Prognostic Relevance of mTORC1 Pathway Components in Papillary Renal Cell Carcinoma
Maryam Kherad Pezhouh, Dinesh Rakheja, Ramy F Yousser, Yair Lotan, Vitaly Margulis, Payal Kapur. University of Texas Southwestern Medical Center, Dallas, TX
Background: The mammalian target of rapamycin complex 1 (mTORC1) pathway is dysregulated in many human cancers and agents targeting the mTORC1 are being clinically used. mTORC1 pathway interacts with effectors of cell cycle progression and ultimately regulates protein translation and cell proliferation. We undertook this study to ascertain if Papillary Renal Cell Carcinoma (PRCC) demonstrates significant expression of mTORC1 pathway components and if the expression of activated mTORC1 has any prognostic significance.
Design: Standard immunohistochemical analysis was performed for p-S6, p-mTOR, p-4EBP1, HIF-1a, p-AKT, PI3K, PTEN on sections of tissue microarrays constructed from 76 primary PRCC treated at our hospital with nephrectomy (1998-2008). Duplicate 1.0 mm cores of representative tumor were obtained from each case to construct the tissue microarrays. Cytoplasmic expression was assessed for each marker as the percentage of positive cells (0-3) and intensity of staining (0-3). A final Histo-score was calculated as the product of intensity and percentage and correlated with clinic-pathologic parameters using T-test, Fisher's exact test, Pearson's correlation, or log-rank (Mantel-Cox) test.
Results: In our cohort, M:F ratio was 3.00 and mean age at diagnosis was 58.67 years. Mean tumor size was 5.08 cm. Fuhrman's nuclear grade was G1 in 7, G2 in 41, G3 in 25, and G4 in 3 cases. 9 (11.84%) patients had high pathologic stage (pT3-4), 10 (13.16%) developed subsequent metastases/ recurrence, and 5 (6.58%) died of the disease. Compared to normal proximal renal tubules, we found increased expression of p-S6 in 14 (18.4%) tumors, p-mTOR in 70 (92.1%), p-4EBP1 in 43 (56.6%), HIF-1a in 34 (44.7%), PI3K in 40 (52.6%), and p-AKT in 41 (53.9%). PTEN expression was reduced in 40 (52.6%) tumors. Increased expression of p-S6 was significantly associated with higher tumor grade (P=0.03). Higher grade tumors also showed reduced expression of HIF-1α (P=0.01) and increased expression of PTEN (P=0.00). There was a trend for tumors with metastases/ recurrence to show higher expression p-S6 (P=0.08). Increased expression of p-S6 also correlated with poor patient survival (P=0.01).
Conclusions: In this current work in clinically annotated PRCC where the patients had received no previous treatment, we found that increased expression of p-S6 correlates with higher grade, metastases, and poor patient outcome. Our results support consideration of therapeutically targeting mTORC1 pathway in PRCC.
Category: Genitourinary (including renal tumors)
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 133, Monday Morning