Characteristics and Impact of HPV-Associated p16 Expression on Head and Neck Squamous Cell Carcinoma in Thai Patients

Background: Head and neck squamous cell carcinoma (HNSCC) is a common malignancy in Asia. Infection by human papilloma virus (HPV) has been recognized as an etiological risk for HNSCC, especially oropharyngeal region. While the association between HPV and HNSCC has been well evaluated in Western countries, only a few investigated the HPV-associated HNSCC in Southeast Asia. This study evaluated the prevalence, the characteristics, and the impact of HPV on the treatment outcomes in Thai HNSCC patients. Methods: Non-nasopharyngeal HNSCC patients treated at Ramathibodi Hospital during 2007-2013 were identified through the cancer registry database. Baseline patient, treatment data and survivals were retrospectively reviewed. The formalin-fixed paraffin-embedded (FFPE) tissue sections were retrieved for p16 analysis. The HPV status was determined by p16 immunohistochemistry. The survival outcomes were analyzed in cases which p16 status was confirmed. Results: Total of 200 FFPE tissues of HNSCC patients was evaluated for p16 expression. Positive p16 status was observed in 24 cases (12%); majority of p16-positive were men (20:4 cases). The oropharynx (37.9%) was the most common site found in p16-positive while oral cavity (3.2%) was the least common site. Interestingly, 66.7% of p16-positive were former/current smokers, and 70.8% of this subgroup was categorized as clinical AJCC stage III-IV. The p16-positive HNSCC was significantly superior in 5-year overall survival [5-yrs OS 63% vs. 40%, p=0.03], 5-year disease-free survival [5-yrs DFS 61% vs. 36%, p=0.03] and in 5-year locoregional relapse-free survival [5-yrs LRFS 93% vs. 68%, p=0.018] when compared with p16-negative. Conclusions: In comparison to the results from the Western countries, the prevalence of HPV-related HNSCC in Thai patients was less, and differences in some characteristics were observed. Nevertheless, improvement in OS, DFS and LRFS were observed in p16-positive patients. Our analyses suggested that p16 status is also a strong prognostic marker for HNSCC patients in Thailand.     

Elderly Patients With Squamous Cell Carcinoma of the Head and Neck and the Benefit of Multimodality Therapy

Background.

Limited data are available regarding outcomes in elderly head and neck cancer patients. This retrospective study was designed to characterize head and neck cancer in geriatric patients.

Patients and Methods.

This study included all patients in a large university-based tumor registry who were diagnosed with head and neck cancer from January 1, 1990, to December 31, 2005. Patients aged ≥70 years at the time of diagnosis were defined as older. Overall survival and progression-free survival were censored at 60 months. Survival differences were compared using the log-rank test. Hazard ratios were estimated using a Cox proportional hazards model, adjusting for potential confounders.

Results.

Of 1,598 patients identified, 1,166 patients were aged <70 years (i.e., younger) and 281 patients were aged ≥70 years (older). When controlling for possible confounders, older patients were nearly twice as likely to die within 5 years as their younger counterparts (hazard ratio: 1.92). The median life expectancy for older patients was nearly 5 years for stage I–II disease and <2 years for stage III–IV disease. Older patients with stage III–IV disease who received multimodality therapy had 5-year survival similar to that younger patients with stage III–IV disease who were treated similarly (33.2% vs. 44.0%). Older patients with stage III–IV disease who received single-modality therapy had extremely poor survival compared with all other patients (hazard ratio for progression-free survival: 1.5).

Conclusion.

This study highlights the need for better understanding of the factors affecting head and neck cancer outcomes in elderly patients. Information about life expectancy in elderly head and neck cancer patients may help guide treatment decisions.     

High p16 Expression Predicts a Positive Response to Chemoradiotherapy in Stage IVa/b Head and Neck Squamous Cell Carcinoma

Background: The objective of this study was to evaluate the effect of p16 expression on response tochemoradiation in stage IVa/b head and neck squamous cell carcinoma (HNSCC) patients. Methods: Weretrospectively identified 64 patients with stage IVa/b HNSCC who received chemoradiation. Eligibility criteriaincluded presence of biopsy-proven stage IVa/b HNSCC without a prior history of chemotherapy or radiotherapy.Immunohistochemistry was used to assess p16 protein expression in pretreatment biopsy specimens. Results: Ofthe 64 patients, 38 showed high p16 expression, and 50 patients responded to chemoradiotherapy, 32 exhibitinga complete and 18 a partial response. Response was significantly associated with p16 expression (P<0.001)and multivariate analysis indicated that that p16 expression (HR: 2.62, 95%C.I.: 1.14-6.06; P=0.024) was anindependent prognostic factor for overall survival. Conclusions: High p16 expression predicts a better responseto chemoradiation in patients with stage IVa/b HNSCC.     

头颈鳞癌的术前化疗效果

[目的]研究术前化疗能否提高手术切除率,降低局部复发率。［方法］104例头颈鳞癌病人分成试验组（58例）：术前化疗 手术 术后放疗组;对照组（46例）：手术 术后放疗,但不用术前化疗。手术方式为原发癌切除 颈淋巴结清扫术,用或不用肌皮瓣修复头颈部组织缺损。术后放疗剂量50Gy～60Gy。术前化疗用PFP方案即DDP＋5－Fu＋PYM。［结果］试验组部分缓解67.2%,微效17.2%。试验组和对照组3年局部复发率分别为27.6%、52．2％（P＜0.01）;但3年内远处转移率无差异,分别为34．5%、34．8%,中位生存期分别为23个月和22个月,3年生存率分别为65．5%和56．5%（P＞0.05）。［结论］术前新辅助化疗,可以缩小瘤体,提高手术切除率,减少局部复发。     

头颈部鳞癌肿瘤间质液压的检测

目的：为了检测头颈部鳞癌病人的肿瘤间质液压（TIFP）。方法：采用国产ZYH－3型组织液压测量仪，检测了16例头颈部鳞癌原发灶及4例转移灶的TIFP。结果：发现头颈部鳞癌原发灶和转移灶的TFFP都增高，测得的TIFP值与肿瘤体积具有良好的相关关系。结论：TIFP增高是恶性肿瘤的一项重要病理生理学特征。TIFP增高是抗癌药和免疫因子进入肿瘤的病理学障碍，因此，设法降低TIFP具有重要意义。     

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: A Review

Research indicates that a small population of cancer cells is highly tumorigenic, endowed with the capacityfor self-renewal, and has the ability to differentiate into cells that constitute the bulk of tumors. These cells areconsidered the ‘‘drivers’’ of the tumorigenic process in some tumor types, and have been named cancer stemcells (CSC). Epithelial-mesenchymal transition (EMT) appears to be involved in the process leading to theacquisition of stemness by epithelial tumor cells. Through this process, cells acquire an invasive phenotype thatmay contribute to tumor recurrence and metastasis. CSC have been identified in human head and neck squamouscell carcinomas (HNSCC) using markers such as CD133 and CD44 expression, and aldehyde dehydrogenase(ALDH) activity. Head and neck cancer stem cells reside primarily in perivascular niches in the invasive frontswhere endothelial-cell initiated events contribute to their survival and function. Clinically, CSC enrichment hasbeen shown to be enhanced in recurrent disease, treatment failure and metastasis. CSC represent a novel targetof study given their slow growth and innate mechanisms conferring treatment resistance. Further understandingof their unique phenotype may reveal potential molecular targets to improve therapeutic and survival outcomesin patients with HNSCC. Here, we discuss the state-of-the-knowledge on the pathobiology of cancer stem cells,with a focus on the impact of these cells on head and neck tumor progression, metastasis and recurrence due totreatment failure.     

Early Detection of Recurrent Disease by FDG‐PET/CT Leads to Management Changes in Patients With Squamous Cell Cancer of the Head and Neck

Objective.

The objective of this study was to compare the efficacy of surveillance high-resolution computed tomography (HRCT) and physical examination/endoscopy (PE/E) with the efficacy of fluorodeoxyglucose (FDG)-positron emission tomography (PET)/HRCT for the detection of relapse in head and neck squamous cell carcinoma (HNSCC) after primary treatment.

Methods.

This is a retrospective analysis of contemporaneously performed FDG-PET/HRCT, neck HRCT, and PE/E in 99 curatively treated patients with HNSCC during post-therapy surveillance to compare performance test characteristics in the detection of early recurrence or second primary cancer.

Results.

Relapse occurred in 19 of 99 patients (20%) during a median follow-up of 21 months (range: 9–52 months). Median time to first PET/HRCT was 3.5 months. The median time to radiological recurrence was 6 months (range: 2.3–32 months). FDG-PET/HRCT detected more disease recurrences or second primary cancers and did so earlier than HRCT or PE/E. The sensitivity, specificity, and positive and negative predictive values for detecting locoregional and distant recurrence or second primary cancer were 100%, 87.3%, 56.5%, and 100%, respectively, for PET/HRCT versus 61.5%, 94.9%, 66.7%, and 93.8%, respectively, for HRCT versus 23.1%, 98.7%, 75%, and 88.6%, respectively, for PE/E. In 19 patients with true positive PET/HRCT findings, a significant change in the management of disease occurred, prompting either salvage or systemic therapy. Of the 14 curatively treated patients, 11 were alive with without disease at a median follow-up of 31.5 months.

Conclusion.

FDG-PET/HRCT has a high sensitivity in the early detection of relapse or second primary cancer in patients with HNSCC, with significant management implications. Given improvements in therapy and changes in HNSCC biology, appropriate modifications in current post-therapy surveillance may be required to determine effective salvage or definitive therapies.     

Wnt Signaling: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Cellular maintenance and development are two fundamental mechanisms regulated by the canonical Wnt signalingpathway. Wnt/beta-catenin signaling pathway controls a myriad of cellular processes that are essential for normal cellfunctioning. Cell cycle progression, differentiation, fate determination, and migration are generally orchestrated bycanonical Wnt signaling. Altered Wnt/beta-catenin signaling has been considered a promoting event for different typesof cancers and the oncogenic potential of Wnt signaling have been discussed in many cancer types, including breast,colon, pancreatic as well as head and neck. Furthermore, Wnt signaling is critical for the maintenance and stemnessof both the normal as well as cancer stem cells. This review sheds new light on Wnt signaling and explains how it canregulate normal physiological processes and curtail the development of cancer. It depicts the vital functions of Wntsignaling in the stem cell growth and differentiation by focusing on current druggable targets that have been ascribedby recent studies. Thus, Wnt signaling pathway retains a tremendous potential in eradicating head and neck squamouscell carcinoma.     

Curative-Intent Radiotherapy for Squamous Cell Carcinoma of the Head and Neck in Sri Lanka: The Impact of Radiotherapy Technique on Survival

AimsWe conducted a retrospective analysis of patients with squamous cell carcinoma of the head and neck (SCCHN) treated with curative-intent radiotherapy at the National Cancer Institute of Sri Lanka to determine the impact of the treatment technique on disease-free survival (DFS).Materials and methodsSCCHN patients treated with radical radiotherapy or adjuvant postoperative radiotherapy from 2016 to 2017 were included in the study. Data on the following variables were collected by reviewing clinical and radiotherapy treatment records: age, gender, tumour site, stage, time to delivery of radiotherapy, use of neoadjuvant chemotherapy, use of concurrent radiosensitising chemotherapy and treatment technique. DFS, defined as the time to death, tumour recurrence or loss to follow-up, was the primary end point and outcomes were compared between patients treated with intensity-modulated radiotherapy (IMRT) in linear accelerators and those treated with conventional radiotherapy in cobalt teletherapy units. Univariate and multivariate analyses were carried out on known prognostic variables.ResultsIn total, 408 patients were included in the study, with 138 (34%) being treated with IMRT in the linear accelerator. More than 75% of patients were of stage III or IV at diagnosis. The 2-year DFS of the whole cohort was 25% (95% confidence interval 21–30%). Patients treated with IMRT in the linear accelerator had a superior DFS in comparison with those treated with conventional radiotherapy in the cobalt teletherapy units (P < 0.001, hazard ratio 0.64, 95% confidence interval 0.5–0.82). Higher stage, cobalt treatment and use of neoadjuvant chemotherapy were adversely associated with DFS on multivariate analysis.ConclusionA large proportion of patients with SCCHN treated with curative-intent radiotherapy in Sri Lanka had locally advanced disease and DFS was superior in patients treated with IMRT in the linear accelerator.     

国内外头颈部鳞癌指南循证评价(鼻咽癌除外)

目的 了解国内外头颈部鳞癌指南的发布状况、评价其质量,为我国制定头颈部鳞癌指南提供借鉴。方法 计算机检索PubMed、Embase、NGC(U.S. National Guideline Clearing-house), CMAInfobase(the Canadian Medical Association Infobase), GIN(the Guidelines International Network), SIGN(theScottish Intercollegiate Guidelines Network), the CMAdisc等中英文数据库和指南网站,按既定的纳入与排除标准,筛选文献,纳入符合标准的指南,用指南评价工具AGREE( Appraisal of Guideline forREsearch and Evaluation) Ⅱ对其进行质量评价。结果 共检索出514篇相关文献,最终纳入49篇头颈部鳞癌指南,共覆盖15个国家、地区。现有指南主要由美国、加拿大、英国发布。49篇指南6个领域的得分分别为：71.63%、43.37%、45.63%、68.08%、32.41%、42.55%。结论 国内外头颈部鳞癌指南的质量中等,国内可借鉴AGREE的评价体系结合国内实际制定高水平的临床指南。     

Induction Chemotherapy to Weekly Paclitaxel Concurrent with Curative Radiotherapy in Stage IV (M0) Unresectable Head and Neck Squamous Cell Carcinoma: a Dose Escalation Study

Abstract

The purpose was to determine the maximum tolerated dose (MTD) of weekly paclitaxel with concurrent, daily irradiation in patients with unresectable head and neck squamous cell carcinoma previously submitted to induction chemotherapy. Patients with stage IV, and unresectable tumor and/or node/s were enrolled. Nine male patients were submitted to a course of paclitaxel 175 mg/m² day 1 and cis-platin 75 mg/m² day 2 given every 3 weeks for three courses. Curative radiothera-py (RT) started 3 weeks after the last cycle of chemotherapy with the goal of deliv-ering a total dose of 66-70 Gy. During RT weekly paclitaxel was administered for 6 courses if feasible; paclitaxel was given according to a dose escalation schema in cohorts of three patients. Dose level A, 30 mg/m²; dose level B, 40 mg/m²; dose level C, 50 mg/m². During weekly paclitaxel the major toxicity was mucositis that required a treatment break in two of three patients in dose level C; mucositis grade 4 required interruption of paclitaxel administration in all these patients. RT can be given in a continuous fashion with weekly paclitaxel after induction chemotherapy. The MTD of weekly paclitaxel was 40 mg/m².     

Accuracy of Response Assessment Positron Emission Tomography-Computed Tomography Following Definitive Radiotherapy Without Chemotherapy for Head and Neck Squamous Cell Carcinoma

Aim

There are few data to inform on the use of response assessment 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography-computed tomography (PET-CT) following radical radiotherapy without chemotherapy for head and neck squamous cell carcinoma (HNSCC). This retrospective study evaluated the accuracy of PET-CT in HNSCC following radical radiotherapy.

无法切除的复发头颈部鳞癌的姑息放疗

为评价头颈部鳞癌术后复发患者行姑息放疗的疗效及其影响因素，对１９８８年７月至１９９６年２月在我科接受姑息放疗的１０６例患者的资料行回顾性分析。结果：放疗后ＣＲ２２．６％（２４／１０６），ＰＲ３８．７％（４１／１０６），ＮＲ３８．７％（４１／１０６）；总有效率为６１．３％（６５／１０６）；放疗后挽救性手术成功率为４／９；疗后６３．２％（６７／１０６）的患者Ｋａｒｎｏｆｓｋｙ得分上升，症状减轻，生存质量提高；１、２、３年生存率分别为５４．７％（５８／１０６）、２１．７％（２３／１０６）和５．７％（６／１０６）；远处转移率２９．２％（３１／１０６），放疗并发症１０．４％（１１／１０６）。结论：姑息放疗是晚期头颈部鳞癌术后复发患者一种较好的治疗选择；为了提高疗效，放射剂量应尽可能高于５０Ｇｙ，采用超分割连续放疗技术和避免分段。     

Influence of Tumor Site on Survival in Young Patients with Head and Neck Squamous Cell Carcinoma

The number of patients under the age of 45 diagnosed with head and neck squamous cell carcinomas (HNSCC) is increasing, probably due to the incidence of oropharyngeal cancers. Comparisons of HNSCC in young and old patients regarding tumor site and survival in sample sizes of relevance are rarely published. The aim of the study was to analyze the differences in survival between age groups dependent on tumor site and the influence of oropharyngeal cancers on the rising rates of HNSCC in the young. The records of 4466 patients diagnosed with HNSCC were reviewed retrospectively. Patients younger than 45 years were divided further into four subgroups for specific age differences in the young. The influences of patient and clinicopathological characteristics on survival were assessed using Kaplan–Meier analyses. Among the patient cohort, 4.8% were younger than 45 years. Overall survival (OS) in these patients was better, with a 5-year OS of 66.1% (vs. 46.4%), while relapse-free survival (RFS) was better in the older patient population, with a 5-year RFS of 74.9% (vs. 68.1%). Decreased RFS in the young was found for advanced tumor stages and tumor sited at the larynx. Hypopharynx and advanced stages were independent risk factors for OS under 45 years. Overall, 44.4% of all HNSCC in patients under 30 years were nasopharyngeal cancers, and incidence decreased with age. The incidence of oropharyngeal cancers increased significantly with age. Better OS in the young may be explained by lower tumor and disease stages, whereas oropharyngeal tumors and HPV were not found to cause rising rates of HNSCC. Laryngeal malignancies in young patients might be related to an increased malignant potential and should, consequently, be treated as such.     

乙酰肝素酶和VEGF在头颈鳞癌组织中的表达及其临床意义

目的: 探讨HPSE、VEGF蛋白在头颈鳞癌组织中的表达及其临床意义,并探讨其相关性。 方法: 采用免疫组织化学(S-P法)和流式细胞检测方法对62例头颈鳞癌组织中HPSE和VEGF蛋白的表达进行检测,并采用计算机图像分析进行定量分析。 结果: HPSE和VEGF蛋白在头颈鳞癌组织中的表达均高于正常粘膜组织(P<0.01);淋巴结转移组鳞癌组织中HPSE和VEGF的表达高于无淋巴结转移组(分别为P<0.05和P<0.01);淋巴结转移组中原发灶与转移灶中HPSE和VEGF的表达差异无统计学意义(P值均>0.05),但原发灶与转移灶之间的表达成正相关(分别r=0.9162,r=0.9278,P均<0.01);HPSE和VEGF的表达均与头颈鳞癌组织中TNM分期有关(P均<0.05);HPSE与VEGF在头颈鳞癌组织中的表达呈正相关关系(r=0.7602,P<0.01);HPSE和VEGF的表达分别与患者的生存期存在负相关关系(分别为r=-0.647,r=-0.568,P均<0.01)。 结论: 头颈鳞癌组织中HPSE和VEGF蛋白的表达与TNM分期、淋巴结转移和预后有密切关系,两种基因起头颈鳞癌发生、发展中起重要作用。