P53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome.

Abstract

Testicular germ cell tumors (TGCTs) are highly sensitive to platinum-based chemotherapy, and wild-type p53 seems to play a pivotal role in this susceptibility. On the other hand, overexpression of MDM2 seems to entail treatment resistance and unfavorable prognosis. We aimed to describe p53 and MDM2 immunoexpression in a well-characterized cohort of primary and metastatic TGCTs and evaluate associations with clinicopathological and prognostic variables, including survival. 237 primary tumor samples and 12 metastases were evaluated for p53 and MDM2 immunoexpression using digital image analysis. Clinical records of all patients were reviewed for baseline clinical/pathologic characteristics and follow-up. A significant positive correlation between p53 and MDM2 H-scores was found (rs =0.590, P<.0001). Non-seminomas showed significantly higher expression levels of both p53 and MDM2 (P=.0002, P<.0001), which peaked in embryonal carcinomas and choriocarcinomas. Percentage of immunoexpressing cells and H-score were significantly higher in chemo-treated metastases compared with chemo-naïve primary tumors for MDM2 (P≤.0001 for both), but not for p53 (P=.919 and P=.703, respectively). Cases with higher MDM2 immunoexpression showed a statistically significant trend for association with poorer prognosis (P=.043). Relapse/progression-free survival at 12months post-diagnosis was lower in the "MDM2-high" (≥P50) vs. the "MDM2-low" (<P50) expression groups. In TGCTs, MDM2 overexpression may indicate a more aggressive tumor phenotype, with propensity for therapy resistance and recurrence. If validated in larger multi-institutional studies with precise quantification, it may be envisioned as a useful predictive biomarker of poor response to cisplatin.