DISCUSSION
We described a rare case of pediatric endotracheal IMT with a not-previously reported ALK fusion transcript successfully treated with ALK inhibitor.
Since the first report in 198911; upper airways IMT- including trachea and main bronchus- have been reported in 16 patients. The median age at diagnosis was 9 years, with a male/female ratio of 1. All the patients have a histological diagnosis of IMT, but ALK status was reported in only five cases. Treatment strategy are listed in Supplemental Table 111-25. Aggressive surgery was the primary approach considering the critical condition in more than 50% of patients. Moreover, some reports were published before 2008, when surgery and chemotherapy were recommended, but ALK-inhibitors trials were not yet developed.
In our case, a prompt diagnosis with molecular characterization was achieved. Considering the IMT diagnosis with a TRAF3-ALK fusion transcript, Crizotinib was suddenly started with a rapid recovery and impressive lesion reduction.
The Crizotinib is a small molecule targeting multiples tyrosine-kinases such as ALK, ROS, ROS1, MET, and interferes with ALK-pathway, blocking oncogenic proliferation26. It was approved firstly for advanced ALK-positive or ROS1-positive non-small cells lung cancer27.
ALK fusions were detected also in neuroblastoma, rhabdomyosarcoma, anaplastic large-cell lymphoma, and IMT1,28; several trials investigating the safety and efficacy in these subsets were run.
In 2010, in a phase I/II clinical trial, Butrynski et al. reported a brilliant response to Crizotinib of ALK-positive IMT29. The COG phase I/II trial on pediatric anaplastic large cell lymphoma and IMT treated with Crizotinib reported five complete and seven partial responses among fourteen pediatric patients, with an 86% response rate30.
Furthermore, a phase II pediatric clinical trial by the EORTC reported an objective response in 50% of patients, with mild adverse events in among 10% of patients (more frequently nausea, fatigue, blurred vision and diarrhea, without any severe or life-threating adverse events)31.
Recently, further reports studied others ALK inhibitors, like Alectinib and Ceritinib32.
Craig et al. described 29 patients affected by ALK-positive IMT who underwent therapy with an ALK-inhibitor. Twelve experienced complete response (41.3%), fourteen a partial response (48.3%) and three (7%) stable disease. Two (7%) had recurrence at the stop-therapy; anyway, they achieved a second complete response after restarting the therapy33.
The TRAF3-ALK fusion transcript (involving exons 10 and 20) has never been reported before in literature; in IMT, more than 10 different genes have been identified as ALK fusion partners, including TPM3/4, RANBP2, TFG, CARS, ATIC LMNA, PRKAR1A, CLTC, FN1, SEC31A, and EML434. ALK status is known to correlate with survival35.
Rarely, IMT can harbor mutations of ROS1, PDGFRb, NTRK or RET, needing further studies to correlate with clinical presentations and outcome36.
In conclusion, the endotracheal IMT diagnosis, even if rare, should be considered in children with respiratory symptoms, radiological atypical findings and no response to medical treatment.
The standard approach with primary huge surgery may be delayed, considering the high risk of life-threatening complications related to anatomical localization, and a conservative approach should be instead considered, according also to recent molecular findings and the ALK inhibitors option.
This report stress the role of target therapy, underlying their rapid clinical results, with a quickly control of respiratory distress and without a demolitive surgical approach.