Activation of mTOR Pathway in Malignant Pheochromocytoma: A Potential Therapeutic Target.
Fadi Brimo, Alcides Chaux, Luciana Schultz, Jonathan I Epstein, Angelo M Demarzo, Pedram Argani, George J Netto. McGill University Health Center, Montreal, Canada; Johns Hopkins Hospital, Baltimore
Background: mTOR pathway activation regulates protein translation and cell proliferation. Dysregulation of the mTOR pathway is present in several types of malignancies in which agents targeting mTOR are being evaluated. We herein assess the status of mTOR pathway components and their prognostic role in a series of benign and malignant pheochromocytomas.
Design: Immunohistochemical analysis was performed for PTEN, phos Akt, phos S6, p27, and c-myc using a tissue microarray constructed from 47 pheochromocytomas treated at our hospital (1996-2009). Duplicate tumor samples were used. For each marker the percentage of positive cells (extent) and the intensity of staining (0, 1, 2, 3) were recorded and an H-score (intensity x extent) was calculated. Markers exression was correlated with tumor biologic behavior (benign vs malignant) and tumor primary vs metastatic status.
Results: 39 primary (20 benign and 19 with indeterminate clinical course) and eight metastatic pheochromocytomas were included. 28 patients were males and 19 were females with a mean age of 47 years and a mean tumor size of 5.3 cm (range 0.9-12.5). While the expression of PTEN, phos S6, p27, and c-myc did not differ between benign and malignant (metastatic) tumors, phos AKT was significantly overexpressed in malignant pheochromocytomas (p=0.01). see table 1. Similar findings were obtained when comparing primary (n=39) and metastatic (n=8) tumors.
|No. Cases||Benign (%)||Malignant (%)||P value|
|Negative||24||20 (100)||4 (57.1)|
|Positive (H>210)||3||0 (0)||3 (42.9)|
|Negative||15||11 (57.9)||4 (57.1)|
|Positive (H>10%)||11||8 (42.1)||3 (42.9)|
|Negative||18||13 (65)||5 (83.3)|
|Positive (H>0)||8||7 (35)||1 (16.7)|
|Negative||13||10 (50)||3 (37.5)|
|Positive (H>0)||15||10 (50)||5 (62.5)|