ALK is a serine/threonine-specific protein kinase that directly or indirectly stimulates PI3K/AKT/mTOR, Ras GTPase, ERKs, Janus kinase, STAT proteins, and other cell signaling elements. Activation of these elements stimulates cell growth, proliferation, survival, and other tumor-promoting behaviors. As an example of this chromosomal translocation, the ALK gene located on the short or "p" arm of chromosome 2 at position 23 (notated as 2p23) merges with the CLTC gene on the long, i.e. "q" arm of chromosome 17 at position 13 (notated 17q23) to form a chimeric gene notated as t(2;17)(p23;q23). This chimeric gene makes a CLTC-ALK fusion protein with uncontrolled ALK serine/threonine-specific protein kinase activity. Other genes that fuse with AKT found in IMT include: TFG, DCTN1, EML4, TPM3, TPM4, ATIC RANBP2 (most if not all RAMB2-ALK chimeric genes occur in the EMIS form of IMT), CARS1, and SEC31L1. IMT cases may express other chimeric genes in which the active parts of ROS1 (found in 10% of IFT cases and coding for a tyrosine kinase which promotes cell growth), PDGFRB (coding for a protein that may promote the development of cancer), and NTRK (coding for a receptor tyrosine kinase that may promote the development of cancer) merge with other genes. The fusion protein products of these chimeric genes, like those of ALK fusion proteins, are overproduced, overactive, and thereby may contribute to the development of IMT. Diagnosis
Histopathologic examination of the tumors in IMT generally reveals myofibroblastic spindle cell sheets in a myxoid background (i.e.
A review of previously published IMT patients of all ages found that: 1) 4 patients (3 with unifocal, 1 with multifocal disease) without prior treatment had complete responses to crizotinin; 2) 2 patients (1 with unifocal, 1 with multifocal disease) that had persistent disease after surgery and previously treated with chemotherapy had partial responses to crizotinib while 1 patient previously treated with a corticosteroid, prednisone, continued to have progressive disease on crizotinib; and 3) 6 patients with progressive disease after surgery (due to multifocal or unifocal disease in inaccessible sites) had complete responses (2 cases), partial responses (2 cases), stable disease (1 case), or progressive disease (1 case) in response to crizotinib. Two of these crizotinib-treated patients with progressive disease had near complete responses to second generation ALK inhibitors Another study reviewed 29 pediatric patients (age 15 months to 17 years) who were treated with an ALK inhibitor followed by surgical removal of the tumor (5 cases), surgical tumor removal followed by an ALK inhibitor (12 cases), or an ALK inhibitor without surgery. Twelve patients had complete responses, 14 partial responses, 2 stable disease, and 2 recurrences after finishing ALK inhibitor treatment. The latter two patients obtained complete responses to retreatment with crizotinib (1 case) or a second generation ALK inhibitor, ceritinib (1 case). A study of 14 pediatric patients with metastatic or inoperable ALK-positive IMT were treated with crizotinib: 5 patients obtained complete responses, 7 partial responses, and 2 stable disease. Over the study period (2–63 months), no patient developed progressive disease.