Human papillomavirus 16/18 E7 viral loads predict distant metastasis in oral cavity squamous cell carcinoma

https://doi.org/10.1016/j.jcv.2014.07.007Get rights and content

Highlights

  • •

    We examine the effect of HPV viral load on distant metastases prediction in oral cavity cancer.

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    HPV 16/18 E7 viral loads are confirmed to be independent predictors of 5-year distant metastases.

  • •

    We developed a novel prediction model comprising HPV and clinical factors for distant metastases.

  • •

    This stratification system may help the prognostic evaluation of oral cavity cancer patients.

Abstract

Background

Human papillomaviruses (HPV) seem to be related to distant metastasis (DM) in advanced oral cavity squamous cell carcinoma (OSCC) patients.

Objectives

This study aimed to investigate whether high-risk HPV viral load may predict DM among OSCC patients and stratify patients for risk-adapted treatment.

Study design

Viral loads of E7 oncogenes for HPV 16/18 were measured by quantitative PCR tests in paraffin-embedded lesional specimens from 312 OSCC of which the HPV genotypes had been determined previously. Multivariable Cox regression analysis was used to identify the independent prognostic factors for 5-year DM and C statistics were further computed.

Results

By multivariable analysis, high HPV 16 E7 viral load (≥15.0 copies/genome); high HPV 18 E7 viral load (≥15.0 copies/genome); pathological N2 status (pN2); tumor depth ≥11 mm; extracapsular spread (ECS); and level IV/V metastases were independent risk factors for DM. We further identified three prognostic groups. In the high-risk group (level IV/V metastases or high HPV 16/18 E7 viral load plus pN2, tumor depth ≥11 mm, or ECS), the 5-year distant metastasis rate was 74%. In the intermediate-risk group (high HPV 16/18 E7 viral load, pN2, tumor depth ≥11 mm, or ECS), the 5-year DM rate was 17%. Finally, the 5-year DM rate was 1% in the low-risk group (no risk factors). The value of the C statistics was 0.78.

Conclusions

Among OSCC patients, high HPV 16/18 E7 viral load identifies a small subgroup of patients at high-risk of 5-year DM and suggest the need for more intensive treatments and follow-up strategies.

Section snippets

Background

Oral cavity squamous cell carcinoma (OSCC) is the eighth most common cancer worldwide, accounting for 2% of the overall incident cases of cancer [1]. Although this malignancy is a serious problem in many parts of the globe, its incidence is much higher in countries with a heavy indulgence in oral risk habits [2].

Distant metastasis (DM) from OSCC portends a dismal prognosis [3] and has been independently associated with clinical stage and treatment modality [4]. Moreover, numerous

Objectives

The primary aim of the current study was to determine the prognostic significance of HR-HPV viral load in a representative group of patients with OSCC undergoing radical surgery either with or without adjuvant therapy. To this aim, we used the HPV genechip assay (L1 gene) and quantitative polymerase chain reaction (qPCR) tests (E7 oncogene) to identify HR-HPV (HPV 16/18) infection and to quantify E7 viral load in lesional specimens with OSCC. In addition, we were able to stratify OSCC patients

Study population and design

The study protocol was reviewed and approved by the Institutional Review Board of the Chang Gung Memorial Hospital (99-0112B) and all provided written informed consent to take part in the study. We retrospectively reviewed paraffin-embedded tissue sections from 312 OSCC patients treated with radical surgery either with or without adjuvant therapy between January 2004 and December 2006. HPV status had been determined previously [14], [15]. The eligibility criteria, follow-up procedures,

Results

Table 1 summarizes the HPV and clinocopathological data. The mean HPV 16 E7 viral load (copies/genome) was 15.6 ± 13.4. The mean HPV 18 E7 viral load was 24.5 ± 52.6. Within the 5-year follow-up period, 37 (11.9%) patients had DM. Patients with high HPV 16 E7 viral load (≥15 copies/genome) had a significantly higher DM rate than patients without HPV 16 infection or with low viral load (p = 0.002). However, the factor of HPV16 infection is not significant for DM (Fig. 1). Meanwhile, neither HPV 18

Discussion

Our study identified for the first time high HPV 16/18 E7 viral loads as independent prognostic factors for DM in OSCC patients, regardless of the pathological staging. Notably, the incorporation of high HPV 16/18 E7 viral load into a pathological stratification system not only stratified patients for the risk of DM but also significantly predicted other survival outcomes at 5 years. Taken together, these findings suggest that the effect of HPV 16/18 infection on the development of DM in OSCC

Funding

This work was supported by grants from the Department of Health, Taiwan (DOH100-TD-C-111-006), National Science Council Taiwan (NSC 99-2628-B-182A-002-MY3, 100-2320-B-182A-003, and 101-2325-B-182A-006), and the Chang Gung Memorial Hospital, Taiwan (CMRPG370952, 390301-3, 391431-4, and 396101-3), Taoyuan, Taiwan.

Competing interests

All authors declare no potential conflicts of interest.

Ethical approval

This study received approval from the Institutional Review Board of the Chang Gung Memorial Hospital in Taoyuan, Taiwan (99-0112B).

Acknowledgments

We thank Mr. Jung-Chin Li and Miss Jing-Ru Li, Chang Gung Memorial Hospital Taoyuan, Taiwan for their excellent technical assistance.

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