title: Tyrosine kinase receptor status in endometrial stromal sarcoma:  an immunohistochemical and genetic-molecular analysis.
abstract: Endometrial stromal sarcomas (ESS) are rare uterine malignant mesenchymal neoplasms, which are currently treated by surgery, as effective adjuvant therapies have not yet been established. Tyrosine kinase inhibitors have rarely been applied in ESS therapy, with few reports describing imatinib responsivity. The aim of this study was to analyze the status of different tyrosine kinase receptors in an ESS series, in order to evaluate their potential role as molecular targets. Immunohistochemistry was performed for EGFR, c-KIT, PDGFR-α, PDGFR-β, and ABL on 28 ESS. EGFR, PDGFR-α, and PDGFR-β gene expression was investigated by real-time polymerase chain reaction (qRT-PCR) on selected cases. "Hot-spot" mutations were screened for on EGFR, c-KIT, PDGFR-α, and PDGFR-β genes, by sequencing. All analysis was executed from formalin-fixed, paraffin-embedded specimens. Immunohistochemical overexpression of 2 or more tyrosine kinase receptors was observed in 18 of 28 tumors (64%), whereas only 5 tumors were consistently negative. Gene expression profiles were concordant with immunohistochemical overexpression in only 1 tumor, which displayed both high mRNA levels and specific immunoreactivity for PDGFR-α, and PDGFR-β. No activating mutations were found on the tumors included in the study. This study confirms that TKRs expression is frequently observed in ESS. Considering that the responsiveness to tyrosine kinase inhibitors is known to be related to the presence of specific activating mutations or gene over-expression, which are not detectable in ESS, TKRs immunohistochemical over-expression alone should not be considered as a reliable marker for targeted therapies in ESS. Specific post-translational abnormalities, responsible for activation of TKRs, should be further investigated.
authors.affiliation: Departments of Clinical and Experimental Medicine, Biomedical Sciences, University of Sassari, Sassari, Italy. pcossurocca@yahoo.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Cossu-Rocca
authors.forename: Marcella
authors.initials: M
authors.lastname: Contini
authors.forename: Maria Gabriela
authors.initials: MG
authors.lastname: Uras
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Muroni
authors.forename: Francesca
authors.initials: F
authors.lastname: Pili
authors.forename: Ciriaco
authors.initials: C
authors.lastname: Carru
authors.forename: Luisanna
authors.initials: L
authors.lastname: Bosincu
authors.forename: Giovannino
authors.initials: G
authors.lastname: Massarelli
authors.forename: Francisco F
authors.initials: FF
authors.lastname: Nogales
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: De Miglio
mesh_terms: D000328:Adult; D000368:Aged; D016889:Endometrial Neoplasms / Q000737:chemistry* / Q000235:genetics; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis / Q000235:genetics; D018203:Sarcoma, Endometrial Stromal / Q000737:chemistry* / Q000235:genetics
chemical_list: D066246:ErbB Receptors; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta