Lower prevalence but favorable survival for human papillomavirus-related squamous cell carcinoma of tonsil in Taiwan

doi:10.1016/j.oraloncology.2007.01.018

Oral Oncology

Volume 44, Issue 2, February 2008, Pages 174-179

https://doi.org/10.1016/j.oraloncology.2007.01.018 Get rights and content

Summary

Human papillomavirus (HPV) is frequently detected in squamous cell carcinoma of tonsil (TSCC) among the Western population. However, the only reported study on Chinese patients in the English literature demonstrated absence of HPV in TSCC. To evaluate the prevalence and clinical significance of HPV-related TSCC in Taiwan, we performed PCR with MY09/MY11 consensus primers and in situ hybridization to study 111 TSCC samples. The results showed that only 12.6% TSCC were HPV-positive. The favorable 5-year survival rate correlated significantly with HPV positivity (p = 0.007), female (p = 0.046), and early tumor (T) stage (p < 0.001), but Cox’s regression analysis revealed that only the status of HPV (p = 0.04) and T stage (p = 0.004) were independent prognostic factors for survival. In conclusion, the prevalence of HPV-related TSCC is much lower in Taiwan comparing with the Western population, and the prognosis of HPV-positive TSCC is better than that of HPV-negative TSCC.

Introduction

Squamous cell carcinoma of the head and neck regions (HNSCC) is a common worldwide malignancy. It is usually associated with alcohol and tobacco use, but chewing of betel quid is also an important risk factor in Asia.¹ The incidence of HNSCC in men is higher than that in women, and the cancer-associated mortality is around 50% of the incidence.2, 3 In contrast, a subset of HNSCC, frequently occurring in young adults and women without the exposure history of alcohol and tobacco use or betel quid chewing, has been found to be associated with human papillomavirus (HPV) infection.4, 5 There are growing evidences that high-risk types of HPV account for the occurrence of these kinds of HNSCC especially HPV 16.6, 7, 8, 9, 10

The oncogenic types of HPV produce two viral oncoproteins, E6 and E7, which functionally inactivate two important human tumor suppressor proteins, p53 and pRb, respectively. These would result in loss of cell cycle regulation and immortalize the oral keratinocytes.11, 12 The most common HPV-related HNSCC has been found to be in squamous cell carcinoma of tonsil (TSCC).9, 13, 14 Lots of studies revealed that more than 50% of TSCC contained HPV genomes in the tumor cell nuclei.7, 15, 16, 17, 18 High-risk HPV 16 DNA has been known to play a role in the process of tumorigenesis of HNSCC,7, 10, 19 and is present with high copy number in the tumor cells in both the primary and metastatic areas.²⁰

However, the only documented HPV study on 16 Chinese TSCC patients failed to identify HPV.²¹ Furthermore, different from that in the Western population, betel-quid chewing is an emerging threat to public health and a major cause of HNSCC in Taiwan.¹ Hence, this study was aimed to explore the prevalence of HPV in TSCC in Taiwan and examined its relationship with the clinicopathological parameters.

Section snippets

Study population and tissue samples

There were 111 TSCC patients included in this retrospective study, who underwent either surgical resection with postoperative adjuvant radiotherapy and/or chemotherapy or primary radiotherapy after biopsy between 1992 and 2005 at Chang Gung Memorial Hospital-Kaohsiung Medical Center. The clinicopathological information including age, gender, tumor (T) stage, nodal (N) status, TNM stage, tumor differentiation and survival was obtained from the clinical records. The histories of betel quid,

Results

There were 100 men and 11 women with an average age of 50.3 years (ranged 20 to 83). Sixty-five patients underwent curative surgery with postoperative adjuvant radiotherapy and/or chemotherapy and the others underwent primary radiotherapy after biopsy. Nine patients were classified as T1, 55 as T2, 29 as T3, and 18 as T4. Twenty-three patients were classified as N0, 15 as N1, 57 as N2 and 16 as N3. There were 0 stage I, 15 stage II, 20 stage III and 76 stage IV carcinomas. The differentiation

Discussion

It is known that the risk factors for the development of TSCC include the use of alcohol and/or tobacco, and recent investigations have shown that HPV may also be a unique risk factor in a subset of TSCC patients.⁵ Some studies reported that patients with HPV-positive TSCC tend to be younger,14, 17 but others studies did not find the same trend.13, 27 The current study showed that the greater incidence of HPV in TSCC was associated with females, non-smokers and non-betel-quid chewers, but not

Conflict of interest statement

All authors hereby declare that there were no financial and personal relationships with other people or organisations that could inappropriately influence (bias) this work.

Acknowledgements

The authors thank Professor Dr. E-M de Villiers at German Cancer Research Center, Heidelberg, Germany for kindly providing them HPV 6, 11, 16, and 18 as DNA templates to generate the HPV DNA probes for in situ hybridization.

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Data from the Taiwan Cancer Registry and Taiwan’s National Health Insurance Research Database were used to identify patients with HNC from 2011 to 2017. All the identified patients were monitored until the date of death or the end of 2017. Poisson regression models were employed to estimate the incidence rate ratios (IRRs) and 95% confidence intervals (CIs) associated with the effect of ABC habits on mortality.
A total of 31,246 patients with HNC were analyzed in this study. The results revealed that betel nut chewing alone exhibited the strongest effect, significantly increasing the risk of overall mortality (adjusted IRR = 1.44, 95% CI = 1.27–1.63). Additionally, betel nut chewing alone was significantly associated with cancer-specific mortality (adjusted IRR = 1.51, 95% CI = 1.30–1.44). Stratified analyses by sex and tumor location indicated that the effect of betel nut chewing alone on overall or cancer-specific mortality remained significant across both sexes, and among patients with oral cancer and patients with oropharyngeal cancer.
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Fifth, details on p16 and human papillomavirus (HPV) status were only available for a small proportion of patients (28.6%) with oropharyngeal carcinoma, which precluded us an analysis on the prognostic significance of this variable. However, the prevalence of HPV infections in Taiwanese patients with oropharyngeal carcinoma is relatively low (13–50%) [74,75]. Further research is necessary to shed more light on the prognostic significance of delta-LMR with respect to the patient’s HPV status.
We sought to investigate whether dynamic changes in lymphocyte-to-monocyte ratio (LMR) occurring during the course of radiotherapy (RT) may have prognostic value in patients with head and neck cancer (HNC).
We retrospectively reviewed the clinical records of patients with HNC who underwent RT at our center between 2005 and 2013. Generalized estimating equations were used to longitudinally assess changes in LMR through the course of RT. Delta-LMR was calculated as the difference between LMR measured during treatment and baseline LMR values. Freedom from metastasis (FFM) and overall survival (OS) served as the main outcome measures.
A total of 1431 patients with HNC were enrolled. After a median follow-up of 9 years, 636 (44.4%) patients died and 240 (16.8%) had distant metastases. Compared with patients with low delta-LMR at two weeks, those with high delta-LMR experienced less favorable outcomes (five-year OS: 73% versus 59%, respectively, p < 0.001; five-year FFM: 87% versus 80%, respectively, p = 0.015). Similar findings were observed for delta-LMR measured at four weeks (five-year OS: 72% versus 60%, p < 0.001; five-year FFM: 86% versus 79%, respectively, p = 0.002) and six weeks (five-year OS: 72% versus 57%, p < 0.001; five-year FFM: 87% versus 79%, respectively, p = 0.002). Multivariate analysis identified delta-LMR as an independent prognostic factor for both FFM and OS.
Delta-LMR is a simple and inexpensive biomarker that may be clinically useful for predicting FFM and OS in patients with HNC treated with RT.
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The incidence of HPV positive oropharyngeal cancer is increasing in Taiwan. Given this, it is critical to understand the prevalence of oral HPV infection since this cancer is potentially preventable. A community-based study was conducted to evaluate the prevalence of oral HPV infection and sexual behavior changes.
Between January and December 2016, 100 subjects between 20 and 70 years-old with current/ever betel nut chewing or current cigarette smoking visited the Department of Health, New Taipei City. Subjects with cancer history or known HIV/AIDS were excluded. Sexual behavior information was collected through a questionnaire. Oral rinse samples and oropharyngeal swabs were obtained for HPV genotyping using the EasyChip HPV genotyping array (King-Car, Taiwan).
92 men and 8 women were recruited. The prevalence of oral HPV infection was 3%, present between 60 and 70 (11%) and between 30 and 40 years old (4%). The prevalence of the first sexual contact at younger than 20 years old were 71.4%, 53.6%, 15.4% and 44% in <40, 40–49, 50–59 and 60+ years old, respectively (p for trend = 0.0036). The prevalence of 3 or more lifetime sexual partners were 60.7%, 57.1%, 23.1% and 16.7%, respectively for <40, 40–49, 50–59 and 60+ years old (p for trend = 0.0005).
The prevalence of oral HPV infection is 3%, in current/ever betel nut chewers or current cigarette smokers in Northern Taiwan. Younger generation have more lifetime sexual partners and younger first sexual contact. This could explain the rising incidence of HPV positive oropharyngeal cancer in Taiwan.
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In RTOG 0129 trial [12,13], 68% patients were HPV-positive cancers. In Taiwan, about 12–16% patients were HPV-positive oropharyngeal cancer [14,15]. Only 17 (15%) oropharyngeal cancer in this study and lower rate of HPV-positive cancer in Taiwan, these factors decreased the effects of HPV status in this study.
To compare the treatment outcomes and toxicity of both cisplatin and cisplatin plus 5FU chemotherapy in head and neck cancer patients who have received surgery, in addition to postoperative chemoradiotherapy.
From May 1991 to December 2012, a total of 113 head and neck cancer patients who received surgery, along with postoperative chemoradiotherapy were analyzed. The primary sites were oral cavity (86), oropharynx (17), hypopharynx (4), and larynx (6). Thirty-nine patients received cisplatin (P), while 74 patients received cisplatin plus 5FU (PF). The endpoints were overall survival (OS), local failure-free survival (LFFS), and distant metastasis-free survival (DMFS).
The median follow up time was 43 months, with a range of 4–222 months. The 3-year rates of OS, LFFS, and DMFS were 62.1%, 71.3%, and 82.4%, respectively. The 3-year OS for P and PF were 71.3% and 57.5% (p = 0.27).
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Lower prevalence but favorable survival for human papillomavirus-related squamous cell carcinoma of tonsil in Taiwan

Summary

Introduction

Section snippets

Study population and tissue samples

Results

Discussion

Conflict of interest statement

Acknowledgements

The incidence of oropharyngeal cancer in Taiwan: an endemic betel quid chewing area

J Oral Pathol Med

Comparison of cancers of the oral cavity and pharynx worldwide: etiological clues

Oral Oncol

Global cancer statistics, 2002

CA Cancer J Clin

Human papillomavirus type 16 and squamous cell carcinoma of the head and neck

Clin Cancer Res

Current management of tonsillar cancer

Oral Oncol

Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control

Cancer Res

Evidence for a causal association between human papillomavirus and a subset of head and neck cancers

J Natl Cancer Inst

Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival

Int J Cancer

Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas

Cancer

Human papillomavirus (HPV) in head and neck cancer

J Clin Virol

HPV-16 oncogenes E6 and E7 are mutagenic in normal human oral keratinocytes

Oncogene

Human papillomavirus immortalization and transformation functions

Virus Res

Presence of HPV in head and neck tumours: high prevalence in tonsillar localization

J Exp Clin Cancer Res

Clinical implications of human papillomavirus in head and neck cancers

J Clin Oncol

Human papillomavirus (HPV) in head and neck cancer. An association of HPV 16 with squamous cell carcinoma of Waldeyer’s tonsillar ring

Cancer

Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection

J Natl Cancer Inst

Squamous cell carcinoma of the tonsils: a molecular analysis of HPV associations

Clin Cancer Res