Biological correlates of prostate cancer perineural invasion diameter

Abstract

Perineural invasion is a symbiotic relationship between cancer cells and nerves and is most frequently seen in "neurotropic" cancers such as prostate cancer. It results in increased perineural space cancer cell growth and decreased apoptosis and induces nerve growth. Tissue microarrays were constructed from 640 radical prostatectomy specimens with prostate cancer. The perineural diameter was measured as previously described. Multiple biomarkers have been previously performed on this tissue microarray cohort, and all data were kept in the same database. The biomarker results database was queried for correlations between perineural invasion diameter and tissue biomarkers. Increased perineural invasion diameter correlated with increased proliferation of prostate cancer cells and with apoptosis. It also correlated with proteins involved in survival pathways such as nuclear factor κB, c-Myc, phosphorylated AKT, and its downstream effector FHKR, but not with GSK. Unlike nerve density, it did not correlate with decreased PTEN expression. Increased perineural invasion diameter was associated with higher levels of hormonal receptors such as androgen receptor, but not estrogen receptor. Also associated with perineural invasion diameter were coregulators and corepressors including SRC1 and TIF2. Perineural invasion diameter had the strongest correlation with tumor volume (ρ = 0.579, P = .000), not identified with nerve density. These data demonstrate that perineural invasion has the same biologic correlations as neural density. However, we found a distinct and very strong correlation with increased tumor volume. These data confirm that perineural invasion is the ultimate and most successful interaction between cancer cells and nerve fibers, resulting in increased tumor growth.

Keywords: Perineural invasion diameter; Prostate cancer.

Figure 1

A, B - Examples of PNI with very large PNI diameter. The PNI diameter’s value is established by measuring the tumor diameter (yellow double arrows) around the nerve (red arrow head) perpendicular to the large axis of the nerve (H&E 20X). C – Higher magnification (40X) of A. D - For comparison purposes, this image (H&E, 40X) shows PNI with low PNI diameter.

Figure 2

Visualization of the correlation between biomarkers previously stained in this cohort and nerve density as measured by PGP 9.5 immunoexpression (blue line) and PNI diameter (red line). Absence of correlation is plotted as a dot on the 0 (zero) line, positive correlations are plotted outwards, while negative correlations are plotted inwards, towards the center. The correlation coefficients are labeled at approximately 12:00 o’clock.