Discussion
Our cohort represents a group of children with IMFT with varied presentations. A low-dose oral out-patient based combination chemotherapy, including prednisolone, 6-mercaptopurine, methotrexate, and celecoxib, was well-tolerated and showed good efficacy. In children with abdominal disease, where complete surgical excision was not possible, recurrence was noted, which responded to targeted therapy with crizotinib.
Diagnosis can be challenging, and a high index of suspicion is essential. IMFTs are characterized by a variably cellular spindle cell proliferation in a myxoid to collagenous stroma with a prominent inflammatory infiltrate composed primarily of plasma cells and lymphocytes, with occasional eosinophils and neutrophils (4, 6). The absence of anaplasia, lack of mitotic figures, and the inflammatory background differentiate IMFT from soft tissue sarcomas. IHC may not be definitive because of variable expression and lack of specificity of these markers such as smooth muscle actin, muscle-specific actin, and vimentin. Rearrangements involving the ALK locus on chromosome 2p23 have been documented in approximately 50% of IMFTs (7, 8).
Surgery has been known to be the mainstay of treatment. Surgical resection should be recommended for all lesions if not limited by anatomic location or morbidity. Recurrence is rare following complete excision of a solitary lesion, depending upon the anatomical site, from 2% for tumors confined to the lung to 25% for extrapulmonary lesions (9, 10). We performed surgery for 3 of our cases (child#1, 2, and 4). In child #3 and 5, surgery was not offered because of the tumor’s difficult anatomic location.
Various adjuvant chemotherapy regimens have been used in the past with limited efficacy (3, 9, 11). Oral methotrexate and 6-MP have been found to be potentially active chemotherapeutic agents. Several groups have published encouraging results with steroids and non-steroidal anti-inflammatory agents (NSAIDS) with or without concomitant chemotherapy (12, 13). Applebaum et al . described the inhibitory effect of NSAIDs through disruption of angiogenesis by interfering with vascular endothelial growth factor signaling via cyclooxygenase 2 (COX-2) inhibition (14).
Crizotinib is a small-molecule tyrosine kinase inhibitor targeting several kinases, including ALK and MET. Recent studies have shown the efficacy of crizotinib in the management of ALK-positive IMFTs (15, 16, 17). In the Children’s Oncology Group study, an overall response rate of 86% was noted with crizotinib in refractory IMFTs, with the most common adverse effect being neutropenia (16).
IMFT requires a multidisciplinary team of pediatric surgeons, pathologists, nursing, and oncologists. Long term follow-up and prolonged therapy are essential to sustain remission. Maximal safe resection followed by oral chemotherapy with low-dose prednisolone, methotrexate, 6-MP, and celecoxib helps achieve remission in two-thirds of the children. Crizotinib is a useful salvage agent in recurrent tumors that are ALK-positive.
Acknowledgments: We would like to acknowledge the contribution of the histopathology department in the management of these children
Conflicts of interest: none
Funding: none