Molecular predictors of locoregional and distant metastases in oropharyngeal squamous cell carcinoma

Abstract

BackgroundThe incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing due to fundamental changes in oncogenesis related to effects of the human papilomavirus (HPV). Virally-mediated tumours behave and respond to treatment differently than their classic, carcinogenically-mediated counterparts despite similar stage and grade of disease. This difference in behaviour has lead to investigation of etiologies of OPSCC at the molecular level.Molecular biomarkers offer potential insight into the behaviour of OPSCC. Identifying a subset of patients that are more likely to have recurrence and distant metastasis is valuable for prognostication and treatment planning. There is limited information regarding the profiles of these biomarkers in locoregional and distant metastases in OPSCC.ObjectiveThis study was designed to identify biomarker profiles predictive of locoregional and distant metastases and recurrence in OPSCC.MethodsCross-sectional study of a prospectively-collected oropharyngeal tumour database was undertaken. All patients with OPSCC presenting to the University of Alberta Hospital from 2002-2009 were included in the study. Data collection from the Alberta Cancer Registry, including demographics, nodal status, distant metastases, treatment, recurrence, and survival, was undertaken. Tissue micro-arrays (TMAs) were constructed for each tumour specimen using triplicate cores (0.6mm) of formalin-fixed, paraffin-embedded (FFPE) pre-treatment tumour tissue. TMAs were processed using immunohistochemistry for p16, EGFR, Ki67, p53, and Bcl-XL. Positivity for each biomarker was determined using quantified AQUAnalysis ® scores on histoplots. Multivariate statistics were utilized to assess the relationship between each biomarker and locoregional and distant metastases, as well as recurrence-free survival (RFS).ResultsHigh expression of p16 (p=0.000) and Bcl-XL (p=0.039) independently demonstrated a significant association with nodal disease at presentation. Kaplan-Meier analysis demonstrated improved RFS in patients with high p16 and decreased RFS in patients with high p53 expression. Cox regression analysis supported p16 as an independent prognosticator for improved RFS. p53 demonstrated an association with recurrence, but when compared to p16 status, nodal status, and staging, was not an independent predictor of recurrence.ConclusionsBiomarker profiling using p16, Bcl-xL, and p53 may be useful in prognostication and treatment planning in patients with OPSCC.

Primary Surgery vs Chemoradiation Treatment of Advanced-Stage Hypopharyngeal Squamous Cell Carcinoma

“…Multivariate analyses were performed with a Cox regression hazard model. 13,14 Differences between groups were calculated using the t test for continuous variables and the χ 2 test for categorical variables. P < .05 was used to indicate statistical significance.…”

Ki67 Expression has Prognostic Significance in Relation to Human Papillomavirus Status in Oropharyngeal Squamous Cell Carcinoma

“…14 Furthermore, overall survival was also found to be poorer in Ki67-positive head and neck SCCs compared with Ki67-negative tumours in two studies, 12,21 although others reported no significant difference in time to recurrence or recurrence-free survival by Ki67 status. 23,24 While previous studies have reported the prognostic significance of HPV and Ki67 as biomarkers in oropharyngeal cancers separately, only one other study has examined these in conjunction. In a retrospective, singleinstitutional study of 56 OSCC cases, Ritta et al reported a favourable outcome in the HPV-positive/Ki67-negative subgroup, with the survival benefit amounting to 2.5-fold relative mortality reduction at 5 years compared with HPV-negative/Ki67-positive patients (although survival graphs for this interaction were not reported).…”

“…7,8 This is particularly true for Ki67, where arbitrary cut-offs of 20, 25, 40 %, or using median values as a cut-off for positivity, have been utilized [12][13][14]21,24 compared with the 50 % cut-off used in the current study. There needs to be consensus on the definition of Ki67 positivity in order for the findings of different studies to be compared.…”

Role of primary surgery in the treatment of advanced oropharyngeal cancer

“…Tissue microarrays (TMAs) were constructed with formalin‐fixed paraffin‐embedded (FFPE) tumor tissue blocks from either pretreatment biopsies or primary surgical specimen, as recently described . A head and neck pathologist (L.P.) reviewed the blocks and excluded cases with inadequate tissue.…”