title: Gastrointestinal stromal tumor after tyrosine kinase inhibition therapy: a review of biopsies of 34 patients with clinically suspected relapse and/or progression of the tumor.
abstract: Implementation of combined surgical and targeted therapy strategies using tyrosine kinase inhibitors improved the prognosis of patients with aggressive GISTs. The therapeutic answer may be individually different, some patients do not respond properly, or even progress in spite of the therapy. This together with intratumoral heterogeneity and possible development of secondary phenotypical and genetical changes represents a challenge for pathologists examining a biopsy of relapsed tumors and/or their metastases. For this study biopsy files of the national Slovak GIST registry were reviewed to identify patients examined bioptically both prior the therapy and during the TKI treatment due to suspected tumor relapse and/or progression. All the GIST biopsies were analyzed using a standardized algorithm of histological, immunohistochemical and molecular analyses of exon 7, 9, 11, 13 of c-KIT and exons 12, 14, and 18 of PDGFRA genes, with the aim to identify posttherapeutical changes of these parameters. From 34 patients fulfilling the criteria of selection, all were histologically examined during their clinically suspicious first GIST relaps, eight during the 2nd, three during 3rd and one during 4th and 5th relapse resp. All but one posttherapeutical biopsies showed "viable" GIST tissue and so 44 relapses of 33 patients could be evaluated in comparison with identical parameters of diagnostic biopsies. Distinguishing three major histological types (spindle-, epitheloid-cell and mixed cell type), a change of the GIST type was identified in 1/3 of 1st relapse and ¼ of all relapse biopsies. Evaluation of three phenotypical GIST parameters CD117, CD34 and DOG-1, showed that phenotype alteration was always represented by a single change. The most common was either a gain or loss of CD34 positivity appearing in 1/3 of 1st relapse biopsies, while a loss of CD117 positivity was identified in one patient´s biopsy only. Altogether, the phenotypical changes were in ¼ of all relapses. A changed mutational profile was recognized in 38,2% first relaps biopsies and in 33% of all relapses, the change was mostly isolated (in 10/45 relapses) and less often (in 4/45 relapses) it represented a gain of a new mutation in association with persisting original one. In conclusion, the biopsies of patients showing relapse and/or progression on TKI treatment show predominance of viable GIST cells with limited or even absent signs of scaring, as well as relatively low incidence of morphological, pheno- and genotypical changes.
authors.forename: L
authors.initials: L
authors.lastname: Plank
authors.forename: V
authors.initials: V
authors.lastname: Buzalkova
authors.forename: P
authors.initials: P
authors.lastname: Szepe
authors.forename: Z
authors.initials: Z
authors.lastname: Lasabova
authors.forename: K
authors.initials: K
authors.lastname: Jasek
authors.forename: A
authors.initials: A
authors.lastname: Stanclova
authors.forename: G
authors.initials: G
authors.lastname: Minarik
authors.forename: J
authors.initials: J
authors.lastname: Sufliarsky
mesh_terms: D001706:Biopsy; D018450:Disease Progression; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D012008:Recurrence
chemical_list: D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: PDGFRA mutations; c-KIT mutations; gastrointestinal stromal tumor; targeted therapy postherapeutical changes.; tyrosine kinase inhibition