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

He X., Wang Y.

Sinonasal inverted papilloma is a benign tumor but has a potential for recurrence and malignant transformation. The aim of this article is to analyze the clinical characteristics of sinonasal inverted papilloma associated with recurrence and malignant transformation.A retrospective study was performed in all patients with sinonasal inverted papilloma diagnosed between in our hospital during May 2013 and May 2018.A total of 151 patients were enrolled in this study. The average age of these patients was 52.24 years, with a male-to-female ratio of 2.775:1, and the most frequent clinical symptom was nasal obstruction. The recurrence rate was 39.07% (59/151), the mean time of recurrence was 35.8 months and most recurrences occur within the first three years after surgery. There was no significant difference in recurrence rate between all four stages and between after endoscopic surgery and a combined endoscopic and external approach. The malignant transformation rate was 5.96% (9/151) and the mean time of malignant transformation was 9.06 months.Because of its high recurrence rate and the potential of malignant transformation, so it is important to determine the primary site of the tumor and to make a complete removal and a follow-up of at least five years after surgery is recommended.

Brown N.A., Plouffe K.R., Yilmaz O., Weindorf S.C., Betz B.L., Carey T.E., Seethala R.R., McHugh J.B., Tomlins S.A., Udager A.M.

Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with a synchronous or metachronous sinonasal carcinoma in a subset of cases. Our group recently identified mutually exclusive EGFR mutations and human papillomavirus (HPV) infection in inverted sinonasal papillomas and frequent KRAS mutations in oncocytic sinonasal papillomas. We also demonstrated concordant mutational and HPV infection status in sinonasal papilloma-associated sinonasal carcinomas, confirming a clonal relationship between these tumors. Despite our emerging understanding of the oncogenic mechanisms driving formation of sinonasal papillomas, little is currently known about the molecular mechanisms of malignant progression to sinonasal carcinoma. In the present study, we utilized targeted next-generation DNA sequencing to characterize the molecular landscape of a large cohort of sinonasal papilloma-associated sinonasal carcinomas. As expected, EGFR or KRAS mutations were present in the vast majority of tumors. In addition, highly recurrent TP53 mutations, CDKN2A mutations, and/or CDKN2A copy-number losses were detected; overall, nearly all tumors (n = 28/29; 96.6%) harbored at least one TP53 or CDKN2A alteration. TERT copy-number gains also occurred frequently (27.6%); however, no TERT promoter mutations were identified. Other recurrent molecular alterations included NFE2L2 and PIK3CA mutations and SOX2, CCND1, MYC, FGFR1, and EGFR copy-number gains. Importantly, TP53 mutations and CDKN2A alterations were not detected in matched sinonasal papillomas, suggesting that these molecular events are associated with malignant transformation. Compared to aerodigestive tract squamous cell carcinomas from The Cancer Genome Atlas (TCGA) project, sinonasal papilloma-associated sinonasal carcinomas have a distinct molecular phenotype, including more frequent EGFR, KRAS, and CDKN2A mutations, TERT copy-number gains, and low-risk human papillomavirus (HPV) infection. These findings shed light on the molecular mechanisms of malignant progression of sinonasal papillomas and may have important diagnostic and therapeutic implications for patients with advanced sinonasal cancer.

Stepp W.H., Farzal Z., Kimple A.J., Ebert C.S., Senior B.A., Zanation A.M., Thorp B.D.

Ikegami T., Hirakawa H., Tsukahara N., Murakami A., Kise N., Kiyuna A., Kosugi T., Agena S., Kinjyo H., Hasegawa N., Touyama M., Kondo S., Maeda H., Suzuki M., Ganaha A.

Laryngeal papilloma (LP) associated with human papillomavirus (HPV)-6 or -11 infection shows aggressive growth. However, the detailed molecular mechanism of virus-driven tumorigenesis has not been uncovered fully. HPV-6 viral gene expression and dynamic alterations were investigated with in situ localization of viral DNA and RNA in 13 patients with HPV-6-infected laryngeal papilloma. The average viral load was 4.80 × 105 ± 1.86 × 105 copies/ng DNA. E4, E5a, and E5b mRNAs accounted for 96% of the expression of 9 mRNAs. The alteration of viral DNA load during recurrence paralleled the mRNA expression levels, and the expression of all mRNAs showed a similar curve. E4, E5a, and E5b were expressed in the middle to upper part of the epithelium and were co-expressed in the same cells. E4 immunohistochemistry demonstrated an extensively positive reaction in the upper cell layer in accordance with E4 mRNA expression. These results suggest that individual viral genes are coordinately expressed for viral replication, virus release, and immunosurveillance avoidance. The newly developed E4-specific monoclonal antibody can be applied to further functional studies and clinical applications such as targeted molecular therapies.

Syrjänen S., Rintala M., Sarkola M., Willberg J., Rautava J., Koskimaa H., Paaso A., Syrjänen K., Grénman S., Louvanto K.

Human papillomavirus (HPV) infections are found in children, but transmission modes and outcomes are incompletely understood. We evaluated oral samples from 331 children in Finland who participated in the Finnish Family HPV Study from birth during 9 follow-up visits (mean time 51.9 months). We tested samples for 24 HPV genotypes. Oral HPV prevalence for children varied from 8.7% (at a 36-month visit) to 22.8% (at birth), and 18 HPV genotypes were identified. HPV16 was the most prevalent type to persist, followed by HPV18, HPV33, and HPV6. Persistent, oral, high-risk HPV infection for children was associated with oral HPV carriage of the mother at birth and seroconversion of the mother to high-risk HPV during follow-up (odds ratio 1.60-1.92, 95% CI 1.02-2.74). Children acquire their first oral HPV infection at an early age. The HPV status of the mother has a major impact on the outcome of oral HPV persistence for her offspring.

Tou A.M., Al-Nimr A.O.

Objectives Esophageal squamous papilloma (ESP) is a rare epithelial lesion most commonly seen in adults, with an unclear etiology and limited pediatric data available. The aim of this study was to provide an estimated prevalence of this lesion in our pediatric population, as well as to identify any demographic, clinical, or pathologic associations-including human papilloma virus (HPV) infection, which has been linked with ESP in adult literature. Methods ESP cases at University Hospitals Rainbow Babies & Children's Hospital were identified by conducting a retrospective search through all esophagogastroduodenoscopies (EGDs) performed in children under 18 years old, from January 1, 2000 to December 31, 2014. Histopathology reports were analyzed including Fluorescence In Situ Hybridization (FISH) for HPV, and a comprehensive chart review was performed for demographic data. Results Of 12,459 children who required an EGD, 10 children were identified with ESP on biopsy, with ages ranging from 2 to 17 years. This provides an estimated prevalence of 0.08% over the entire study period. Seventy percentage of patients underwent endoscopy for abdominal pain, and 40% presented with gastroesophageal reflux. Sixty percentage of lesions were in the proximal esophagus, and 80% of patients had isolated lesions. Notably, none of the lesions tested were positive for HPV on FISH analysis. Conclusions ESP is a rare benign lesion found incidentally in the pediatric population. The prevalence at our institution was 0.08%. All samples tested for HPV via FISH analysis were negative. As a result, regular analysis for HPV may not be necessary in pediatric patients with ESP in the future.

El Korbi A., Sondes J., Naourez K., Rachida B., Leila N., Emna B., Mehdi F., Khaled H., Jamel K.

Labedz G., Scatolini M.L., Ruvinsky S., Rodriguez H.A.

OBJECTIVES/HYPOTHESIS To identify factors associated to increased risk of extra-laryngeal spread in pediatric patients with recurrent respiratory papillomatosis (RRP). STUDY DESIGN Retrospective chart review. METHODS A retrospective study was conducted evaluating the clinical charts of patients younger than 16 years with histopathologically confirmed RRP treated between January 2014 and December 2018. Characteristics of patients with and without extra-laryngeal disease dissemination were compared. Odds ratios were calculated and multivariate logistic regression analysis was performed. RESULTS Data from 82 patients were analyzed. Mean age at symptom onset was 42 months. Fifteen (18.29%) patients had extra-laryngeal spread (ELS) at time of diagnosis and in four, the disease continued to spread to other sites. Of 67 patients with disease restricted to the larynx, 17 (25.37%) developed ELS during the disease course. Human papilloma virus (HPV) typing was performed in 49 (59.8%) patients; in 28 (57.1%) HPV subtype 6 was identified and in 21 (42.9%) HPV subtype 11. ELS was found in 11 patients with serotype 11 (52.38%) and in seven patients with serotype 6 (25%) (P = .048). Statistically significant differences for ELS were also found for age at diagnosis younger than 5 years (P = .045), presence of tracheostomy (P = .031), and need for adjuvant therapy (P = .010). CONCLUSIONS Age at diagnosis of RRP younger than 5 years and presence of tracheostomy were factors related to ELS. A statistically significant association between infection with HPV subtype 11 and ELS were also observed. Adjuvant medication might be considered a protective factor against ELS. Laryngoscope, 131:1652-1656, 2021.

Ding R., Sun Q., Wang Y.

Gupta R., Rady P.L., Sikora A.G., Tyring S.K.

Sinonasal inverted papillomas (IPs) are rare tumours arising from the nasal epithelial mucosa. Most lesions are benign, but a subset of IPs progress to dysplasia and squamous cell carcinoma. Although the epidemiology and clinical features of IPs are well known, the pathogenesis is still unclear. Given the established role of human papillomaviruses (HPVs) in the formation of other mucosal tumours including cervical and oropharyngeal cancer, some have suggested the virus may play a role in IP development. However, the association between HPV and IPs has not yet been proven, and the variable detection of HPV DNA in IPs has cast uncertainty on whether the virus plays a major role in pathogenesis. In this review, we summarize early clinical reports and synthesize recent studies that may elucidate the association between HPV and IPs. We also discuss the role HPV may have in the progression of benign IP to dysplasia and malignancy, as well as potential pathological mechanisms. We hope that synthesizing the initial and recent studies on this topic will not only lead to a better understanding of research in the role of HPV in IP development, but also help guide and contextualize future studies.

Dassi L., Annunziata C., Botti C., Micillo A., Cerasuolo A., Starita N., Buonaguro F.M., Tornesello M.L.

Vertical transmission of human papillomaviruses (HPVs) from mother to infant is known to occur during labor, delivery or breastfeeding. Infection with mucosal HPV 6 and 11 may cause recurrent respiratory papillomatosis in children, which is a rare and severe respiratory disease. The cutaneous HPV genotypes have also been described to be transmitted from mother to newborn through skin-to-skin contacts and during breastfeeding. To investigate the perinatal transmission of alpha and beta HPVs we collected nasopharyngeal specimens from 0–12-months-old infants born by vaginal delivery and breastfed at the time of sample collection. The mucosal and cutaneous HPVs were searched by nested PCR using the MY09/11-MGPs and CP65/70-CP66/69 primer sets, respectively, and genotypes identified by direct sequencing analysis. Fourteen out of 113 (12.4%) samples tested positive for HPV and sequence analysis allowed us to identify eight beta genotypes (HPV 5b, 20, 25, 100, 107, 124, 152 and RTRX7). Moreover, we performed a comprehensive review of published studies on the prevalence of mucosal and cutaneous HPVs among 5126 newborns and observed that 10% and 53% were positive for alpha and beta HPVs, respectively. In all studies there was an inverse correlation between the rate of alpha HPV positivity and age, while a significant positive trend was observed in beta HPV detection and age with the highest rate among children older than 12 months (Χ2 test for trend of 10.6, p < 0.001). Further studies are needed to confirm the hypothesis that beta HPVs are transmitted to breastfeeding infants through shedding of viruses in the breast milk or on the external breast epithelium.

Sichero L., Ferreira S., López R.V., Mello B.P., Costa V., El‐Achkar V.N., Carlos R., Ribeiro‐Silva A., Pignatari S., Kaminagakura E., Villa L.L.

Human papillomavirus (HPV) types 6 and 11 are the etiological agents of recurrent respiratory papillomatosis (RRP). We examined the prevalence and distribution of HPVs 6 and 11 genetic variants in juvenile onset (JORRP) and adult onset (AORRP) laryngeal papillomas. Cases of JORRP and AORRP were collected, retrospectively. HPV detection and genotyping were accessed by polymerase chain reaction-sequencing in 67 RRP samples. Overall, the most prevalent HPV-6 variants were from B1 (55.8%) and B3 (27.9%) sublineages, whereas among HPV-11 positive samples A2 (62.5%) variants were predominant. A higher prevalence of HPV-6 B1 was observed in JORRP (83.3% B1 and 16.7% B3), compared with AORRP cases (58.3% B1 and 41.7% B3). HPV-11 A2 variants were more prevalent both in JORRP (57.2%) and in AORRP cases (70.0%). Nevertheless, with the exception that HPV-6 B1 were significantly less likely to recur, there was a lack of association between any particular HPVs 6 or 11 variant and clinicopathological features. Our data do not support an association between HPVs 6 and 11 variability and RRP.

Nogueira R.L., Küpper D.S., Bonfim C.M., Aragon D.C., Damico T.A., Miura C.S., Passos I.M., Nogueira M.L., Rahal P., Valera F.C.

This study aimed to compare the prognosis according to age, genotype or human papillomavirus (HPV) variant in patients with recurrent respiratory papillomatosis (RRP).Non-concurrent cohort.Forty one patients with RRP.Tertiary referral hospital.Disease severity was defined by the number of surgeries performed, and Derkay score at surgeries, obtained from medical records. HPV was detected and genotyped, and HPV-6 variants were also assessed.Fifteen (36.58%) individuals belonged to the juvenile RRP group (JoRRP, less than 18 years), while 26 patients (63.41%) were allocated at the adult group (AoRRP, equal or more than 18 years). JoRRP patients needed, in average, a higher number of surgeries to control the disease than AoRRP patients (mean difference: 3.36). Also, JoRRP patients showed a higher Derkay score at each surgery (mean difference: 3.76). There was no significant difference in the number of surgeries when we compared patients infected with HPV-6 or HPV-11, neither in accordance to HPV-6 variants. Patients with HPV-11 presented a higher mean Derkay score at surgery than those with HPV-6 (mean difference: 4.39); when co-variated by age, we observed that this difference occurred only among JoRRP patients (mean difference: 6.15).Age of onset of RRP has an important impact on number of surgeries to control disease. Patients with JoRRP and HPV-11 tend to present worse Derkay score at each surgery. HPV genotype among adults and HPV-6 variants had no impact on the outcome of the disease.

Hongo T., Yamamoto H., Jiromaru R., Nozaki Y., Yasumatsu R., Hashimoto K., Yoneda R., Sugii A., Taguchi K., Masuda M., Nakagawa T., Oda Y.

Sinonasal squamous cell carcinoma (SNSCC) is sometimes associated with high-risk human papillomavirus (HR-HPV) infection and inverted sinonasal papilloma or oncocytic sinonasal papilloma. Frequent mutations of EGFR and KRAS are reported in inverted sinonasal papilloma-related sinonasal squamous cell carcinoma (ISP-SCC) and oncocytic sinonasal papilloma-related SNSCC, respectively. Here, we attempted to determine the prevalence and the prognostic significances of these alterations in SNSCC. We retrospectively collected 146 SNSCCs, including 14 ISP-SCCs, and comprehensively analyzed the HR-HPV infection by human papillomavirus (HPV)-RNA in situ hybridization, EGFR gene copy number gain (CNG) by chromogenic in situ hybridization, and gene mutations in EGFR and KRAS by Sanger sequencing. HR-HPV was detected in 11 cases (7.5%), whereas all 14 ISP-SCCs were negative. EGFR mutations were present in 21 (14.7%) of 143 SNSCCs, including 13/14 (92.9%) ISP-SCCs and 8/129 (6.2%) non-ISP-SCCs (P

Teutsch S.M., Nunez C.A., Morris A., Booy R., McGregor S., King J., Brotherton J.M., Novakovic D., Jones C.A., Rawlinson W., Thorley B.R., Elliott E.J.

The Australian Paediatric Surveillance Unit (APSU) has been prospectively collecting national data on rare childhood conditions since 1993, with monthly reporting of cases by paediatricians. In this report we describe annual results from studies for ten communicable diseases and complications of communicable diseases that were conducted using APSU surveillance in 2019 and place these in an historic context. Results are reported on acute flaccid paralysis, congenital cytomegalovirus infection, neonatal herpes simplex virus infection, perinatal exposure to HIV, paediatric HIV infection, severe complications of seasonal influenza, juvenile onset recurrent respiratory papillomatosis (JoRRP), congenital rubella syndrome, congenital varicella syndrome and neonatal varicella infection. APSU provides rich clinical data to complement data collected from other surveillance systems and to improve understanding and response to rare childhood infections.

López-Aguilar K.K., Vargas-Camaño M.E., Lozano-Patiño F., Castrejón Vázquez M.I.

Sutter D., Topouzian A., Young B.

The oropharynx serves as a mechanical and immunological conduit from the oral cavity and nasopharynx to the aerodigestive tract. In the geriatric population, disorders of the oropharynx are associated with major complications in nutrition, respiratory illness, depression, increased length of hospital stays, and mortality. Dermatologic assessment of the head and neck extends beyond the identification of lesions whose primary site is the oropharynx and should encompass systemic diseases with secondary oropharyngeal involvement. First, this chapter reviews the clinical similarities and differences between benign, precancerous, and cancerous lesions of the oropharynx. Second, it discusses the variety of viral, bacterial, and fungal infectious agents and distinct symptomatology. Third, it presents pathophysiology and concomitant systemic findings of autoimmune diseases which can manifest in the oropharynx. This chapter aims to elucidate diverse presentations, diagnostic challenges, and therapeutic considerations of disorders of the oropharynx in the geriatric context.

Vageli D.P., Doukas P.G., Paraskeva A.N., Zacharouli K., Judson B.L., Ioannou M.

Laryngeal rare tumors include benign and malignant tumors of epithelial, non-epithelial, or mesenchymal origin. Chondrosarcomas are the most common mesenchymal malignant tumors of the larynx. We performed a literature review (Pubmed/Medline; PRISMA 2020) to detect the frequency of published studies from 2021 to April 2024 regarding benign and malignant epithelial, non-epithelial, or mesenchymal rare tumors of the larynx, emphasizing laryngeal chondrosarcoma (LC) cases. Articles including cases discussed before 2021 were excluded and articles without available English translations. We included 154 articles investigating rare tumors of the larynx, the majority of them discussed non-epithelial or mesenchymal entities (75 %). Specifically, a high proportion of studies examined benign non-epithelial or mesenchymal tumors (79.5 %) or mesenchymal rare malignancies (72 %) of the larynx concerning epithelial tumors in the last three years. Sarcomas were discussed in 74 % of mesenchymal laryngeal malignancies and more than 50 % of rare laryngeal tumor studies, and LC was discussed in ∼50 % of laryngeal sarcoma studies. LC studies reported 174 cases, 21 % of them of high-grade LC (II), including a new case of LC presented here in the supraglottic (grade II), which showed intense staining for the S100 marker. Our study highlights the awareness of rare laryngeal tumors emphasizing non-epithelial benign tumors and laryngeal sarcomas, including chondrosarcomas, as pathologic entities of the larynx. Although the majority of LC included low-grade neoplasms, a markedness proportion of LC cases was evaluated as high-grade. Future research approaches, including a range of low and high-grade tumors, would reveal prognostic markers or therapeutic targets for LC and other rare laryngeal malignancies of non-epithelial or mesenchymal origin.

Jauhiainen M.K., Pyöriä L., Viitasalo S., Aaltonen L., Söderlund‐Venermo M., Hagström J., Mäkitie A.A., Perdomo M.F., Sinkkonen S.T.

ObjectivesSinonasal inverted papilloma (IP) has a locally destructive growth pattern, can relapse, and can undergo malignant transformation (IP‐associated sinonasal squamous cell carcinoma (IP‐SNSCC)). Human papillomaviruses (HPV)‐6 and ‐16 are frequently detected in IPs. To clarify the possible roles of other DNA viruses in IPs, we explored viruses not studied in this context before. With the setting of pre‐ and post‐malignant transformation samples, we investigated HPV genomes in depth to assess the integration of HPV into the human genome and the presence of minor intratypic variants.Materials and MethodsWe analyzed 35 IP samples representing 28 individuals, of which six had IP‐SNSCC. For virus screening, we applied qPCR to detect 16 different DNA viruses in three virus families, comprising herpesviruses, parvoviruses, and polyomaviruses. In addition, targeted next generation sequencing (NGS) was used for detailed HPV analysis.ResultsWe detected herpes‐, parvo‐, and polyomaviruses in 13/28 (46%) patients, with codetections of multiple viruses in six (21%) patients. NGS revealed HPV16 DNA in 2/6 IP‐SNSCC and in their respective earlier benign IP samples, as well as in a plasma sample from one of these patients. HPV6 was detected in two IP samples without subsequent malignant transformation. We identified sequence reads containing junctions of HPV6 and HPV16 and host genome suggestive of viral integration. HPV6 and HPV16 minor intratypic variants were present across pre‐ and post‐malignant transformation, with mostly nonsynonymous mutations.ConclusionsMultiple DNA viruses were present in IPs. HPV16 was detected only in IP‐SNSCCs or in tumors that later underwent malignant transformation.Level of Evidence3 Laryngoscope, 2024

Cutarelli A., De Falco F., Brunetti R., Napoletano M., Fusco G., Roperto S.

Virological evaluation was performed on equine semen to detect the presence of papillomaviruses (PVs) using droplet digital polymerase chain reaction (ddPCR) as the aim of this study was to investigate whether the sperm from asymptomatic stallions harbors ovine papillomaviruses (OaPVs). Twenty-seven semen samples were analyzed, 18 of which were commercially acquired. The remaining nine samples comprising semen and peripheral blood, were collected from nine stallions with no apparent signs of PV-related diseases during clinical examination at the Didactic Veterinary University Hospital (DVUH) of Naples. OaPV was detected in 26 semen samples. OaPV1 was the most prevalent virus infecting equine semen. OaPV1 infected 21 semen samples (~80.8%) and showed a high number of DNA and RNA copies per microliter. qPCR was used to detect OaPV1 DNA in the 18 semen samples. ddPCR was used to detect and quantify the expression of OaPV2, OaPV3, and OaPV4. qPCR failed to detect DNA for these genotypes. Additionally, ddPCR was used to detect the transcriptionally active OaPV1 in six blood and semen samples from the same stallion. ddPCR failed to detect any nucleic acids in OaPVs in peripheral blood samples from the three stallions. In one semen sample, ddPCR detected OaPV1 DNA but failed to detect any nucleic acid in the remaining two semen samples, and peripheral blood from the same animals of the remaining 18 semen samples was not available, OaPV1 and OaPV4 were responsible for nine and five single infections, respectively. No single infections with either OaPV3 or OaPV4 were seen.

Kwak J., Ahn D., Kim M.

Human papillomavirus (HPV) infection has emerged as an etiologic factor of squamous papilloma (SP). The oropharynx and larynx are common sites of SP, but studies on the prevalence of HPV infection in these sites are lacking. This study aimed to evaluate and compare the prevalence and characteristics of HPV infection in oropharyngeal SP (OPSP) and laryngeal SP (LSP). HPV detection and genotyping data of patients with pathologically confirmed OPSP and LSP were retrospectively analyzed. A total of 119 patients were enrolled, consisting of 93 patients with OPSP and 26 patients with LSP. Of those patients, 13 patients with OPSP and 14 patients with LSP were positive for HPV infection, accounting for a prevalence of 14.0% and 53.8%, respectively (p < 0.001). The most prevalent genotype was HPV16 in OPSP and HPV6 in LSP. Over two-thirds (69.2%) of HPV(+)-OPSP infections were high-risk types compared with 14.3% of HPV(+)-LSP infections (p = 0.004). The prevalence of HPV infection in patients with OPSP and LSP demonstrated no differences in terms of age, sex, and smoking status. These results could provide a better understanding of HPV infection in OPSP and LSP and serve as a background for the epidemiology of HPV-related tumorigenesis of the oropharynx and larynx.

De Falco F., Cutarelli A., Leonardi L., Marcus I., Roperto S.

There is very little information available about transplacental infections by the papillomavirus in ruminants. However, recent evidence has emerged of the first report of vertical infections of bovine papillomavirus (BPV) in fetuses from naturally infected, pregnant cows. This study reports the coinfection of BPV and ovine papillomavirus (OaPV) in bovine fetuses from infected pregnant cows suffering from bladder tumors caused by simultaneous, persistent viral infections. Some molecular mechanisms involving the binary complex composed of Eras and platelet-derived growth factor β receptor (PDGFβR), by which BPVs and OaPVs contribute to reproductive disorders, have been investigated. A droplet digital polymerase chain reaction (ddPCR) was used to detect and quantify the nucleic acids of the BPVs of the Deltapapillomavirus genus (BPV1, BPV2, BPV13, and BPV14) and OaPVs belonging to the Deltapapillomavirus (OaPV1, OaPV2, and OaPV4) and Dyokappapapillomavirus (OaPV3) genera in the placenta and fetal organs (heart, lung, liver, and kidneys) of four bovine fetuses from four pregnant cows with neoplasia of the urinary bladder. A papillomaviral evaluation was also performed on the bladder tumors and peripheral blood of these pregnant cows. In all fetal and maternal samples, the genotype distribution of BPVs and OaPVs were evaluated using both their DNA and RNA. A BPV and OaPV coinfection was seen in bladder tumors, whereas only BPV infection was found in peripheral blood. The genotype distribution of both the BPVs and OaPVs detected in placentas and fetal organs indicated a stronger concordance with the viral genotypes detected in bladder tumors rather than in peripheral blood. This suggests that the viruses found in placentas and fetuses may have originated from infected bladders. Our study highlights the likelihood of vertical infections with BPVs and OaPVs and emphasizes the importance of gaining further insights into the mechanisms and consequences of this exposure. This study warrants further research as adverse pregnancy outcomes are a major source of economic losses in cattle breeding.

Lamouroux C., Brochet L., Zrounba P., Charbotel B., Fervers B.

BackgroundWhile overall head and neck cancer incidence decreases due to reduced tobacco and alcohol consumption, the incidence of HPV negative oral cavity squamous cell carcinoma (SCC) is raising in several industrialized countries, especially in non-smoking and non-drinking patients.Case presentationWe document a case of gingiva SCC in a 56 years old never-smoker patient reporting low alcohol consumption and unusual occupational solvent exposure. The HPV-negative lesion was surgically removed in 2018, and the patient remains in complete remission 4 years after recurrent surgery in 2019. In 2021, the patient was referred to the occupational cancer consultation. The patient worked as screen printer for 18 years. He reported mouth siphoning every 2–3 days to transfer organic solvents (mainly aromatic hydrocarbons and ketones) from containers into smaller recipients, with regular passage of solvents into his mouth.ConclusionAccording to the literature, the frequency of solvent siphoning using mouth is likely to be underestimated. While our review did not find studies reporting longterm consequences to the oral cavity of mouth siphoning, current evidence supports a positive association of upper aero digestive tract SCC with occupational exposures to organic solvents and printing processes. In absence of major extraprofessional factors, the HPV-negative gingiva SCC of this patient might be attributable to the regular occupational oral solvent exposure. While the available evidence remains limited to formally establish a causal relationship, clinicians should investigate this hazardous work practice in patients with OSCC and history of solvent exposures.

Liu S., Wu J., Yang D., Xu J., Shi H., Xue B., Ding Z.

MER proto-oncogene tyrosine kinase (MerTK) is a key receptor for the clearance of apoptotic cells (efferocytosis) and plays important roles in redox-related human diseases. We will explore MerTK biology in human cells, tissues, and diseases based on big data analytics. The human RNA-seq and scRNA-seq data about 42,700 samples were from NCBI Gene Expression Omnibus and analyzed by QIAGEN Ingenuity Pathway Analysis (IPA) with about 170,000 crossover analysis. MerTK expression was quantified as Log2 (FPKM + 0.1). We found that, in human cells, MerTK is highly expressed in macrophages, monocytes, progenitor cells, alpha-beta T cells, plasma B cells, myeloid cells, and endothelial cells (ECs). In human tissues, MerTK has higher expression in plaque, blood vessels, heart, liver, sensory system, artificial tissue, bone, adrenal gland, central nervous system (CNS), and connective tissue. Compared to normal conditions, MerTK expression in related tissues is altered in many human diseases, including cardiovascular diseases, cancer, and brain disorders. Interestingly, MerTK expression also shows sex differences in many tissues, indicating that MerTK may have different impact on male and female. Finally, based on our proteomics from primary human aortic ECs, we validated the functions of MerTK in several human diseases, such as cancer, aging, kidney failure and heart failure. Our big data analytics suggest that MerTK may be a promising therapeutic target, but how it should be modulated depends on the disease types and sex differences. For example, MerTK inhibition emerges as a new strategy for cancer therapy due to it counteracts effect on anti-tumor immunity, while MerTK restoration represents a promising treatment for atherosclerosis and myocardial infarction as MerTK is cleaved in these disease conditions.

Channir H.I., Bendtsen S.K., Melchior L.C., Sandholm P.R., Mordhorst C., Carlander A.F., von Buchwald C., Kiss K.

Abstract Background The detection of human papillomavirus (HPV) has several implications in the diagnostic work-up and management of oropharyngeal squamous cell carcinoma (OPSCC). The choice of HPV detection assay and testing algorithms differ across institutions and vary in cost, detection targets, technical feasibility, and turnaround time. In this study, we aimed to validate the VisionArray® HPV Chip for formalin-fixed and paraffin-embedded (FFPE) samples of OPSCC using the previously applied standard pan-HPV DNA PCR assay as a reference. Methods The validation cohort consisted of FFPE tissue samples from patients previously diagnosed with HPV DNA-positive OPSCC (n = 80), HPV DNA-negative OPSCC (n = 21), and a benign group of tumor samples consisting of Warthin’s tumors (n = 20) and branchial cleft cysts of the lateral neck (n = 14). All samples were tested with p16 immunohistochemistry, pan-HPV DNA PCR, and the VisionArray® HPV Chip. Results The overall sensitivity and specificity of the VisionArray® HPV Chip assay were 100% [95% CI 95.5%; 100.0%] and 96.3% [95% CI 87.3%; 99.6%] and the positive predictive value and negative predictive value were 97.6% [95% CI 91.5%; 99.7%] and 100% [95% CI 93.2%; 100%], respectively. Conclusions The VisionArray® HPV Chip assay can be recommended for high-risk HPV testing in FFPE tissue samples from OPSCC, providing both a fast and simultaneous genotyping for 41 clinically relevant HPV types.

Malone J.C., Abrol R., Reep G.L., Othman M.O.

Esophageal squamous papilloma (ESP) is an uncommon, normally benign epithelial neoplasm with rare potential for malignant transformation. These lesions are oftentimes found incidentally on upper endoscopy and are typically managed with endoscopic excision, dissection, or ablation. However, there remains a paucity of published management guidelines in the current literature. We present a case of an older female who was found to have an extensive mid-esophageal ESP with recurrence despite endoscopic intervention. We highlight the multi-institutional management approach to her morphologically atypical ESP and the nuance involved in treating recurrent lesions of this type.

Liu D.

Human papillomaviruses (HPVs) are strictly epitheliotropic viruses with a circular double-stranded DNA genome of approximately 8 kb that harbors the early genes E1, E2, E4, E5, E6, and E7 and the late genes L1 and L2. HPVs (at least 227 types/genotypes identified to date) show disparate pathogenic capacity and are divided into low-risk (LR) and high-risk (HR) types. While LR HPV types cause benign proliferative lesions in human skin (warts or papillomas) and mucosa (condylomas), which rarely become malignant, HR HPV types often produce epithelial malignancies in various organs (e.g., the anus, vagina, vulva, ovary, uterine cervix, penis, oral cavity, and oropharynx). Indeed, HR HPV 16 and HPV 18 account for >80% of cervical cancer, while other HR HPV types (e.g., 31, 33, 45, and 58) are linked to cervical and anogenital cancers. Relying heavily on oncoproteins E6 and E7 that bind and degrade tumor suppressors p53 and pRB, respectively, HPVs demonstrate the capacity to modify host cell cycle for replication and persistence, to integrate into host cell genome for localized infection and subsequent tumorigenesis, and to modulate and evade host immune responses for enhanced survival. Despite the availability of several noninfectious vaccines, HPVs are far from under complete control. Additional research is warranted to improve our understanding on HPV interaction with human host, and to design innovative and effective prophylactive measures for eventual eradication of HPVs.

Rizzo A., Salari F., Eplite A., Giacomelli A., Moschese D., Dalu D., Cossu M.V., Lorusso R., Pozza G., Morelli L., Fasola C., Tonielli C., Fusetti C., De Cristofaro V., Gori A., et. al.

Kuan E.C., Wang E.W., Adappa N.D., Beswick D.M., London N.R., Su S.Y., Wang M.B., Abuzeid W.M., Alexiev B., Alt J.A., Antognoni P., Alonso‐Basanta M., Batra P.S., Bhayani M., Bell D., et. al.

AbstractBackgroundSinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represents a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology‐based topics spanning the field.MethodsIn accordance with prior ICAR documents, ICSNT assigned each topic as an Evidence‐Based Review with Recommendations, Evidence‐Based Review, and Literature Review based on level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses format, and completed sections underwent a thorough and iterative consensus‐building process. The final document underwent rigorous synthesis and review prior to publication.ResultsThe ICNST document consists of 4 major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology‐based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention.ConclusionAs an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.This article is protected by copyright. All rights reserved

Baudouin R., Hans S.