Associations between Histogram Analysis Parameters Derived from DCE-MRI and Histopathological Features including Expression of EGFR, p16, VEGF, Hif1-alpha, and p53 in HNSCC

Abstract

Background: Our purpose was to elucidate possible correlations between histogram parameters derived from dynamic contrast-enhanced MRI (DCE-MRI) with several histopathological features in head and neck squamous cell carcinomas (HNSCC).

Methods: Thirty patients with primary HNSCC were prospectively acquired. Histogram analysis was derived from the DCE-MRI parameters: K _trans, K _ep, and V _e. Additionally, in all cases, expression of human papilloma virus (p16) hypoxia-inducible factor-1-alpha (Hif1-alpha), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), and tumor suppressor protein p53 were estimated.

Results: K _ep kurtosis was significantly higher in p16 tumors, and V _e min was significantly lower in p16 tumors compared to the p16 negative tumors. In the overall sample, K _ep entropy correlated well with EGFR expression (p=0.38, P=0.04). In p16 positive carcinomas, K _trans max correlated with VEGF expression (p=0.46, P=0.04), K _trans kurtosis correlated with Hif1-alpha expression (p=0.46, P=0.04), and K _trans entropy correlated with EGFR expression (p=0.50, P=0.03). Regarding K _ep parameters, mode correlated with VEGF expression (p=0.51, P=0.02), and entropy correlated with Hif1-alpha expression (p=0.47, P=0.04). In p16 negative carcinomas, K _ep mode correlated with Her2 expression (p=-0.72, P=0.03), V _e max correlated with p53 expression (p=-0.80, P=0.009), and V _e p10 correlated with EGFR expression (p=0.68, P=0.04).

Conclusion: DCE-MRI can reflect several histopathological features in HNSCC. Associations between DCE-MRI and histopathology in HNSCC depend on p16 status. K _ep kurtosis and V _e min can differentiate p16 positive and p16 negative carcinomas.

Figure 1

DCE-MRI and histopathological findings in a patient with histologically proven squamous cell carcinoma of the oropharynx. The p16 status is negative for this patient. (a) K_trans map of the tumor. (b) Histogram of K_trans values. The histogram analysis parameters (min⁻¹) are as follows: mean = 0.25, min = 0.05, max = 0.80, p10 = 0.10, p25 = 0.16, p75 = 0.32, p90 = 0.40, median = 0.24, mode = 0.27, kurtosis = 4.5, skewness = 0.93, and entropy = 3.17. (c) K_ep map of the tumor. (d) Histogram of K_ep values. Estimated histogram analysis parameters (min⁻¹) are as follows: mean = 0.63, min = 0.23, max = 1.0, p10 = 0.38, p25 = 0.46, p75 = 0.80, p90 = 0.92, median = 0.62, mode = 0.57, kurtosis = 1.89, skewness = 0.11, and entropy = 3.86. (e) V_e map of the tumor. (f) Histogram of V_e values. Estimated histogram analysis parameters are as follows: mean = 0.40, min = 0.08, max = 0.91, p10 = 0.18, p25 = 0.27, p75 = 0.53, p90 = 0.64, median = 0.39, mode = 0.25, kurtosis = 2.37, skewness = 0.29, and entropy = 3.72. (g) EGFR staining, 106866 µm² stained area. (h) Her2 staining, 57694 µm² stained area. (i) VEGF staining, 1177 µm² stained area. (j) Hif1-alpha staining, 27708 µm² stained area. (k) P53 staining, no staining is detectable in the carcinoma.

Figure 2

A p16 positive oropharyngeal HNSCC. (a) K_trans map of the tumor. (b) Histogram of K_trans values. The histogram analysis parameters (min⁻¹) are as follows: mean = 0.42, min = 0.09, max = 0.70, p10 = 0.24, p25 = 0.35, p75 = 0.50, P90 = 0.57, median = 0.42, mode = 0.47, kurtosis = 2.78, skewness = −0.18, and entropy = 3.29. (c) K_ep map of the tumor. (d) Histogram of K_ep values. Estimated histogram analysis parameters (min⁻¹) are as follows: mean = 0.60, min = 0.18, max = 1.04, p10 = 0.38, p25 = 0.45, p75 = 0.75, p90 = 0.88, median = 0.58, mode = 0.45, kurtosis = 2.20, skewness = 0.24, and entropy = 2.93. (e) V_e map of the tumor. (f) Histogram of V_e values. Estimated histogram analysis parameters are as follows: mean = 0.71, min = 0.22, max = 0.99, p10 = 0.49, p25 = 0.58, p75 = 0.86, p90 = 0.92, median = 0.73, mode = 0.63, kurtosis = 2.33, skewness = −0.38, and entropy = 2.68. (g) EGFR staining, 49020 µm² stained area. (h) Her2 staining, 56207 µm² stained area. (i) VEGF staining, 42720 µm² stained area. (j) Hif1-alpha staining, 11134 µm² stained area. (k) P53 staining, 45011 µm² stained area.

Figure 3

(a) Comparison between p16 and p16 negative tumors. K_ep kurtosis was significantly higher in p16 positive tumors (Mann–Whitney U test, p=0.049). (b) V_e min was significantly lower in p16 positive tumors (Mann–Whitney U test, p=0.044).

Figure 4

Correlation analysis between K_ep entropy and EGFR expression in the overall patient sample. Spearman's correlation coefficient (p=0.38, P=0.04).