Malignant peripheral nerve sheath tumor (MPNST), often arising from a (plexiform) neurofibroma, is one of the hallmark complications of neurofibromatosis type 1 (NF1) characterized by aggressive behavior [10]. The genetic background is complex and heterogeneous, with the initiating biallelic NF1 inactivation followed by a cascade of acquired mutations driving malignant progression. Amplification of receptor tyrosine kinase genes, have also been observed, and models demonstrated responses to the corresponding therapeutic blockades [7,8,9]. Fusion genes are rarely investigated in NF1-related MPNSTs [5]. We describe subclonal NTRK fusion genes in a subset of such tumors (Fig. 1), thereby potentially providing additional treatment options.

Fig. 1
figure 1

Morphological features of Case 1. a Primary biopsy showing an atypical cellular spindle cell tumor consistent with MPNST. Inset: partial pan-TRK expression. Magnification × 8. b First resection specimen depicted ~ 60% tumor necrosis. Magnification × 3

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Three out of 21 (14%) cases of our cohort harbored a NTRK1 fusion gene. The partner genes were TPM3, LMNA and CACYBP (Fig. 2). TPM3::NTRK1 and LMNA::NTRK1 are common driver fusion genes in NTRK-related spindle cell neoplasms [1], whereas CACYBP::NTRK1 has not been reported in the literature so far. One could argue that these three tumors represent classical NTRK-rearranged spindle cell neoplasms unrelated to the NF1. Nonetheless, two tumors originated in a plexiform neurofibroma and harbored biallelic NF1 mutations. The third case showed clinical signs of NF1, but failed to show two hits, possibly due to technical limitations (Tables 1, 2).

Fig. 2
figure 2

Detected fusion transcripts and the resulting fusion proteins in the three NF1-related MPNSTs with a NTRK1 rearrangement. Functional regions and domains are annotated. Transmembrane Domain (TMD)

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Table 1 Clinical characteristics of NF1 patients with MPNSTs harboring NTRK rearrangements
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Table 2 Molecular characteristics of MPNSTs with NTRK1 rearrangements
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By WGS, FISH and/or immunohistochemistry, the NTRK1 rearrangement presented as a subclonal molecular event in all three cases, further influencing MAPK signaling due to autoactivation of the corresponding transmembrane tyrosine kinase. NTRK genes, encoding for the neurotrophin family of growth factor receptors, have a crucial role in cell survival and proliferation, especially of neural tissue. Hence, it is not surprising that alterations in these genes can result in tumor development of MPNSTs [2].

Detection of NTRK chimeric fusion transcripts in NF1-associated MPNSTs might be of clinical importance as they may allow for targeted treatment with Trk-i as shown in one of our cases (Fig. 1a). While neurofibromin acts downstream of Trk, the sole blockade of the latter might be insufficient to fully abrogate MAPK signaling. In fact, a recent study showed that combined targeting of Trk and MEK, further downstream in the MAPK signaling pathway, in tumors harboring a NTRK fusion gene in combination with another activating alteration in the MAPK signaling pathway (i.e., activating KRAS and BRAF mutations) is paramount to prevent progression under Trk-i therapy and increase efficacy [3]. Whereas single agent treatment efficacy of MEK-i in NF1-related MPNSTs is questionable [4], the combination of a Trk-i and a MEK-i warrants further investigation.

In accordance with the intrinsic resistance against monotherapeutic Trk-i, the tumor of our treated case, initially showing good response, progressed during continuation of Trk-i treatment. A typical “escape” mutation in the kinase domain could not be detected by WES [2, 6]. Although the underlying resistance mechanism remains unclear so far, one could hypothesize that, besides another undetected mutation, quiescent cancer stem cells with specific genetic alterations are responsible for sustaining tumor growth [9].

Our study for the first time describes NF1-related MPNSTs harboring subclonal NTRK rearrangements with primarily good response to Trk-i treatment which could be an (additional) therapeutic agent.