Significance Of Human Papillomavirus Research Articles

HPV16 E6 enhances the radiosensitivity in HPV-positive human head and neck squamous cell carcinoma by regulating the miR-27a-3p/SMG1 axis

BackgroundHead and neck squamous cell carcinoma (HNSCC) is the 6th most common malignant cancer type worldwide. Radiosensitivity has been shown to be significantly increased in patients with human papillomavirus (HPV)-positive HNSCC compared with HPV-negative patients. However, the clinical significance of HPV and its regulatory mechanisms in HNSCC are largely unknown. The aim of our study was to explore the regulatory mechanism of miR-27a-3p in the radiosensitivity of HPV-positive HNSCC cells.MethodsE6-overexpressing and E6-knockdown HNSCC cell lines were generated and the transfection efficiencies were evaluated by quantitative real-time PCR (RT-qPCR) and western blotting. The expression of miR-27a-3p and DiGeorge syndrome critical region 8 (DGCR8) was examined by RT-qPCR after transfection with E6 overexpressing plasmid or E6 siRNA. The effects of miR-27a-3p on the radiosensitivity of HNSCC cells were explored by a colony formation and TUNEL staining assays. Bioinformatic tools and luciferase reporter assays were used to identify that SMG1 is the direct target of miR-27a-3p. Furthermore, the effect of E6 overexpression on the regulation of the miR-27a-3p/SMG1 axis was investigated.ResultsIn our study, we found overexpression of HPV E6 upregulated the expression of DGCR8 and miR-27a-3p in HNSCC cells. We next confirmed that DGCR8 positively regulated the expression of miR-27a-3p in HNSCC cells. The luciferase reporter gene results verified that miR-27a-3p targeted the 3’UTR of SMG1 mRNA. MiR-27a-3p mimics transfection resulted in a decrease in SMG1 expression and miR-27a-3p inhibitor transfection increased SMG1 expression. Apoptotic activity of HNSCC cells was significantly increased in miR-27a-3p mimics HNSCC cells compared with control HNSCC cells. After treatment with 4 Gy irradiation, UM-SCC47 cells transfected with miR-27a-3p inhibitor or SMG1 overexpressing plasmid formed more colonies than the corresponding control cells. Furthermore, the rescue experiments demonstrated that HPV16 E6 improved the radiosensitivity of HNSCC cells by targeting miR-27a-3p/SMG1.ConclusionOur study demonstrated that HPV16 E6 activated the DGCR8/miR-27a-3p/SMG1 axis to enhance the radiosensitivity. Our findings might provide a novel therapeutic target to improve the response of HNSCC to radiotherapy.

Human Papillomavirus in Patients With Hypopharyngeal Squamous Cell Carcinoma.

Assess the testing rates and prognostic significance of human papilloma virus (HPV) status in hypopharynx malignancies. Historical cohort study. National Cancer Database. Review of the National Cancer Database was conducted between 2010 and 2017 for squamous cell carcinomas (SCCs) of the hypopharynx. We investigated how often the tumors were tested for HPV and whether it was associated with survival outcomes. A total of 13,269 patients with hypopharynx malignancies were identified. Most cases were not tested for HPV status (n = 8702, 65.6%). Of those tested, 872 (19.1%) were positive for HPV and 3695 (80.9%) were negative. The proportion of nonoropharyngeal SCCs tested for HPV increased nearly every year during the study, with roughly one-third of cases (31.9%) being tested in 2017. In the facilities classified as high-testing centers of nonoropharyngeal SCCs of the head and neck, 18.7% of hypopharyngeal tumors were HPV positive. HPV-negative status was associated with worse survival on multivariable analysis. In propensity score-matched analysis controlling for all factors significant in multivariable regression, 2-year survival remained higher in the HPV-positive cohort (77.7% vs 63.1%, P < .001). HPV-positive tumors constitute a sizable minority of hypopharynx tumors and are associated with improved survival. Expansion of HPV testing to hypopharynx malignancies may be warranted.

Prognostic significance of human papilloma virus (HPV) in penile cancer: A National Cancer Database (NCDB) study.

5 Background: HPV is associated with 30 - 50% of penile cancers, with some studies showing improved outcomes in these patients. This study evaluated the effect of HPV infection on penile cancer outcomes. Methods: The national cancer database (NCDB) was utilized to identify HPV tested penile cancer patients at the time of diagnosis from 2004 – 2016. Chi-squared tests and Cox regression models were used in analysis. Results: Out of 486 patients with penile squamous cell cancer, 139 (29%) were HPV +ve, and 347 (71%) were HPV -ve. Greater than 50% of HPV +ve were &lt; 65 years old, Caucasian, from low-income areas ( &lt; $48,000), and had public or no insurance. Similar incidence patterns were noted in HPV- ve patients. 77% pts who were HPV +ve had a moderate to poorly differentiated tumor. Most HPV +ve presented with early-stage cancer, and 12% were stage IV at diagnosis. 5-year overall survival (OS) was better among HPV +ve 62% vs. 50% in HPV -ve patients. Multivariable analysis (MVA) shows superior survival among patients with age &lt; 65 years, low comorbidity score (0-1), and earlier stage at diagnosis. Patients with HPV +ve adjusted for age, comorbidities, stage, and treatment showed significantly improved survival. HPV -ve patients had 1.49 times increased risk of death compared to HPV +ve. Conclusions: HPV positive penile cancer is associated with significantly improved survival independent of age, comorbidities, stage, and treatment modality. This study reiterates the prognostic significance of HPV status and testing for HPV status at diagnosis should be a standard practice. [Table: see text]

Knowledge, attitude and practice study about HPV and its vaccination among medical college students in North India

Background: Cervical cancer is one of the most important cancers in women. Cervical cancer is primarily caused by sexually transmitted human papilloma virus (HPV) infection. It has been proven that HPV vaccination, preferably before initiation of sexual life, is highly effective in HPV and cervical cancer prevention. So, this study was conducted to study the knowledge, attitude and practice about the significance of HPV and its vaccination among medical students. Methods: This was a cross-sectional observational study conducted in a medical college. 200 medical students were requested to fill a questionnaire which covered demographic details, knowledge, attitude and practice towards HPV vaccination for cervical cancer prevention. Results: Majority of the students knew that HPV may cause cancer in humans (94%), leading to cervical cancer in females (84.5%) and about the availability of its vaccine in India (79%). But only a few students were aware that it may even lead to cancer in males (52.5%), knew the correct dosing schedule (60%) and that even vaccinated female may develop cancer (36.5%). 74.5% considered its vaccine to be safe, 71.5% considered it effective and 68% considered it protective against sexual partner. Only 33.5% were vaccinated but 92.5% said that they would recommend HPV vaccine to their family. Conclusions: Though the knowledge and attitude about the significance of HPV and its vaccination is good among the medical college students, but the practice of vaccination is poor.

The prognostic significance of human papilloma virus in sinonasal squamous cell carcinoma.

BackgroundHuman papilloma virus (HPV) has been implicated in the pathology of oropharyngeal head and neck cancers, but its role in sinonasal squamous cell carcinoma (SNSCC) has not been well established.MethodsThirty‐two patients with SNSCC diagnosed between 2011 and 2018 were identified and stratified by HPV status and viral serotype, as determined by PCR. Endpoints including recurrence, metastases and survival were analyzed using the Kaplan‐Meier method.ResultsSeventeen (53%) patients were HPV‐positive and 15 (47%) were HPV‐negative. The median follow‐up time of living patients was 30.7 months (range 4‐123 months). Survival did not differ by HPV status, but HPV+ tumors were more likely to locally recur and metastasize. When stratifying by treatment type, the lowest rate of recurrence occurred in patients receiving surgery and chemoradiation.ConclusionA significant proportion of sinonasal tumors appear to be associated with HPV. Testing for HPV might be justified in all cases of sinonasal cancers. Further investigation is warranted to better understand the role of HPV in SNSCC.

Survival of patients with oropharyngeal squamous cell carcinomas (OPSCC) in relation to TNM 8 – Risk of incorrect downstaging of HPV-mediated non-tonsillar, non-base of tongue carcinomas

BackgroundTNM-8 staging separates oropharyngeal squamous cell carcinomas (OPSCC) into human papillomavirus (HPV)-mediated and -unrelated OPSCC based on p16INK4a overexpression (p16+), as surrogate marker for HPV. However, OPSCC is histologically and clinically heterogenous including tonsillar and base of tongue squamous cell carcinomas (TSCC and BOTSCC respectively), and carcinomas of soft palate and walls (otherOPSCC). The significance of HPV is established in TSCC/BOTSCC, while its role in otherOPSCC is unclear, which is not considered in TNM-8. Here, p16+ was therefore evaluated in relation to overall survival (OS) and tumor stage per OPSCC subsite. Patients and methodsAll 932 patients, treated with curative intent in Stockholm 2000–2016 with OPSCC, previously analyzed for p16 expression, were included. Clinical data, including stage and OS, was collected retrospectively. ResultsPatients with p16+ otherOPSCC had significantly poorer OS compared to patients with p16+ TSCC/BOTSCC (p = 0.005) and their survival was similar to that of patients with p16-otherOPSCC/TSCC/BOTSCC. Moreover, patients with TNM-8 stage I-II and p16+ otherOPSCC had a significant poorer OS compared to patients with p16+ TSCC/BOTSCC and similar stage (p = 0.02). Lastly, patients with otherOPSCC and low TNM-7 stage had a significant better OS, as compared to those with a high stage (p = 0.019) while no hazard discrimination was observed with TNM-7 in TSCC/BOTSCC. ConclusionOur results indicate a risk of misclassification of patients with otherOPSCC and low TNM-8 stage. We suggest that p16 should only be evaluated in TSCC/BOTSCC and that patients with otherOPSCC should all be staged as patients with HPV-unrelated (p16-) OPSCC.

Evaluation of p16 in Epithelial Ovarian Cancer for a 10-Year Study in Northeast China: Significance of HPV in Correlation with PD-L1 Expression.

BackgroundHuman papillomavirus (HPV) is a high-risk etiological factor for cervical and ovarian carcinomas. p16 protein can be used as a surrogate biomarker for HPV infection in high-risk tumors. A strong correlation between HPV infection and programmed death ligand 1 (PD-L1) protein expression has consistently been reported.ObjectiveGiven this background, this study investigates the prevalence, prognostic and clinicopathologic features of HPV-related epithelial ovarian cancer (EOC) for the last 10 years in Northeast China to elucidate the involvement of p16 in the PD-L1 protein expression, tumorigenesis, and progression of EOC.MethodsSpecimens from 310 patients diagnosed with EOC collected from 2006 to 2016 were analyzed by polymerase chain reaction (PCR) for HPV DNA, and overexpression of p16 by immunohistochemistry was also evaluated. Statistical analysis was performed to estimate the significant difference between HPV positive and negative patients, the correlation among HPV state, p16 and PD-L1 expression, and clinical presentation.ResultsOverexpression of p16 protein and HPV DNA were present in 100 (32.3%) of the 310 cases, and correlated with high PD-L1 expression. There was a good concordance between HPV positivity, p16 protein overexpression and PD-L1 expression. The etiological fraction of HPV in EOC is substantially higher in Northeast China than other cohorts previously reported.ConclusionOur study demonstrates that HPV infection and p16 overexpression is significantly associated with PD-LI expression in EOC, through the cooperative roles of dendritic cells (DCs) and IFN-γ, which may represent a promising strategy for therapeutic intervention in EOC.

Clinical significance of human papillomavirus 16/18 E6 protein detection in shunting and prognosis of patients with atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions

Objective To evaluate the value of human papillomavirus (HPV) 16/18 E6 protein detection in shunting and prognosis in patients with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL). Methods A total of 98 patients with ASCUS or LSIL from the Affiliated Cancer Hospital of Shanxi Medical University between May 2014 and May 2015 were selected as the subjects. All of them received the thin-cytologic test (TCT), HPV DNA, HPV16/18 E6 protein tests and colposcopy examination. After 3-year follow-up of patients with cervical intraepithelial neoplasia (CIN) grade Ⅰor bellow lesions diagnosed by biopsy and 30 negative controls, the above tests were performed again. The efficacies of all the tests were analyzed. The value of CIN grade Ⅱ or above was predicted. Results The sensitivity, specificity, positive predictive value and negative predictive value in predicting CIN grade Ⅱ or above lesions of HPV16/18 E6 protein, HPV DNA and HPV16/18 DNA was 30.8%, 95.3%, 50.0%, 90.0%, respectively; 84.6%, 37.6%, 17.2%, 94.1%, respectively and 61.5%, 67.1%, 22.2%, 91.9%, respectively in shunting study. The relative risk (RR) of CIN grade Ⅱor above lesions in patients with positive HPV16/18 E6 protein, persistent positive HPV16/18 DNA and positive HPV16/18 DNA was 13.429, 10.231 and 8.343, respectively in the follow-up study. Odds ratio (OR) of HPV16/18 E6 positive protein presenting persistent positive HPV16/18 DNA was 34.833 (95% CI 5.020-241.711). Conclusions In patients with ASCUS and LSIL, the specificity and positive predictive value of HPV16/18 E6 protein in predicting CIN grade Ⅱ or above lesions are higher than those of HPV DNA and HPV16/18 DNA. Moreover, these patients with HPV16/18 E6 protein positive have a higher risk of developing CIN grade Ⅱ or above lesions and persistent positive HPV16/18 DNA. Key words: Atypical squamous cells of undetermined significance; Low-grade squamous intraepithelial lesions; Human papillomavirus 16; Human papillomavirus 18; E6 protein

Prognostic Significance of Human Papilloma Virus and p16 Expression in Patients with Vulvar Squamous Cell Carcinoma who Received Radiotherapy

AimsHuman papilloma virus (HPV) has been identified as an aetiological agent in a subset of patients with vulvar squamous cell carcinoma (VSCC). The prognostic role of HPV status in VSCC patients treated with radiotherapy has not yet been determined. We investigated the associations between HPV, p16 and clinical outcome in these women. Materials and methodsPatients undergoing potentially curative radiation treatment for VSCC at a single institution from 2000 to 2009 were retrospectively identified. Those who received definitive or peri-operative radiotherapy as part of treatment, and who had available pathological specimens, were included for analysis. HPV infection was detected using Roche Linear array hybridisation and p16 by immunohistochemistry. The locoregional relapse (LRR) rate was estimated using a cumulative incidence function to account for competing risks. Disease-free survival (DFS) and overall survival were analysed using the Kaplan–Meier method. The median follow-up was 4.9 years. ResultsForty patients were suitable for analysis, with a median age of 69.5 years. HPV was detected in 14/40 (35%) patients, HPV16 being the most common serotype (79%). Patients with HPV-positive tumours had lower 5 year LRR compared with those with HPV-negative tumours (14.3% versus 79.3%, Gray test P = 0.003). Tumour p16 positivity was also associated with lower 5 year LRR (15.4% versus 81.2%, Gray test P = 0.002). Patients with p16-positive tumours had higher 5 year DFS compared with those with p16-negative tumours (62% versus 7%, Log-rank test P = 0.02). ConclusionsWe have identified a favourable prognostic group in VSCC, with p16-positive patients showing improved outcomes. p16 has the potential to be a predictive marker allowing the identification of women more likely to have a favourable response to radiotherapy.

Influence of human papillomavirus on the clinical presentation of oropharyngeal carcinoma in the United States.

Much of what is known about the significance of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma is derived from single-institution retrospective studies, post hoc analyses of tissue specimens from clinical trials, and tissue bank studies with a small sample size. The objective of this study is to investigate the impact of HPV on the frequency and clinical presentation of oropharyngeal carcinoma in a large, national sample with information from patients who underwent HPV testing. Retrospective, cross-sectional study. We identified a comprehensive national sample of 8,359 patients with oropharyngeal carcinoma and known HPV status diagnosed between 2010 and 2011 within the National Cancer Database. Multivariable logistic regression was used to assess correlates of patient and tumor characteristics on HPV status. Among patients with oropharyngeal carcinoma, the frequency of HPV-related squamous cell carcinoma in the United States was 65.4%. HPV-related oropharyngeal carcinoma was associated with younger age, male sex, and white race (P < 0.001). Advanced primary tumor stage was associated with HPV-negative disease (P < 0.001), whereas increasing nodal burden was associated with HPV-positive disease (P < 0.001). Despite less-advanced nodal disease, HPV-negative tumors were associated with a higher likelihood of metastasis at presentation (P < 0.001). HPV now accounts for the majority of newly diagnosed oropharyngeal carcinoma in the United States and is associated with a distinct clinical profile, supporting efforts to re-evaluate the staging and treatment paradigm for HPV-associated oropharyngeal cancer. 4. Laryngoscope, 127:2270-2278, 2017.

The ratio of CD4/CD8 T-cells in human papillomavirus-positive laryngeal squamous cell carcinoma accounts for improved outcome

Conclusion: Improved prognosis associated with HPV-positive status may depend on lower CD4/CD8 ratio. Th1 CD4+ T cells were found to be the major sub-set of T lymphocytes in the HPV positive laryngeal squamous cell carcinoma microenvironment. Background: To examine the prognostic significance of human papillomavirus (HPV) status in relation to the ratio of CD4/CD8 in LSCC. Methods: In this study, 46 LSCC biopsy samples were retrospectively assessed using immunohistochemistry for CD4+ and CD8+ tumor infiltrating lymphocytes (TILs). HPV status was determined by HPV in situ hybridization (ISH) and p16INK4A immunohistochemistry. Of the 46 samples, 21 were evaluated for the expression of IFN-γ and IL-4 by quantitative real-time PCR (qRT-PCR). The influence of HPV status on locoregional tumor control and T-cell sub-sets infiltrating tumor microenvironment were investigated. Results: Nineteen patients (41.3%) were classified as HPV positive, who had improved disease-free survival (28% in reduction, hazard ratio =0.10; 95% CI =0.011–0.938). A direct correlation between the HPV status and the ratio of CD4/CD8 or mean levels of CD8+ T cells was observed. Compared with the HPV-negative samples, HPV-positive samples had a higher ratio of IFN-γ/IL-4 (24.43 ± 29.89 vs 3.90 ± 4.03; p = 0.0375).

Abstract 3834: Validation of potential methylation biomarkers in HPV-associated HNSCC

Abstract Epidemiological and laboratory evidence indicate the human papilloma virus (HPV) as a causative agent for some squamous head and neck cancer (HNSCC). The biologic significance of HPV as independent risk factor is also underscored by the improved prognosis for patients with HPV positive HNSCC relative to HPV negative HNSCC, due in part to a better therapeutic response to chemoradiotherapy. The mechanism for this improved prognosis remains underexplored. To assess the potential of HPV specific methylation biomarkers, we evaluated the status of 10 genes (CDH8, CRMP1, HTRE1, ELMO1, MEI1, MSX2, PCDH10, PCDHB11, C14orf162, and PITX2) in a cohort of 18 HPV positive and 14 HPV negative HNSCC using targeted sequencing (Illumina MiSeq). The genes were previously reported as significantly differentially methylated between HPV positive and HPV negative HNSCC using the Infinium HumanMethylation450 BeadChip (Lechner et al., 2013). In our sample, of the 10 genes, targeted sequencing confirmed significant differential methylation between HPV positive and negative for C14orf162 (p = 0.007), MEI1(p = 0.004), MSX2 (p = 0.002), and PCDHB11(p = 0.002). PCDHB11 and MSX2 were hypermethylated; MEI1 and C14orf162 were hypomethylated, concordant with the Lechner et al., study. In this independent sample set, confirmation of 4 of the 10 genes as differentially methylated in HPV positive vs HPV negative HNSCC with concordance of methylation direction (hypo- vs hypermethylated), validates their potential for differentiating HPV positive and HPV negative HNSCC. Cadherins are implicated in tumor progression and metastasis and are targets of the Polycomb group (PcG) proteins, which form chromatin-modifying complexes that are essential for embryonic development and stem cell renewal and are commonly deregulated in cancer. Our study further supports cadherin PCDHB11, together with C14orf162, MEI1, and MSX2 as likely biomarkers in HPV-associated HNSCC. Support: Komen KG110218 Citation Format: Kang Mei Chen, Josena K. Stephen, George Divine, Dhananjay Chitale, Tamer Ghanem, Steven Chang, Maria J. Worsham. Validation of potential methylation biomarkers in HPV-associated HNSCC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3834. doi:10.1158/1538-7445.AM2015-3834

Significance of Human Papillomavirus in Head and Neck Cancers.

Significance of Human Papillomavirus in Head and Neck Cancers.

P31 Prevalence of human papillomavirus in laryngeal and hypopharyngeal squamous cell carcinomas

Background Recent studies support a role for human papillomavirus (HPV) in oropharyngeal squamous cell carcinomas (SCCs); however, the significance of HPV in non-oropharyngeal head and neck cancers is uncertain. In addition, the incidence varies widely depending on the geographic location and time period studied. The aim of this study was to determine the prevalence of HPV in a large cohort of oropharyngeal, laryngeal and hypopharyngeal SCCs in northern Spain. Methods Clinical records and paraffin-embedded tumor specimens of consecutive patients surgically treated for oropharyngeal (248 cases), laryngeal (62 cases) and hypopharyngeal (62 cases) SCCs between 1990 and 2009 were retrieved. All cases were histologically evaluated, and presence of HPV was assessed by p16INK4A-immunohistochemistry followed by GP5+/6+-PCR-based DNA detection. Samples positive in both assays were subjected to HPV genotyping and HPV E6 transcript analysis. Results Immunostaining of p16 INK4A was positive for 30/248 (12%) oropharyngeal, 14/62 (23%) laryngeal and 3/62 (5%) hypopharyngeal SCC. Subsequent GP5+6+-PCR on these cases showed presence of HPV type 16 DNA in 8 (3.2%) oropharyngeal and in 1 case (1.6%) each of larungeal and hypopharyngeal SCC. Conclusions Patients in northern Spain demonstrated a low HPV involvement in oropharyngeal SCC patients in northern Spain is very low and occurs only occasionally in laryngeal and hypopharyngeal SCC.

Prevalence of human papillomavirus in laryngeal and hypopharyngeal squamous cell carcinomas in northern Spain

BackgroundRecent studies support a role for human papillomavirus (HPV) in oropharyngeal squamous cell carcinomas (SCCs); however, the significance of HPV in non-oropharyngeal head and neck cancers is uncertain. The aim of this study was to determine the prevalence of HPV in a large cohort of laryngeal and hypopharyngeal SCCs in northern Spain. Materials and methodsClinical records and paraffin-embedded tumor specimens of 124 consecutive patients surgically treated for laryngeal (62 cases) and hypopharyngeal (62 cases) SCCs between 2002 and 2007 were retrieved. All cases were histologically evaluated, and presence of HPV was assessed by p16-immunohistochemistry followed by GP5+/6+-PCR-based DNA detection. Samples positive in both assays were subjected to HPV genotyping and HPV E6 transcript analysis. ResultsSeventeen cases (14%) were positive for p16 immunostaining, of which 2 (1 larynx, 1 hypopharynx, 1.6% of total series) were found positive for HPV DNA by subsequent GP5+6+-PCR. Both SCCs contained HPV type 16 and showed HPV16 E6 mRNA expression. ConclusionsHPV is only occasionally involved in laryngeal and hypopharyngeal SCC patients in northern Spain.

Human papillomavirus and Epstein–Barr virus in nasopharyngeal carcinoma in a low‐incidence population

The significance of human papillomavirus (HPV) in nasopharyngeal carcinomas (NPCs) in a low-incidence population remains unknown. Samples from 90 patients with NPC (years, 1957-2012) were analyzed for Epstein-Barr virus (EBV). Clinical data, EBV, HPV, and p16 status were correlated with overall survival (OS; 63 cases; years, 1981-2012). Of 9 HPV-positive cases, 3 extended from extra-nasopharyngeal sites. Nasopharyngeal origin was confirmed in 6 cases. HPV-positive NPC had OS similar to EBV-positive NPC (85 vs 141 months; p > .05). The OS of patients with EBV/HPV-negative NPC was worse (34 months; p = .004). Nonkeratinizing histology was associated with better outcome than keratinizing (115 vs 25 months; p = .001). Over the last several decades, the proportion of keratinizing NPC decreased from 34.5% to 14.3% (p = .026). The etiologic role of HPV in NPC is confirmed. The favorable prognostic significance of HPV positivity is similar to that of EBV positivity.

Detection and significance of human papillomavirus, CDKN2A(p16) and CDKN1A(p21) expression in squamous cell carcinoma of the larynx

Although a strong etiologic relationship between human papillomavirus (HPV) and a majority of oropharyngeal squamous cell carcinomas has been established, the role of HPV in non-oropharyngeal head and neck carcinomas is much less clear. Here, we investigated the prevalence and clinicopathologic significance of HPV and its reported biomarkers, CDKN2A(p16) and CDKN1A(p21), in laryngeal squamous cell carcinomas in patients treated either with primary surgery and postoperative radiation or with definitive radiation-based therapy. Nearly all of 76 tumors were keratinizing and none displayed the nonkeratinizing morphology that is typically associated with HPV infection in the oropharynx. However, CDKN2A(p16) immunohistochemistry was positive in 21 cases (28%) and CDKN1A(p21) in 34 (45%). CDKN2A(p16) and CDKN1A(p21) status strongly correlated with each other (P=0.0038). Yet, only four cases were HPV positive by DNA in situ hybridization or by reverse transcriptase PCR E6/E7 mRNA (all four were CDKN2A(p16) and CDKN1A(p21) positive). Unexpectedly, 9 additional tumors out of 20 CDKN2A(p16) positive cases harbored high-risk HPV DNA by PCR. For further investigation of this unexpected result, in situ hybridization for E6/E7 mRNA was performed on these nine cases and all were negative, confirming the absence of transcriptionally active virus. Patients with CDKN1A(p21)-positive tumors did have better overall survival (69% at 3 years) than those with CDKN1A(p21)-negative tumors (51% at 3 years) (P=0.045). There was also a strong trend towards better overall survival in the CDKN2A(p16)-positive group (P=0.058). Thus, it appears that the role of HPV is more complex in the larynx than in the oropharynx, and that CDKN2A(p16) and CDKN1A(p21) expression may not reflect HPV-driven tumors in most cases. Because of this, CDKN2A(p16) should not be used as a definitive surrogate marker of HPV-driven tumors in the larynx.

The Prognostic Significance of Human Papilloma Virus and P16 in Patients With Vulvar Squamous Cell Carcinoma Treated With Radiation Therapy

The Prognostic Significance of Human Papilloma Virus and P16 in Patients With Vulvar Squamous Cell Carcinoma Treated With Radiation Therapy

Human papillomavirus: a predictor of better survival in ocular surface squamous neoplasia patients

BackgroundAlthough human papillomavirus (HPV) has been implicated in the pathogenesis of ocular surface squamous neoplasia (OSSN), no study has so far dealt with the prognostic role of HPV. In this...

Human Papillomavirus in Non-Oropharyngeal Head and Neck Cancers: A Systematic Literature Review

Perhaps one of the most important developments in head and neck oncology of the past decade is the demonstration that patients with human papillomavirus (HPV)-mediated oropharyngeal cancers have significantly improved outcomes, compared to HPV-negative counterpart patients. This has become the basis for clinical trials investigating the impact on "treatment deintensification" for patients with HPV-mediated oropharyngeal cancers. Unfortunately, the significance of HPV in non-oropharyngeal head and neck cancers is much less certain. Our goal is to systematically review the published data regarding the role HPV in carcinomas of the oral cavity, larynx, sinonasal tract and nasopharynx with respect to HPV detection frequency, viral activity, and association with outcome. We also present preliminary data on HPV16/18 transcriptional status in oral cavity carcinomas, as well as salivary gland neoplasia, as determined by nested reverse transcription PCR for HPV E6/E7 RNA. The weighted prevalence (WP) of HPV DNA detection in 4,195 oral cavity cancer patients is 20.2 %, (95 % CI 16.0 %, 25.2 %). HPV16 is the most common type detected. Importantly, no data currently demonstrates a significant association between the presence of HPV DNA and improved outcome. The WP of HPV DNA in 1,712 laryngeal cancer patients is 23.6 %, (95 % CI 18.7 %, 29.3 %). Similarly, no association has yet been demonstrated between HPV DNA status and outcome. The WP of HPV DNA detection in 120 sinonasal cancer patients is 29.6 % (95 % CI 17.8 %, 44.9 %), and in 154 nasopharyngeal carcinoma patients is 31.1 %, (95 % CI 20.3 %, 44.5 %). Recent preliminary data also suggests an association between HPV and certain salivary gland neoplasms. The clinical significance of these findings is unclear. The published data strongly support the need for studies on patients with oral and laryngeal carcinomas that will be powered to find any differences in clinical outcome with respect to HR-HPV and p16 overexpression.