recent literature and our shared experience. Laryngoscope, 134:3892-3902, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Purpose: To report an unusual case of ocular surface squamous neoplasia (OSSN) associated with human papilloma virus (HPV)-16 infection with an atypical morphology in a young otherwise healthy patient., Case Description: A 17 year-old healthy male was referred to our department for evaluation of a corneal infiltrate with anterior stromal neovascularization in the right eye. One year before, the patient underwent an excision of a corneo-conjunctival lesion that was located inferiorly in the same eye. Histopathological analysis had shown moderate and severe dysplasia of the conjunctival epithelium and resulted positive for HPV-16. We performed a diagnostic incisional biopsy of the limbal conjunctiva and of the corneal epithelium for histological examination and molecular testing for HPV and Chlamydia by using polymerase chain reaction (PCR). Histopathologic evaluation demonstrated low-grade dysplasia of conjunctiva. PCR testing of the corneal epithelium was positive for HPV-16, similarly to the first biopsy performed by another centre. The patient was successfully treated with topical interferon alfa-2b (1,000,000 IU/ml) for a total of six months. After the treatment, the corneal infiltrate improved dramatically with regression of neovascularization and improvement of corneal transparency and vision., Discussion: The present report described an atypical presentation of HPV-related OSSN due to its unusual morphology, young age of onset and absence of associated comorbidity., Conclusion: Conservative treatment with topical interferon-alpha 2b could be used to treat successfully HPV-16 positive OSSN, with no corneal irregularity or potential loss of vision compared to surgical excision., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The aim of this study was to introduce HPV-associated and HPV-independent histologic classifications to analyze prognostic factors and develop a prognostic nomogram for patients with penile squamous cell carcinoma (PSCC)., Methods: Data of 1502 PSCC patients between 2010 and 2020 were accessed from the SEER database, and the patients were randomly divided into a training set and a validation set. Independent risk factors for PSCC patients prognosis were analyzed by using univariate and multivariate COX proportional hazards regression, and was used for the construction of the nomogram, and the predictive performance of the model was evaluated by C-index, calibration curve and ROC curve. Kaplan-Meier analysis was applied to explore the impact of HPV-related factors on patient survival, while propensity score matching (PSM) and inverse probability treatment weighting (IPTW) techniques were used to balance other confounding factors like individual clinical and pathological factors, and to evaluate the differences in overall survival (OS) and cause-specific survival (CSS) between subgroups., Result: The results indicated that histologic type, Grade classification, T/M stage, surgical methods and chemotherapy were independent risk factors affecting OS and CSS in PSCC patients. In addition, age and marital status were significantly associated with OS, while lymph node metastasis was an independent prognostic factor for CSS, the validation results of the model showed that the nomogram had a superior predictive performance compared with the American Joint Committee on Cancer staging system. In addition, subgroup analyses prior to and after IPTW and PSM adjustments showed that HPV-associated group had better OS and CSS than HPV-independent group., Conclusion: Our study developed and validated a nomogram using a novel histologic classification and achieved satisfactory results, which can better help clinicians to predict the prognosis of penile squamous cell carcinoma patients., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: Circulating tumor DNA assays have robust potential as molecular surveillance tools. They may also exacerbate patient distress without improving outcomes. We investigate patient acceptability of a validated ctHPVDNA assay (NavDx) during cancer surveillance for HPV(+) oropharyngeal cancer (OPC)., Methods: Consented HPV(+) OPC participants completed the NCCN Distress Thermometer, the Hospital Anxiety Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-General (FACT-G) scale both (1) before NavDx blood draw, and (2) after results were provided. Patients then completed a series of focused questions related to their perceptions of the assay., Results: Overall, 55 patients completed the study, with 98.2 % showing no recurrence. For the NCCN Distress Thermometer, median patient distress decreased (2.0 (IQR 1-5) vs. 1.0 (IQR 0-3)) (p < 0.001) in association with NavDx. Using scores ≥ 4 as a cutoff point to define clinically elevated distress, scores also improved (36.4 % vs. 18.2 %, p = 0.031). For HADS, anxiety significantly improved (5.0 (IQR 2.0-7.0) vs. 3.0 (IQR 1.0-6.5)) (p = 0.037), but not depression (3.0 (IQR 1.0-7.0) vs. 3.0 (IQR 1.0-6.5)) (p = 0.870). FACT-G scores showed no substantial differences. On survey questionnaires, 95.5 % of patients believed the test to be helpful, and 100 % felt "somewhat" or "extremely" confident in the assay as a monitoring tool. While 59.1 % felt that it reduced anxiety, 88.4 % concordantly felt that it did not introduce anxiety., Conclusion: ctHPVDNA as a molecular surveillance tool reduced distress levels in HPV(+) OPC patients, with notably high patient confidence in the approach. Further investigation is warranted to judiciously incorporate this emerging modality in surveillance guidelines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Zumsteg’s spouse does legal work for Johnson & Johnson, Merck, Allergan, and Boehringer Ingelheim through her law firm]., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Malignancies of the parotid gland are relatively uncommon and in most cases are primary neoplasms; intraparotid metastases are rare. Oral and oropharyngeal squamous cell carcinoma (O- and OP-SCC) can potentially metastasize to the parotid gland or intraparotid lymph nodes. Fine-needle aspiration cytology (FNAC) serves as the initial diagnostic approach for this purpose. HPV status in FNAC specimens is relevant and can guide the diagnostic workup, indicating a potential oropharyngeal origin of the primary tumor. A small series of occult SCC metastases is presented below, in which HPV-DNA testing of FNAC specimens helped identify primary neoplasms located in the oropharynx. US-guided FNAC of parotid nodules was conducted by an experienced interventional cytopathologist in three cases. Each patient underwent assessment of direct smears, cell blocks, and liquid-based samples for HPV testing. The morphological and immunocytochemical features of SCC were documented, and real-time PCR was employed for the detection and genotyping of HPV. The role of HPV testing on FNAC specimens in pinpointing the primary neoplasms in the oropharynx is highlighted. Consequently, FNAC samples emerge as valuable diagnostic and prognostic tools in this context, providing essential insights for patient management., (© 2024 Wiley Periodicals LLC.)

Background: Merkel cell polyomavirus (MCPyV), a human polyomavirus that is unequivocally linked to merkel cell carcinoma (MCC), has been found in association with keratinocytes carcinomas (KC), especially basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Nevertheless, there is scarce information about the possible involvement of MCPyV in the development of KC., Objectives: To assess the presence of MCPyV DNA and Large-T Antigen (LT-Ag) via Polymerase Chain Reaction (PCR) and Immunohistochemistry (IHC) in cases of KC, and to correlate its presence with immunohistochemical markers p16, p53, and ki67, tumor type and subtype, sun-exposed location, and epidemiological data., Methods: The prevalence of MCPyV DNA, LT-Ag, and immunohistochemical markers p16, p53, and ki67 was assessed by PCR and Immunohistochemistry (IHC) in 127 cases of KC, these results were correlated with tumor type and subtype, sun-exposed location, and epidemiological data., Results: The MCPyV DNA was detected in 42.57% (43 of 101) cases by PCR, the LT-Ag was detected in 16.4% (20 of 122) of cases, p16 in 81.5% (97 of 119), p53 in 66.4% (83 of 125), ki67 in 89% (73 of 82). No correlation between MCPyV LT-Ag and DNA confronted with tumor type, subtype, location site, and immunohistochemical markers was found. A single correlation between the MCPyV LT-Ag and cSCC tumors and peri-tumoral lymphocyte cells was noted., Study Limitations: Further steps need to be taken to better evaluate the MCPyV influence and its possible role in KC carcinogenesis, as the evaluation of the virus genome state, the gene sequence that encodes LT-Ag in the KC tumor cells, and in situ hybridization for viral DNA or RNA in these cells., Conclusions: Despite the frequent detection of MCPyV in KC, the data available so far does not support the hypothesis of a causal relationship between them., (Copyright © 2024. Published by Elsevier España, S.L.U.)

The role of molecular markers is increasingly being recognized for head and neck tumors, ranging from benign lesions like paragangliomas to malignancies like squamous cell carcinomas. Multiple studies have recently validated blood tests for circulating tumor tissue-modified viral human papillomavirus DNA (HPV ct-DNA) for posttreatment surveillance of HPV-driven oropharyngeal squamous cell carcinomas. This technology quantifies fragments of circulating DNA that are shed into the blood stream with very high (>95%) positive and negative predictive values and are also highly sensitive in distinguishing tumor HPV-DNA from a noncancerous source. This study has a cohort of 34 patients with HPV-driven oropharyngeal squamous cell carcinomas, having at least 3 sequential imaging studies and ct-DNA values. The study showed a strong positive correlation between the imaging findings and the ct-DNA level in recurrent HPV-positive oropharyngeal squamous cell carcinomas. Findings also include the 100% negative predictive value of HPV ct-DNA tests to rule out tumor recurrence. At our institution, we are now routinely performing the ct-DNA assay for surveillance of treated HPV oropharyngeal squamous cell carcinomas. Correlation among clinical, radiologic, and biomarker findings are now part of routine discussions during the multidisciplinary tumor boards., (© 2024 by American Journal of Neuroradiology.)

Background: Solid organ transplant recipients are at an increased risk for anogenital Human Papillomavirus (HPV)-related disease, including anal high-grade squamous intraepithelial lesions (HSIL) and anal squamous cell cancer (ASCC). Guidelines for ASCC screening in transplant recipients are limited. Our aim was to understand current practice of ASCC screening in adult liver transplant (LT) candidates and recipients at transplant centers across the United States., Methods: We surveyed medical directors of 113 LT centers across the United States which had publicly available contact information. The survey evaluated center perceptions on cancer and HPV disease risk in transplant populations, ASCC screening, barriers and facilitators for ASCC screening and HPV vaccination practices., Results: We received 26/113 (23%) responses, of which 24 were complete and included in the analysis. Eleven of 24 (46%) centers reported screening for ASCC and 3/24 (12.5%) centers reported having formal guidelines. Centers who perform ASCC screening were more likely to perform transplants in people living with HIV and were more aware of the burden of HPV disease in transplant populations. All respondents believed that additional data on the impact of screening on ASCC incidence would support screening decisions. Increased access to specialists for screening/high-resolution anoscopy was also perceived as a facilitator. Only 7/24 (29%) centers regularly evaluated HPV vaccination status of their patients., Conclusion: This national survey of LT centers reveals non-standardized ASCC screening practices, and identified data, educational and resource needs to improve prevention of ASCC in this population., (© 2024 Wiley Periodicals LLC.)

A subset of head and neck squamous cell carcinomas present solely as metastatic disease in the neck and are of unknown primary origin (SCCUP). Most primary tumors will ultimately be identified, usually in the oropharynx. In a minority of cases, the primary site remains elusive. Here, we examine the role of ancillary testing, including mutational signature analysis (MSA), to help identify likely primary sites in such cases. Twenty-two cases of SCCUP in the neck, collected over a 10-year period, were classified by morphology and viral status; including human papillomavirus (HPV) testing by p16 immunohistochemistry (IHC) and RT-qPCR, as well as Epstein-Barr virus (EBV) testing by EBER-ISH. CD5 and c-KIT (CD117) IHC was done to evaluate for possible thymic origin in all virus-negative cases. Whole exome sequencing, followed by MSA, was used to identify UV signature mutations indicative of cutaneous origin. HPV was identified in 12 of 22 tumors (54.5%), favoring an oropharyngeal origin, and closely associated with nonkeratinizing tumor morphology (Fisher's exact test; p = 0.0002). One tumor with indeterminant morphology had discordant HPV and p16 status (p16+/HPV-). All tumors were EBV-negative. Diffuse expression of CD5 and c-KIT was identified in 1 of 10 virus-negative SCCUPs (10%), suggesting a possible ectopic thymic origin rather than a metastasis. A UV mutational signature, indicating cutaneous origin, was identified in 1 of 10 (10%) virus-negative SCCUPs. A cutaneous auricular primary emerged 3 months after treatment in this patient. Primary tumors became clinically apparent in 2 others (1 hypopharynx, 1 hypopharynx/larynx). Thus, after follow-up, 6 tumors remained unclassifiable as to the possible site of origin (27%). Most SCCUPs of the neck in our series were HPV-associated and thus likely of oropharyngeal origin. UV signature mutation analysis and additional IHC for CD5 and c-KIT for possible thymic origin may aid in further classifying virus-negative unknown primaries. Close clinical inspection of hypopharyngeal mucosa may also be helpful, as a subset of primary tumors later emerged at this site., Competing Interests: Declaration of competing interest The spouse of Wade Thorstad is an employee of Elekta, Inc. (No Elekta products were used for this study and no Electa products are currently used within the Department of Radiation-Oncology at Washington University School of Medicine). Rebecca D. Chernock is a member of Precision Oncology Alliance, Caris Life Sciences (non-financial relationship) and a Steering Committee Member for a Phase III clinical trial of neoadjuvant Pembrolizumab in surgically resectable, locally advanced head and neck squamous cell carcinomas, Merck & Co., Inc. There are no additional potential conflicts of interest relevant to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Malignant basaloid neoplasms of the skin are frequent, and their accurate diagnosis holds paramount importance for treatment and prognosis. However, these neoplasms can present diagnostic challenges because of their extensive differential diagnosis, which encompasses cutaneous metastasis among many other possibilities. We present a case of a 74-year-old man with a history of p16-positive palatine tonsil squamous cell carcinoma (SCC) treated with surgery and adjuvant radiation with no prior evidence of recurrence who presented to the dermatologist with 2 chin papules. The initial histopathologic evaluation of these lesions showed poorly differentiated malignant basaloid neoplasms. Subsequently, these biopsies were compared with the previous biopsies from his tonsil and lymph node, which showed similar findings including positive p16 staining and positive molecular testing for human papillomavirus-16, confirming the diagnosis of cutaneous metastasis from his previously diagnosed human papillomavirus-related tonsil SCC. Additional imaging studies found metastases to internal organs including the brain, and he was started on chemotherapy, immunotherapy, and radiation therapy. Cutaneous metastases from tonsil SCC are exceedingly rare, and only 5 cases have been described. Furthermore, this is the first case confirming the presence of high-risk human papillomavirus by molecular studies within the cutaneous metastases. The presented case underscores the importance of recognizing this unusual manifestation of tonsil SCC metastatic to the skin along with a good clinical patient history, ensuring accurate and prompt diagnosis and treatment of this condition., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Human papillomavirus (HPV) infections are an increasing cause of oropharyngeal squamous cell carcinomas (OPSCC). Integration of the viral genome into the host genome is suggested to affect carcinogenesis, however, the correlation with OPSCC patient prognosis is still unclear. Research on HPV integration is hampered by current integration detection technologies and their unsuitability for formalin-fixed paraffin-embedded (FFPE) tissues. This study aims to develop and validate a novel targeted proximity-ligation based sequencing method (targeted locus amplification/capture [TLA/TLC]) for HPV integration detection in cell lines and FFPE OPSCCs. For the identification of HPV integrations, TLA/TLC was applied to 7 cell lines and 27 FFPE OPSCCs. Following preprocessing steps, a polymerase chain reaction (PCR)-based HPV enrichment was performed on the cell lines and a capture-based HPV enrichment was performed on the FFPE tissues before paired-end sequencing. TLA was able to sequence up to hundreds of 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 detection of integrated papillomavirus sequences PCR data and the literature. TLC detected integrated HPV in 15/27 FFPE OPSCCs and identified simple and complex integration patterns. In general, TLA/TLC confirmed PCR data and detected additional integration sites. In conclusion TLA/TLC reliably and robustly detects HPV integration in cell lines and FFPE OPSCCs, enabling large, population-based studies on the clinical relevance of HPV integration. Furthermore, this approach might be valuable for clonality assessment of HPV-related tumors in clinical diagnostics., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Background and Objective: TP53 loss-of-function (TP53LOF) mutations might be a driver of poor prognosis and chemoresistance in both human papillomavirus (HPV)-independent (HPV-) and HPV-associated (HPV+) penile squamous cell carcinoma (PSCC). Here, we aim to describe transcriptomic differences in the PSCC microenvironment stratified by TP53LOF and HPV status., Methods: We used single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing to obtain a comprehensive atlas of the cellular architecture of PSCC. TP53LOF and HPV status were determined by targeted next-generation sequencing and sequencing HPV-DNA reads. Six HPV+ TP53 wild type (WT), six HPV- TP53WT, and four TP53LOF PSCC samples and six controls were included. Immunohistochemistry and hematoxylin-eosin confirmed the morphological context of the observed signatures. Prognostic differences between patient groups were validated in 541 PSCC patients using Kaplan-Meier survival estimates., Key Findings and Limitations: Patients with aberrant p53 staining fare much worse than patients with either HPV- or HPV+ tumors and WT p53 expression. Using scRNA-seq, we revealed 65 cell subtypes within 83 682 cells. TP53LOF tumors exhibit a partial epithelial-to-mesenchymal transition, immune-excluded, angiogenic, and morphologically invasive environment, underlying their aggressive phenotype. HPV- TP53WT tumors show stemness and immune exhaustion. HPV+ TP53WT tumors mirror normal epithelial maturation with upregulation of antibody-drug-conjugate targets and activation of innate immunity. Inherent to the scRNA-seq analysis, low sample size is a limitation and validation of signatures in large PSCC cohorts is needed., Conclusions and Clinical Implications: This first scRNA-seq atlas offers unprecedented in-depth insights into PSCC biology underlying prognostic differences based on TP53 and HPV status. Our findings provide clues for testing novel biomarker-driven therapies in PSCC., Patient Summary: Here, we analyzed tissues of penile cancer at the level of individual cells, which helps us understand why patients who harbor a deactivating mutation in the TP53 gene do much worse than patients lacking such a mutation. Such an analysis may help us tailor future therapies based on TP53 gene mutations and human papillomavirus status of these tumors., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to describe the response of a papillomatous ocular surface squamous neoplasia (OSSN) to the intramuscular (IM) 9-valent human papillomavirus (HPV) vaccine after failed medical and surgical interventions., Methods: A 79-year-old White man with a conjunctival lesion underwent a biopsy which revealed OSSN and positivity for high-risk HPV. Initially treated with medical therapy and surgical excisions, the patient developed a recurrence and refused further surgery. He was given 4 doses of IM HPV vaccine at the 6-week interval., Results: A dramatic reduction in lesion size and reduced epithelial thickening and hyperreflectivity was noted on slitlamp examination and high-resolution anterior segment optical coherence tomography after receiving the IM HPV vaccine. Although lesion size was markedly reduced, the therapy did not achieve total resolution, resulting in further treatment with topical 1% 5-fluorouracil (5-FU) eye drops and later 0.04% mitomycin C eye drops. The patient then elected to discontinue further treatment and solely observe., Conclusions: This case report adds to the growing literature demonstrating the potential therapeutic use of vaccines in cancer treatment. Although HPV vaccination is currently approved for prophylaxis, the use of HPV vaccines as a therapeutic option for various HPV-mediated diseases, including OSSN, should be further explored. The HPV vaccine yielded significant initial improvement in this patient who refused further surgical interventions. The use of IM HPV vaccine as an adjunctive treatment of papillomatous OSSN may represent a potential therapeutic option in cases refractory to standard treatment modalities., Competing Interests: Drs. C. L. Karp and A. Galor have a pending PCT/US2022/029842 with the University of Miami. Dr. C. L. Karp is on the medical advisory board for Glaukos. Dr T. Ioannides holds patent 10 799 574 for the use of human papillomavirus vaccines for the treatment of malignant lesions. The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Neoplasms in small ruminants are considered uncommon and their reported incidence is variable. The aims of this investigation were to characterize malignant skin neoplasms in adult goats reared in Sicily, Italy, and to evaluate potential correlations between gross and histopathology features of the tumours and signalment, tumour location and/or viral infections. A total of 75 malignant skin masses were examined. In selected animals with perineal masses (n = 28) virological and serological investigations on tissues and blood were also conducted. According to the histological features, the lesions were classified as 67 squamous cell carcinomas (SCCs) (of which 65 were located in the perineum), six melanomas and two fibrosarcomas. In three cases, neoplasms at the base of the horn were associated with nasal polyps. Among the selected perineal SCCs, papillomaviruses (PVs), caprine herpesvirus 1 and parapoxvirus were not detected on polymerase chain reaction or on serological examination. However, further investigation on a larger sample size is required to evaluate the potential role of PVs in the pathogenesis of skin tumours in goats., Competing Interests: Declaration of competing interests The authors declared no conflicts of interest in relation to the research, authorship or publication of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Penile squamous cell carcinomas (SCCs) are common, potentially life-threatening neoplasms of horses. They are well-recognized to be caused by Equus caballus papillomavirus (EcPV) type 2, although EcPV2 cannot be detected in all cases. A 23-year-old standardbred gelding developed multiple penile in situ and invasive SCCs that contained histological evidence of PV infection. By using both consensus and specific PCR primers, these lesions were found to contain EcPV7 DNA, but not DNA from EcPV2 or any other PV type. To determine how frequently EcPV7 is present in equine penile SCCs, specific primers were used to detect EcPV2 and EcPV7 in a series of 20 archived samples. EcPV7 was the only PV detected in one, both EcPV2 and 7 were detected in five, and only EcPV2 was detected in 14 SCCs. EcPV7 DNA was also detected in three of 10 archived oropharyngeal SCCs, although only as a co- infection with EcPV2. This is the first report of EcPV7 causing disease in horses. These results suggest EcPV7 could cause a subset of equine penile SCCs, and this is the first evidence that PV types other than EcPV2 can cause these neoplasms. The detection of EcPV7 in the oropharyngeal SCCs suggests a potential role of this PV type in the development of these SCCs. There were no clinical or histological features that differentiated lesions containing EcPV7 DNA from those containing EcPV2 DNA. If EcPV7 causes a proportion of equine penile SCCs, vaccines to prevent EcPV2 infection may not prevent all equine penile SCCs., Competing Interests: Declaration of Competing Interest None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Human papillomavirus (HPV) infection is a risk factor for the development of penile squamous cell carcinoma (PSCC). It remains inconclusive whether HPV-related PSCC has a different prognosis from non-HPV-related PSCC., Objective: To investigate the relationship between HPV status and survival as well as temporal changes in the proportion of HPV-related PSCC., Design, Setting, and Participants: A retrospective cohort of 277 patients treated in Norway between 1973 and 2022 was investigated for HPV DNA in tumor tissue. Clinicopathological variables and disease course were registered., Outcome Measurements and Statistical Analysis: Kaplan-Meier curves and Cox regression were used to investigate the determinants of cancer-specific survival (CSS). The chi-square test for trend in proportions enabled investigation of temporal changes in the HPV-related proportion of PSCC patients treated in Western Norway (n = 211)., Results and Limitations: HPV DNA was detected in tumor tissue from 131 (47%) patients. Stratified by HPV status, 5-yr CSS did not differ between groups (p = 0.37). When investigating only node-positive patients, however, presence of HPV DNA was an independent predictor of better survival in multivariable Cox regression after adjustment for age, nodal stage, and adjuvant therapy (hazard ratio 0.54, 95% confidence interval: [0.30-0.99], p = 0.04). In cases from Western Norway, an increasing proportion of HPV-related cases over time was found (p = 0.01). The main limitation is the retrospective study design., Conclusions: HPV DNA in tumor tissue was associated with significantly better CSS for node-positive patients. The proportion of HPV DNA-positive PSCC has increased significantly in Western Norway over the past 50 yr., Patient Summary: We investigated the impact of human papillomavirus (HPV) on the survival of penile cancer patients treated over a 50-yr period in Norway. We found that for patients with lymph node metastasis, survival was better for HPV-related cases. We also found that the proportion of cases due to HPV has increased in Western Norway., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: There is a paucity of data on North American cohorts of patients with penile squamous cell carcinoma (pSCC). Herein, we aimed to assess the sensitivity of various modalities to identify human papillomavirus (HPV) status, determine the prevalence of high-risk HPV-positivity, and evaluate the prognostic impact of relevant clinicopathologic variables., Methods: Patients with pSCC (n = 121) consecutively treated with partial/total penectomy (2000-2022) at a single institution were included. HPV status (based on immunohistochemistry [IHC], in situ hybridization [ISH], and panviral metagenomic sequencing [PMS]), histologic features, and outcomes were reviewed. Outcome events included death due to disease and progression., Results: The majority of patients were white (105/121, 86.8%). Thirty-seven (30.6%) were high-risk HPV-positive, and morphologic evaluation had a sensitivity of 97.3% (95% confidence interval [CI], 86.2-99.5) for predicting high-risk HPV status compared to IHC/ISH/PMS. Disease progression was more common among high-risk HPV-negative compared to high-risk HPV-positive patients (HR 2.74, CI 1.12-8.23, P = 0.03). Moreover, among high-risk HPV-negative patients, those with moderate-poorly differentiated tumors had increased disease-specific mortality (32.6%, CI 17.1-48.1) compared to those with well-differentiated tumors (0%). Among high-risk HPV-positive patients, those with basaloid morphology had lower disease-specific mortality (0% vs 14.4%, CI 0.0-33.1)., Conclusions: We demonstrate high-risk HPV-positivity in approximately one-third of patients with pSCC. Morphologic evaluation alone had a high sensitivity in correctly determining HPV status. Our results suggest that high-risk HPV status and morphologic features (differentiation in high-risk HPV-negative, and basaloid subtype in high-risk HPV-positive pSCC) may have prognostic value., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Differences in pretreatment body mass index (BMI) have been associated with survival in squamous cell carcinoma of head and neck (SCCHN). We examined effects of BMI on survival in SCCHN patients after stratifying patients by tumor human papillomavirus (HPV) status and subsite., Methods: Totally 2204 SCCHN patients in a prospective study were included in this secondary analysis. Multivariable Cox models were used to evaluate associations between pretreatment BMI and overall survival, disease-specific survival, and disease-free survival., Results: BMI was significantly higher among patients with HPV-positive tumors than HPV-negative tumors. BMI >25 kg/m 2 was associated with improved survival, while BMI <18.5 kg/m 2 was associated with reduced survival, particularly in patients with HPV-positive oropharyngeal cancer tumors., Conclusions: This exploratory analysis suggests that pretreatment BMI could be an independent prognostic factor of survival outcomes in SCCHN patients, particularly in patients with HPV-positive oropharyngeal cancer tumors. Further prospective investigations are warranted., (© 2024 Wiley Periodicals LLC.)

Purpose: To assess the prevalence and subtypes of Human Papillomavirus (HPV) in Ocular Surface Squamous Neoplasia (OSSN) in Human Immunodeficiency Virus (HIV) positive and negative patients in South Africa., Basic Procedures: This study was a single center retrospective cross-sectional study, conducted at Tygerberg Hospital, Western Cape, South Africa. We assessed 63 histopathologically confirmed OSSN formalin-fixed paraffin-embedded (FFPE) tissue blocks from 2015-2023. The presence of HPV was determined using the Hybrispot Direct Flow Chip Kit. Corresponding clinical data was retrieved from the National Health Laboratory Service (NHLS) central data warehouse., Main Findings: Of the confirmed OSSN samples, 66.7% tested positive for HPV (95% confidence interval [CI] 54-77.3%). Of the 42 HPV positive samples, 38 (90.5%) had one or more known genotypes detected and 4 had unknown genotypes. The most prevalent subtypes were HPV 11, 16 and 18 (found in 61.9%, 52.4% and 33.3% of HPV positive samples respectively). 88.9% of the lesions biopsied were from HIV positive patients, of whom 56.4% had a CD4 + count of < 200 cells/µL. A lower median CD4 + count was detected among HIV positive patients with invasive squamous cell carcinoma compared to those with moderate dysplasia (p < 0.0198)., Conclusions: There is a high prevalence of HPV in OSSN in South Africa. Certain subtypes namely, 11, 16, 18, 31, 33 and 35 may be more carcinogenic. HIV with HPV co-infection may be linked as a causative factor in the development of OSSN., (© 2024. The Author(s).)

Recently, microRNAs (miR) were identified to have potential links with oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) oncogenesis, specifically miR-21. Since HPV is a major risk factor for the development of these diseases, we aimed to search the literature regarding miR-21 expression in both HPV-positive and HPV-negative OSCC/OPSCC. The search was performed in the PubMed (MEDLINE), Scopus, Web of Science, and Cochrane electronic databases. The research question was as follows: Is there a difference in the tissue expression of miR-21 between patients with HPV-positive and those with HPV-negative OSCC/OPSCC? After conducting a meticulous search strategy, four studies were included, and they had a pooled sample size of 621 subjects with OSCC and/or OPSCC. Three studies did not find any significant difference in miR-21 expression between HPV-positive and HPV-negative OSCC/OPSCC. The findings of this systematic review showed that there are no differences in miR-21 expression between HPV-positive and HPV-negative OSCC/OPSCC. Nevertheless, it is worth noting that there are still insufficient studies regarding this important subject, because understanding how HPV influences miR-21 expression and its downstream effects can provide insights into the molecular mechanisms underlying OSCC/OPSCC development and progression.

High-risk human papillomavirus (hrHPV) is the cause of virtually all cervical cancers, most vaginal and anal cancers, and some vulvar cancer cases. With HPV testing becoming the primary screening method for cervical cancer, understanding the link between cervical hrHPV infection and the risk of other anogenital cancers is crucial. We assessed the risk of vulvar, vaginal and anal cancer and precancer (VIN2+, VaIN2+ and AIN2+) in a prospective cohort study including 455,349 women who underwent cervical hrHPV testing in Denmark from 2005 to 2020. We employed Cox proportional hazard models, adjusting for age, calendar year and HPV vaccination status, and estimated hazard ratios (HRs) and 95% confidence intervals (CI). We used the Aalen Johansen estimator to calculate the absolute risks of VIN2+, VaIN2+ and AIN2+. In total, 15% of the women were hrHPV positive at baseline. A positive cervical hrHPV test was associated with increased incidence of vulvar, vaginal and anal squamous cell carcinoma (SCC). Five-year risk estimates of VIN2+, VaIN2+ and AIN2+ among hrHPV-positive women (0.45%, 0.14% and 0.12%) were higher than among hrHPV-negative women (0.14%, 0.01% and 0.05%). Particularly high risk was observed among the hrHPV-positive women of the oldest age, with a history of anogenital precancer and those not HPV vaccinated. In conclusion, our study confirms the association between cervical hrHPV infection and non-cervical anogenital precancers and cancers. Currently, no established risk threshold or guidelines for follow-up. As HPV testing becomes the primary method for cervical cancer screening, future data will help define high-risk groups and acceptable risk thresholds., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Human papillomavirus (HPV) status plays a major role in predicting oropharyngeal squamous cell carcinoma (OPSCC) survival. This study assesses the accuracy of a fully automated 3D convolutional neural network (CNN) in predicting HPV status using CT images., Methods: Pretreatment CT images from OPSCC patients were used to train a 3D DenseNet-121 model to predict HPV-p16 status. Performance was evaluated by the ROC Curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and F1 score., Results: The network achieved a mean AUC of 0.80 ± 0.06. The best-preforming fold had a sensitivity of 0.86 and specificity of 0.92 at the Youden's index. The PPV, NPV, and F1 scores are 0.97, 0.71, and 0.82, respectively., Conclusions: A fully automated CNN can characterize the HPV status of OPSCC patients with high sensitivity and specificity. Further refinement of this algorithm has the potential to provide a non-invasive tool to guide clinical management., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Sinonasal squamous cell carcinoma (SNSCC) is the most commonly encountered cancer within the sinonasal cavity. Ongoing research has sought to ascertain the potential role of human papillomavirus (HPV) in the pathogenesis of SNSCC., Objective: To assess trends in HPV-associated and HPV-independent SNSCC over time, including assessment of clinical demographics, treatment patterns, and survival., Design, Setting, and Participants: This cohort study used patient data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program database between 1975 and 2018. Anatomic sites with a greater predilection for HPV positivity (ie, nasal cavity, ethmoid sinus) were used as a surrogate for HPV-associated SNSCC; meanwhile, patients with SNSCC in the other subsites were classified into the HPV-independent group. Data were analyzed from August 2022 to May 2023., Main Outcomes and Measures: Clinical demographics and mortality trends over time were described for the HPV-associated and HPV-independent groups and further stratified according to stage on presentation., Results: The study population consisted of 3752 patients with SNSCC (mean [SD] age at diagnosis, 65.7 [13.3] years; 2417 [64.4%] male), with 1983 (52.9%) having HPV-associated SNSCC and 1769 (47.1%) with HPV-independent SNSCC. Patients with HPV-associated subsites compared with patients with HPV-independent SNSCC were more likely to present with localized disease (838 [42.3%] vs 162 [9.2%]), whereas more patients in the HPV-independent group than HPV-associated group presented with regional disease (1018 [57.5%] vs 480 [24.2%]). Incidence-based mortality was stable over time within the HPV-associated group (0.32%) and, conversely, showed a significant decrease within the HPV-independent group (-2.29%). Patients with HPV-associated SNSCC had a higher 5-year overall survival when compared with the HPV-independent group (62% vs 35% [difference, 27 percentage points; 95% CI, 23-31 percentage points]). The better 5-year overall survival in the HPV-associated group vs HPV-independent group was present across all disease stages (localized: hazard ratio [HR], 2.67; 95% CI, 1.96-3.65; regional: HR, 1.53; 95% CI, 1.29-1.82; and distant: HR, 1.97; 95% CI, 1.52-2.55)., Conclusions and Relevance: This cohort study showed that the proportion of HPV-associated SNSCC rose over time associated with both a rise in the proportion of nasal cavity SNSCC and a decrease in HPV-independent maxillary sinus SNSCC. These data suggest that HPV-associated SNSCC has a distinct demographic and prognostic profile, given the improved survival seen in patients with HPV-associated SNSCC.

Objectives: Human papillomavirus (HPV) has emerged as a potential etiological factor in sinonasal squamous cell carcinoma (SNSCC), but a clear understanding of HPV prevalence and its temporal patterns in SNSCC remains elusive. This study aimed to investigate temporal trends in HPV testing and positivity rates, and explore demographic and geographic factors associated with these trends., Methods: A retrospective cohort study included patients diagnosed with invasive SNSCC between 2011 and 2017 from the US National Cancer Database (NCDB). Prevalence ratios (PR) of HPV positivity and testing rates were estimated with the corresponding 95% confidence interval (95% CI)., Results: The overall HPV testing rate was 45.4 % (N = 1762/3880), and the prevalence of HPV testing significantly decreased during the study period (adjusted PR: 0.97, 95 % CI: 0.95 - 0.99, p < 0.001). Overall HPV positivity frequency was 37.3 % (N = 650/1741), and the overall prevalence of HPV positive tumors significantly increased during the study period (adjusted PR: 1.04, 95 % CI: 1.02 - 1.05, p < 0.001). The increase in HPV positivity rate was observed solely in the white population (unadjusted PR: 1.10, 95 % CI: 1.06 - 1.14; p < 0.001). A significant geographical variation was observed for both HPV testing (range: 28.6 % - 61.7 %) and positivity (range: 28.3 % - 44.7 %)., Conclusions: This study provides novel insights into the temporal trends and demographic factors associated with HPV testing and positivity in SNSCC. Despite increasing HPV positivity rates, disparities in testing rates persist, highlighting the need for standardized testing protocols and targeted interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Oral squamous cell carcinoma (OSCC) has become the most common HPV-related cancer with high invasion and metastasis. Exploring biomarkers for the screening and monitoring of OSCC, especially for the HPV-OSCC, would benefit patients' diagnosis and prognosis. This study evaluated the significance and mechanism of TMEM161B-AS1 and miR-651-5p in HPV-OSCC aiming to provide novel insight into the mechanism of HPV-OSCC development. Expression of TMEM161B-AS1 and miR-561-5p was analyzed in healthy individuals, HPV-infected non-OSCC patients, and HPV-OSCC patients using PCR. Their significance in HPV-OSCC occurrence and prognosis was evaluated by logistic regression, ROC, Kaplan-Meier, and Cox regression analysis. In OSCC cells, CCK8 and Transwell assays were employed for assessing cell growth and metastasis. The luciferase reporter assay and cell transfection were performed to evaluate the regulatory association between TMEM161B-AS1, miR-561-5p, and BDNF. Significant upregulation of TMEM161B-AS1 and downregulation of miR-561-5p were observed in oral HPV-infected patients. Both TMEM161B-AS1 and miR-651-5p served as risk factors for the occurrence of OSCC in oral HPV-infected patients and could distinguish HPV-OSCC patients from HPV-infected non-OSCC patients. Increased TMEM161B-AS1 and reduced miR-561-5p indicated severe development and adverse prognosis of HPV-OSCC patients. In OSCC cells, silencing TMEM161-AS1 suppressed cell proliferation and motility via negatively modulating miR-561-5p. miR-561-5p negatively regulated BDNF, which was considered the underlying mechanism of TMEM161B-AS1. Increasing TMEM161B-AS expression and decreasing miR-561-5p showed the occurrence of OSCC in HPV-infected patients and predicted malignant development and adverse prognosis. TMEME161B-AS1 served as a tumor promoter via regulating the miR-561-5p/BDNF axis., (© 2024. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)

Purpose: This study compared treatment and outcomes for patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) based on their travel distance to treatment facility., Materials and Methods: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC in the National Cancer Database from 2010 to 2019 were identified and split into four quartiles based on distance to facility, with quartile 4 representing patients with furthest travel distances. Multivariable-adjusted logistic regression and Cox proportional hazards modeling were used to analyze the primary outcome of treatment received, and secondary outcomes of clinical stage, overall survival, surgical approach (i.e., TORS versus other), and 30-day surgical readmissions., Results: 17,207 patients with HPV-positive OPSCC were evenly distributed into four quartiles. Compared to patients in quartile 1, patients in quartile 4 were 40 % less likely to receive radiation versus surgery (OR = 0.60; 95 % CI = 0.54-0.66). Among the patients who received surgery, quartile 4 had a higher odds of receiving TORS treatment compared to quartile 1 (4v1: OR = 2.38; 95 % CI = 2.05-2.77), quartile 2 (4v2: OR = 2.31, 95 % CI = 2.00-2.66), and quartile 3 (4v3: OR = 1.75; 95 % CI = 1.54-1.99). Quartile 4 had a decreased odds of mortality compared to Quartile 1 (4v1: OR = 0.87; 95 % CI = 0.79-0.97). There were no differences among the quartiles in presenting stage and 30-day readmissions., Conclusions: This study found that patients with furthest travel distance to facility were more often treated surgically over non-surgical management, with TORS over open surgery, and had better overall survival. These findings highlight potential disparities in access to care for patients with HPV-positive OPSCC., Competing Interests: Declaration of competing interest The authors have no financial disclosures or conflicts of interests to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The aim was to evaluate the frequency, clinicopathological features, and HPV status of oropharyngeal squamous cell carcinoma (OP-SCC) and benign HPV-related epithelial lesions of the oropharynx over the last 25 years. Moreover, a literature review was performed to investigate HPV frequency in OP-SCC samples diagnosed in Brazilian Centers., Material and Methods: A cross-sectional study analyzed OP-SCC, squamous papilloma, verruca vulgaris, and condyloma accuminatum, diagnosed from 1997 to 2021. HPV status of OP-SCC was determined by immunohistochemistry and "in situ" hybridization. Bivariate statistics were performed (p≤0.05). For the literature review, MEDLINE/PubMed, Web of Science, EMBASE, and Scopus were searched. Two independent reviewers assessed the studies for eligibility., Results: Cross-sectional: 211 OP-SCC (63.0%) and 124 benign lesions (37.0%) were included. OP-SCC frequency increased gradually over time, whereas benign lesions had steady trends. OP-SCC affected more males (n= 171; 81.0%), though the relative frequency in females rose over time. Smoking (n= 127; 60.2%) was common in OP-SCC. Nineteen OP-SCC (13.0%) were positive for HPV. HPV-positive and HPV-negative tumors had similar clinicopathological features (p>0.05). Benign lesions predominated in middle-aged (n= 32; 26.7%) women (n= 71; 57.3%), in the soft palate (n=101; 81.5%)., Literature Review: 32 studies were included, and in 60% of them, HPV frequency in OP-SCC was less than 25%., Conclusions: OP-SCC prevalence has been increasing, and it was mostly associated with smoking and alcohol rather than with HPV infection in Brazil. Benign lesions had a stationary frequency over the evaluated period.

Two etiological pathways have been implicated in the pathogenesis of vulvar squamous cell carcinoma (VSCC): a high-risk human papillomavirus (HPV)-associated route and an HPV-independent pathway characterized by TP53 mutations. Programmed cell death ligand 1 (PD-L1) has become increasingly useful in predicting the response to checkpoint inhibitor therapy in squamous cell carcinomas at various anatomical sites. This study aimed to assess the association between PD-L1 expression and the VSCC subtype to evaluate the utility of PD-L1 in prognostication and therapeutic selection based on HPV status. PD-L1 status was assessed using 3 separate metrics for the extent of PD-L1 staining in various cell types: immune cell score, tumor proportion score (TPS), and combined positive score. The study group consisted of 25 HPV-associated and 28 HPV-independent VSCCs. PD-L1 expression was positive in the majority of VSCCs according to all 3 scoring metrics (84.9% by immune cell score, 77.3% by TPS, and 90.6% by combined positive score). PD-L1 expression was observed in the majority of cases in both groups (60%-96.4%). PD-L1 expression using the TPS method was greater in HPV-independent tumors than in HPV-associated tumors ( P = 0.004), and high PD-L1 expression was also more common in the HPV-independent subtype ( P = 0.016 using the TPS method and P = 0.013 using the combined positive score method). Our findings contribute to the growing evidence that PD-L1 is expressed in the majority of invasive VSCCs, and thus may serve as an attractive therapeutic target. PD-L1 expression is higher in HPV-independent tumors, suggesting that this subtype may be more responsive to PD-L1 inhibitor therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Oropharyngeal squamous cell carcinoma (OPSCC) related to human papillomavirus (HPV) infection has better survival outcomes compared to non-HPV-related OPSCC, leading to efforts to de-escalate the intensity of treatment to reduce associated morbidity. This article reviews recent clinical efforts to explore different de-escalation frameworks with a particular emphasis on the emergence of transoral robotic surgery and surgically driven de-escalation approaches. It discusses the current evidence for incorporating surgery into an evolving treatment paradigm for HPV-related OPSCC., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Head and neck squamous cell carcinomas (HNSCCs), a heterogeneous group of cancers that arise from the mucosal epithelia cells in the head and neck areas, present great challenges in diagnosis, treatment and prognosis due to their complex aetiology and various clinical manifestations. Several factors, including smoking, alcohol consumption, oncogenic genes, growth factors, Epstein‑Barr virus and human papillomavirus infections can contribute to HNSCC development. The unpredictable tumour microenvironment adds to the complexity of managing HNSCC. Despite significant advances in therapies, the prediction of outcome after treatment for patients with HNSCC remains poor, and the 5‑year overall survival rate is low due to late diagnosis. Early detection greatly increases the chances of successful treatment. The present review aimed to bring together the latest findings related to the molecular mechanisms of HNSCC carcinogenesis and progression. Comprehensive genomic, transcriptomic, metabolomic, microbiome and proteomic analyses allow researchers to identify important biological markers such as genetic alterations, gene expression signatures and protein markers that drive HNSCC tumours. These biomarkers associated with the stages of initiation, progression and metastasis of cancer are useful in the management of patients with cancer in order to improve their life expectancy and quality of life.

Objectives: Investigating the expression and prognostic significance of adenovirus receptors DSG-2, CXADR and CD46 in head and neck cancer., Methods: 104 patients with HNSCC (77 OPSCC, 27 LSCC) were retrospectively included in the study. Immunohistochemical staining was performed on all selected slides to detect the expression of DSG-2, CXADR, CD46 and the immunoreactive score (IRS) was determined from the number of positively stained tumor cells and their staining intensity. Furthermore, the respective HPV status was determined by immunohistochemical staining against p16 and HPV-PCR., Results: 81.7 % of the tumors showed DSG-2, 34.6 % of the tumors showed CXADR and 57.7 % of the tumors showed CD46 expression. A high DSG-2 IRS correlated significantly with an advanced tumor size (p= 0.003), increased grading (p=0.012) and positive HPV status (p=0.024) in OPSCC. A high CXADR IRS was significantly associated with a positive lymph node status (p= 0.041) in LSCC and an advanced AJCC stage (p= 0.012) and a positive HPV status (p= 0.009) in OPSCC. No significant correlation could be shown regarding CD46 expression and clinical tumor data. There was no effect of DSG-2, CXADR, and CD46 expression on 5-year overall and on 5-year disease-free survival., Conclusion: No prognostic significance of the expression of DSG-2, CXADR or CD46 in HNSCC was seen. DSG-2, CXADR and CD46 are expressed in HNSCC, so that optimization of oncotherapy with adenoviral vectors appears promising. Due to the significantly increased expression of DSG-2 and CXADR in advanced OPSCC tumors, there is potential for optimizing oncotherapy here in particular., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The article "Characterization of oral microbiota in HPV and non-HPV head and neck squamous cell carcinoma and its association with patient outcomes" by Chan et al. investigates the relationship between oral microbiota, HPV infection, and patient outcomes in head and neck squamous cell carcinoma (HNSCC). This comprehensive study, involving 166 Chinese adults, utilized advanced sequencing techniques to profile bacterial and HPV regions in paired tumor and control tissues. The findings highlight the complex interplay between microbiota dysbiosis, HPV infection, and HNSCC progression. Despite the robustness of the study, limitations include potential biases in DNA extraction and PCR amplification, and unaccounted environmental factors. Recommendations for future research include increasing sequencing depth, comparing DNA extraction methods, using multiple bioinformatics pipelines, and controlling for environmental variables. Longitudinal studies and microbiota-targeted interventions are suggested to further elucidate the role of oral microbiota in HNSCC and improve patient outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Despite the better prognosis associated with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), some patients experience relapse and succumb to the disease; thus, there is a need for biomarkers identifying these patients for intensified treatment. Leucine-rich repeats and immunoglobulin-like domain (LRIG) protein 1 is a negative regulator of receptor tyrosine kinase signaling and a positive prognostic factor in OPSCC. Studies indicate that LRIG1 interacts with the LIM domain 7 protein (LMO7), a stabilizer of adherence junctions. Its role in OPSCC has not been studied before., Methods: A total of 145 patients diagnosed with OPSCC were enrolled. Immunohistochemical LMO7 expression and staining intensity were evaluated in the tumors and correlated with known clinical and pathological prognostic factors, such as HPV status and LRIG1, CD44, Ki67, and p53 expression., Results: Our results show that high LMO7 expression is associated with significantly longer overall survival (OS) (p = 0.044). LMO7 was a positive prognostic factor for OS in univariate analysis (HR 0.515, 95% CI: 0.267-0.994, p = 0.048) but not in multivariate analysis. The LMO7 expression correlated with LRIG1 expression (p = 0.048), consistent with previous findings. Interestingly, strong LRIG1 staining intensity was an independent negative prognostic factor in the HPV-driven group of tumors (HR 2.847, 95% Cl: 1.036-7.825, p = 0.043)., Conclusions: We show for the first time that high LMO7 expression is a positive prognostic factor in OPSCC, and we propose that LMO7 should be further explored as a biomarker. In contrast to previous reports, LRIG1 expression was shown to be an independent negative prognostic factor in HPV-driven OPSCC., (© 2024. The Author(s).)

Several studies have emphasised how positive and negative human papillomavirus (HPV+  and HPV-, respectively) oropharyngeal squamous cell carcinoma (OPSCC) has distinct molecular profiles, tumor characteristics, and disease outcomes. Different radiomics-based prediction models have been proposed, by also using innovative techniques such as Convolutional Neural Networks (CNNs). Although some of these models reached encouraging predictive performances, there evidence explaining the role of radiomic features in achieving a specific outcome is scarce. In this paper, we propose some preliminary results related to an explainable CNN-based model to predict HPV status in OPSCC patients. We extracted the Gross Tumor Volume (GTV) of pre-treatment CT images related to 499 patients (356 HPV+ and 143 HPV-) included into the OPC-Radiomics public dataset to train an end-to-end Inception-V3 CNN architecture. We also collected a multicentric dataset consisting of 92 patients (43 HPV+ , 49 HPV-), which was employed as an independent test set. Finally, we applied Gradient-weighted Class Activation Mapping (Grad-CAM) technique to highlight the most informative areas with respect to the predicted outcome. The proposed model reached an AUC value of 73.50% on the independent test. As a result of the Grad-CAM algorithm, the most informative areas related to the correctly classified HPV+ patients were located into the intratumoral area. Conversely, the most important areas referred to the tumor edges. Finally, since the proposed model provided additional information with respect to the accuracy of the classification given by the visualization of the areas of greatest interest for predictive purposes for each case examined, it could contribute to increase confidence in using computer-based predictive models in the actual clinical practice., (© 2024. The Author(s).)

The increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) is primarily due to human papillomavirus, and understanding the tumor biology caused by the virus is crucial. Our goal was to investigate the proteins present in the serum of patients with OPSCC, which were not previously studied in OPSCC tissue. We examined the difference in expression of these proteins between HPV-positive and -negative tumors and their correlation with clinicopathological parameters and patient survival. The study included 157 formalin-fixed, paraffin-embedded tissue samples and clinicopathological data. Based on the protein levels in the sera of OPSCC patients, we selected 12 proteins and studied their expression in HPV-negative and HPV-positive OPSCC cell lines. LRG1, SDR16C5, PIP4K2C and MVD proteins were selected for immunohistochemical analysis in HPV-positive and -negative OPSCC tissue samples. These protein´s expression levels were compared with clinicopathological parameters and patient survival to investigate their clinical relevance. LRG1 expression was strong in HPV-negative whereas SDR16C5 expression was strong in HPV-positive tumors. Correlation was observed between LRG1, SDR16C5, and PIP4K2C expression and patient survival. High expression of PIP4K2C was found to be an independent prognostic factor for overall survival and expression correlated with HPV-positive tumor status. The data suggest the possible role of LRG1, SDR16C5 and PIP4K2C in OPSCC biology., (© 2024. The Author(s).)

Background: The incidence rate of oropharyngeal squamous cell carcinoma (OPSCC) worldwide is alarming. In the clinical community, there is a pressing necessity to comprehend the etiology of the OPSCC to facilitate the administration of effective treatments., Methods: This study confers an integrative genomics approach for identifying key oncogenic drivers involved in the OPSCC pathogenesis. The dataset contains RNA-Sequencing (RNA-Seq) samples of 46 Human papillomavirus-positive head and neck squamous cell carcinoma and 25 normal Uvulopalatopharyngoplasty cases. The differential marker selection is performed between the groups with a log2FoldChange (FC) score of 2, adjusted p -value < 0.01, and screened 714 genes. The Particle Swarm Optimization (PSO) algorithm selects the candidate gene subset, reducing the size to 73. The state-of-the-art machine learning algorithms are trained with the differentially expressed genes and candidate subsets of PSO., Results: The analysis of predictive models using Shapley Additive exPlanations revealed that seven genes significantly contribute to the model's performance. These include ECT2 , LAMC2 , and DSG2 , which predominantly influence differentiating between sample groups. They were followed in importance by FAT1 , PLOD2 , COL1A1 , and PLAU . The Random Forest and Bayes Net algorithms also achieved perfect validation scores when using PSO features. Furthermore, gene set enrichment analysis, protein-protein interactions, and disease ontology mining revealed a significant association between these genes and the target condition. As indicated by Shapley Additive exPlanations (SHAPs), the survival analysis of three key genes unveiled strong over-expression in the samples from "The Cancer Genome Atlas"., Conclusions: Our findings elucidate critical oncogenic drivers in OPSCC, offering vital insights for developing targeted therapies and enhancing understanding its pathogenesis., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)