STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion

Abstract

Background: Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein.

Methods: Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: ( NCT01548144 ).

Results: Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria.

Conclusions: For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.

Figures

Fig. 1

IMT infiltrating the myometrium are images 1 and 2. The myxoid areas are infiltrating the muscle of the myometrium. Image 3 is an immunostain for ALK, diffusely positive in the spindle tumor cells

Fig. 2

Representative genome images from the Integrated Genome Viewer (IGV) alterations for deletion of ALK exon 1–19, and fusion of ALK-DCTN1 demonstrating ALK and DCTN1 fusion found in the patient with inflammatory myofibroblastic tumor with myxoid features who had a response to ALK inhibitor based therapy

Fig. 3

The DCTN1-ALK intra-chromosomal rearrangement detected in this case conformed to the common structural organization of ALK fusions, with the vast majority having an ALK intron 19 breakpoint and is a priori suspected to active in vivo. The DCTN1 component of the fusion contains exons including the coiled-coil domains, which is similar to other previously reported ALK fusion partners. Via these domains, DCTN1 is suspected to promote dimerization of ALK and subsequent kinase activation by transphosphorylation

Fig. 4

Imaging studies at baseline and follow-up. a Pre-treatment axial CT image shows a 6.2 × 5.1 cm peritoneal implant in the left upper quadrant (top) and a 4.4 × 4 cm peritoneal implant in the right hepatorenal space (bottom). b Follow-up axial CT image shows interval decrease in the peritoneal implant in the left upper quadrant which measures 4.5 × 3.8 cm, previously 6.2 × 5.1 cm (top). Axial CT image shows that the 4.4 × 4 cm peritoneal implant in the right hepatorenal space (bottom) has not changed much in size (measured 4.4 × 3.7 cm), but the lesion has now become less dense. This is an important observation as this represents response to therapy. Radiologists and clinicians should be aware that many targeted therapies may not result in significant change in size particularly during the early stages but may cause interval decrease in vascularity; on CT, this may be seen as decrease in density of the target lesions and represents response to therapy