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.