p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma

Abstract

Purpose: Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx.

Patients and methods: p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics.

Results: p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes.

Conclusion: Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.

Fig 1.

(A) Progression-free (PFS) and (B) overall survival (OS) by p16 expression for patients with nonoropharynx tumors. Patients with p16-positive tumors had significantly longer PFS (P = .04) and OS (P = .01) than patients with p16-negative tumors. Regarding PFS, 28 of 62 patients with p16-positive tumors and 160 of 260 patients with p16-negative tumors experienced progression; 5-year PFS estimates were 54.7% (95% CI, 41.6 to 67.8) and 34.3% (95% CI, 27.5 to 41.1), respectively. Regarding OS, 21 of 62 patients with p16-positive tumors and 134 of 260 patients with p16-negative tumors died; 5-year OS estimates were 64.4% (95% CI, 50.8 to 77.9) and 44.4% (95% CI, 37.4 to 51.4). (C) PFS and (D) OS by human papillomavirus (HPV) in situ hydridization (ISH) status for patients with nonoropharynx tumors. There was no significant difference in PFS (hazard ratio [HR], 0.77; 95% CI, 0.44 to 1.33; P = .35) or OS (HR, 0.64; 95% CI, 0.34 to 1.21; P = .17) between HPV ISH–positive and –negative patients. (E) PFS and (F) OS by HPV ISH status and p16 expression. There was no significant difference in PFS or OS (HPV positive/p16 positive v HPV positive/p16 negative v HPV negative/p16 positive v HPV negative/p16 negative: PFS, P = .23; OS, P = .21; HPV positive/p16 positive v HPV negative/p16 positive: PFS, P = .66; OS, P = .46; HPV positive/p16 positive v HPV negative/p16 negative: PFS, P = .20; OS, P = .09; HPV positive/p16 positive v HPV negative/p16 positive or p16 negative: PFS, P = .23; OS, P = .12).

Fig 2.

(A) Progression-free (PFS) and (B) overall survival (OS) by p16 expression and primary site (oropharyngeal squamous cell carcinoma [OPSCC] v non-OPSCC); 5-year PFS estimates were 69.3% (95% CI, 65.0% to 73.6%), 54.7% (95% CI, 41.6% to 67.8%), 36.8% (95% CI, 29.8% to 43.9%), and 34.3% (95% CI, 27.5% to 41.1%) for patients with p16-positive OPSCC (p16 pos op), p16-positive non-OPSCC (p16 pos nonop), p16-negative OPSCC (p16 neg op), and p16-negative non-OPSCC (p16 neg nonop), respectively; 5-year OS estimates were 79.8% (95% CI, 76.0% to 83.7%), 64.4% (95% CI, 50.8 to 77.9), 45.8% (95% CI, 38.1% to 53.5%), and 44.4% (95% CI, 37.4% to 51.4%) for patients with p16-positive OPSCC, p16-positive non-OPSCC, p16-negative OPSCC, and p16-negative non-OPSCC, respectively. There was significant interaction between p16 status and primary site for both PFS (P = .01) and OS (P = .01).

Fig A1.

Progression-free survival by p16 expression for patients with (A) oral cavity, (B) hypopharynx, and (C) larynx tumors and (D) for these patients combined. HR, hazard ratio.

Fig A2.

Overall survival by p16 expression for patients with (A) oral cavity, (B) hypopharynx, and (C) larynx tumors and (D) for these patients combined. HR, hazard ratio.