Dysregulation of the Phosphatidylinositol 3' Kinase-Akt-Mammalian Target of Rapamycin (P13K-Akt-mTOR) Pathway in Smooth Muscle Tumors of the Uterus: Clinicopathologic Implications.
Oluwole Fadare, Idris Renshaw, Sandra J Olson, Sharon X Liang. Vanderbilt University, Nashville, TN; Vanguard Pathology, Austin, TX; Long Island Jewish Medical Center, New Hyde Park, NY
Background: Preclinical analyses strongly implicate the phosphatidylinositol 3' kinase-Akt-mammalian target of rapamycin (P13K-Akt-mTOR) signaling pathway in smooth muscle tumorigenesis and differentiation, indicating that this pathway may be a suitable molecular target for the development of anti-cancer chemotherapeutic agents. The purpose of this study is to define the frequency and patterns of expression of 3 proteins in this pathway [mTOR, Akt and phosphatidylinositol 3' kinase (PI3-K)], in smooth muscle tumors of the uterine corpus, and to establish whether the expression of any of these proteins has independent prognostic significance.
Design: The expression of mTOR, pan-Akt, and PI3-K was evaluated by immunohistochemistry in 31 uterine leiomyosarcomas and 10 leiomyomata, and were correlated with clinicopathologic parameters. Associated peritumoral normal myometrium was present in 27 cases. Cases were scored by multiplication of staining intensity (on a 0-3+ scale) and the extent/distribution of immunoreactivity (on a 0-4+ scale) for potential scores that ranged from 0 to a maximum of 12. Cases with scores of 4+ to 12+ (moderate, 4+ to 8+; high, 9+ to 12+ immunoreactivity) were considered positive.
Results: All 31 leiomyosarcomas were pan-Akt positive with 80.6% of positive cases displaying high scores, whereas all 10 leiomyomata and 27 normal myometria were entirely pan-Akt negative. High pan-Akt scores were associated with high tumor grade but not with advanced stage or outcome. Every tumoral and non-tumoral sample evaluated showed immunoreactivity for mTOR. PI3-K was positive in 20 (64.5%) of the 31 leiomyosarcomas but in none of the leiomyomata. High scores of PI3-K were associated with late pathologic stage (p=0.0022). High PI3-K scores, high pan-Akt scores and PI3-K positivity were not independently associated with reduced disease-specific survival on multivariate analysis.
Conclusions: These findings suggest that relative to normal myometrium, there is indeed dysregulation of the P13K-Akt-mTOR pathway in uterine smooth muscle tumors, and especially in uterine leiomyosarcomas. The expression patterns of proteins in this pathway, especially pan-Akt, may be of diagnostic utility in separating benign from malignant smooth muscle tumors. Pan-Akt, mTOR and PI3-K expression lacked independent prognostic significance in this pilot study, but additional and larger corroborative analyses are required.
Category: Gynecologic & Obstetrics
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 185, Wednesday Afternoon