TOP2A expression in pheochromocytoma and abdominal paraganglioma: a novel marker of poor clinical outcome?

Abstract

Introduction:Pheochromocytoma and abdominal paraganglioma (PPGL) are rare neuroendocrine tumors originating from chromaffin cells. Even though only 10-15% of the tumors metastasize, all PPGL are considered potentially malignant. Topoisomerase 2A (TOP2A) is a protein involved in cell proliferation and was recently found to be over-expressed in metastatic PPGL. Aims: To provide support whether TOP2A could serve as a prognostic marker to distinguish metastatic tumors from non-metastatic ones. Material and Methods: A retrospective study including histologically verified PPGL with adequate tissue content to allow molecular studies. The cohort included 88 PPGL and 10 normal adrenal gland samples. The expression of TOP2A was measured using quantitative real-time PCR (qRT-PCR) and immunohistochemistry and compared to clinical parameters connected to metastatic behavior. The Cancer Genome Atlas was used for validation of the results. Results: A significant association between high TOP2A mRNA expression in primary PPGL and subsequent metastatic events (p = 0.009) was found, as well as to specific histological features and clinical parameters connected to metastatic behavior. TOP2A immunoreactivity was calculated as an index of positive nuclei divided by the total amount of nuclei, and this index associated to TOP2A mRNA levels (p = 0.023). Conclusions:TOP2A is a potential prognostic marker as it is frequently elevated in PPGL displaying subsequent metastatic disease, and future studies in larger cohorts are warranted to determine if a TOP2A index as assessed by immunohistochemistry could be a marker of poor outcome. Additionally, elevated levels of TOP2A could indicate a potential actionable event, and future studies with topoisomerase inhibitors would be of interest.