Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after imatinib resistance: a potential diagnostic pitfall

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the digestive tract and characterized by expression of protein-tyrosine kinase (KIT) protein. Treatment of advanced GISTs has been improved dramatically following the development of imatinib. Despite the often long-lasting clinical benefit seen in most patients treated with imatinib, many will eventually suffer disease progression. In general, progressing GISTs retain their typical morphology. In this study, we present a patient with metastatic GISTs, who received more than 16 months of treatment with imatinib and whose tumors changed their morphological and immunohistochemical characteristics after imatinib-resistance. Histological, immunohistochemical and mutational analysis was performed on the prior and post-imatinib treatment GIST samples. The imatinib-resistant tumor cells in the progressing metastases showed marked pleomorphism which proved to be rhabdomyoblastic differentiation with Desmin and Myogenin immunopositivity. However, there was no secondary mutation of KIT, PDGFRA, KRAS and BRAF genes found in the imatinib-resistant lesion, except primary KIT V559D mutation. To our knowledge, this case represents the few reports on this unusual type of transdifferentiation in GISTs under imatinib therapy. Awareness of this phenomenon would help to avoid diagnostic confusion when evaluating post-imatinib samples from GISTs.