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Prognostic Significance of Activated AKT Expression in Soft-Tissue Sarcoma

Authors' Affiliations: Departments of ¹ Pathology and ² Orthopedics, Osaka University Graduate School of Medicine, Suita, Osaka; ³ Division of Orthopedics, Osaka Center for Cancer and Cardiovascular Diseases; and ⁴ Division of Orthopedics, Osaka National Hospital, Osaka, Osaka, Japan

Requests for reprints: Yasuhiko Tomita, Department of Pathology (C3), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3711; Fax: 81-6-6879-3719; E-mail: yt{at}molpath.med.osaka-u.ac.jp.

Purpose: AKT is a serine/threonine kinase which is important in tumorigenesis. Several molecules involved in AKT pathway are dysregulated in various kinds of human cancers.

Patients and Methods: Ninety-three patients (53 males and 40 females), ages ranging from 19 to 77 years (median, 57 years), with localized soft-tissue sarcomas arising in the trunk and extremities, were analyzed. Immunoperoxidase procedure (avidin-biotin complex method) was done on paraffin-embedded sections with anti–phosphorylated AKT (Thr³⁰⁸), anti–phosphorylated p44/42 extracellular signal–regulated kinase 1 and 2 (ERK1/2) (Thr²⁰²/Tyr²⁰⁴), anti–phosphorylated forkhead in rhabdomyosarcoma (FKHR) (Ser²⁵⁶), and anti-Ki 67 antibodies. Expression levels of phosphorylated AKT (p-AKT), phosphorylated ERK1/2 (p-ERK1/2), and phosphorylated FKHR (p-FKHR) were categorized as either weaker (level 1) or equal to or stronger (level 2) compared with those in the endothelial cells of the same specimens. Percentage of cells showing intranuclear staining with Ki-67 was shown as the Ki-67 labeling index (LI). Cases were divided into two groups: level 1, Ki-67 LI < 20%; level 2, Ki-67 LI 20%.

Results: Twenty-six (28.0%), 6 (6.5%), and 46 (44.1%) of the tumors showed level 2 expression for p-AKT, p-ERK1/2, and Ki-67 LI, respectively. Tumors with level 2 p-AKT expression showed a higher ratio of level 2 p-FKHR expression (P < 0.01). Multivariate analysis revealed p-AKT expression and Ki-67 LI to be independent prognosticators for overall survival, and p-AKT expression for disease-free survival.

Conclusion: p-AKT expression level is a significant prognosticator in soft-tissue sarcoma.

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