p16 (INK4a) has clinicopathological and prognostic impact on oropharynx and larynx squamous cell carcinoma

Abstract

CDKN2A encodes proteins such as p16 (INK4a), which negatively regulate the cell-cycle. Molecular genetic studies have revealed that deletions in CDKN2A occur frequently in cancer. Although p16 (INK4a) may be involved in tumor progression, the clinical impact and prognostic implications in head and neck squamous cell carcinoma (HNSCC) are controversial. The objective of this study was to evaluate the frequency of the immunohistochemical expression of p16 (INK4a) in 40 oropharynx and 35 larynx from HNSCC patients treated in a single institution and followed-up at least for 10 years in order to explore potential associations with clinicopathological outcomes and prognostic implications. Forty cases (53.3%) were positive for p16 (INK4a) and this expression was more intense in non-smoking patients (P = 0.050), whose tumors showed negative vascular embolization (P = 0.018), negative lymphatic permeation (P = 0.002), and clear surgical margins (P = 0.050). Importantly, on the basis of negative p16 (INK4a) expression, it was possible to predict a probability of lower survival (P = 0.055) as well as tumors presenting lymph node metastasis (P = 0.050) and capsular rupture (P = 0.0010). Furthermore, increased risk of recurrence was observed in tumors presenting capsular rupture (P = 0.0083). Taken together, the alteration in p16 (INK4a) appears to be a common event in patients with oropharynx and larynx squamous cell carcinoma and the negative expression of this protein correlated with poor prognosis.

Figure 1.. Representative immunohistochemical reactions for p16 (INK4a) in 75 head and neck squamous cell carcinoma (HNSCC) samples. Positive p16 (INK4a) reaction was found in 53.3% of the HNSCC (A), whereas morphologically normal areas (spotted in the tumor microarray as control) and 46.7% of the tumors showed negative expression (B). Bar = 100 µm for both panels.

Figure 2.. Overall survival analysis (A) and disease-free survival (B) of the 75 head and neck squamous cell carcinoma (HNSCC) samples studied. HNSCC cases with negative p16 (INK4a) immunolabeling had a shorter survival rate (C) compared to cases with positive staining (P < 0.057, log-rank test and Kaplan-Meier method). The overall survival probability (D) was shorter for HNSCC patients with positive lymph nodes (N+; P < 0.050, log-rank test and Kaplan-Meier method).