The Use of Pan-Tropomyosin Receptor Kinase Immunohistochemistry as a Screening Tool for the Detection of Neurotrophic Tropomyosin-Related Kinase Fusions: Real-World Data from a National Multicentric Retrospective Study

Abstract

<b><i>Introduction:</i></b> The neurotrophic tropomyosin-related kinase (<i>NTRK</i>) genes encode the tropomyosin receptor kinases (TRKs). Patients with solid tumors harboring an oncogenic <i>NTRK</i> fusion are eligible for treatment with TRK inhibitors. <i>NTRK</i> fusion is often associated with TRK overexpression. Pan-TRK immunohistochemistry (IHC) is used to screen for <i>NTRK</i> fusions, but immunoreactivity patterns are poorly defined. <b><i>Methods:</i></b> Data on pan-TRK immunoreactivity patterns in 2,669 solid tumors (comprising carcinomas, sarcomas, and melanocytic lesions) were retrospectively collected by nine laboratories and comprised tumor type, percentage of pan-TRK-positive tumor cells, staining intensity, cytoplasmic, membrane and/or nuclear staining pattern, and the presence or absence of <i>NTRK</i> fusion. <b><i>Results:</i></b> Overall, 2,457 tumors (92%) were pan-TRK negative and 212 neoplasms (8%) were pan-TRK positive. Twenty-two pan-TRK-positive tumors (0.8%) harbored an <i>NTRK</i> fusion, representing 10% of all pan-TRK-positive tumors. Cytoplasmic immunoreactivity was most often observed, followed by membrane immunoreactivity. Nuclear pan-TRK positivity was least frequent, but was most often (33%) associated with <i>NTRK</i> fusion. <b><i>Conclusion:</i></b> Pan-TRK IHC can be used to screen for <i>NTRK</i> fusions, especially in commonly diagnosed solid tumors with low <i>NTRK</i> fusion prevalence. In case of pan-TRK immunoreactivity, regardless of its intensity and tumor cell percentage, subsequent molecular tests should be performed to formally confirm the presence or absence of <i>NTRK</i> fusions.

Head and Neck Mesenchymal Tumors with Kinase Fusions

“…False positivity has been reported in various other sarcomas, including BCOR sarcoma,20,41 undifferentiated uterine sarcoma,20 Ewing sarcoma,41 leiomyosarcoma,26 synovial sarcoma,26 extraskeletal myxoid chondrosarcoma,26 liposarcoma,26 and myxofibrosarcoma 26. A recent study tested 2669 solid tumors with a low probability (<1%) of NTRK fusions and showed that only 10% of pan-TRK + tumors harbored NTRK fusions 42. Second, the sensitivity of pan-TRK immunohistochemistry has been reported in the range of 75% to 88% and is even lower in detecting NTRK3 fusion 38,40,43.…”

“…26 A recent study tested 2669 solid tumors with a low probability (< 1%) of NTRK fusions and showed that only 10% of pan-TRK + tumors harbored NTRK fusions. 42 Second, the sensitivity of pan-TRK immunohistochemistry has been reported in the range of 75% to 88% and is even lower in detecting NTRK3 fusion. 38,40,43 Such a sensitivity implies that 12% to 25% of tumors with NTRK fusions can be missed when using pan-TRK immunohistochemistry as a stand-alone test.…”