Progressive loss of myogenic differentiation in leiomyosarcoma has prognostic value

Abstract

Aims Well-differentiated leiomyosarcoma show morphologically recognizable smooth muscle differentiation, while poorly differentiated tumors may form a spectrum with a subset of undifferentiated pleomorphic sarcomas. Expression of certain muscle markers has been reported to have prognostic impact. We investigated the correlation between morphologic spectrum and muscle-marker expression profile of leiomyosarcoma and the impact of these factors on patient outcomes. Methods and Results Tissue microarrays including 203 non-uterine and 181 uterine leiomyosarcoma with a spectrum of tumor morphologies were evaluated for expression of immunohistochemical markers of muscle differentiation. Poorly differentiated tumors frequently lost one or more conventional smooth muscle markers (smooth muscle actin, desmin, h-caldesmon and smooth muscle myosin (p<0.0001)), as well as more recently described markers SLMAP, MYLK and ACTG2 (p<0.0001). In primary tumors, both desmin and CFL2 expression predicted improved overall survival in multivariate analyses (p=0.0111 and p=0.043, respectively). Muscle-marker enriched tumors (expressing all 4 conventional markers or any 3 of ACTG2, CFL2, CASQ2, MYLK, and SLMAP, had improved overall survival (p<0.05) in univariate analyses. Conclusions Morphologically and immunohistochemically, poorly differentiated leiomyosarcoma can masquerade as undifferentiated pleomorphic sarcoma with progressive loss of muscle markers. Expression of muscle markers has prognostic significance in primary leiomyosarcoma independent of tumor morphology.

Clinically Relevant Molecular Subtypes in Leiomyosarcoma

“…Subtype I LMS was associated with good outcome in extrauterine LMS, while subtype II was associated with poor outcome in univariate analysis. In this context it is interesting to note that the association between muscle gene expression and better clinical outcome is a finding that was also reported in various ways by other immunohistochemical studies (18, 45). While subtyping of LMS by immunohistochemistry, can help predict clinical outcome, in multivariate analysis the subtype I and II biomarkers were outperformed by the previously described markers ROR2 and the “CSF1 protein response signature” (27, 34).…”

“…Within the 3SEQ cohort, 18% (18) of tumors are low grade, 19% (19) are intermediate grade, and 63% (62) are high grade by histologic analysis. Low grade lesions were more frequent in subtype I LMS, with 10/35 cases showing low grade histology while 3/22 of subtype II and 0/13 of subtype III LMS cases are low grade respectively, however there was no statistically significant correlation between grade and molecular subtype (Table 1, p = 0.0989, Chi-square).…”

Extensive Survey of STAT6 Expression in a Large Series of Mesenchymal Tumors

“…Specimens included in the study included whole tumor sections at 4 μm obtained from UMMC and ISMMS (n= 33 and 3 respectively, including 33 solitary fibrous tumors and 3 other sarcomas), sections from a diverse array of previously published sarcoma-specific tissue microarrays, including: soft tissue and uterine leiomyosarcomata, 28, 29 miscellaneous, predominately complex karyotype sarcomas, 30, 31 desmoid tumors, 32, 33 malignant peripheral nerve sheath tumors, 34 angiosarcomas, 35 , alveolar soft part sarcomas, 36 epithelioid sarcoma, 37 myxoid liposarcoma, 38 pleomorphic liposarcoma, 39 well-differentiated/ de-differentiated liposarcoma, 40 and 5 previously unpublished tumor-specific tissue microarrays, including: solitary fibrous tumors (2 arrays, from UTMDACC and ISMMS, respectively, including meningeal hemangiopericytomas), clear cell sarcoma, an additional well-differentiated/de-differentiated liposarcoma array, and neurofibromatosis-associated malignant peripheral nerve sheath tumors.…”

Clinical Observations and Molecular Variables of Primary Vascular Leiomyosarcoma

“…Immunohistochemical studies were performed on a previously constructed tissue microarray containing 50 vascular leiomyosarcoma specimens from 39 patients 18 . For the survival analysis, only primary tumor tissue was used for analysis (26 patients).…”