Human Papillomavirus-related Oropharyngeal Carcinoma Research Articles

Impact of Tumor-Infiltrating Lymphocytes on Disease Progression in Human Papillomavirus-Related Oropharyngeal Carcinoma.

We aim to explore the prognostic value of tumor-infiltrating lymphocytes (TILs) in the primary tumor and metastatic lymph nodes of patients with HPV(+)OPSCC. We hypothesize that TILS density at both sites is associated with disease-free survival in HPV(+)OPSCC. Matched case-control study among HPV(+)OPSCC patients who underwent intent-to-cure surgery. Cases developed locoregional or distant recurrence. Controls were matched based on age, sex, pathologic T, N, and overall stage, year of surgery, type of adjuvant treatment received, and the Adult Comorbidity Evaluation-27 (ACE-27) score. Single tertiary care center, May 2007 to December 2016. Tumoral TILs (tTILs) density was defined as % TILs; stromal TILs (sTILs) density was defined as absent/sparse or moderate/dense crowding. Associations between TILs and time to disease progression were assessed using Cox regression models. Forty-four case-control pairs (N = 88) were included: 42 (48%) AJCC pStage I, 39 (44%) pStage II, and 7 (8%) pStage III. tTILs density ≥10% (hazard ratio [HR] 0.41, 95% confidence interval [CI] 0.17-0.99, p = .048) and a moderate/dense sTILs density (HR 0.21, 95% CI 0.06-0.75, p = .016) in the primary tumor were significantly associated with decreased risk of progression. TILs density in the lymph node was associated with decreased risk of progressionbut did not reach statistical significance. The tTILs and sTILs density correlated strongly between the primary tumor and lymph node. Concordance between the pathologists' was moderate (60%-70%). In HPV(+)OPSCC, a higher density of tumoral and stromal TILs in the primary tumor and possibly the lymph node may predict a lower risk of disease progression.

Human papillomavirus-related oropharyngeal carcinoma.

It was not until around 2000 that human papillomavirus-related oropharyngeal carcinoma was recognized as carcinoma with clinical presentations different from nonrelated head and neck carcinoma. Twenty years after and with the revision of the tumor-node-metastasis classification in 2017, various clinical trials focused on human papillomavirus-related oropharyngeal carcinoma to improve the prognosis and quality of life of patients with this disease. However, the incidence of human papillomavirus-related cancers is increasing, which is expected to be particularly prominent in Japan, where human papillomavirus vaccination is not widely available. In this review, we describe the current status of clinical trials (mainly focused on initial surgery and radiation dose reduction) for, primary and secondary prevention of, and the present status of human papillomavirus-related oropharyngeal carcinoma in Japan.

Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers

Although promoter-associated CpG islands have been established as targets of DNA methylation changes in cancer, previous studies suggest that epigenetic dysregulation outside the promoter region may be more closely associated with transcriptional changes. Here we examine DNA methylation, chromatin marks, and transcriptional alterations to define the relationship between transcriptional modulation and spatial changes in chromatin structure. Using human papillomavirus-related oropharyngeal carcinoma as a model, we show aberrant enrichment of repressive H3K9me3 at the transcriptional start site (TSS) with methylation-associated, tumor-specific gene silencing. Further analysis identifies a hypermethylated subtype which shows a functional convergence on MYC targets and association with CREBBP/EP300 mutation. The tumor-specific shift to transcriptional repression associated with DNA methylation at TSSs was confirmed in multiple tumor types. Our data may show a common underlying epigenetic dysregulation in cancer associated with broad enrichment of repressive chromatin marks and aberrant DNA hypermethylation at TSSs in combination with MYC network activation.

Clinical features of death cases in human papillomavirus related oropharyngeal carcinoma

Clinical features of death cases in human papillomavirus related oropharyngeal carcinoma

Nodal response after 46 Gy of intensity‐modulated radiotherapy is associated with human papillomavirus–related oropharyngeal carcinoma

This study aimed to analyze the effect of human papillomavirus (HPV)-associated T1-2 node-positive oropharyngeal squamous cell carcinoma (OPSCC) on nodal response, recurrent disease, and survival in patients treated according to the Rotterdam protocol. Retrospective cohort study. In total, 77 patients with T1-2 OPSCC with nodal disease, treated between 2000 and 2012, were included in this study. Patients were treated according to the Rotterdam protocol: 46 Gy of IMRT followed by a local boost using cyberknife or brachytherapy (22 Gy) and neck dissection. The presence of HPV was determined by p16INK4A immunostaining. Outcomes were overall survival, disease-free survival, and the extent of nodal response. Nodal stage was determined following the 7th and 8th American Joint Cancer Committee/Union for International Cancer Control classification. Overall, 68.4% of patients had p16-positive disease, and 35.4% of all patients achieved complete nodal response (pN0) after 46 Gy of intensity-modulated radiotherapy (IMRT). Based on the 7th TNM classification, nodal response (partial or complete) was significantly associated with HPV status (P = .002). Patients with p16-positive OPSCC had an odds ratio (OR) of 4.6 to achieve complete nodal response. However, smoking interacted with this effect. Applying the 8th TNM classification, complete or partial response was associated with HPV status but was not significant (OR: 1.7, P = .138). Complete nodal response led to 100% overall survival in p16-positive OPSCC patients. HPV-related OPSCCs are associated with complete nodal response after 46 Gy of IMRT. Patients with full regional control (pN0) after IMRT and subsequent neck dissection show a significantly better overall survival, but smoking negatively interacts with this effect. 4. Laryngoscope, 128:2333-2340, 2018.

Extracapsular extension is associated with worse distant control and progression-free survival in patients with lymph node-positive human papillomavirus-related oropharyngeal carcinoma

ObjectivesTo determine the prognostic utility of pathologic extracapsular extension (ECE) in human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC). Materials and MethodsRetrospective analysis was performed on patients who underwent surgery for primary HPV-related OPSCC and received adjuvant radiotherapy (RT) between 2006 and 2015. Locoregional control (LRC), distant control (DC), progression-free survival (PFS) and overall survival (OS) were compared between the groups with and without ECE using univariate Kaplan-Meier and multivariate Cox regression survival analyses. Results75 patients were identified and ECE was demonstrated on the surgical pathology of 26 patients. ECE(+) patients more frequently received chemotherapy (76.9% vs. 32.7%; p<0.0001) and RT doses>66Gy (76.9% vs. 16.3%; p<0.001). With a median follow-up of 29months, patients with ECE had a significantly worse 5-year DC rate than those without ECE (76.7% vs. 97.9%; p=0.046), and patients with ECE had a significantly worse 5-year PFS (54.5% vs. 93.6%; p=0.021) than those without ECE. On multivariate Cox regression analysis, ECE was independently prognostic of worse DC (hazard ratio: 8.26; 95% confidence interval: 1.24–55.21; p=0.029) and worse PFS(HR: 4.64; 95% CI: 1.18–18.29; p=0.028). There was no statistically significant difference in 5-year LRC (93.3% vs. 95.7%) or OS (66.9% vs. 97.0%) between ECE(+) and ECE(−) patients, respectively. ConclusionThis study suggests that ECE is independently prognostic of worse DC and PFS in patients who undergo surgery prior to adjuvant RT for primary HPV-related OPSCC.

Radiologic Differences between Human Papillomavirus-Related and Human Papillomavirus-Unrelated Oropharyngeal Carcinoma on Diffusion-Weighted Imaging

Background and Purpose: Human papilloma virus-related oropharyngeal carcinoma (HPV+ OPC) is a unique entity compared to HPV-unrelated (HPV-) OPC. Previous studies were inconclusive regarding the differences between HPV+ and HPV- OPCs on diffusion-weighted imaging (DWI). This study sought to determine if there is an association between HPV status and apparent diffusion coefficient (ADC) values as an imaging biomarker in OPCs. Materials and Methods: OPC patients with pretreatment MRI including DWI were retrospectively reviewed and analyzed as a blinded, controlled cohort. HPV status was biopsy-ascertained with p16 staining. ADC values were determined by placing the largest possible circular region of interest in solid portions of primary tumors and/or metastatic lymph nodes. Necrotic and cystic portions were excluded. Results: Twenty-eight HPV+ and 12 HPV- patients were included. Adjusted for age and sex, ADC values were significantly lower in HPV+ OPC primary tumors (p = 0.013) and lymph node metastases (p = 0.013). The area under the curve (AUC) was 0.85 and 0.90, respectively. A model with a linear combination of the 2 variables yielded an AUC of 0.92. Conclusion: ADC values were significantly lower in both the primary tumors and lymph node metastases in HPV+ OPCs compared to HPV- OPCs. These results confirm the results of prior studies.

Challenges in establishing the diagnosis of human papillomavirus-related oropharyngeal carcinoma.

To describe initial presentations and idiosyncrasies in establishing the diagnosis for human papillomavirus-related (HPV(+) ) compared to HPV-unrelated (HPV(-) ) oropharyngeal carcinoma (OPC). A single institution retrospective series derived from an institutional prospectively compiled database supplemented by chart review. We reviewed consecutive OPC patients referred to an academic tertiary cancer center from 2009 to 2011. HPV status was evaluated by p16 staining. Signs/symptoms and procedures to establish diagnosis were recorded independently by two abstractors blinded to the HPV status during data retrieval. Initial presentations (signs/symptoms), interval, and the procedures to establish the diagnosis were compared between HPV(+) and HPV(-) OPC. The most common initial presentation was an asymptomatic nodal mass for HPV(+) patients (n = 208; 69% vs. 29%, P < .001) in contrast to dysphagia/odynophagia for HPV(-) (n = 96; 34% vs. 63%, P < .001). Protracted interval (>12 months) from onset of signs/symptoms to diagnosis was observed in 18 (9%) HPV(+) versus three (3%) HPV(-) patients (P = .058). More HPV(+) patients required repeated (≥2) biopsy procedures (56% vs. 10%, P < .001). Misattribution to other disease occurred in eight (4%) HPV(+) patients (seven were mistaken as having a "branchial cleft cyst" when there were cystic lymph nodes and one as having a "lymphoma") compared to none in HPV(-) . About two-thirds of HPV(+) patients present with an asymptomatic neck mass and often require multiple biopsy procedures to establish the diagnosis. Idiosyncrasies in appreciating the diagnostic setting (cystic lymph node, misattribution to other entities, or submucosal location of the tumor) or patient-related factors could delay the diagnosis of HPV(+) OPC. 4 Laryngoscope, 126:2270-2275, 2016.

Investigation of the presence of HPV related oropharyngeal and oral tongue squamous cell carcinoma in Mozambique

BackgroundCervical cancer caused by the human papillomavirus (HPV) is endemic in East Africa. Recent, dramatic, increases in the incidence of oropharyngeal cancer in the United States and Europe are linked to the same high risk HPV genotypes responsible for cervical cancer. Currently, there is extremely limited data regarding the role of HPV in head and neck cancers in Africa. Evidence of HPV as an etiologic agent in head and neck cancers in Africa would have important prevention and treatment implications. MethodsA retrospective single institution review of oral tongue and oropharyngeal squamous cell carcinomas diagnosed between 2005 and 2013 was performed. Individual case data for 51 patients with biopsy proven squamous cell carcinoma (SCC) from the oropharynx (n=22) and oral tongue (n=29) were identified. Formalin fixed, paraffin embedded biopsy samples were obtained and evaluated for p16 by immunohistochemistry and HPV genotype 16 specific oncogenes, E6 and E7, by PCR. ResultsAll of the positive controls, but none of the oropharyngeal samples stained positively for p16. Two of the oral tongue samples stained positive for p16. None of the oropharyngeal or oral tongue cases demonstrated PCR products for HPV-16 E6 or E7. ConclusionsThough Mozambique has extremely high levels of HPV positive cervical cancer this study demonstrates an absence of HPV positive oropharyngeal or oral tongue squamous cell carcinoma within biopsy samples from a single referral hospital in Maputo, the capital of Mozambique.

Prognostic Implication of Persistent Human Papillomavirus Type 16 DNA Detection in Oral Rinses for Human Papillomavirus-Related Oropharyngeal Carcinoma.

Human papillomavirus-related oropharyngeal carcinoma (HPV-OPC) is increasing in incidence in the United States. Although HPV-OPC has favorable prognosis, 10% to 25% of HPV-OPCs recur. Detection of human papillomavirus (HPV) DNA in oral rinses is associated with HPV-OPC, but its potential as a prognostic biomarker is unclear. To determine whether HPV DNA detection in oral rinses after treatment for HPV-OPC is associated with recurrence and survival. Prospective cohort study of patients with incident HPV-OPC diagnosed from 2009 to 2013 at 4 academic tertiary referral cancer centers in the United States. Oral rinse samples were collected at diagnosis and after treatment (9, 12, 18, and 24 months after diagnosis), and evaluated for HPV DNA. Among an initial cohort of 157 participants with incident HPV-OPC treated with curative intent, 124 had 1 or more posttreatment oral rinses available and were included in this study. Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and the association of HPV DNA detection in oral rinses with survival was evaluated using Cox regression analysis. Oral HPV type 16 (HPV16) DNA was common at diagnosis (67 of 124 participants [54%]). In contrast, oral HPV16 DNA was detected in only 6 participants after treatment (5%), including 5 with HPV16 DNA also detected at diagnosis (persistent oral HPV16 DNA). Two-year DFS and OS were 92% (95% CI, 94%-100%) and 98% (95% CI, 93%-99%). Persistent oral HPV16 DNA was associated with worse DFS (hazard ratio, 29.7 [95% CI, 9.0-98.2]) and OS (hazard ratio, 23.5 [95% CI, 4.7-116.9]). All 5 participants with persistent oral HPV16 DNA developed recurrent disease, 3 with local disease involvement. In contrast, just 9 of 119 participants (8%) without persistent oral HPV16 DNA developed recurrent disease, only 1 (11%) with local disease involvement. Median (range) time from earliest posttreatment oral HPV16 DNA detection to recurrence was 7.0 (3.7-10.9) months. Human papillomavirus type 16 DNA in oral rinses is common at diagnosis but rare after treatment for HPV-OPC. Our data suggest that, although infrequent, persistent HPV16 DNA in posttreatment oral rinses is associated with poor prognosis and is a potential tool for long-term tumor surveillance, perhaps more so for local recurrence.

Induction of epithelial-mesenchymal transition and loss of podoplanin expression are associated with progression of lymph node metastases in human papillomavirus-related oropharyngeal carcinoma.

To examine human papillomavirus (HPV) status, the expression of podoplanin and epithelial-mesenchymal transition (EMT) markers and lymphatic vessel counts (LVC) in oropharyngeal squamous cell carcinoma (OPSCC) tissues, and to evaluate whether these factors were associated with survival and nodal status. A total of 53 OPSCC specimens were evaluated for HPV status and expression of proteins such as podoplanin and EMT markers by immunohistochemistry. E-cadherin-negative and vimentin-positive specimens were defined as EMT-positive. Twenty-two OPSCCs were HPV-positive. There was significant progression of nodal status in patients with HPV-positive tumours (P = 0.0475). HPV-positive cases had significantly lower expression of podoplanin (P = 0.0016) and were more frequently EMT-positive (P = 0.0172). Podoplanin-negative cases and EMT-positive cases showed significantly more advanced nodal status than their respective counterparts (P = 0.0082 and P = 0.0186, respectively). LVC correlated with neither HPV nor nodal status. Multivariate analyses revealed that HPV infection was an independent marker of longer disease-specific survival (P = 0.014). HPV-positivity in OPSCC was associated with loss of podoplanin expression and with EMT induction, which resulted in progression of nodal status. The mechanisms leading to an improved prognosis in HPV-positive OPSCC patients requires elucidation, as this is inconsistent with the aggressive phenotype with lymph node metastases.

770 An Increased CD8+ Cytotoxic T Cell Immune Response in Human Papillomavirus-related Oropharyngeal Carcinoma Correlates With Patients' Improved Prognosis

770 An Increased CD8+ Cytotoxic T Cell Immune Response in Human Papillomavirus-related Oropharyngeal Carcinoma Correlates With Patients' Improved Prognosis

Human Papillomavirus-related Oropharyngeal Carcinoma: Current Understanding and Enduring Uncertainties

The etiological role of high risk human papillomavirus (HPV) has been widely accepted in carcinomas of cervix, but this has only recently been confirmed in a subset of oropharyngeal carcinomas (OPC). The HPV-related OPC has now been clinically differentiated from the classic smoking/drinking-related OPC, and is considered a distinct molecular and clinical entity. This literature review aims to provide a summary of the current understanding and enduring uncertainties in the field of HPV-related OPC, specifically related to: the natural history and carcinogenic effect of HPV infection, the clinicopathology and treatment response of HPV-related OPC, and broader HPV-related social and medico-ethical issues.