NTRK-Rearranged Spindle Cell Neoplasm (Emerging)

Staging is only applicable to the malignant subset. The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system may be used.

Most tumors harbor NTRK1 fusions with a variety of partners, resulting mostly from intrachromosomal interstitial deletions (LMNA) or inversions (TPR, TPM3). Rare cases involving NTRK2 and NTRK3 fusions have also been reported. The NTRK fusions result in oncogenic pathway activation via chimeric proteins that contain the tropomyosin receptor kinase domains of TRK-A, TRK-B, and TRK-C. Tumors with similar morphology resembling PNSTs have also been shown to harbor alternative RAF1 and BRAF fusions. None of these tumors have been reported to be associated with neurofibromatosis type 1.

The macroscopic appearance of NTRK-rearranged spindle cell neoplasms has not yet been defined.

NTRK-rearranged spindle cell neoplasms appear to form a morphological spectrum. At one end of this spectrum is the so-called lipofibromatosis-like neural tumor, which is defined by haphazardly arranged monomorphic spindle cells, with tapering nuclei and indistinct cytoplasm. It shows a highly infiltrative pattern within subcutaneous fat, resembling lipofibromatosis. Although some examples have areas of increased cellularity and mild cytological atypia, they are associated with a low mitotic count and lack necrosis.

Another subset of cases have a solid growth pattern, comprising a moderately to highly cellular proliferation of uniform spindle cells arranged in streaming or patternless patterns. A diagnostic hallmark of this subset is the prominent stromal bands and perivascular rings of keloid-like hyalinized collagen. A few cases showing infiltrative growth within the fat resembling lipofibromatosis-like neural tumor have also been reported, suggesting a potential pathogenetic link between these two phenotypes. Several tumors have a zoned appearance, where cellular areas merge with paucicellular zones with collagenous or myxoid stroma, resembling malignant PNST. Tumors in this group encompass a wide histological spectrum, with most being of low grade, but some display a higher-grade phenotype, with markedly increased cellularity arranged in intersecting fascicles, with a high mitotic count. Necrosis may be present. A less common presentation of NTRK1-rearranged sarcoma includes tumors with a myopericytoma-like architecture.

Immunohistochemically, most tumors show coexpression of S100 and CD34, in the absence of SOX10 reactivity, whereas H3K27me3 expression is retained. The majority of tumors with NTRK fusions are reactive with an anti–pan-TRK monoclonal antibody; the staining can be either cytoplasmic or nuclear. TRK-A immunohistochemistry is useful for the detection of NTRK1-rearranged tumors. Importantly, pan-TRK and TRK-A immunoreactivity is not completely specific, and additional molecular genetic testing is often required for a conclusive diagnosis. Tumors with similar morphology but alternative RAF1 or BRAF fusions share a similar S100 and CD34 immunoprofile.

Not clinically relevant

The prognosis of NTRK-rearranged adult tumors appears to be related to histological grade. Due to their infiltrative growth pattern, the benign lipofibromatosis-like neural tumors have a propensity for local recurrence if incompletely excised, but none were shown to metastasize. Tumors with high-grade morphological features may show aggressive clinical behavior, with metastatic spread to lungs and other organs. Importantly, the aberrantly expressed oncogenic receptor tyrosine kinases TRK-A, TRK-B, and TRK-C in NTRK-rearranged sarcomas have proven to be therapeutically targetable, which may potentially improve patient outcome.

Molecular detection of NTRK fusions can be useful.

Essential: tumors span a wide spectrum of morphologies and histological grades; characterized by haphazardly arranged monomorphic spindle cells; infiltrative growth within fat resembling lipofibromatosis; distinctive stromal and perivascular keloid collagen; immunohistochemically tumors are positive for S100 and CD34 in many cases, whereas SOX10 is negative; tumors with NTRK1 fusions will show NTRK1 immunoreactivity.

Desirable: detection of NTRK fusions is usually required for determination of therapy.