HPV相关性口咽癌诊治现状及研究进展

人乳头瘤病毒(human papillomavirus,HPV)感染可引起多种疾病,其中高危型人乳头瘤病毒与头颈部鳞状细胞癌及宫颈癌关系更加密切.近年来,大量研究表明口咽癌的发病率呈现逐年上升的趋势,其中又以HPV感染所造成的HPV相关性口咽鳞状细胞癌(oropharyngeal squamous cell carci...     

Oncological outcome following initiation of treatment for stage III and IV HPV negative oropharyngeal cancers with transoral robotic surgery (TORS)

ObjectiveTo report long-term oncological and functional outcome of Transoral Robotic Surgery escalated treatment including radiotherapy or chemoradiotherapy for Stage III-IV HPV negative oropharyngeal malignancies.MethodFrom March 2013 to September 2015, 153 patients with oropharyngeal carcinoma were included in the study. Patients were evaluated for disease free survival, overall survival and post-treatment functional outcomes.Results153 patients (96 males and 57 females) underwent TORS for oropharyngeal carcinoma. 142 patients on final histopathology had stage III and IV disease and received adjuvant treatment based on final histopathology. One hundred and sixteen (81.7%) patients were disease free on average follow-up of 48 months with an overall survival of 91.5% at mean follow-up of 48 months.ConclusionTORS can be used to intensify treatment of Stage III/IV oropharyngeal carcinoma and avoid early and late toxicities due to higher doses of upfront RT/CTRT and achieve better oncological outcome.     

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.     

HPV16 increases the number of migratory cancer stem cells and modulates their miRNA expression profile in oropharyngeal cancer

Human papillomavirus type 16 (HPV16) is a major risk for development of oropharyngeal squamous‐cell‐carcinoma (OPSCC). Although HPV⁺ OPSCC metastasize faster than HPV^? tumors, they have a better prognosis. The molecular and cellular alterations underlying this pathobiology of HPV⁺ OPSCC remain elusive. In this study, we examined whether expression of HPV16‐E6E7 targets the number of migratory and stationary cancer stem cells (CSC). Furthermore, we wanted to elucidate if aberrantly expressed miRNAs in migratory CSC may be responsible for progression of OPSCCs and whether they may serve as potential novel biomarkers for increased potential of metastasis. Our studies revealed that HPV16‐E6E7 expression leads to an increase in the number of stationary (CD44^high/EpCAM^high) stem cells in primary keratinocyte cultures. Most importantly, expression of E6E7 in the cell line H357 increased the migratory (CD44^high/EpCAM^low) CSC pool. This increase in migratory CSCs could also be confirmed in HPV⁺ OPSCC. Differentially expressed miRNAs from HPV16‐E6E7 positive CD44^high/EpCAM^low CSCs were validated by RT‐qPCR and in situ hybridization on HPV16⁺ OPSCCs. These experiments led to the identification of miR‐3194‐5p, which is upregulated in primary HPV16⁺ OPSCC and matched metastasis. MiR‐1281 was also found to be highly expressed in HPV⁺ and HPV^? metastasis. As inhibition of this miRNA led to a markedly reduction of CD44^high/EpCAM^low cells, it may prove to be a promising drug target. Taken together, our findings highlight the capability of HPV16 to modify the phenotype of infected stem cells and that miR‐1281 and miR3194‐5p may represent promising targets to block metastatic spread of OPSCC.     

The potential impact of prophylactic human papillomavirus vaccination on oropharyngeal cancer

The incidence of oropharyngeal cancer (OPC) is significantly increasing in the United States. Given that these epidemiologic trends are driven by human papillomavirus (HPV), the potential impact of prophylactic HPV vaccines on the prevention of OPC is of interest. The primary evidence supporting the approval of current prophylactic HPV vaccines is from large phase 3 clinical trials focused on the prevention of genital disease (cervical and anal cancer, as well as genital warts). These trials reported vaccine efficacy rates of 89% to 98% for the prevention of both premalignant lesions and persistent genital infections. However, these trials were designed before the etiologic relationship between HPV and OPC was established. There are differences in the epidemiology of oral and genital HPV infection, such as differences in age and sex distributions, which suggest that the vaccine efficacy observed in genital cancers may not be directly translatable to the cancers of the oropharynx. Evaluation of vaccine efficacy is challenging in the oropharynx because no premalignant lesion analogous to cervical intraepithelial neoplasia in cervical cancer has yet been identified. To truly investigate the efficacy of these vaccines in the oropharynx, additional clinical trials with feasible endpoints are needed. Cancer 2016;122:2313–2323 . © 2016 American Cancer Society.     

Diagnostic accuracy of p16INK4a immunohistochemistry in oropharyngeal squamous cell carcinomas: A systematic review and meta‐analysis

The accurate diagnosis of human papillomavirus (HPV) causality in oropharyngeal squamous cell carcinomas (OPSCC) is likely to influence therapeutic decisions in affected patients in the near future. We conducted a systematic review and meta‐analysis to determine the diagnostic accuracy of p16^INK4a immunohistochemistry (IHC) to identify HPV‐induced OPSCC. We identified all studies that performed p16^INK4a IHC (index test) and HPV E6/E7 mRNA detection using an amplification‐based method (gold standard to indicate a transforming relevance of HPV) in OPSCC. Testing with one or more comparator tests (HPV DNA PCR, HPV DNA in situ hybridization (ISH) and p16^INK4a IHC/HPV DNA PCR combined testing) was an optional criterion for inclusion. Among 1,636 retrieved studies 24 fulfilled the inclusion criteria. The pooled sensitivity of p16^INK4a IHC, HPV DNA PCR, HPV DNA ISH and p16^INK4a IHC/HPV DNA PCR combined testing was 94% (95%‐confidence interval (CI) 91–97%), 98% (CI 94–100%), 85% (CI 76–92%) and 93% (CI 87–97%), respectively. The pooled specificity was 83% (CI 78–88%), 84% (CI 74–92%), 88% (CI 78–96%) and 96% (CI 89–100%), respectively. p16^INK4a IHC/HPV DNA PCR combined testing was as sensitive as either p16^INK4a IHC or HPV DNA PCR alone but significantly more specific than either separate test. In conclusion, p16^INK4a IHC is highly sensitive but moderately specific to diagnose HPV‐transformed OPSCC when used as a single test. Combined p16^INK4a IHC and HPV DNA PCR testing significantly enhances specificity while maintaining high sensitivity. This diagnostic test combination thus represents an attractive testing strategy for the reliable diagnosis of HPV‐induced OPSCC in the clinical setting and may constitute an inclusion criterion for future therapeutic trials.     

口咽鳞癌中HPV感染与血管生成的关系

目的:研究口咽鳞癌(oropharyngeal squamous cell carcinomas,OSCC)中人乳头瘤病毒(human papillomavirus,HPV)感染与血管内皮生长因子(vascular endothelial growth factor,VEGF)、CD31标记的微血管密度(microvessel density,MVD)表达的关系,探讨它们在口咽鳞癌发生中的相互关系.方法:采用多重实时荧光定量聚合酶链反应(multiplex real-time polymerase chain reaction,MT-PCR)检测60例口咽鳞癌HPV DNA及型别,通过HPV DNA分析进行HPV感染状况的测定;同时采用半定量免疫组化检测HPV(+)组和HPV(-)组中VEGF、CD31(MVD标志)蛋白表达情况.结果:口咽鳞癌中HPV感染率36.7％(22/60),HPV-16型占所有感染者的比例86.4％ (19/22),明显高于其他型别;VEGF高度表达者出现MVD＞ 15个/高倍视野的几率较VEGF低度表达者高(P =0.001);MVD＞ 15个/高倍视野的肿瘤为低分化的可能性较高(P =0.004);VEGF和MVD表达与患者年龄、性别、TNM分期、HPV感染状况之间无相关性.结论:HPV感染与口咽鳞癌的发生存在相关性.口咽鳞癌中HPV感染状况和VEGF之间无相关性.     

Multiple imputation and clinico-serological models to predict human papillomavirus status in oropharyngeal carcinoma: An alternative when tissue is unavailable

In cancer epidemiological studies, determination of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) typically depends on the availability of tumor tissue testing, and/or tumor tissue access. Identifying alternative methods for estimating HPV status can improve the quality of such studies when tissue is unavailable. We developed multiple predictive models for tumor HPV status and prognosis by combining both clinico-epidemiological variables and either serological multiplex assays of HPV or multiple imputation of HPV status (HPV_mi). Sensitivity, specificity and accuracy of these methods compared to either p16 immunostaining (p16 IHC) or survival were assessed. When compared to a reference of tumor tissue p16 IHC in 783 OPSCC patients, the clinic-HPV_sero model incorporating a composite of 20 HPV serological antibodies (HPV_sero) and 4 clinical factors (c-index: 0.96) performed better than using HPV_sero (c-index: 0.92) or HPV_mi (c-index: 0.76) alone. However, the model that contained a single HPV16 E6 antibody combined with four clinical variables, performed extremely well (clinic-s1-16E6; c-index: 0.95). When defining HPV status by HPV_sero, s1-16E6, HPV_mi or through p16 IHC, each of these definitions demonstrated improved overall and disease-free survival in HPV-positive OPSCC patients, when compared to HPV-negative patients (adjusted hazard ratios between 0.25 and 0.63). Our study demonstrates that when blood samples are available, a model that utilizes a single s1-16E6 antibody combined with several clinical features has excellent test performance characteristics to estimate HPV status and prognosis. When neither blood nor tumor tissue is available, multiple imputation, calibrated on local population characteristics, remains a viable, but suboptimal option.     

Past sexual behaviors and risks of oropharyngeal squamous cell carcinoma: a case–case comparison

The incidence of oropharyngeal squamous cell carcinomas (SCCs) is increasing and is believed to reflect changing sexual practices in recent decades. For this case–case comparative study, we collected medical and life‐style information and data on sexual behavior from 478 patients treated at the head and neck clinic of a tertiary hospital in Brisbane, Australia. Patients were grouped as (i) oropharyngeal SCC (n = 96), (ii) oral cavity, larynx and hypopharynx SCC (“other HNSCCs,” n = 96), (iii) other SCCs (n = 141), and (iv) other diagnoses (n = 145). We fitted multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associated with lifestyle factors and sexual behaviors. Compared to the other three patient groups, the oropharyngeal SCC patients had overall more sexual lifetime partners (kissing, oral sex and sexual intercourse). Oropharyngeal SCC patients were significantly more likely to have ever given oral sex compared to the other three patient groups—93% of oropharyngeal SCC patients, 64% of other HNSCC patients, and 58% of patients with other SCC or other diagnoses. Oropharyngeal SCC patients were significantly more likely to have given oral sex to four or more partners when compared to patients with other HNSCC (odds ratio [OR] 11.9; 95% CI 3.5–40.1), other SCC (OR 16.6; 95% CI 5.3–52.0) or patients with other diagnoses (OR 25.2; 95% CI 7.8–81.7). The very strong associations reported here between oral sex practices and risks of oropharyngeal SCC support the hypothesis that sexually transmitted HPV infections cause some of these cancers.