Expression of Group I Leiomyosarcoma Markers by Gene Expression Analysis and Immunohistochemistry in a Subset of Undifferentiated Pleomorphic Sarcomas
AM Mills, AH Beck, M van de Rijn, RB West. Stanford University, Stanford, CA
Background: Leiomyosarcomas (LMS) form a broad group of tumors that are defined by relatively subjective morphologic criteria and/or reactivity for actin or desmin. The distinction from undifferentiated pleomorphic sarcoma (UPS) can be problematic. We recently described 3 novel distinct LMS subtypes based on gene expression profiling and array comparative genomic hybridization that are distributed equally over LMS of GYN and non-GYN origin. The Group I subtype shows an improved disease-specific survival compared to the other 2 groups that is independent of histologic grade (Beck et al., Oncogene 2009 in press). Group I comprises ∼25% of all LMS and is defined by a shared pattern of gene expression, a distinct pattern of genomic changes, and reactivity for 5 immunohistochemistry (IHC) markers (ACTG2, CASQ2, CFL2, MYLK, SLMAP) that have not been well characterized in sarcoma. Here we provide a characterization of these 5 markers across a wide range of sarcomas with a focus on UPS. In addition we examine the gene expression profiles of 29 UPS analyzed on microarrays for LMS subset specific gene sets.
Design: IHC staining with ACTG2, CASQ2, CLF2, MYLK, and SLMAP was performed on tissue arrays containing 565 sarcomas and benign soft tissue processes from 44 diagnostic entities. Staining was scored as strongly positive, weak/absent, or uninterpretable. Only cores for which ≥3/5 stains were interpretable were included in analysis. The expression of the top 500 genes from the Group 1 LMS expression signature was evaluated in 29 cases of UPS by 44,000 spot cDNA microarrays.
Results: IHC staining revealed strong immunopositivity for ≥3/5 Group I markers in 32% of LMS (n=59), 5% of UPS (n=57), 22% of leiomyoma (n=22), 16% of gastrointestinal stromal tumor (n=43), and 18% of endometrial stromal sarcoma (n=11). Other soft tissue tumor types had negligible staining. Unsupervised hierarchical clustering of the 29 UPS expression profiled by cDNA microarrays revealed that 2 (7%) had coordinated high levels of expression of genes from the Group I LMS signature.
Conclusions: The Group I LMS IHC markers ACTG2, CASQ2, CLF2, MYLK, and SLMAP show specificity for a subset of LMS when compared to other sarcomas and benign entities and could be used as differential diagnostic tools. A subset of UPS demonstrates Group I LMS markers by microarray analysis and IHC. These markers may define a population of Group 1 LMS-derived UPS with improved prognosis and could suggest future therapeutic targets.
Category: Bone & Soft Tissue
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 10, Monday Morning