SPINK1 expression in relation to PTEN and ERG in matched primary and lymph node metastatic prostate cancer: Implications for biomarker development

•In the primary site of this PCA, SPINK 1 expression is noted in 25% of cases vs. 5% to 15% of cases as reported in localized cohorts.•Up-regulation of SPINK 1 expression in high-risk primary sites is because of a dynamic expansion of a PCA subpopulation harboring the SPINK1 +/ERG+ phenotype.•SPINK1 expression status shows a lower rate of concordance between primary PCA site and nodule metastases, than those of ERG and PTEN.•SPINK1+/ERG+ phenotype may mark a subpopulation of more aggessive PCA's with higher risk for LN metastases.•Future studies will be required to determine if coexpression of SPINK1, ERG, and PTEN in prostate cancer (PCA) may be of added prognostic value.

BackgroundSPINK1, ERG, and PTEN are proposed prognostic biomarkers in prostate cancer (PCA). However, their relations and patterns of expression in primary and metastatic lymph node (LN) PCAs are not fully explored.MethodsA tissue microarray of matched primary PCA and LN metastasis was constructed from 36 patients. SPINK1, ERG, and PTEN expression statuses were assessed by immunohistochemistry and correlated with each other.ResultsSPINK1 and ERG were expressed in 25% and 42.7% of primary PCA cases, respectively. PTEN loss of any degree was observed in 91.7% of primary PCA cases, with 54.2% showing complete loss. In primary PCA, 12.5% of the cases showed SPINK1+/ERG−phenotype, 16.7% showed SPINK1+/ERG+phenotype, 25.0% showed SPINK1−/ERG+phenotype, and 45.8% showed SPINK1−/ERG−phenotype. All PCAs with expression of either SPINK1 or ERG also exhibited PTEN loss, whereas PCA without PTEN loss (2 cases) expressed neither SPINK1 nor ERG. In primary PCA, evaluation of combined ERG and SPINK1 status, but not SPINK1 individually, was associated with a significant difference in proportion of Gleason patterns (P = 0.013), with the SPINK1+/ERG+and SPINK1−/ERG−phenotypes represented more in Gleason pattern>7 PCAs. In LN metastases, the overall SPINK1 protein expression frequency was significantly lower (6.5% of cases) compared with primary PCA (P = 0.03). Only 16.7% of cases with positive SPINK1 expression in primary PCA maintained expression in LN metastases. The down-regulated SPINK1 expression in LN was primarily because of a reduction in the SPINK1+/ERG+PCA subpopulation to 3.5% of cases (P = 0.16 compared with primary PCA). The frequencies of ERG expression and PTEN loss were relatively stable in primary PCA and LN metastases.ConclusionSPINK1 expression is dynamically regulated with up-regulation in primary sites of nodal metastatic PCA and down-regulation in LN metastases. The increased SPINK1 expression in primary site of nodal metastatic PCA is secondary to an increased frequency of SPINK1+/ERG+tumors. In primary PCAs, the SPINK1+/ERG+phenotype is associated with higher Gleason grade, suggesting that this phenotype may mark a more aggressive PCA subpopulation with higher risk of LN metastases.