A 33-year-old Han Chinese woman was admitted to a local hospital due to irregular vaginal bleeding. The patient had no sexual history, so a transrectal ultrasound was performed instead of a gynecological examination, but no apparent abnormalities were found. So, the patient received hemostasis treatment but still experienced abnormal vaginal bleeding. Then, reexamination ultrasonography revealed a mass with rich blood supplies in the vagina, which had no clear boundary with the cervix, and subsequent magnetic resonance imaging (MRI) also found a 4.5 cm lesion filling the vagina, which was considered endometriosis or tumor. Then, the patient underwent hysteroscopy, and an elliptic mass was found at the cervical-vaginal junction. The mass was partially lobulated, with a smooth surface and a wide pedicle, and no noticeable abnormal vessels were observed. Later, the transvaginal cervical tumor resection was performed for the patient. Intraoperative investigation revealed that the tumor was in the anterior cervix lip and extended to the vaginal dome. It was pink, brittle, and had a rich blood supply. The histopathology of the excised specimen showed that the tumor tissue was composed of diffused spindle cells, and mitosis was active [>30/10 high power fields (HPFs)]. Collagen fiber degeneration around the vessels and lymphocyte infiltration were also observed, but necrosis was not detected. Immunohistochemical (IHC) staining was performed at the local hospital to differentiate it from other malignancies, such as high-grade endometrial stromal sarcoma or uterine leiomyosarcoma, and to determine its molecular subtype. It was found that the tumor was positive for S-100, CD34, vimentin, and cyclinD1 and negative for EMA, CK7, P53, P16, desmin, caldesmon, myoD1, myogenin, ALK, ER, PR, CD10, catenin-B, CD99, SATB2, BCL-2, CD117, BCOR, SOX10, HMB45, and melan-A. The tumor was suspected to be a special type of sarcoma, and then, the pathological sections were consulted by our hospital. We found that Pan-TRK, S-100, and CD34 were positive by IHC analysis, while SOX10 and desmin were negative in the tumor. Combined with its morphological characteristics and immunophenotype, it was suspected an NTRK fusion sarcoma. Since NTRK1 is the most common fusion type, it was investigated by fluorescence in situ hybridization (FISH) assay. The results showed that approximately 11% of cells were 0r-1Gr-1Fu, which did not support the existence of NTRK1 rearrangement (NTRK1 gene signal was mostly 1-3FU) in the tumor (Supplementary Figure 1).
The patient was transferred to our hospital for further treatment. The MRI in our hospital showed a neoplastic lesion on the anterior wall of the cervical-vaginal junction (Figure 1A). The serum levels of tumor markers were as follows: HE4 25.2 pmol/L, CA125 62.9 U/ml , SCC 0.8 ng/ml, beta-HCG <0.1 mIU/ml, AFP 1.92 ng/ml, CEA 0.71 ng/ml, CA199 7.27 U/ml, and NSE 12.17 mug/L. Meanwhile, a hysteroscopy examination was performed to distinguish it from endometrial stromal sarcoma. During the operation, a 0.5 x 1.5 cm neoplasm was found on the posterior wall of the uterus, and the pathological examination revealed an endometrial polyp (Supplementary Figure 2). Then, the patient underwent an extensive laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, and partial vaginal resection. The histopathology revealed the macroscopic feature of the tumor: the tumor tissue was composed of diffused spindle cells with fascicular, nested, or uniform patterns, and vascularization and nuclear atypia (low to moderate) were observable (Figure 1B). Meanwhile, there was no lymph node metastasis, lymph vascular space invasion (LVSI), and parauterine/interstitial infiltration. Furthermore, IHC analysis revealed that the Ki-67 labeling index (LI) was 30-40%, indicating highly proliferative tumor cells, and a large portion of tumor cells strongly expressed Pan-TRK, S-100, and CD34, while negative for vimentin, SOX10, and desmin (Figures 1C,D). Consequently, based on the morphological and IHC results, we diagnosed the patient as NTRK fusion cervical sarcoma. According to the 2018 Federation International of Gynecology and Obstetrics (FIGO) staging system for cervical cancer, the stage of the patient was IIA2. Postoperatively, the patient received 6 courses of adjuvant chemotherapy with doxorubicin hydrochloride liposomes and nedaplatin. On the completion of chemotherapy, the patient received pelvic MRI and abdominal computed tomography (CT) examinations, and the results showed no abnormalities. Meanwhile, she visited our hospital to monitor the CA125 level in the next 3 months, which were 46.3 U/ml , 25.7 U/ml, and 20.5 U/ml, respectively.
Two months after her last follow-up, the patient visited our hospital for diplopia in the right eye and right facial numbness, and the MRI examination revealed a mass in the right trigeminal nerve area, which was considered trigeminal schwannoma (Figure 2A). Consequently, she underwent cerebellopontine angle lesion resection in the Neurosurgery Department. During the operation, it was found that the tumor was, in fact, undemarcated with the trigeminal nerve. Grossly, the tumor was gray and fragmentary. Microscopic examination revealed that the tumor was spindle cell sarcoma (Figure 2B), which was diffusely expressed of CD34, vimentin, S-100, and Pan-TRK (Figures 2C,D), but negative for SOX10, EMA, SSTR2, PR, and STAT6. More importantly, the next-generation sequencing (NGS) identified an EML4 (NM_019063.5: exon 2)-NTRK3 (NM_001012338.2: exon 14) gene fusion variation in the tumor tissue. Together, the IHC and NGS results confirmed that the patient had a spindle cell sarcoma with EML4-NTRK3 fusion in the middle cranial fossa. To assess the condition of the lungs, the patient received the chest CT scan, which showed multiple metastatic lesions in both lungs, and the largest lesion was approximately 1.9 x 2.4 cm (Supplementary Figure 3). One month later, the patient presented vaginal bleeding, a gynecological examination found a mass protruding from the vaginal external orifice, and MRI revealed a 1.5 x 1.6 cm mass from the posterior of the vagina to the vulva, which was considered tumor recurrence (Figure 3A). The patient suffered from bleeding due to the mass and underwent lesion resection. Microscopically, the resected specimen was also composed of spindle cells (Figure 3B) and showed strongly positive for Pan-TRK, S-100, CD34, and vimentin but negative for SOX10 and desmin (Figures 3C,D). The results pointed to the recurrence and invasion of the NTRK rearrangement tumor. Also, the diagnosis indicated that the patient might benefit from TRK inhibitors, which, unfortunately, were not widely available in China currently. We sought a clinical trial of TRK inhibitor for this patient, but her condition progressively worsened and presented drowsiness, salivation, and left leg weakness. Unfortunately, the patient passed away one month later without being enrolled in the clinical trial.