NTRK-rearranged spindle cell sarcoma of the uterine cervix with a novel NUMA1::NTRK1 fusion

In recent years, several new, molecularly defined subtypes of uterine sarcomas have been described, which may have previously been diagnosed as fibrosarcoma, adenosarcoma or neurofibrosarcoma/fibroblastic peripheral nerve sheath tumour [1]. One of these newly defined entities is NTRK-rearranged uterine sarcoma. This tumour, which has a fibrosarcoma-like morphology and propensity to the uterine cervix, was first described by Mills et al. [1] and later characterised as an NTRK-rearranged sarcoma by Chiang et al. in 2018 [2]. These tumours generally consist of the proliferation of relatively monomorphic spindle cells with only mild to moderate nuclear atypia. Despite their morphologically bland appearance and often organ-confined nature at the first diagnosis, these tumours show a propensity for an aggressive clinical course with rapid recurrence and metastatic spread. Based on the relevant literature, less than 50 NTRK-rearranged uterine sarcomas have been described thus far, and various NTRK fusion partners have been identified [3‐7]. In this study, we present an additional NTRK-rearranged uterine sarcoma with a novel NTRK fusion partner, which, to the best of our knowledge, has not been described to date.

NTRK-rearranged uterine sarcoma was first described by Mills et al. as a fibroblastic malignant peripheral nerve sheath tumor (neurofibrosarcoma) in 2011 [1] and later characterised as an NTRK-rearranged sarcoma by Chiang et al. in 2018 [2]. It represents a subset of uterine sarcomas with distinct clinicopathological features. The tumour occurs mainly in premenopausal women. The most common presentation is abnormal vaginal bleeding. The tumours are usually located in the uterine cervix and less often in the uterine corpus [8, 9]. Macroscopically, the tumour is usually poorly circumscribed or rarely polypoid with a yellow, pink or white cut surface [5, 8]. The majority of the lesions are FIGO stage IA or IB at the time of presentation [3, 5]. Microscopically, the tumours have a fibrosarcoma-like morphology with relatively uniform spindle cells and scant cytoplasm. Nuclear atypia is usually mild to moderate. The mitotic activity varies highly between tumours. The tumour cells are typically arranged haphazardly, but a fascicular growth pattern can also be seen. Most of the tumours have an infiltrative or occasionally a pushing border. The presence of a lymphoid infiltrate within the lesion is also common. Perivascular hyalinization and necrosis are present in approximately half of cases [5, 8]. On immunohistochemistry, the tumour cells demonstrate pan-Trk-positive staining in the vast majority of the tumours. Pan-Trk immunoreactivity is associated with a fusion partner-specific pattern of staining [2] NTRK-rearranged tumours also commonly express CD34, often with coexpression of S100, but lack SOX10 expression [4]. Our lesion showed strong membranous pan-Trk staining and CD34 positivity, but S100 was negative (Fig. 2A–C). The tumours tend to lack smooth muscle differentiation and are usually negative for desmin and h-caldesmon but may show focal positivity for SMA. While this tumour was h-caldesmon negative, a small number of tumour cells were positive for SMA and desmin (Fig. 2D). Hormone receptors are usually negative [6, 8].

In a recent study, the presence of lymphovascular invasion, necrosis, mitotic count ≥ 8/10 HPF and NTRK3 fusion were considered poor prognostic factors in NTRK-rearranged uterine sarcomas. Tumours without any of these characteristics can be classified as low risk, while tumours with one or more of these characteristics can be considered high risk [3]. Our lesion fulfilled all but one of these criteria; thus, it was considered high risk.

The presence of NTRK fusions has been reported in a variety of tumour types with different morphologies and aetiologies. The NTRK genes—NTRK1, NTRK2 and NTRK3—encode members of the tropomyosin receptor kinase (Trk) family, which include three transmembrane protein receptors TrkA, TrkB and TrkC. These are primarily involved in neuronal development and maintenance. Gene fusions involving NTRK genes lead to constitutive activation or overexpression of Trk receptors, promoting oncogenesis by activating the PI3K and MAPK pathways [10]. The significance of these genetic alterations lies in the new therapeutic opportunities they offer. Larotrectinib and entrectinib are first-generation NTRK inhibitors that have demonstrated a 57% therapeutic response in solid adult tumours harbouring NTRK fusions [8]. In NTRK-rearranged uterine sarcomas, NTRK1 is more frequently involved in gene fusions than NTRK3 [3], and TPM3::NTRK1 fusion is the most common translocation reported [4]. Other reported NTRK1 fusion partners include TPR, C16orf72, IRF2BP2 and LMNA, while SPECC1L, EML4, TFG, RBPMS and STRN were reported in cases of NTRK3 involvement [3, 8]. Rearrangement of NUMA1 with a protein tyrosine kinase or other partners (PDGFRB, ALK and RARA) has been previously reported only in a handful of haematological and mesenchymal tumours [11‐13], but to the best of our knowledge, NUMA1 as an NTRK fusion partner has not been reported thus far in NTRK-rearranged uterine sarcomas or any other NTRK-rearranged tumours. NuMA1 (Nuclear Mitotic Apparatus protein 1) is a high molecular weight protein that plays an essential role in mitotic spindle assembly and maintenance during mitosis [14]. The detected NUMA1::NTRK1 fusion in our patient included the N-terminal globular and coiled-coil domains of NUMA1 and the transmembrane and kinase domains of NTRK1 (Fig. 3). This is a consistent feature of NTRK fusions, where the 3′ region of an NTRK gene, which encodes the full kinase domain, is translocated to the 5′ region of the partner gene, which encodes an oligomerization or other protein-association domain [15]. The coiled-coil domain of the NuMA1 protein is an oligomerization domain; hence, it is predicted to promote dimerization of the fusion protein, resulting in constant activation of the tyrosine kinase domain of NTRK1.

In summary, we report a case with a novel NUMA1::NTRK1 fusion in an NTRK-rearranged spindle cell sarcoma of the uterine cervix. The clinical, morphological and immunohistochemical features of this lesion are consistent with those reported in the literature, but to the best of our knowledge, this is the first description of a novel NUMA1::NTRK1 fusion in an NTRK-rearranged uterine sarcoma or any other tumour type. This entity has only recently been described, but the accurate diagnosis of these rare tumours is important. The presence of CD34 and/or S100 positivity on immunohistochemistry in a uterine sarcoma of the lower uterine segment or the cervix should trigger further NTRK testing, as an NTRK fusion may provide targeted therapeutic options with a potential positive impact on patient survival.