Response to imatinib in villonodular pigmented synovitis (PVNS) resistant to nilotinib

Abstract

Background: Pigmented villonodular synovitis (PVNS) is a rare locally aggressive tumor. PVNS is characterized in most cases by a specific t(1;2) translocation, which fuses the colony stimulating factor-1 (CSF1) gene to the collagen type VIa3 (COL6A3) promoter thus leading through a paracrine effect to the attraction of non-neoplastic inflammatory cells expressing CSF1-receptor. Imatinib is a tirosin-kinase inhibitors (TKI) active against CSF1-receptor whose activity in naïve PVNS was already described. We report on two PVNS patients who responded to imatinib after failure to nilotinib, another CSF1-receptor inhibitor.

Methods: Since August 2012, 2 patients with progressive, locally advanced PVNS resistant to nilotinib (Patient 1: man, 34 years; Patient 2: woman, 24 years) have been treated with second-line imatinib 400 mg/day. Both patients are evaluable for response.

Results: Both patients are still on treatment (7 and 4 months). Patient 1 had a dimensional response by MRI after 2 months from starting imatinib, together with symptomatic improvement. In Patient 2 a metabolic response was detected by [18F]fluorodeoxyglucose-positron emission tomography (PET) at 6 weeks coupled with tumor shrinkage by MRI, and symptomatic improvement.

Conclusions: Imatinib showed antitumor activity in 2 patients with nilotinib-resistant PVNS. This observation strengthen the idea that targeted agent with similar profile can give a different clinical result, as already described for gastrointestinal stromal tumor (GIST) patients treated with the same agents. Molecular studies are needed to clarify the biologic mechanism(s) underlying the response.

Figure 1

Path evaluation of Patient 1, Hematoxilin and Heosin-stained (H&H) section. Tumor biopsy consistent with the diagnosis of PVNS. Histology shows a tumor characterized by a cleft-like space growth lined by synovial-like cells (panel A, 50x original magnification, red arrow) and a mixed cellular component made-up of mononuclear round small and large discohesive cells (panel B, 100x magnificent magnification, green arrows), rare osteoclast-like giant cells (panel B, violet arrow), inflammatory cells (panel B, blue arrow).

Figure 2

Path and phospho-receptor tirosine kinase (phRTK) array evaluation of Patient 1. The phRTK array analysis showed PDGFRB and CSFR1 activation, as indicated in panel A by the red and blue arrows, respectively. Immunohistochemistry resulted positive for platelet-derived growth factor receptor beta (PDGFRB) and colony-stimulating-factor1-receptor (CSF1R) expression (panel B and C, respectively).

Figure 3

[18F]fluorodeoxyglucose (FDG) PET/CT tumor assessment of Patient 2. Baseline PET/CT maximum projection image (MIP) (panel A1) showed abnormal FDG focal uptakes in the right knee PVN with a SUVmax of 14.7 g/ml, as detailed by fused PET/CT transaxial slice (panel A2). After 6 weeks of treatment, PET/CT MIP (panel B1) and fused PET/CT transaxial slice (panel B2) showed a marked decrease of tumor FDG uptake (SUVmax 4.1 g/ml, i.e. 72% reduction).

Figure 4

Magnetic resonance imaging (MRI) tumor assessment of Patient 2. Sagittal contrast enhanced (ce) TSE T1 weighted (w) MRI images at baseline showed a lesion located behind the rotula (panel A). After 2 months of imatinib a decrease in tumor size was detected (panel B).