Smooth muscle differentiation identifies two classes of poorly differentiated pleomorphic sarcomas with distinct outcome

Pérot, Gaëlle; Mendiboure, Jean; Brouste, Véronique; Velasco, Valérie; Terrier, Philippe; Bonvalot, Sylvie; Guillou, Louis; Ranchère-Vince, Dominique; Aurias, Alain; Coindre, Jean‐Michel; Chibon, Fréderic

doi:10.1038/modpathol.2013.205

Cited by 14 publications

(6 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whereas we found that increased muscle marker expression predicted improved outcomes in leiomyosarcomas, other studies have found that UPS with expression of muscle markers behave more aggressively than those without . Thus, we are left with the seeming paradox that evidence of myoid differentiation is a positive predictor in leiomyosarcomas, and a negative one in true UPS.…”

Section: Discussioncontrasting

confidence: 84%

Progressive loss of myogenic differentiation in leiomyosarcoma has prognostic value

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

Section: Discussioncontrasting

confidence: 84%

Progressive loss of myogenic differentiation in leiomyosarcoma has prognostic value

et al. 2015

View full text Add to dashboard Cite

show abstract

“…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).…”

Section: Discussionsupporting

confidence: 75%

“…Several molecular prognosticators (28, 39, 41, 44, 45) have previously been reported in LMS. By genomic and expression profiling of 183 sarcomas, Chibon et al established a prognostic signature called Complexity Index in Sarcoma (CINSARC), that includes 67 genes related to mitosis and chromosome management.…”

Section: Discussionmentioning

confidence: 99%

Clinically Relevant Molecular Subtypes in Leiomyosarcoma

Guo

Mills

et al. 2015

Clinical Cancer Research

127

136

View full text Add to dashboard Cite

Purpose Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for LMS. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 LMS, we identified three molecular subtypes in LMS. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts. Experimental Design 99 cases of LMS were expression profiled with 3′end RNA-Sequencing (3SEQ). Consensus Clustering was conducted to determine the optimal number of subtypes. Results We identified 3 LMS molecular subtypes and confirmed this finding by analyzing publically available data on 82 LMS from The Cancer Genome Atlas (TCGA). We identified two new FFPE tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I LMS and ARL4C for subtype II LMS. An LMS tissue microarray with known clinical outcome was used to show that subtype I LMS is associated with good outcome in extrauterine LMS while subtype II LMS is associated with poor prognosis in both uterine and extrauterine LMS. The LMS subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that LMS subtypes may respond differentially to these targeted therapies. Conclusion We confirm the existence of 3 molecular subtypes in LMS using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating LMS in a subtype-specific targeted approach.

show abstract

“…27 Furthermore, it confers aggressive outcome in soft tissue sarcomas. 30 Hu et al 25 found a gain of 17p in 38% of the uterine leiomyosarcomas and interestingly, no 17p gain was found in alive patients (4/19). Chromosome 13 was lost in 80% of the leiomyosarcomas in our series and is the most common genomic event in uterine (76%) 25 and extra-uterine leiomyosarcomas (ranging from 54% 28,24 to 71% 26 ) and in the majority of the cases, correlation between this event and follow-up was not established.…”

Section: Discussionmentioning

confidence: 97%

Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions: a comprehensive array-genomic hybridization analysis of 77 tumors

Croce¹,

Ducoulombier²,

Ribeiro³

et al. 2018

Modern Pathology

Self Cite

View full text Add to dashboard Cite

The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Here, we analyzed a large series of 77 uterine smooth muscle lesions (from 76 patients) morphologically classified as 19 leiomyomas, 14 STUMP and 44 leiomyosarcomas with clinicopathological and genomic correlations. We confirmed that genomic index with a cut-off=10 is a predictor of recurrence (P<0.0001) and with a cut-off=35 is a marker for poor overall survival (P=0.035). For the tumors confined to the uterus, stage as a prognostic factor was not useful in survival prediction. At stage I, among the tumors reclassified as molecular leiomyosarcomas (ie, genomic index ≥10), the poor prognostic markers were: 5p gain (overall survival P=0.0008), genomic index at cut-off=35 (overall survival P=0.0193), 13p loss including RB1 (overall survival P=0.0096) and 17p gain including MYOCD gain (overall survival P=0.0425). Based on these findings (and the feasibility of genomic profiling by array-comparative genomic hybridization), genomic index, 5p and 17p gains prognostic value could be evaluated in future prospective chemotherapy trials.

show abstract

Smooth muscle differentiation identifies two classes of poorly differentiated pleomorphic sarcomas with distinct outcome

Cited by 14 publications

References 25 publications

Progressive loss of myogenic differentiation in leiomyosarcoma has prognostic value

Progressive loss of myogenic differentiation in leiomyosarcoma has prognostic value

Clinically Relevant Molecular Subtypes in Leiomyosarcoma

Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions: a comprehensive array-genomic hybridization analysis of 77 tumors

Contact Info

Product

Resources

About