The relationship between perineural invasion, tumor grade, reactive stroma and prostate cancer-specific mortality: A clinicopathologic study on a population-based cohort

Abstract

Background: In vitro and in vivo studies have shown that nerves, tumor epithelium, and stroma interact and promote prostate cancer (PC) progression. Perineural invasion (PNI) is established amidst these interactions and may therefore indicate an aggressive PC phenotype. The purpose of the present study was to determine the relationship between PNI, tumor grade, reactive stroma, and PC-specific mortality.

Methods: A population-based study on 318 patients, encompassing all cases of PC diagnosed by needle biopsies and without evidence of systemic metastasis at the time of diagnosis in Aust-Agder County in the period of 1991-1999. Patients were identified by cross-referencing the Cancer Registry of Norway. Clinical data were obtained by review of medical charts. Diagnostic prostate needle biopsies were reviewed with respect to presence of PNI, percentage of biopsy cores with PNI, Gleason score (GS), and reactive stromal grade (RSG). The endpoint was PC-specific mortality.

Results: The presence of PNI was significantly associated with high tumor grade and abundant reactive stroma. The 10-year PC-specific survival for patients with and without PNI was 72% and 91%, respectively (P = 0.001, log rank). PNI predicted PC-specific mortality independently of clinical factors, though the effect of PNI was attenuated when adjusting for GS and RSG. However, a percentage of biopsy cores with PNI >50% was found to predict PC-specific mortality independently of other clinicopathologic parameters.

Conclusions: The present population-based study shows that PNI on diagnostic prostate needle biopsy is associated with increased risk of PC-specific mortality. Our findings demonstrate that the prognostic effect of PNI is dependent on an association with high grade carcinoma and reactive stroma. However; the impact of PNI on clinical outcome becomes stronger and independent of other clinicopathologic factors upon increased percentage of PNI positive biopsy cores. Thus, our study highlights the importance of PNI and microenvironmental interactions for the long-term outcome of PC.

Keywords: Gleason score; biopsy; mortality; perineural invasion; prostate cancer; reactive stroma.