Use of combined molecular biomarkers for prediction of clinical outcomes in locally advanced tonsillar cancers treated with chemoradiotherapy alone

Abstract

Background. Environmental exposures to tobacco, alcohol, human papillomavirus (HPV) and/or Epstein-Barr virus (EBV), all of which can perturb multiple cell cycle proteins or tumor suppressors, have been implicated in the pathogenesis of different subsets of head and neck cancers. The aim of this study was to investigate to which extent the virus infection by itself, and/or the altered cell cycle proteins, contributes to prognosis in locally advanced tonsillar squamous cell carcinomas (TSCCs) treated with concurrent chemoradiotherapy (CCRT) alone.Methods. Serial tumor tissue arrays from archival samples were tested for the presence of HPV genome integration or EBV episome by means of DNA sequencing, realtime polymerase chain reaction (PCR), and in situ hybridization. Alterations of cell cycle proteins (p53, pRb, and p21) were evaluated by immunohistochemical staining. The association of viral presence with altered cell cycle proteins was correlated to clinical outcomes.Results. Of the 46 patients with the same T2N2bM0 stage IVA among consecutive patients with TSCC, 23 (50%) had integrated HPV DNA and only 1 (2%) had EBV episome. The HPV types detected were almost all HPV-16. A reduced expression pattern of p53, pRb, and p21 was noted in HPVpositive tumors, and the incremental number of alterations in the 3 proteins was significantly associated with HPV-negative tumors. The presence or absence of HPV together with the number of altered expression of the 3 cell cycle markers resulted in further identification of 4 biologically and clinically distinct subgroups with different outcomes after CCRT.Conclusions. Use of combined biomarkers of oncogenic HPV and tumor suppressors of p53, pRb, and p21 in advanced TSCC provides prognostic molecular classification superior to the TNM stage system and identifies low-risk patients for organ preservation by CCRT alone and high-risk patients who might benefit from planned tonsillectomy and neck dissection before

Incidence trends of human papillomavirus‐related head and neck cancer in Taiwan, 1995–2009

“…Very few studies have assessed the prevalence of HPV among oropharyngeal cancer cases in Taiwan. Depending on the methods used, the prevalence of HPV in tonsillar cancer in Taiwan ranged from 13 to 75% . Because these studies are hospital‐based and have a small sample size (sample size ranged from 46 to 111), they may not accurately represent the true HPV prevalence of the tonsillar cancer diagnosed in Taiwan.…”

“…Several limitations must be considered when interpreting the results of the current study. A major limitation is that the definition of "HPV-related HNC" is based on anatomical [32][33][34] Because these studies are hospital-based and have a small sample size (sample size ranged from 46 to 111), they may not accurately represent the true HPV prevalence of the tonsillar cancer diagnosed in Taiwan. In addition, these studies did not provide information regarding the temporal change in the prevalence of HPV in oropharyngeal cancer.…”

Detection and significance of human papillomavirus, CDKN2A(p16) and CDKN1A(p21) expression in squamous cell carcinoma of the larynx

“…CDKN1A(p21), a tumor suppressor protein in the TP53 cascade, was also strongly associated with favorable patient outcome (15). Fury (2010) similarly found a correlation between CDKN1A(p21) and CDKN2A(p16) positivity in tonsillar squamous cell carcinoma, although two other studies found no association between HPV and CDKN1A(p21) (16, 17, 28). Previous studies have also found CDKN1A(p21) overexpression in cervical carcinomas and intraepithelial neoplasia (CIN), the majority of which were HPV-related lesions, suggesting that CDKN1A(p21) could play a role in HPV-mediated oncogenesis (29, 30).…”

“…However, the association of CDKN1A(p21) expression with HPV and good prognosis in tonsillar squamous cell carcinoma has not been a universal finding (16, 17). …”

Prognostic significance of tumour progression and human papillomavirus in advanced tonsillar cancer classified as stage IVa

“…12 Although the prognostic significance of HPV infection for head and neck cancers is not yet certain, recent studies have reported a better prognosis for patients with HPV-positive tumours than those with HPV-negative tumours. Some authors have suggested that the combined biomarkers oncogenic HPV positivity and p53, pRb and p21 tumour suppressor expression may provide prognostic molecular classification superior to that of the TNM staging system for advanced tonsillar squamous cell carcinomas.…”