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

Viruses

2021 Jul 09

Carlander, A;Jakobsen, K;Bendtsen, S;Garset-Zamani, M;Lynggaard, C;Jensen, J;Grønhøj, C;Buchwald, C;
| DOI: 10.3390/v13071326

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

Clinicopathological and prognostic significance of immunophenotypic characterization of endocervical adenocarcinoma using CLDN18, CDH17, and PAX8 in association with HPV status

Virchows Archiv : an international journal of pathology

2021 Sep 28

Asaka, S;Nakajima, T;Ida, K;Asaka, R;Kobayashi, C;Ito, M;Miyamoto, T;Uehara, T;Ota, H;
PMID: 34581850 | DOI: 10.1007/s00428-021-03207-1

In 2020, the WHO published a new system for classifying invasive endocervical adenocarcinoma based on histological features and high-risk human papillomavirus (HPV) infection. However, immunophenotypes of each histological subtype require further investigation. We immunohistochemically analyzed 66 invasive endocervical adenocarcinomas using three cell-lineage-specific markers: claudin 18 (CLDN18) for gastric, cadherin 17 (CDH17) for intestinal, and PAX8 for Müllerian epithelial cells. We identified five immunophenotypes of endocervical adenocarcinoma: gastric (21%); intestinal (14%); gastrointestinal (11%); Müllerian (35%); and not otherwise specified (NOS) (20%). Adenocarcinomas with gastric immunophenotype, characterized by aging (p = 0.0050), infrequent HPV infection (p < 0.0001), concurrent lobular endocervical glandular hyperplasia (p = 0.0060), lymphovascular invasion (p = 0.0073), advanced clinical stage (p = 0.0001), and the poorest progression-free (p < 0.0001) and overall (p = 0.0023) survivals, were morphologically compatible with gastric-type adenocarcinoma of the WHO 2020 classification. Conversely, most adenocarcinomas with Müllerian (91%) and intestinal (89%) immunophenotypes were HPV associated and morphologically compatible with usual- or intestinal-type adenocarcinomas of the WHO 2020 classification. The morphology of adenocarcinomas with gastrointestinal immunophenotype was intermediate or mixed between those of gastric and intestinal immunophenotypes; 57% were HPV associated. Adenocarcinomas with NOS immunophenotype were mainly HPV associated (85%) and histologically poorly differentiated. Multivariate analysis revealed that gastric (p = 0.008), intestinal + gastrointestinal (p = 0.0103), and NOS (p = 0.009) immunophenotypes were independent predictors of progression-free survival. Immunophenotypes characterized by CLDN18, CDH17, and PAX8 exhibited clinicopathological relevance and may improve the diagnostic accuracy and prognostic value of conventional histological classification.

Role of HPV status and PD-L1 expression in prognosis of laryngeal squamous cell carcinoma

International journal of clinical and experimental pathology

2021 Jan 01

Yang, SM;Wu, M;Han, FY;Sun, YM;Yang, JQ;Liu, HX;
PMID: 33532028

Human papillomavirus (HPV) infection has been recognized as a cause of head and neck squamous cell carcinomas (HNSCC). Laryngeal squamous cell carcinoma (LSCC) is one of the most common pathologic types of HNSCC. Clinical trials show that there are differences in response to immunotherapy according to HPV status. It was reported that a high level of programmed cell death-ligand 1 (PD-L1) is correlated with better survival in HPV-positive head and neck cancer. In this study, we investigated the expression of PD-L1 in HPV-positive and HPV-negative LSCC to determine its prevalence and prognostic value. 52 cases of LSCC were collected from Tangshan Head and Neck Disease Pathology Research Base. PCR-reverse dot blot hybridization and RNAscope in situ hybridization were used to detect HPV status. PD-L1 expression was evaluated by immunohistochemistry and all cases were followed up for survival. SPSS24.0 was used for data entry and statistical analysis. Kaplan-Meier method and Log-rank time series analysis were used for single factor analysis. Multivariate analysis was performed using Cox proportional hazard regression model, and HR and 95% CI were calculated. Of the 52 LSCC patients, 32.7% (17/52) were HPV-positive by RNAscope in situ hybridization, and 51.9% (27/52) of patients were positive for PD-L1 expression by immunohistochemistry. Regression analysis showed that with a median follow-up period of 69 months, smoking and late stage were associated with poor overall survival (OS), whereas HPV positivity and PD-L1 expression showed a better overall survival outcome. Smoking status, tumor stage, HPV status, and PD-L1 expression in tumor cells may represent useful prognostic biomarkers in patients with LSCC. IJCEP

MEK/ERK signaling is a critical regulator of high-risk human papillomavirus oncogene expression revealing therapeutic targets for HPV-induced tumors

PLoS pathogens

2021 Jan 22

Luna, AJ;Sterk, RT;Griego-Fisher, AM;Chung, JY;Berggren, KL;Bondu, V;Barraza-Flores, P;Cowan, AT;Gan, GN;Yilmaz, E;Cho, H;Kim, JH;Hewitt, SM;Bauman, JE;Ozbun, MA;
PMID: 33481911 | DOI: 10.1371/journal.ppat.1009216

Intracellular pathogens have evolved to utilize normal cellular processes to complete their replicative cycles. Pathogens that interface with proliferative cell signaling pathways risk infections that can lead to cancers, but the factors that influence malignant outcomes are incompletely understood. Human papillomaviruses (HPVs) predominantly cause benign hyperplasia in stratifying epithelial tissues. However, a subset of carcinogenic or "high-risk" HPV (hr-HPV) genotypes are etiologically linked to nearly 5% of all human cancers. Progression of hr-HPV-induced lesions to malignancies is characterized by increased expression of the E6 and E7 oncogenes and the oncogenic functions of these viral proteins have been widely studied. Yet, the mechanisms that regulate hr-HPV oncogene transcription and suppress their expression in benign lesions remain poorly understood. Here, we demonstrate that EGFR/MEK/ERK signaling, influenced by epithelial contact inhibition and tissue differentiation cues, regulates hr-HPV oncogene expression. Using monolayer cells, epithelial organotypic tissue models, and neoplastic tissue biopsy materials, we show that cell-extrinsic activation of ERK overrides cellular control to promote HPV oncogene expression and the neoplastic phenotype. Our data suggest that HPVs are adapted to use the EGFR/MEK/ERK signaling pathway to regulate their productive replicative cycles. Mechanistic studies show that EGFR/MEK/ERK signaling influences AP-1 transcription factor activity and AP-1 factor knockdown reduces oncogene transcription. Furthermore, pharmacological inhibitors of EGFR, MEK, and ERK signaling quash HPV oncogene expression and the neoplastic phenotype, revealing a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression and treat HPV neoplasia.

High-risk human papillomavirus and ZEB1 in ocular adnexal sebaceous carcinoma

Journal of cutaneous pathology

2021 Mar 21

Moore, RF;Zhang, XR;Allison, DB;Rooper, LM;Campbell, AA;Eberhart, CG;
PMID: 33745190 | DOI: 10.1111/cup.13987

Ocular adnexal (OA) sebaceous carcinoma is an aggressive malignancy. Oncologic drivers of ocular sebaceous carcinoma are incompletely understood. A retrospective search of our pathology archives for OA sebaceous carcinoma identified 18 primary resection specimens. Immunohistochemistry for p16 and ZEB1 and RNA in situ hybridization for high-risk human papillomavirus (HPV) subtypes were performed. High-risk HPV was demonstrated in 2/11 (18%) cases. p16 overexpression was observed in 10/11 (91%). No association between gender, age at presentation, tumor location, intraepithelial spread, tumor size, and T stage was observed between HPV-driven and nonviral cases. High expression of ZEB1 was observed in the intraepithelial component of 4/14 (28%) cases and in the subepithelial component of 1/13 (7%) cases. ZEB1 overexpression was not associated with HPV-status, T stage, or tumor size. As previously described by others, our findings suggest that a subset of OA sebaceous carcinomas may arise via an HPV-dependent pathway. However, unlike high-risk HPV-driven carcinomas of the oropharynx, we did not identify an association between HPV-status and prognostic features. Furthermore, p16 expression was not a useful surrogate marker for HPV-driven disease. ZEB1 overexpression is not associated with HPV in our cohort of ocular sebaceous carcinoma.

A clinical analysis of oropharyngeal squamous cell carcinoma: a single-institution's experience

European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery

2022 Jan 03

Jiromaru, R;Yasumatsu, R;Yamamoto, H;Kuga, R;Hongo, T;Nakano, T;Manako, T;Hashimoto, K;Wakasaki, T;Matsuo, M;Nakagawa, T;
PMID: 34978590 | DOI: 10.1007/s00405-021-07236-z

We herein report the treatment outcome of oropharyngeal squamous cell carcinoma (OPSCC) at Kyushu University Hospital, the total number of OPSCC cases, and changes in the proportion of human papilloma virus (HPV)-related carcinomas over time.We performed a retrospective analysis of 237 cases treated for OPSCC at Kyushu University Hospital between 2013 and 2019. We performed HPV-mRNA in situ hybridization and p16 immunohistochemistry.This study included 197 males (82.1%) and 40 females (17.9%). The disease-specific, progression-free and overall survival (OS) were 69%, 62% and 61%, respectively, over the decade-long study period. p16-Immunohistochemistory and highrisk HPV mRNA in situ hybridization were positive in 114 (48.1%) and 105 (44.3%) cases, respectively. The number of HPV-related OPSCC cases increased according to an annual analysis. HPV+ cases had a significantly better prognosis than HPV- cases. In addition, p16+/HPV- cases had a significantly worse prognosis than p16+/HPV+ cases (OS: p = 0.0484). HPV+ OPSCC cases were associated with a younger age (< 60 years old) (p = 0.0429), non-smoker (p = 0.0001), lateral tumor site (< 0.00001), lymphoid metastasis (< 0.0001) and low clinical stage (< 0.0001).The frequency of HPV-related OPSCC cases is increasing in Japan as well as worldwide, and such cases are characterized by no smoking habit, a young age, and a good prognosis. Even in p16+ OPSCC, HPV- cases had a poor prognosis, suggesting the importance of accurate HPV determination. To determine the intensity of treatment for HPV-related and non-related OPSCC, it is necessary to accumulate cases for the accurate HPV determination and comparison of treatment effects.

Biologic and behavioral associations of estrogen receptor alpha positivity in head and neck squamous cell carcinoma

Oral oncology

2021 Jul 22

Drake, V;Bigelow, E;Fakhry, C;Windon, M;Rooper, LM;Ha, P;Miles, B;Gourin, C;Mandal, R;Mydlarz, W;London, N;Vosler, PS;Yavvari, S;Troy, T;Waterboer, T;Eisele, DW;D'Souza, G;
PMID: 34304004 | DOI: 10.1016/j.oraloncology.2021.105461

Tumor HPV status is an established independent prognostic marker for oropharynx cancer (OPC). Recent studies have reported that tumor estrogen receptor alpha (ERα) positivity is also associated with prognosis independent of HPV. Little is known about the biologic and behavioral predictors of ERα positivity in head and neck squamous cell cancer (HNSCC). We therefore explored this in a multicenter prospective cohort study.Participants with HNSCC completed a survey and provided a blood sample. Tumor samples were tested for ERα using immunohistochemistry. ERα positivity was defined as ≥1%, standardized by the American Society of Clinical Oncology/College of American Pathologists in breast cancer. Characteristics were compared with χ2 and Fisher's exact test. Odds ratios (OR) were calculated using logistic regression.Of 318 patients with HNSCC, one third had ERα positive tumors (36.2%, n = 115). Odds of ERα expression were significantly increased in those with HPV-positive tumors (OR = 27.5, 95% confidence interval[CI] 12.1-62), smaller tumors (≤T2, OR = 3.6, 95% CI 1.9-7.1), male sex (OR = 2.0, 95% CI 1.1-3.6), overweight/obesity (BMI ≥ 25, OR = 1.9, 95% CI 1.1-3.3), and those married/living with a partner (OR = 1.7, 95% CI 1.0-3.0). In a multivariate model, HPV-positivity (aOR = 27.5, 95% CI 11.4-66) and small tumor size (≤T2, aOR = 2.2, 95% CI 1.0-4.8) remained independently associated with ERα status. When restricted to OPC (n = 180), tumor HPV status (aOR = 17.1, 95% CI 2.1-137) and small tumor size (≤T2, aOR = 4.0 95% CI 1.4-11.3) remained independently associated with ERα expression.Tumor HPV status and small tumor size are independently associated with ERα expression in HNSCC.

Presence of Human Papillomavirus and Epstein–Barr Virus, but Absence of Merkel Cell Polyomavirus, in Head and Neck Cancer of Non-Smokers and Non-Drinkers

Frontiers in Oncology

2021 Jan 20

Mulder, F;Klufah, F;Janssen, F;Farshadpour, F;Willems, S;de Bree, R;zur Hausen, A;van den Hout, M;Kremer, B;Speel, E;
| DOI: 10.3389/fonc.2020.560434

ObjectiveDetermine the presence and prognostic value of human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCPyV), and cell cycle proteins in head and neck squamous cell carcinoma (HNSCC) of non-smokers and non-drinkers (NSND).MethodsClinical characteristics and tumors of 119 NSND with HNSCC were retrospectively collected and analyzed on tissue microarrays. RNAscope in situ hybridization (ISH) was used to screen for the presence of HPV and MCPyV mRNA. Immunohistochemistry was performed for expression of p16 as surrogate marker for HPV, Large T-antigen for MCPyV, and cell cycle proteins p53 and pRb. Positive virus results were confirmed with polymerase chain reaction. For EBV, EBV encoded RNA ISH was performed. Differences in 5-year survival between virus positive and negative tumors were determined by log rank analysis.ResultsAll oropharyngeal tumors (OPSCC) (n = 10) were HPV-positive, in addition to one oral (OSCC) and one nasopharyngeal tumor (NPSCC). The other three NPSCC were EBV-positive. MCPyV was not detected. Patients with HPV or EBV positive tumors did not have a significantly better 5-year disease free or overall survival. Over 70% of virus negative OSCC showed mutant-type p53 expression.ConclusionIn this cohort, all OPSCC and NPSCC showed HPV or EBV presence. Besides one OSCC, all other oral (n = 94), hypopharyngeal (n = 1), and laryngeal (n = 9) tumors were HPV, EBV, and MCPyV negative. This argues against a central role of these viruses in the ethiopathogenesis of tumors outside the oro- and nasopharynx in NSND. So, for the majority of NSND with virus negative OSCC, more research is needed to understand the carcinogenic mechanisms in order to consider targeted therapeutic options.

Dynamics of papillomavirus in vivo disease formation & susceptibility to high-level disinfection-Implications for transmission in clinical settings

EBioMedicine

2021 Jan 01

Egawa, N;Shiraz, A;Crawford, R;Saunders-Wood, T;Yarwood, J;Rogers, M;Sharma, A;Eichenbaum, G;Doorbar, J;
PMID: 33421945 | DOI: 10.1016/j.ebiom.2020.103177

High-level disinfection protects tens-of-millions of patients from the transmission of viruses on reusable medical devices. The efficacy of high-level disinfectants for preventing human papillomavirus (HPV) transmission has been called into question by recent publications, which if true, would have significant public health implications. Evaluation of the clinical relevance of these published findings required the development of novel methods to quantify and compare: (i) Infectious titres of lab-produced, clinically-sourced, and animal-derived papillomaviruses, (ii) The papillomavirus dose responses in the newly developed in vitro and in vivo models, and the kinetics of in vivo disease formation, and (iii) The efficacy of high-level disinfectants in inactivating papillomaviruses in these systems. Clinical virus titres obtained from cervical lesions were comparable to those obtained from tissue (raft-culture) and in vivo models. A mouse tail infection model showed a clear dose-response for disease formation, that papillomaviruses remain stable and infective on fomite surfaces for at least 8 weeks without squames and up to a year with squames, and that there is a 10-fold drop in virus titre with transfer from a fomite surface to a new infection site. Disinfectants such as ortho-phthalaldehyde and hydrogen peroxide, but not ethanol, were highly effective at inactivating multiple HPV types in vitro and in vivo. Together with comparable results presented in a companion manuscript from an independent laboratory, this work demonstrates that high-level disinfectants inactivate HPV and highlights the need for standardized and well-controlled methods to assess HPV transmission and disinfection. Advanced Sterilization Products, UK-MRC (MR/S024409/1 and MC-PC-13050) and Addenbrookes Charitable Trust.

HPV-16 Expression and Loss of Cell Differentiation in Primary Bladder Tumors

BioMed research international

2022 Oct 15

Pang, L;Ding, Z;Li, F;Chai, H;Wu, M;Shao, J;
PMID: 36281460 | DOI: 10.1155/2022/6565620

Primary bladder tumors have a high degree of malignancy. To investigate the expression of human papillomavirus type 16 (HPV-16) in primary bladder tumors and the loss of cell differentiation and to explore the significance of HPV-16 detection, it is expected to be a disease. Treatment provides a theoretical basis.Fifty-seven patients with primary bladder tumors admitted to our hospital from January 2019 to January 2022 were selected as the research subjects, and they were divided into HPV-related groups according to the human papillomavirus (HPV) infection status (n = 28) and HPV unrelated group (n = 29). The general data of patients were collected, the expression of HPV-16 in bladder tissue samples was detected, and the correlation between pathological parameters and HPV-16 expression was analyzed.Among HPV subtypes, HPV 16 subtype accounted for the highest proportion, followed by HPV-18 and HPV-6 subtypes; there was no significant difference in tumor stage (stage 1, stage a, stage 2a) between the HPV-related group and the HPV-unrelated group (stage 1, stage a, and stage 2a). P > 0.05); there was no significant difference in postoperative pathological expression (high expression and low expression) of patients (P > 0.05); there was no statistical difference in age and gender between HPV-related and HPV-unrelated groups (P > 0.05), HPV-related group and HPV-unrelated group compared daily regular drinking and smoking status, the difference was statistically significant (P < 0.05); HPV-16 expression was not correlated with tumor differentiation degree and age of patients (P > 0.05); the area under the curve (AUC) of HPV-16 for judging primary bladder tumor expression and cellular molecular deletion was 0.891, with a sensitivity of 83.94% and a specificity of 88.57%.HPV-16 is an upper, expressed in primary bladder tumors and will participate in the differentiation and loss of cells, which can provide effective guidance and basis for the diagnosis of primary bladder tumors, which is an important factor for judging the pathological stage and prognosis of patients and can provide a theoretical reference for the formulation of therapeutic measures.

Metastatic HPV-Mediated Adenocarcinoma Arising from a Base of Tongue Primary: A Case Report with Cytomorphology and Molecular Findings with Review of the Literature

Head and neck pathology

2022 Jan 11

Zheng, S;Magliocca, KR;Reid, MD;Kaka, AS;Lubin, D;
PMID: 35015191 | DOI: 10.1007/s12105-021-01407-4

Human papillomavirus (HPV)-mediated squamous cell carcinomas of the oropharynx are common, however only rare cases of HPV-mediated oropharyngeal adenocarcinoma have been reported to date. In this report, we describe a 50 year old nonsmoking male who originally presented with an enlarging neck mass. Fine needle aspiration cytology confirmed an HPV-mediated adenocarcinoma. Subsequent surgery identified a 0.7 cm base of tongue primary HPV-mediated carcinoma with focal glandular differentiation and a 4.0 cm cystic lymph node metastasis demonstrating entirely glandular differentiation. Next generation sequencing of the metastasis detected a pathogenic NOTCH1 mutation.

Oro- and Nasopharyngeal Papillomas with Squamous and Respiratory Features: A Case Series of Schneiderian-Like Papillomas of the Pharynx

Head and neck pathology

2021 Oct 25

Ababneh, EI;Shah, AA;
PMID: 34694538 | DOI: 10.1007/s12105-021-01389-3

There is limited literature detailing the histology of pharyngeal papillomas. Herein, we report our experience with papillomas occurring in the oro-and nasopharynx that have both squamous and respiratory features akin to the sinonasal Schneiderian papilloma. We retrospectively reviewed pharyngeal papillomas that were composed of both squamous and respiratory epithelium received at our institution between 2010 and 2020. Cases of sinonasal papillomas directly extending into the pharynx were excluded. Immunohistochemistry for p16 as well as RNA in situ hybridization to evaluate for 6 low-risk and 18 high-risk HPV genotypes were performed on all cases. Thirteen cases were included. Mean age was 61 with 12 males and 1 female. While often incidentally found, presenting symptoms included globus sensation, hemoptysis, and hoarseness of voice. Histologically, all tumors consisted of squamous and respiratory epithelium with neutrophilic infiltrates arranged in an exophytic/papillary architecture that was reminiscent of the exophytic type of Schneiderian papilloma. Immunohistochemistry for p16 was negative in all papillomas. 85% were positive for low-risk human papillomavirus (HPV) subtypes and all were negative for high-risk HPV subtypes. A well-differentiated, invasive squamous cell carcinoma was associated with two of the cases. Papillomas with squamous and respiratory features similar to the sinonasal exophytic Schneiderian papilloma can arise in the oro- and nasopharynx and like their sinonasal counterparts show an association with HPV. While many in this series were benign, they can be harbingers for invasive squamous cell carcinoma.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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