Human papillomavirus-16 in oral squamous cell carcinoma: clinical correlates and 5-year survival

We examined 66 oral squamous cell carcinomas (OSCCs) for human papillomavirus-16 (HPV-16) infection to evaluate its prognostic significance. Cox regression analysis of 5-year survival demonstrated that patients without nodal metastasis or with intratumoural HPV-16 showed better prognoses compared with each counterpart. In Kaplan-Meier survival analysis, nodal status but not HPV-16 status was statistically significant. The 5-year survival rate of HPV-16 positive patients without nodal metastasis (94%) was extremely high, compared with that of HPV-16 negative patients with nodal metastasis (25%). These results suggest that HPV-16 status as well as nodal status may provide prognostic significance in patients with OSCC.     

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。     

Influence of close resection margins on local recurrence and disease-specific survival in oral and oropharyngeal carcinoma

There is a lack of consistency among published reports in the definition of what constitutes close resection margins (1-5mm) in the surgical treatment of oral and oropharyngeal squamous cell carcinoma (SCC). Our aim was to define what would constitute close resection margins in predicting local recurrence and disease-specific survival. The study comprised 192 previously untreated patients with oral and oropharyngeal SCC who were recruited at the Southern General Hospital, Glasgow, from 2001 to 2007 with a minimum follow-up of 2 years. Resection was the primary treatment and the surgical margins were recorded for all patients. Statistical analyses were aided by the Statistical Package for the Social Sciences, version 15.0, and MedCalc software. The status of the surgical margins was evaluated using a receiver operating characteristic (ROC) curve to define the cut-off point. Cox's proportional hazard model was used to establish predictive factors for local recurrence and disease-specific survival. Of 192 patients, 23 (12%) had involved margins (<1.0mm), 107 (56%) had close margins (1.0-2.0mm (16.1%); 2.1-3.0mm (12%); 3.1-4.0mm (10.4%); 4.1-5.0mm (17.2%), and 62 (32.3%) had clear margins (>5mm). No predictive cut-off point was found that related close surgical margins to local recurrence. However, there was a significant adverse association between surgical margins ≤1.6mm and disease-specific survival. In recommending postoperative adjuvant treatment for oral and oropharyngeal SCC, we suggest that surgical margins within 2mm should be considered as the cut-off. However, other clinical and pathological prognostic factors should also be taken into consideration when recommending further treatment.     

2019年NCCN口腔口咽癌诊疗指南更新解读

美国癌症联合委员会2017年第8版《AJCC肿瘤分期手册》出版,口腔及口咽癌TNM分期标准中新增侵袭深度（DOI）、淋巴结外扩展（ENE）、人乳头瘤病毒（HPV）等指标,并将口咽癌分为HPV阳性（p16+）与HPV阴性（p16-）,分别制定了不同的TNM分期标准。2018年,美国国立综合癌症网（NCCN）首次为HPV阳性（p16+）口咽癌制定了诊疗指南。2019年第1版NCCN头颈癌诊疗指南已经发布,其中对口腔口咽癌指南做了部分修订。为临床工作需要,本文结合2版变化进行部分解读。     

Human papillomavirus, p53 and cyclin D1 expression in oropharyngeal carcinoma

Forty-two specimens from oropharyngeal (tonsil and base of tongue) squamous cell carcinoma patients (SCC) were studied for presence of HPV 16 by in situ hybridization and by immunohistochemistry for p53 and Cyclin D1 protein overexpression. Thirty-one per cent of cases were HPV-16 positive, which correlates with the prevalence reported worldwide. 74% of cases showed p53 protein overexpression and 79% showed Cyclin D1 overexpression. There was no correlation between HPV status and either p53 or Cyclin D1 overexpression (P>0.05). These three variables also did not correlate with factors such as grade of the tumour, stage of the disease or lymph nodal metastasis at presentation.     

Survey of the use of tests for human papilloma virus and epidermal growth factor receptor for squamous cell carcinoma of the head and neck in UK head and neck multidisciplinary teams

Human papilloma virus (HPV), usually type 16, has emerged as an aetiological and prognostic marker of oropharyngeal carcinomas, and epidermal growth factor receptor (EGFR) has been associated with poor prognosis in patients with carcinoma of the head and neck. This makes the identification of cancers associated with these biomarkers important in the management of patients. We surveyed UK head and neck multidisciplinary teams by email using an online form to assess the use of biomarker testing. Overall 33 cancer networks were contacted and 28 (85%) responded. HPV tests were used in departments by 22 (79%) of our respondents, while only 3 (11%) used EGFR tests. The commonest reasons for not using them were lack of availability and lack of clinical indication.     

Epidemiology and survival outcomes of lip,oral cavity,and oropharyngeal squamous cell carcinoma in a southeast Brazilian population

Background Lip, oral cavity, and oropharyngeal squamous cell carcinoma (SCC) represent a major health problem in the global scenario. In South America, the highest incidence rates are seen in Brazil. Therefore, the epidemiological and clinical profile and survival outcomes of lip, oral cavity, and oropharyngeal SCC was studied in São Paulo State, Brazil.Material and Methods The clinicopathological data of 12,099 patients with lip, oral cavity, and oropharyngeal SCC were obtained from hospital cancer registries of the Fundação Oncocentro de São Paulo, Brazil (2010–2015). Survival rates and other analyses were performed using SPSS software.Results A clear male predominance was observed, particularly for patients with oropharyngeal SCC (88.3%). The average age of patients was higher for lip cases (65 ± 13.5 years) compared to other sites. The schooling level was low for most patients, especially in lip cases (87.9%). Most of the patients with oral cavity (71.8%) and oropharyngeal (86.3%) SCC had advanced-stage (III–IV) disease. However, the majority of lip cases (83.3%) were at an early stage (I–II). Surgical excision was the main treatment for lip (72%) and oral cavity SCC (23.5%), and chemoradiotherapy was the main treatment for oropharyngeal SCC (40.2%). The 5-year overall survival (OS) for patients with lip, oral cavity, and oropharyngeal SCC were 66.3, 30.9, and 22.6%, respectively. Multivariate analysis revealed that the determinants of OS were different for lip, oral cavity, and oropharyngeal SCC, except for those at the clinical stage, which was an independent predictor for all sites.Conclusions OS-independent determinants varied according to the affected site. Oral cavity and oropharyngeal SCC presented worse survival rates than those for lip SCC. Key words:Squamous cell carcinoma of head and neck, lip neoplasms, mouth neoplasms, oropharyngeal neoplasms, survival analysis.     

Prognostic significance of lymph node ratio in patients with squamous cell carcinoma of the floor of the mouth

The lymph node ratio (LNR) has been proposed as an independent prognostic factor for survival in patients with oral squamous cell carcinoma (OSCC). However, little attention has been paid to its role in the specific subsite of the floor of the mouth (FOM). The purpose of this study was to evaluate the prognostic significance of the LNR in patients with FOM SCC. A retrospective analysis of 92 patients with FOM SCC who were treated with primary curative resection and neck dissection was conducted. Overall survival (OS) and disease-free survival (DFS) were used to evaluate the prognostic significance of the LNR. Both of these parameters were significantly worse (P < 0.001) in patients with neck metastases. The mean LNR was 0.145 in patients with positive lymph nodes. A LNR <0.145 was predictive of longer DFS, while the receiver operating characteristic curve analysis demonstrated that a LNR ≥0.175 indicated a significantly lower OS. This study confirms that metastatic cervical lymph nodes correlate with an adverse prognosis in patients with FOM SCC, and specifically, a LNR ≥0.145 is predictive. Therefore, the LNR in patients with FOM SCC may be a predictor of survival in these patients.     

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.     

Detection of human papillomavirus-16 and HPV-18 DNA in normal,dysplastic, and malignant oral epithelium

OBJECTIVE: Our aim was to clarify the association of human papillomavirus (HPV) with oral carcinogenesis, especially its early stage. STUDY DESIGN: Tissue specimens of normal mucosa, epithelial dysplasia, oral squamous cell carcinoma (OSCC), and OSCC cell lines were examined for the presence of HPV-16 and HPV-18 E6 DNA by means of the polymerase chain reaction test. RESULTS: The detection rate of HPV-16 in epithelial dysplasia (31/51) was higher than that in normal mucosa (16/44) and in OSCC (30/86) and was statistically different from that in OSCC. The cases that progressed from epithelial dysplasia to carcinoma showed a significantly higher HPV-16 detection rate than the other cases in both epithelial dysplasia and OSCC. HPV-16 and HPV-18 were detected only at early passages of 2 of 10 OSCC cell lines. CONCLUSIONS: These results strongly suggest that HPV-16 may be involved in the early stages of the development of some oral carcinomas.     

The role of thoracic computed tomography in staging newly-diagnosed oral squamous cell carcinoma

Patients who present with squamous cell carcinoma (SCC) in the head and neck have a serious risk of coincident thoracic malignancy. The aim of this study was to identify the incidence of thoracic malignancy in newly diagnosed, previously untreated, oral and oro-pharyngeal SCC, and to evaluate the role of thoracic computed tomography (CT) in its management. Of 116 consecutive patients who were identified prospectively 81(70%) had oral and 35 (30%) oropharyngeal SCC. Ten patients (9%) had suspicious thoracic CT findings. After investigation or follow up, four (3.5%) of these patients were shown to have coincident thoracic malignancies. This large prospective series of newly diagnosed oral and oropharyngeal SCC had a lower incidence of coincident thoracic malignancy than had previously been shown.     

Hypercalcemic complication in patients with oral squamous cell carcinoma

Hypercalcemia is one of the metabolic complications associated with cancer. To assess the frequency of hypercalcemia in patients with squamous cell carcinoma (SCC), 242 patients who were evaluated as having SCC in the oral cavity between July 1995 and June 2001 were investigated. All patients were periodically monitored for their serum level of calcium (Ca). Hypercalcemia was defined as a serum Ca concentration higher than 11 mg/dl. By this definition, hypercalcemia was detected in 12 of the 242 patients (5.0%). All 12 patients were at an advanced stage of oral SCC. In these 12 patients, the serum level of parathyroid hormone-related protein (PTH-rP) was also significantly elevated. Therefore, we diagnosed these diseases as humoral hypercalcemia of malignancy (HHM). Moreover, we studied the efficacy of anti-hypercalcemic therapy on the quality of life (QOL). The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 was used for estimation of QOL. The patients with HHM who were administrated drugs such as bisphosphonate and calcitonin showed a reduction in their Ca and PTH-rP levels, and the six of ten EORTC QLQ-C30 subscales (emotional functioning, cognitive functioning, fatigue, dyspnoea, nausea/vomiting and appetite loss) were also improved after the anti-hypercalcemic therapy. However, these suppressive effects were temporary. The median survival time after the diagnosis of HHM was only 54.9+/-18.3 days (range 27-86 days). Therefore, HHM in SCC appears to be an ominous prognostic sign. Although anti-hypercalcemic therapy has a palliative role, the patients may be in less discomfort during the terminal stage of their illness.     

Cancer of the buccal mucosa: a tale of two continents

Squamous cell carcinoma (SCC) of the buccal mucosa in North America is thought to be different from that in the Indian subcontinent. This study compared the treatment outcomes and prognostic factors in 64 patients with SCC of the buccal mucosa treated at Cancer Care Manitoba (CCMB), Canada, and 64 similar patients treated at the Tata Memorial Hospital (TMH), India. Overall, cause-specific and disease-free survival for the two geographical groups were calculated and the impact of individual prognostic factors on survival was assessed. CCMB patients were significantly older (p<0.001), had less differentiated tumour (p=0.053) and had higher chances of positive or close surgical margins (p=0.012). At 5 years, they had lower 5-year overall survival (57.4% versus 80.1%; p<0.001), cancer-specific survival (76.4% versus 85.0%; p=0.043) and disease-free survival (42.9% versus 66.4%; p=0.004). Age had an independent influence on overall survival and cause-specific survival. After adjusting for age there was no difference in cause-specific survival between the two groups (HR=1.20; 95% CI=0.46,3.17; p=0.710). The apparent survival difference between the CCMB and TMH patients was due to the difference in the age of presentation and not because of different biological behaviour.     

Maximum standardised uptake value is prognostic in patients with early-stage squamous cell carcinoma of the tongue

The aims of this paper were to evaluate the relation between the preoperative primary tumour maximum standardised uptake value (SUVmax, tSUVmax) and clinicopathological features, including depth of invasion (DOI), recurrence factors, and survival outcomes, and to compare the prognostic value of tSUVmax with that of other factors associated with the recurrence of early-stage oral squamous cell carcinoma (OSCC) of the tongue. We retrospectively analysed data from 155 patients. All patients were treated and regularly monitored at the Changhua Christian Hospital (CCH). Only those who had undergone ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the 14 days before surgery were included. A tSUVmax of >5.2 was found to be the sole strong predictor of a DOI of >4 mm. A tSUVmax of >7.6 was strongly associated with pT2 SCC of the tongue, more aggressive DOI, and perineural invasion. DOI and tSUVmax could be used to predict disease-free survival (DFS) for early-stage SCC of the tongue, and they showed stronger predictive power than the traditional American Joint Committee on Cancer (AJCC) T stage. Therefore tSUVmax could be a prognostic tool for DFS in AJCC early-stage SCC of the tongue.     

Involved surgical margins in oral and oropharyngeal carcinoma—an anatomical problem?

A previous audit conducted in the West of Scotland (WoS) suggested that anatomical factors accounted for a substantial proportion of invaded surgical margins after resection of an oral or oropharyngeal squamous cell carcinoma (SCC). Since then a number of technical improvements have taken place, the most important of which has been advanced digital imaging that has enabled better surgical planning. In this study we compare the incidence of involved surgical margins in a recent group with those found in the earlier audit. The earlier (WoS) group comprised a consecutive series of patient operated on for a primary SCC of the oral cavity or oropharynx between November 1999 and November 2001 (n = 296). The later series comprised 178 patients operated on for oral or oropharyngeal SCC at the Southern General Hospital (SGH), Glasgow, between 2006 and 2009. A total of 245 patients in the WoS cohort had information available on the invasion of the margins of whom 68 (28%) had an invaded margin. Of 177 patients in the SGH group, 9 (5%) had an invaded margin (p = 0.001). An anatomical approach to the resection of oral and oropharyngeal SCC is appropriate, as it results in a rate of invaded margins of less than 10% irrespective of size and site of the primary lesion.     

Impact of epidermal growth factor receptor,mesenchymal–epithelial transition factor,and insulin-like growth factor receptor 1 expression on survival of patients with oral and oropharyngeal cancer

The aim of this study was to evaluate the impact of expression of epidermal growth factor receptor (EGFR), mesenchymal–epithelial transition factor (c-Met), and insulin-like growth factor receptor 1 (IGF-1R) protein on response to treatment and survival in patients with oral and oropharyngeal squamous cell carcinoma (SCC). EGFR, c-Met, and IGF-1R immunohistochemical (IHC) scores were generated based on the incidence and intensity of expression of the biomarkers evaluated in paraffin-embedded sections of biopsy specimens taken before treatment from 113 patients given neoadjuvant chemoradiotherapy followed by resection for primary locally advanced oral and oropharyngeal SCC. Correlations were assessed between the IHC of the biomarkers and the patients’ clinicopathological variables using Spearman's rank test. Cox's regression models were used to evaluate the impact of EGFR, c-Met, and IGF-1R, expression on survival.     

Prognostic importance of DNA from human papillomavirus in patients with oral squamous cell carcinoma

Background Survival of patients with oral squamous cell carcinoma (OSCC) is generally low, with the likelihood of locoregional recurrence or disease progression (LR/DP). Knowledge of prognostic factors for survival is key to achieving an understanding and increased survival. The present study aimed to identify prognostic factors for patients with OSCC, especially the presence of DNA from human papillomavirus (HPV).Material and Methods Retrospective cohort study including 119 patients with OSCC treated at the National Cancer Institute in Mexico City (2009-2013). Clinical information was obtained from patient records including LR/DP. Formalin-fixed, paraffin-embedded tissues were obtained and used for detecting DNA from different types of HPV. Potential prognostic factors for Overall Survival (OS) were analyzed using the Cox proportional hazards model.Results After model adjustment, factors associated with longer OS were a pre-treatment platelet count above 400,000/mm3 (HR=0.09, p=0.026) and response to primary treatment (HR=0.26, p=0.001). HPV DNA was present in 23 (19.3%) of the patients and importantly, type 16 found in 19 of them. Although survival of HPV-positive patients was longer, difference was not significant. However, among patients with LR/DP, HPV positivity was significantly associated with increased survival (HR=0.23, p=0.034). Importantly, survival was significantly different for HPV-positive patients with LR/DP > 6 months (HR=0.20, p=0.002), had higher absolute lymphocyte count at start of treatment (HR=0.50, p=0.028) or had local rescue treatment (HR=0.24, p=0.019).Conclusions Although HPV positivity was not associated with a longer OS of OSCC patients, a better prognosis was significantly associated with HPV positivity and recurring or progressing disease, particularly with HPV type 16. Key words:HPV, human papillomavirus, HPV-16, oral squamous cell carcinoma, oral cancer, survival, locoregional recurrence, disease progression.     

New malignancy grading is a better prognostic indicator than Broders'' grading in oral squamous cell carcinomas

The prognostic value of histopathologic grading of oral squamous cell carcinomas (SCC) has varied from not any to highly significant. We have retrospectively studied all (130) SCCs registered in Norway 1963-72 in the buccal and maxillary alveolar mucosa. From 68 of these cases biopsy specimens of acceptable quality were obtained. Broders' method of grading was compared with a modification of a recent malignancy grading system recommended by Anneroth et al. which was performed only within the histologically most invasive areas of the tumors. Cox's multivariate survival analyses showed that this grading in the invasive sites had highly significant prognostic value. Broders grade had no prognostic value. The stage of tumor had also prognostic value. These highly significant results indicate that the histologically invasive areas may be primarily responsible for the clinical behavior of the tumor, and this may be of importance for the choice of therapy for oral SCC.     

Oral and oropharyngeal cancer in the West of Scotland—long-term outcome data of a prospective audit 1999-2001

We prospectively studied patients from the west of Scotland who presented with a primary cancer of the oral cavity or oropharynx over a period of 24 months from November 1999, and report long-term outcomes and prognostic factors. A total of 481 patients had squamous cell carcinoma (SCC), 5-year disease-specific survival (DSS) was 50%, and overall survival (OS) was 35%. One hundred were not suitable for treatment with curative intent, and factors other than stage were important in this decision. Of those treated with curative intent, 249 had SCC of the oral cavity (5-year DSS 67%; OS 42%), and 132 had SCC of the oropharynx (5-year DSS 62%; OS 42%). Multivariate analysis showed that pathological nodal stage (p = 0.051, 95% CI 0.998-1.955), and perineural invasion (p = 0.001, 95% CI 0.186-0.666) were prognostic indicators. Improved results using intensive treatment protocols that have been seen in trials are not likely to translate directly into a general population of patients with head and neck cancer. Algorithms that allow several pathological prognostic indicators to be incorporated into decisions about adjuvant treatment should be used.     

Serum p53 antibodies as a prognostic indicator in oral squamous cell carcinoma

The purpose of the present study was to investigate the clinical usefulness of the detection of serum p53 antibodies (p53 Abs) in patients with oral squamous cell carcinoma (SCC). Preoperative values of p53 Abs were measured by enzyme-linked immunosorbent assay in 113 patients with primary oral SCC and seropositive patients were reevaluated postoperatively. The positivity rate of p53 Abs was 16%, and the 5-year survival rate of patients positive for p53 Abs was significantly lower than that of patients negative for p53 Abs (56.2% vs. 80.7%; P = 0.018). The preoperative presence of p53 Abs was found to be an independent prognostic factor in a multivariate analysis (P = 0.028, hazards ratio = 3.34), and its positivity was significantly related to secondary cervical lymph node metastases (P = 0.029). Six of nine patients who remained seropositive for p53 Abs through the disease course and the one with seropositive reversion from temporary negative status developed treatment failure. Therefore, the detection of p53 Abs in the serum of patients with SCC may be a useful prognostic marker.