口腔及口咽癌新版TNM分期与NCCN诊治指南部分解读

美国癌症联合委员会《AJCC肿瘤分期手册》与美国国立综合癌症网(NCCN）肿瘤学临床实践指南已广泛用于临床实践中。NCCN肿瘤诊治指南与TNM分期密切相关,指南为不同TNM分期的肿瘤制定了较为详细的诊治标准,作为依据指导临床应用。2017年第8版口腔及口咽癌TNM分期新增了较多内容,如侵袭深度（DOI）、淋巴结外扩展（ENE）、人乳头瘤病毒（HPV）等指标用于了新的分期中,并且为HPV相关的口咽癌制定了一个新的TNM分期。2018年版NCCN口腔与口咽癌指南及时反映了第8版口腔及口咽癌TNM分期中新的变化,同时亦为HPV相关的口咽癌制定了相应的诊治指南。新的TNM分期及NCCN诊治指南对口腔与口咽癌患者诊疗策略的制定及治疗方案的选择具有较大的指导意义。为了临床工作的需要,本文结合两者的变化进行了部分解读。     

68例HPV相关口咽鳞癌患者生存分析

目的 探讨口咽癌HPV适用检测方法并比较HPV阳性患者新、旧版肿瘤TNM分期降级后的预后差异,为指导HPV相关口咽癌的精准诊疗提供临床依据。方法 对171例口咽鳞状细胞癌（简称鳞癌）患者,分别行脱落细胞学、P16免疫组织化学及HPV-RNA PCR检测HPV,比较3种检测方法的结果。分析68例HPV相关口咽鳞癌患者的临床及病理资料,根据新、旧版TNM分期标准对其重新分期,了解降级情况,统计各期患者生存率,比较新、旧2版分期患者的预后,应用 Kaplan-Meier方法建模,采用SPSS 22.0 软件包进行统计学分析。结果 免疫组织化学P16检测、口咽脱落细胞检测和PCR检测的口咽癌HPV阳性检出率分别为25.7%、14.6%和24.0%,脱落细胞检测与其他2种检测均有统计学差异（P=0.000）,免疫组织化学和PCR检测无统计学差异（P=0.205）。68例HPV阳性口咽鳞癌患者按照第7版与第8版TNM标准分期,分别为Ⅰ期3和42例,Ⅱ期7和14例,Ⅲ期17和9例,Ⅳ期41和3例。第7版与8版分期患者3年生存率比较,Ⅰ期100.0%和89.7%（P=0.672）,Ⅱ期68.6%和61.9%（P=0.961）,Ⅲ期66.8%和37.0%（P= 0.043）,Ⅳ期74.8%和0.00%（P=0.000）。第7与8版分期的早期患者（Ⅰ、Ⅱ期）生存率比较,78.8%和82.7%（P=0.585）,晚期患者（Ⅲ、Ⅳ期）生存率比较,71.2%和27.8%（P =0.000）。HPV阳性患者按照第7版分期,早期与晚期患者生存率为78.8%和71.2%（P=0.982）;按照8版分期,早期与晚期患者生存率为82.7%和27.8%（P=0.000）。结论 脱落细胞检查不宜作为诊断HPV阳性口咽鳞癌的单一标准,P16免疫组织化学检测和PCR基因检测各有优缺点,应根据实际情况选择。对于HPV阳性口咽鳞癌患者,新版分期更符合临床实际情况,预后分层更加清晰,能更好指导临床决策,值得临床推广应用。     

336例HPV相关性与非相关性口咽鳞癌患者生存分析

目的: 分析比较HPV相关性与非相关性口咽鳞癌（oropharyngeal squamous cell carcinoma,OPSCC）患者在新、旧版TNM不同分期情况下,患者生存及预后差异,为OPSCC的治疗策略与预后评估提供临床依据。方法: 收集2010年1月—2016年12月青岛大学附属医院手术治疗的原发OPSCC患者,采用p16免疫组织化学检测方法对病理标本重新进行评估,统计患者生存信息,并分别运用第7版、第8版TNM分期系统对肿瘤进行分期,记录新、旧版的降级情况,分析、比较HPV相关性与非相关性OPSCC患者两版不同分期对生存率及预后的影响。采用SPSS 25.0软件包对数据进行统计学分析。结果: 最终纳入336例OPSCC患者,其中HPV相关性OPSCC患者101例（30.1%）,5年生存率为47.5%（48/101）,中位生存时间58个月;非相关性OPSCC患者5年生存率为34.0%（80/235）,中位生存时间37个月。HPV相关性OPSCC患者第8版TNM分期与第7版TNM分期对比,其总体降级率为77.2%（78/101）,晚期患者降级率为100%（69/69）,晚期患者中降至早期的患者占比69.6%（48/69）。结论: HPV相关性OPSCC患者的生存率和生存中位时间明显优于非相关性OPSCC患者,第8版TNM分期手册的OPSCC分期相比第7版更符合临床实际,预后分层更加清晰,能更好指导临床决策。     

NCCN头颈癌诊治指南（2007版）（6）

2002年美国癌症联合会（AJCC）咽（包括舌根、软腭和腭垂）癌TNM分期系统     

口腔癌浸润深度对改进肿瘤TNM分期及预后评价的影响

目的:分析比较美国癌症联合委员会(AJCC)第8版与第7版TNM分期系统在口腔癌临床治疗决策、预后分层以及提高预后评价准确性中的意义.方法:收集2009年1月—2015年6月手术治疗的原发口腔鳞状细胞癌患者,分别应用第7版、第8版TNM分期系统对肿瘤进行分期,比较2种分期的变化情况.采用SPSS 26.0软件包,运用K...     

人类乳头瘤病毒阳性口咽癌对放疗敏感的研究进展

口咽癌(oropharyngeal carcinoma)是一种高度异质性疾病,其主要病因是烟草、酒精的滥用或高危人类乳头瘤病毒(human papillomavirus,HPV)感染的结果。HPV阳性口咽癌与HPV阴性口咽癌存在明显的病因、流行病学、预后等方面的差异,因此治疗上应采取不同的方法。目前已知HPV阳性口咽癌对放射治疗敏感,认为其对放疗敏感可能通过多种机制共同完成。HPV阳性口咽癌存在低表达的野生肿瘤蛋白p35(tumor protein p53,TP53)基因,放射治疗可通过DNA双链断裂损伤方式激活p53并诱导细胞发生凋亡;细胞对DNA损伤存在常见的非同源末端连接(non?homologous end joining,NHEJ)修复路径,HPV癌蛋白抑制该路径可使肿瘤对放疗更为敏感;此外,免疫应答在放疗作用下进一步激活也参与对肿瘤的消除作用。本文就HPV阳性口咽癌对放疗敏感的研究进行综述,为未来临床上针对口咽癌不同致病因素及临床分期采取针对性的治疗手段提供科学依据。     

P16蛋白在口咽癌和口腔癌中的表达及临床意义

目的:分析口咽癌和口腔癌中P16蛋白表达情况及临床意义.方法:采用免疫组织化学染色法检测70例口咽癌和60例口腔癌中P16蛋白的表达情况,分析其与患者临床病理学指标的相关性及临床意义.结果:口咽癌中P16蛋白的阳性率为22.9％(16/70),与P16阴性组相比,患者的年龄、吸烟、病理分化、N分期和TNM临床分期具有统计学意义(P＜0.05);口腔癌中P16蛋白的阳性率为8.3％ (5/60),与P16阴性组相比,病理分化和TNM临床分期有统计学意义(P＜0.05).结论:口咽癌中P16蛋白阳性率明显高于口腔癌,HPV感染是口咽癌和口腔癌不可忽视的诱发因素.     

淋巴结外扩展对口腔鳞癌患者TNM分期及生存预后的影响

目的 ：通过分析淋巴结外扩展（extranodal extension, ENE）指标纳入到肿瘤分期后对口腔鳞癌患者TNM分期变化及生存的影响,了解ENE对口腔鳞癌治疗决策及预后评估的意义。方法：回顾分析2014年1月—2017年6月青岛大学附属医院接受手术治疗的485例原发口腔鳞癌（OSCC）患者,对所有患者按AJCC第7版与AJCC第8版TNM分期标准分别进行N分期、TNM分期,采用SPSS 26.0软件包处理数据,以Kaplan-Meier法绘制患者总体生存率（overall survival, OS）和疾病别生存率（disease-specific survival, DSS）的生存曲线,并进行Log-rank检验,使用C指数和AIC评价预测性能。结果：485例OSCC患者中,69例ENE阳性患者（14.43%）发生pN分期改变（pN2a期16例、pN3b期53例）,67例ENE阳性患者（13.81%）发生pTNM改变（ⅣA期14例,ⅣB期53例）。N分期、TNM分期与ENE相关的患者,OS和DSS生存模型分析显示,ENE阳性患者生存率（OS:27.1%,DSS:31.2%）显...     

3种方法修复口腔及口咽癌术后缺损1年后生存质量分析

目的：分析3种修复方式(拉拢缝合、颏下岛状皮瓣、前臂皮瓣)修复口腔及口咽癌患者术后缺损1年后的生存质量及相关影响因素。方法对 2012年1月—2012年10月在中山大学孙逸仙纪念医院口腔颌面外科行口腔及口咽癌术后1年的47例患者进行问卷调查。采用华盛顿大学生存质量问卷第4版及欧洲癌症研究与治疗组织生存质量问卷第3版、头颈问卷第1版。将伤口直接缝合、颏下岛状瓣、前臂皮瓣修复口腔及口咽癌术后缺损分为3组后,分析不同修复方式对患者术后1年生存质量的影响。采用SPSS 20.0软件包对数据进行统计学分析。结果47例患者完成相关问卷。前臂皮瓣组在吞咽、咀嚼、语言和UW-QOL整体项中显著优于直接拉拢缝合组（P<0.05）,在UW-QOL问卷中的总分也好于后者（P<0.05）,与颏下瓣组相比,2组患者的总体生存质量无显著差异（P>0.05）;颏下瓣组在咀嚼、语言和食欲丧失项中显著好于直接拉拢缝合组（P<0.05）。结论口腔及口咽癌术后1年患者中,吞咽、语言和咀嚼成为近期患者生存质量的主要方面,术后应加强对患者进行语言和吞咽等训练。术中同期对口腔及口咽癌进行皮瓣修复,可以显著提高患者的生存质量。     

ASCO指南解读：“口腔和口咽鳞状细胞癌颈部管理”

为提供口腔和口咽鳞状细胞癌颈部管理的循证建议,美国临床肿瘤协会（ASCO）成立了专家组,对1990—2018年相关文献进行了分析,包括系统评价、荟萃分析、随机对照试验、前瞻性和回顾性观察对照试验。共纳入124篇,形成2019版指南。该指南设定了6种常见临床情形,其中口腔和口咽鳞状细胞癌各3种。从生存率、疾病控制情况、复发率及生存质量等角度,讨论了高质量颈淋巴清扫术、术后辅助放疗或放化疗、手术或非手术治疗的适应证,以及单独放化疗是否充足等问题,分条依次提出临床治疗建议。对多种慢性病患者、指南的局限性和适用范围也进行了阐述。本文就2019版ASCO指南进行解读,为诊治口腔颌面部肿瘤提供临床指导。     

The increasing clinical relevance of human papillomavirus type 16 (HPV-16) infection in oropharyngeal cancer

Human papillomavirus type 16 (HPV-16) has been established beyond doubt as a causative agent in oropharyngeal squamous cell carcinoma (SCC). The incidence of oropharyngeal cancer has risen in recent decades, as has the proportion of patients who have a biologically relevant HPV-16 infection. Combined data from 14 recently published studies (2006-2010) show that 57% of 1316 reported cases of oropharyngeal SCC were HPV-16 positive. They had significantly better prognosis (hazard ratio (HR) for 5-year overall survival range 0.05-0.64), although smoking and higher T stage often appear as confounding factors to this favourable prognostic benefit. HPV-16 therefore has increasing importance as a clinically useful prognostic biomarker, but a benefit in survival has been seen in the use of surgery, radiotherapy, and chemotherapy, so specific changes in the preferred methods of treatment are hard to justify. Future trials that include oropharyngeal SCC will consider HPV-16 routinely as a stratification factor, and its use as a predictive biomarker awaits the development of effective targeted treatments. The undeniable and impressive prognostic significance of HPV-16 should hasten its addition to standard pathological reporting of oropharyngeal SCC, and ultimately to its inclusion in TNM staging systems of the American Joint Committee on Cancer (AJCC) and the International Union against Cancer (UICC).     

HPV and other risk factors of oral cavity/oropharyngeal cancer in the Czech Republic

OBJECTIVE: An association between high-risk human papillomavirus (HR HPV) infection and a risk of development of a subgroup of head and neck cancers has been proposed recently. The main risk factors of oral and oropharyngal cancer observed in our population are smoking and alcohol consumption. The incidence of oral/oropharyngeal tumours in the Czech Republic is relatively high and there are no data available about the prevalence of HPV DNA presence in these tumours. MATERIALS AND METHODS: Eighty patients with a primary oropharyngeal cancer were enrolled. The presence of HPV DNA has been evaluated by polymerase chain reaction in 68 cases from which the tumour tissue and demographical and clinical data were available. The typing of HPV was performed by nucleotide DNA sequencing. RESULTS: The HPV DNA was detected in 51.5% of samples tested. Among the HPV DNA positive tumours, 80% contained HPV16. In the analysed group there were 54 men and 14 women. The prevalence of HPV DNA was lower in oral (25%) than in oropharyngeal (57%) tumours, and higher in never smokers (100%) and never drinkers (68.8%). HPV DNA presence was not related to gender, age, number of lifetime sexual partners or practice of oral-genital sex, size of tumour or presence of regional metastases. CONCLUSIONS: The difference in the prevalence of HPV DNA positive tumours between cases of oral cavity and oropharyngeal carcinoma exposed and not exposed to tobacco or alcohol support the theory that HPV DNA positive tumours form an aetiologically distinct subgroup of head and neck tumours.     

The prevalence of human papilloma virus (HPV) infections in oral squamous cell carcinomas: A retrospective analysis of 88 patients and literature overview

In addition to tobacco and alcohol consumption, the two main risk factors for oral squamous cell carcinoma (OSCC), recent studies have revealed infections with human papilloma virus (HPV) as an additional risk factor for OSCC development. In the field of head and neck malignancies, the prevalence of HPV infections in oropharyngeal cancer (OC) ranges in different studies up to 84%. While HPV infection is discussed as an independent risk factor in this region, its distinguished role in carcinogenesis of tumours localized to the oral cavity remains still uncertain.In this study, we analysed the HPV status in 88 consecutive patients with OSCCs localized anterior of the palatoglossal arch who were treated in the Department of Oral and Maxillofacial Surgery at the University Medical Center Mainz. The HPV status analysis was performed using DNA-PCR and immunostaining of p16 protein.The prevalence of HPV-positive OSCCs was about 6% (5 patients). In 3 patients the HPV subtypes 16/18 were found. No significant differences between the HPV positive and negative patients regarding age, gender, smoking and alcohol consumption, localization and TNM level could be detected. Contrary to other studies focussing on cancers of the lingual and palatine tonsil, the prevalence of HPV infections was much lower in the oral cavity. Therefore HPV infection might play a less important role in oral carcinogenesis.     

Is the 8th edition of the Union for International Cancer Control staging of oral cancer good enough?

Depth of invasion is an important predictor of survival. A study by the International Consortium (ICOR) for Outcome Research proposed incorporation of it (together with the greatest surface dimension, or the anatomical criteria, or both) into the T stage. This has been adopted in part by the 8th edition of the Union for International Cancer Control (UICC) TNM 8 classification of malignant tumours for oral squamous cell carcinoma (SCC). Our aim was to verify depth of invasion as an independent prognostic factor, and to validate the staging by comparing it with that specified in the 7th edition (TNM 7) and the T-staging model proposed by the International Consortium. We retrospectively studied 449 patients who had had operations for a previously untreated primary oral cancer between 2006 and 2014 at a single centre, and analysed the independent predictive value of depth of invasion for both disease-specific and overall survival. It was an independent predictor of disease-specific survival as were sex, perineural invasion, and N stage. It was also an independent predictor of overall survival together with sex and N status. Staging in TNM 8 gave a better balance of distribution than that in TNM 7, but did not discriminate between prognosis in patients with T3 and T4 disease. The proposed International Consortium rules for T-staging gave an improved balance in distribution and hazard discrimination. The incorporation of depth of invasion into the T-staging rules for oral SCC improved prognostic accuracy and is likely to influence the selection of patients for adjuvant treatment. Our findings suggest that the TNM 8 staging lacks hazard discrimination in patients with locally-advanced disease because its T4 staging is restricted to anatomical criteria.     

An analysis of distant metastasis cases from HPV-associated oropharyngeal squamous cell carcinoma

Although mostly associated with good survival outcomes, some patients with HPV-positive oropharyngeal squamous cell carcinoma develop distant metastasis and face dire prognosis. The aim of this study was to analyze distant metastatic patients in regards to survival, clinical staging, therapy approach and p16/HPV status.This retrospective single-centre study assessed patients with HPV-associated oropharyngeal cancer with distant metastasis treated in a tertiary referral center from 2005 to 2019. Overall- (OS) and survival after diagnosis of distant metastasis (OMS), clinical staging and different therapy approaches were assessed. Moreover, the overall mortality was assessed, as well as the association of different therapy approaches and p16/HPV status with the survival outcome.Out of 211 patients with HPV-associated oropharyngeal cancer that were treated in the study period, 15 developed distant metastases (7.1%). Median OS and OMS of the total group were 11 months (range 0.1–32 months) and 3 months (range 0.1–21 months), respectively. The overall mortality rate was 53.3% (n = 8). Significantly better outcome was present in patients treated with primary chemoradiotherapy (median OS 17 months vs. not reached, p = .03, median OMS 8 months vs not reached, p = .05). The OMS was significantly better in patients treated with chemotherapy initially after diagnosis (mean OMS 21 months vs 4 months; P = .001). Surgical resection after initial diagnosis was associated with a significantly shorter OMS (median OMS 3 vs. 21 months, p = .005). Interestingly, postoperative adjuvant therapy was delayed in all of these cases due to surgical site complications.Systemic treatment after initial diagnosis may be beneficial in clinical outcome of HPV associated distant metastases. Furthermore, surgical site complications should be treated with immediate care in order to avoid delay of adjuvant therapy. Further studies are warranted for validation of our results.     

Oral cancer,HPV infection and evidence of sexual transmission

The incidence of oropharyngeal cancer and oral cancer is growing worldwide, both in young non-smokers and in young non-drinkers (smoking and drinking are considered the main risk factors). Epidemiologic studies suggest a strong association between the infection by human papillomavirus (HPV), especially types 16 and 18 (high oncological risk) which have already demonstrated their etiological role in anal tumours as well as in cervix cancer. There is clear epidemiologic evidence that both types of tumours relate to changes in sexual behaviour and that both are linked to sexual transmission of HPV. The number of oral and oropharyngeal cancer cases is rising nowadays, especially among young individuals with no typical toxic habits, such as tobacco and/or alcohol. In this review we set out to update the aspects related to the onset of oral cancer, its relationship with HPV infection and whether this association may be due to the sexual transmission of the virus. Key words:Human papillomavirus, oral sex, head and neck cancer, oral cancer, squamous cell carcinoma, oropharyngeal cancer.     

Human papillomavirus type 16 and 18 DNA in oral squamous cell carcinoma and normal mucosa

The aim of this study was to ascertain the prevalence of HPV 16/18 DNA in oral squamous cell carcinoma (OSCC) vs. normal oral mucosa, and to correlate the virologic data with other factors obtained from the patients' records. One hundred and thirteen paraffin embedded tissue samples (73 OSCC and 40 normal oral mucosa) were studied using HPV type specific primer-mediated polymerase chain reaction (PCR). Seventy-four per cent (54/73) of OSCC and 55% (22/44) of normal oral mucosa were positive for HPV 16/18 DNA. Statistical analysis indicated there was a significant difference between HPV16/18 positive OSCC vs. normal oral mucosa (P=0.040), and that age (<60 years) and gender (male) were correlated with the presence of HPV16/18 in the tumour. No significant association was found between the presence of HPV and other risk factors, including tobacco use, alcohol use, tumour location, histologic grade or TNM staging. We found a significant association of HPV16/18 with oral squamous cell carcinoma. Also, HPV16/18 is a co-factor in oral carcinogenesis, particularly in male patients and patients under the sixth decade. In addition, we found that HPV infection is a common event in the normal oral mucosa.