Human Papillomavirus-related Oropharyngeal Cancer Research Articles

Geographic variation in human papillomavirus-related oropharyngeal cancer: Data from 4 multinational randomized trials.

BackgroundThere are variations in the proportions of head and neck cancers caused by the human papillomavirus (HPV) between countries and regions. It is unclear if these are true variations or due to different study designs and assays.MethodsWe tested formalin‐fixed paraffin‐embedded diagnostic biopsies for p16 immunohistochemistry and HPV‐DNA (by polymerase chain reaction [PCR] and in situ hybridization [ISH]) using validated protocols on samples from 801 patients with head and neck cancer recruited prospectively between 2006 and 2011 in 4 randomized controlled trials (RCTs).ResultsTwenty‐one percent of patients (170 of 801) showed both HPV‐DNA and p16‐positivity, detected almost exclusively in oropharyngeal cancer (55%; 15 of 302); and only 1% of the patients (5 of 499) with nonoropharyngeal cancer were HPV positive. HPV‐positive oropharyngeal cancer differed between Western and Eastern Europe (37%, 155 of 422 vs 6%, 8 of 144; p < .0001) and between Western Europe and Asia (37% vs 2%; 4 of 217; p < .0001). Other independent determinants of HPV positivity were tumor site and smoking.ConclusionThis is the first study to establish geographic variability as an independent risk factor in HPV‐positive oropharyngeal cancer prevalence, with higher prevalence in Western Europe. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E1863–E1869, 2016

Advanced oropharyngeal squamous cell carcinoma: Pathogenesis, treatment, and novel therapeutic approaches.

Oropharyngeal cancer accounts for approximately 2.8% of newly cancer cases. Although classically a tobacco related disease, most cases today are related to infection with human papilloma virus (HPV) and present with locally advanced tumors. HPV related tumors have been recognized as a molecularly distinct entity with higher response rates to therapy, lower rates of relapse, and improved overall survival. Treatment of oropharyngeal cancer entails a multi-disciplinary approach with concomitant chemoradiation. The role of induction chemotherapy in locally advanced tumors continues to be controversial however large studies have demonstrated no difference in survival or time to treatment failure. Surgical approaches may be employed with low volume oropharyngeal cancers and with development new endoscopic tools, more tumors are able to be resected via an endoscopic approach. Given advances in the understanding of HPV related oropharyngeal cancer, ongoing research is looking at ways to minimize toxicities via de-intensification of therapy. Unfortunately, some patients develop recurrent or metastatic disease. Novel therapeutics are currently being investigated for this patient population including immunotherapeutics. This review discusses the current understanding of the pathogenesis of oropharyngeal cancer and treatment. We also discuss emerging areas of research as it pertains to de-intensification as well novel therapeutics for the management of metastatic disease.

E6 viral protein ratio correlates with outcomes in human papillomavirus related oropharyngeal cancer

ABSTRACTBackground: The study aimed to identify prognostic markers to improve the management of patients with HPV positive OSCC Methods: We determined the ratio of HPV E6*I and E6*II splice variants by quantitative RT-PCR in 177 HPV positive OSCC and correlated the findings with other clinicopathological data Results: There was no significant difference in locoregional recurrence (HR 1.72 p = 0.24) and death (HR 1.65, p = 0.13) among patients whose tumors had an E6*I/*II ratio ≥1 compared with an E6*I/*II ratio of <1. Univariate analysis showed that patients with E6*I/*II ≥1 OSCC were more likely to have an event. In the multivariable analysis, there was a trend for more events in patients with E6*I/*II ratio ≥1 (HR 1.70, 95% CI 0.95-3.03, p = 0.07) Conclusion: Our data suggest that the use of HPV 16 spliced transcripts may help to predict for poorer outcomes in patients with HPV positive OSCC.

Reaffirming Metastatic Risk Profiles in Human Papillomavirus-related Oropharyngeal Cancer Following Definitive Radiation Therapy With or Without Chemotherapy

A prior publication from our group identified profiles of patients (pts) with differing risk of distant metastasis (DM), the main form of failure for HPV-related (HPV[+]) oropharyngeal cancer (OPC). These profiles are currently influencing the design of trials in HPV(+) OPC. The aim of this study is to reaffirm DM risk groups following definitive radiation therapy (RT) +/- chemotherapy (CTx) in a substantially expanded HPV(+) OPC cohort. All p16-confirmed newly diagnosed HPV(+) OPC patients treated with RT +/- CTx between 2000 and 2012 were included. Overall survival (OS), locoregional control (LRC), distant control (DC), and grade 3 to 4 late toxicity (LT) were estimated. Multivariable analysis (MVA) identified predictors for DC and OS. Recursive partitioning analysis (RPA) derived low and high DM risk groups. Within the low and high DM risk subgroup identified by RPA, we compared DC between RT with or without CTx to identify potential candidates for omission of CTx. A total of 757 HPV(+) (stage I, II, III, and IV: 8, 34, 93, and 622, respectively) pts were identified, including 605 (80%) men and 389 (51%) >10 pack-per-year (PY) smokers. Median age was 58 years. Tonsil or tongue base primary tumors were detected in 718 (95%) pts. Concurrent CTx (cisplatin 100 mg/m2 every 3 weeks) with RT was given in 382 (50%) cases. Median follow-up was 5.1 years. A total of 40 local, 35 regional, and 98 DM were identified. Five-year OS, LRC, DC, and LT were 76%, 92%, 87%, and 20%, respectively. MVA identified T4 (hazard ratio [HR] = 1.95, P < .01) or N2c-3 (HR = 3.5, P < .01), and absence of CTx (1.7, P = .03) as DM predictors; neither smoking PYs (HR = 0.99, P = .41) nor age (HR = 1.01, P = .43) were predictive for DM, but they were predictive for OS (age: HR = 1.02; smoking: 1.01, both P < .01). RPA divided the entire cohort into low-risk (T1–3N0–2b, n = 441) and high-risk (T4 or N2c–3, n = 316) subgroups with 5-year DC of 94% versus 76% and OS of 84% versus 66%, respectively (both P < .01). In the low-risk subgroup, DC was similar between RT (N = 247) versus RT + CTx (n = 194) (95% vs 93%, P = .67). Five-year DC rates by smoking ≤10 (n = 47) versus >10 (n = 52) PYs were also similar in the T1–3N2b (93% vs 90%, P = .53) subset. In the high-risk subgroup, DC was lower in the RT (n = 128) versus CRT (n = 188) (65% vs 83%, P < .01). This expanded cohort study (the sample doubled from 382 in the previous publication to 757 in the current cohort) confirms that DM is the main form of treatment failure for HPV(+) OPC pts. The T1–T3N0–N2b subgroup has low DM risk, which is not influenced by smoking PY, although smoking adversely affects survival for all groups. While these findings require prospective confirmation, the low DM risk subgroup represents a candidate for deintensification approaches, and high-risk patients merit consideration of new strategies.

Matted nodes: High distant-metastasis risk and a potential indication for intensification of systemic therapy in human papillomavirus-related oropharyngeal cancer.

The purpose of this study was to determine whether matted nodes uniquely identify patients with human papillomavirus (HPV)-positive oropharyngeal cancer at disproportionately high distant failure risk who may benefit from intensified systemic therapy. One hundred seventy-eight patients with stage III/IV HPV-positive oropharyngeal cancer who completed definitive chemoradiotherapy were stratified by risk group (low-risk = T1-3/N0-2c/<10 pack-years; intermediate-risk = T1-3/N0-2c/≥10 pack-years; and high-risk = T4 or N3). Prognostic impact of matted nodes was assessed. At the 52-month median follow-up, event rates with and without matted nodes were: locoregional failure: 23.3% versus 12.8% (p = .16), distant failure: 50.0% versus 1.4% (p < .01), any failure: 73.3% versus 14.2% (p < .01); cause-specific mortality: 56.7% versus 5.4% (p < .01), and death: 56.7% versus 13.5% (p < .01). In multivariate analyses, including risk group and individual risk factors, matted nodes were the strongest predictor for all endpoints except locoregional failure. Among patients without matted nodes, risk-group discriminated locoregional failure (at 3 years: low-risk = 2.0%; intermediate-risk = 14.4%; and high-risk = 24.2%; p < .01), but not distant failure (low-risk = 0.0%; intermediate-risk = 2.1%; and high-risk = 3.8%; p = .53). Matted nodes portended dramatically increased distant failure and death risks in HPV-positive oropharyngeal cancer, identifying a candidate population for consideration of chemo-intensification. © 2015 Wiley Periodicals, Inc. Head Neck 38: E805-E814, 2016.

Rising prevalence of human papillomavirus-related oropharyngeal cancer in Australia over the last 2 decades.

This study provides Australian data on the characteristics of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) over the last 2 decades. The HPV status of 515 patients with oropharyngeal SCC diagnosed between 1987 and 2010 was determined by HPV E6-targeted multiplex real time polymerase chain reaction assay (PCR) and p16 immunohistochemistry. The HPV positivity rate increased from 20.2% (1987-1995) to 63.5% (2006-2010). Among HPV-positive oropharyngeal SCC over the study period, the median age increased from 55.4 years to 59.8 years (p = .004) and there was a trend of an increasing proportion of never smokers (19.2% to 34.0%). The use of radiation therapy (RT) in patients with HPV-positive oropharyngeal cancer increased from 26.9% to 68.1% (p = .007) and we also observed a trend of improved outcomes. Our data show a rising prevalence of HPV-positive oropharyngeal SCC in Australia over the last 2 decades. These patients with HPV-positive oropharyngeal SCC are now presenting at an older age and about one third have never smoked.

Trends in human papillomavirus-related oropharyngeal cancer in Israel.

The role of human papillomavirus (HPV) infection in oropharyngeal cancer (SCC) is well established. The annual incidence of oropharyngeal SCC in Israel is considerably lower than that in the United States. The purpose of this study was to assess the rate of HPV-related oropharyngeal SCC in Israel. The cohort included patients with oropharyngeal SCC who were treated during 1999 to 2011 in Israel. HPV typing was carried out using reverse hybridization and immunohistochemistry. Of the 74 patients analyzed, 25 (33.7%) had detectable HPV DNA. Patients in the HPV-positive group tended to be younger, with a higher rate of nodal metastases, and no history of smoking (p < .02). This study demonstrated a rate of HPV-related oropharyngeal SCC in Israel as approximately 3-fold lower than in Western countries. Low exposure to HPV-16, a lower rate of transformation, to cancer or protective genetic factors may contribute to the lower rate of oropharyngeal SCC in Israel. © 2015 Wiley Periodicals, Inc. Head Neck 38: E274-E278, 2016.

Impact of retropharyngeal adenopathy on distant control and survival in HPV-related oropharyngeal cancer treated with chemoradiotherapy

PurposeRetropharyngeal adenopathy (RPA) is poor prognostic factor in head and neck (HN) cancer. However, the prognostic significance of RPA in Human Papillomavirus-related (HPV+) oropharyngeal cancer (OPC) is unknown. Patients and methods185 patients with HPV+OPC were assessed. Pre-therapy images reviewed by a HN radiologist to determine presence of RPA. Doses to the RPAs were determined from treatment plans. Outcomes analyzed using Kaplan–Meier method, log-rank tests, and correlations determined using Spearman’s rank analyses. Results29 (16%) of the HPV+patients had RPA. At median follow-up 49months, 5-year overall survival (OS), failure-free survival (FFS) and distant failure-free survival (DFFS) were 57% vs. 81% (P=0.02), 63% vs 80% (P=0.015) and 70% vs 91% (P=0.002) for patients with/without RPA, respectively. No differences observed in local/ regional control rates, exceeding 90% in both groups, and No RPA recurrences were observed. In multivariable analysis, stages T4 or N3, and RPA, were independently, statistically significantly associated with both OS and distant failure, while N2c, age, disease site, and smoking status, were not. ConclusionRPA in HPV+OPC is an independent prognostic factor for distant failure, translating into worse OS. Patients with RPA may not be suitable candidates for trials of systemic treatment de-escalation.

Human papilloma virus-related oropharyngeal cancer: opportunities and challenges in dysphagia management.

Human papilloma virus (HPV) has emerged as the most common cause of oropharyngeal cancer (OPC) compared with traditional causes of excess alcohol and tobacco use. In this article, we will discuss HPV-related OPC and the challenges and opportunities presented in dysphagia management relative to efforts to de-escalate treatment and improve outcomes. It is becoming increasingly apparent that patients with HPV-positive disease appear to respond favourably to chemoradiation. Targeted chemoradiation is associated with severe early and late toxicities related to swallow function. Research is in progress to ascertain the benefit of treatment de-escalation with a particular focus on swallowing outcomes. Patients are younger and, with the improved outcomes reported in the literature, surviving longer with the consequences of their treatment. Given the changing demographic of this patient group, there are a number of opportunities to optimize swallowing outcomes, and this should be underpinned by detailed swallowing evaluation and counselling prior to treatment. A number of strategies have been suggested to improve swallowing outcomes; however, persisting and late-onset swallowing effects continue to be a risk. Transoral surgery is evolving as an option for the treatment of HPV-positive disease; however, more studies are required to understand functional outcomes. Clinical trials are now underway to ascertain the effectiveness of tailored treatments for HPV-positive OPC with a focus on swallowing outcomes. It is encouraging that studies are now including detailed, multidimensional swallowing evaluation. Until such time as longitudinal data are available, patients should be treated by speech-language pathologists based on existing radiation treatment protocols and in the knowledge that patients may experience significant late swallowing difficulties.

Advances in the Chemopreventive Targeting of Oral Carcinogenesis

Control of oral cancer associated with the frequent exposure to traditional risk factors such as tobacco, betel quid, and alcohol, together with the recent rise in human papillomavirus-related oropharyngeal cancer is a major public health concern worldwide. Late diagnosis and “field cancerization,” where multifocal malignant lesions compromise standard surgical treatments and chemoradiotherapy are among the most critical challenges faced by clinical oncologists. In addition to improving methods of early diagnosis and periodic monitoring, halting tumor progression through long-term chemoprevention of at risk premalignant lesions with well-tolerated drugs or natural products remains an attractive strategy. This review discusses recent progress and challenges on the chemopreventive targeting of oral cancer, especially as it relates to the genomic and molecular characterization of oncogenic drivers underlying tumor development and progression. These emerging data may ultimately serve as the basis for novel early and predictable interventions to significantly reduce morbidity and mortality associated with oral cancer.

Primary surgery versus (chemo)radiotherapy in oropharyngeal cancer: the radiation oncologist's and medical oncologist's perspectives.

Radiotherapy is the traditional treatment for oropharyngeal cancer (OPC) because of its ability to preserve anatomic form and function compared with other conventional curative options. Recently, transoral robotic surgery (TORS) and transoral laser microsurgery (TLM) have emerged prominently for T1-T2 OPC. This review summarizes the recent literature pertaining to OPC outcomes following primary TORS/TLM versus primary radiotherapy with or without chemotherapy and addresses controversies surrounding indications for adjuvant treatment following TORS/TLM. Articles regarding OPC outcomes after primary TORS/TLM or radiotherapy/chemoradiotherapy published over the past 12 months were identified. TORS/TLM studies reported encouraging oncologic and functional outcomes. Primary radiotherapy alone showed exemplary results for a similar group of patients. However, comparisons of outcomes between these two primary modalities rely on historical data vulnerable to selection bias, even in a matched cohort study. The majority of cases treated with TORS/TLM also received adjuvant treatment. Soft tissue necrosis complicating this approach has also been reported. Controversies exist regarding the definition of resection margin status, prognostic value of extracapsular spread in human papillomavirus-related OPC and indications for adjuvant treatment following TORS/TLM. TORS/TLM is an attractive approach for selected T1-T2 OPC, but its role should be refined based on a high level of evidence.

Long-Term Quality of Life After Swallowing and Salivary-Sparing Chemo–Intensity Modulated Radiation Therapy in Survivors of Human Papillomavirus–Related Oropharyngeal Cancer

To evaluate long-term health-related quality of life (HRQOL) in 2 prospective studies of chemo-intensity modulated radiation therapy (chemo-IMRT) for oropharyngeal cancer (OPC). Of 93 patients with stage III/IV OPC treated on prospective studies of swallowing and salivary organ-sparing chemo-IMRT, 69 were eligible for long-term HRQOL assessment. Three validated patient-reported instruments, the Head and Neck QOL (HNQOL) questionnaire, the University of Washington quality of life (UWQOL) questionnaire, and the Xerostomia Questionnaire (XQ), previously administered from baseline through 2years in the parent studies, were readministered at long-term follow-up, along with the Short-Form 36. Long-term changes in HRQOL from before treatment and 2years were evaluated. Forty patients (58%) with a median follow-up of 6.5years participated, 39 of whom (97.5%) had confirmed human papillomavirus-positive OPC. Long term, no clinically significant worsening was detected in mean HRQOL scores compared with 2years, with stable or improved HRQOL from before treatment in nearly all domains. "Moderate" or greater severity problems were uncommon, reported by 5% of patients for eating, 5% for swallowing, and 2.5% and 5% by HNQOL and UWQOL summary scores, respectively. Freedom from percutaneous endoscopic gastrostomy tube dependence and stricture dilation beyond 2years was 97.5% and 95%, respectively. Eleven percent and 14% of patients reported "moderate" or "severe" long-term worsening in HNQOL Pain and Overall Bother domains, respectively, which were associated with mean dose to the cervical esophagus, larynx, and pharyngeal constrictors. At more than 6 years' median follow-up, OPC patients treated with swallowing and salivary organ-sparing chemo-IMRT reported stable or improved HRQOL in nearly all domains compared with both before treatment and 2-year follow-up. New late toxicity after 2years was uncommon. Further emphasis on sparing the swallowing organs may yield additional HRQOL gains for long-term OPC survivors.

PO-100: E6 viral protein ratio correlates with outcomes in human papillomavirus related oropharyngeal cancer

PO-100: E6 viral protein ratio correlates with outcomes in human papillomavirus related oropharyngeal cancer

Chemoradiotherapy-Induced Upregulation of PD-1 Antagonizes Immunity to HPV-Related Oropharyngeal Cancer

While viral antigens in human papillomavirus (HPV)-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from patients with stage III-IV oropharyngeal cancer undergoing concomitant chemoradiotherapy with or without induction chemotherapy. Circulating immunocytes including CD4(+) and CD8(+) T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T-cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T-cell assays in the presence of blocking antibody. While HPV-specific T-cell responses were present in 13 of 18 patients before treatment, 10 of 13 patients lost these responses within 3 months after chemoradiotherapy. Chemoradiotherapy decreased circulating T cells and markedly elevated MDSCs. PD-1 expression on CD4(+) T cells increased by nearly 2.5-fold after chemoradiotherapy, and ex vivo culture with PD-1-blocking antibody enhanced HPV-specific T-cell responses in 8 of 18 samples tested. Chemoradiotherapy suppresses circulating immune responses in patients with HPVOPC by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4(+) T cells. These data strongly support testing of PD-1-blocking agents in combination with standard-of-care chemoradiotherapy for HPVOPC.

Human papillomavirus-related oropharyngeal cancer: HPV and p16 status in the recurrent versus parent tumor.

Although typically associated with a favorable prognosis, a minority of human papillomavirus (HPV)-related (+) oropharyngeal cancers recur after chemoradiation. We postulated that a minor HPV-negative tumor subfraction may be responsible for recurrences of HPV+ oropharyngeal cancer. Paired untreated primary and recurrent tumor specimens were identified for 37 patients with oropharyngeal cancer who received definitive chemoradiotherapy at our institution. Concordance in HPV/p16 expression between primary and recurrent tumors was assessed. Among 31 patients with HPV+/p16+ primary tumors, 30 (97%) retained evidence of both HPV and p16 expression at recurrence (27 HPV+/p16+; 3 HPV+/p16-partial). One (3%) initially HPV+/p16+ patient developed an HPV-negative/p16-negative lung squamous cell carcinoma (SCC), representing either a discordant oropharyngeal cancer metastasis or second primary tumor. HPV-related oropharyngeal cancers retain HPV+/p16+ expression at recurrence. Our results fail to provide evidence that a minor HPV-negative tumor subfraction is responsible for biologically aggressive behavior of HPV+ oropharyngeal cancer that recurs after chemoradiation.

Human Papillomavirus in Head and Neck Cancer: Several Questions

Received April 14, 2013 Accepted May 14, 2013 Address for correspondence Yuh-S. Jung, MD, PhD Department of OtolaryngologyHead and Neck Surgery, Head and Neck Oncology Clinic, Center for Thyroid Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 410-769, Korea Tel +82-31-920-1685 Fax +82-31-920-1157 E-mail jysorl@ncc.re.kr The past decade has seen changes in the global trends for head and neck cancers in terms of incidence, etiologic and demographic patterns. Several case-control studies have consistently shown human papillomavirus (HPV) exposure dramatically increases the occurrence of oropharyngeal cancer. HPV related (+) oropharyngeal cancer has been found to be epidemiologically and clinically distinctive disease, characterized by younger age at onset, and strong association with reproductive behavior. The incidence of this disease is increasing sharply worldwide, whilst HPV negative (-) cancers are declining. HPV(+) cancers have significantly better survival and responses to chemoradiation, than HPV(-) counterparts. Given this superior survival, de-escalated therapies and organ preservation surgeries are being considered and on the clinical trial. Currently available prophylactic virus-like particle vaccines might be efficacious for primary prevention of HPV(+) cancers, although not validated yet. More researches are needed for the effective secondary prevention, through the deeper understanding of precancerous, molecular and pathologic changes. Korean J Otorhinolaryngol-Head Neck Surg 2014;57(3):143-50

Reliability of post-chemoradiotherapy F-18-FDG PET/CT for prediction of locoregional failure in human papillomavirus-associated oropharyngeal cancer

Although widely adopted, the accuracy of post-chemoradiotherapy (CRT) 18F-fluorodeoxygluocose positron emission tomography/computed tomography (PET/CT) for predicting locoregional failure (LRF) in human papillomavirus-related (HPV+) oropharyngeal cancer (OPC) remains poorly characterized. We assessed the predictive value of 3-month PET/CT response for LRF in this population. 101 consecutive patients with stage III-IV HPV+ OPC who underwent definitive CRT with pre-treatment and 3-month post-CRT PET/CT at our institution from 3/2005-3/2011 were included. 3-month PET/CT response was re-classified as complete-response (CR), near-CR, or incomplete-response (<CR) for each the primary site and neck. Accuracy of 3-month PET/CT for predicting local failure (LF) and regional failure (RF) was analyzed. Among 98 patients with an evaluable primary tumor, LF occurred in 2/67 patients with CR, 0/20 with near-CR, and 1/11 with <CR on 3-month PET/CT. Of 98 node-positive patients, RF occurred in 6/80 with CR, 2/9 with near-CR, and 0/7 with <CR in the neck at 3 months. Sensitivity and positive predictive value (PPV) of 3-month PET/CT response for LF and RF were low (0-33%), despite a high negative predictive value (NPV) (91-98%). SUVmax thresholds or % change did not improve the accuracy of 3-month PET/CT. Use of additional PET/CT surveillance after 3 months in 67 patients accurately detected both LF (96%) and RF (97%). In the largest study to-date of PET/CT response assessment in HPV+ OPC, 3-month PET/CT response demonstrated high NPV for LRF, though with disappointing sensitivity and PPV. Subsequent PET/CT surveillance showed potential utility for early detection of LRFs.

Incidence of human papillomavirus-related oropharyngeal cancer and outcomes after chemoradiation in a population of heavy smokers

Incidence of human papillomavirus (HPV)-related oropharyngeal carcinomas is increasing worldwide. The purpose of this study was to report the incidence in our region, and to determine the influence of HPV status on survival among a heavy smoking population. p16 expression was analyzed in 102 patients with stage II to IV treated with chemoradiation. Overall survival (OS), locoregional control, and disease-free survival (DFS) were compared for HPV+ and HPV- status. The majority of patients were smokers (86%). p16 positivity was found in 26.7%. Patients who were HPV+ were younger (56 vs 59 years old; p = .052). No differences were observed regarding tumor stage, sex, or smoking between HPV+ and HPV-. Three-year OS was 67.4% for patients who were HPV+ versus 49.7% for HPV- (hazard ratio [HR], 0.55; p = .095). Incidence of HPV-related oropharyngeal carcinoma in Spain is similar to that reported in other European countries. In this sample of heavy smokers, we observed a nonsignificant trend for better outcomes in patients who were HPV+.

Highly aggressive human papillomavirus-related oropharyngeal cancer: clinical, radiologic, and pathologic characteristics

Although the majority of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas have a favorable prognosis, we search for markers of poor prognosis by carefully examining a subset of highly aggressive cases. Seven patients with HPV-positive oropharyngeal cancer who presented with non-pulmonary distant metastasis or developed distant metastasis posttreatment were identified. Eight control cases were chosen which responded well to treatment. Pathologic and radiologic studies were reviewed and compared. Two cases displayed a small cell carcinoma (SmCC) component upon pathologic review. Biomarker analysis revealed lower expression of NOTCH1 in the aggressive cohort in comparison to controls (P = .04). Cases showed a predominance of clustering of lymph nodes, extracapsular spread, and central tumor necrosis. Although most HPV-related oropharyngeal cancers display a positive prognosis, it is evident that there is a subset, which behaves more aggressively. This early investigation identifies pathologic and radiologic features that may help to predict this behavior.

Deintensification Candidate Subgroups in Human Papillomavirus–Related Oropharyngeal Cancer According to Minimal Risk of Distant Metastasis

To define human papillomavirus (HPV) -positive oropharyngeal cancers (OPC) suitable for treatment deintensification according to low risk of distant metastasis (DM). OPC treated with radiotherapy (RT) or chemoradiotherapy (CRT) from 2001 to 2009 were included. Outcomes were compared for HPV-positive versus HPV-negative patients. Univariate and multivariate analyses identified outcome predictors. Recursive partitioning analysis (RPA) stratified the DM risk. HPV status was ascertained in 505 (56%) of 899 consecutive OPCs. Median follow-up was 3.9 years. HPV-positive patients (n = 382), compared with HPV-negative patients (n = 123), had higher local (94% v 80%, respectively, at 3 years; P < .01) and regional control (95% v 82%, respectively; P < .01) but similar distant control (DC; 90% v 86%, respectively; P = .53). Multivariate analysis identified that HPV negativity (hazard ratio [HR], 2.9; 95% CI, 2.0 to 5.0), N2b-N3 (HR, 2.9; 95% CI, 1.8 to 4.9), T4 (HR, 1.8; 95% CI, 1.2 to 2.9), and RT alone (HR, 1.8; 95% CI, 1.1 to 2.5) predicted a lower recurrence-free survival (RFS; all P < .01). Smoking pack-years > 10 reduced overall survival (HR, 1.72; 95% CI, 1.1 to 2.7; P = .03) but did not impact RFS (HR, 1.1; 95% CI, 0.7 to 1.9; P = .65). RPA segregated HPV-positive patients into low (T1-3N0-2c; DC, 93%) and high DM risk (N3 or T4; DC, 76%) groups and HPV-negative patients into different low (T1-2N0-2c; DC, 93%) and high DM risk (T3-4N3; DC, 72%) groups. The DC rates for HPV-positive, low-risk N0-2a or less than 10 pack-year N2b patients were similar for RT alone and CRT, but the rate was lower in the N2c subset managed by RT alone (73% v 92% for CRT; P = .02). HPV-positive T1-3N0-2c patients have a low DM risk, but N2c patients from this group have a reduced DC when treated with RT alone and seem less suited for deintensification strategies that omit chemotherapy.