Two Different Paths of Treatment for Relapsed‐Refractory Infantile Fibrosarcoma: Classical or Trendy?

Although infantile fibrosarcoma accounts for less than 1% of all childhood cancers, it is one of the most common non-rhabdomyomatous soft tissue tumours, mostly seen in the first 2 years of life, with an estimated incidence of 5 in 1 000 000 infants [1-3]. They are typically locally aggressive, single, rapidly growing tumours. Although MRI and/or CT are important for the diagnosis, pathological demonstration of the proliferation of fibroblasts is the gold standard. In 85% of infantile fibrosarcomas, it is associated with ETV6-NTRK3 gene fusion resulting from t(12:15)(p13:25) chromosomal translocation, which has paved the way for targeted therapies [4, 5]. Although the mainstay of treatment is surgery, chemotherapeutic agents can be used as neoadjuvant/adjuvants [6]. Here, we present a patient who was diagnosed in the neonatal period, recurred and progressed a few times despite surgery and chemotherapy, and whose residual mass completely disappeared after the start of Larotrectinib treatment. After birth, our patient was hospitalised in the neonatal care unit due to a prominent, non-tender, solid, localised nodular lesion with defined margins of a 4 × 3 cm diameter in the upper medial side of the right arm (Figure 1). Physical examination showed no other pathological findings. Laboratory findings were within normal limits. Ultrasonography showed a mass of 26 × 11 mm, having a harmonious appearance with heterogeneous character with high and low echogenicity containing areas within. MRI images revealed a heterogeneous, peripherally and at some regions centrally, diffusely dense contrast enhancement solid mass lesion with rare cystic regions at the level of the proximal humerus of the right arm, within the muscle fibres of the posteromedial region, with dimensions of 36 × 26 mm (Figure 2). Thorax-abdomen-pelvis CT showed no signs of metastasis except for an 8 × 4 mm suspicious reactive lymph node in the right axillary region. The true-cut biopsy of the mass was consistent with a spindle cell malignant mesenchymal tumour with negative S100, MyoD1, synaptophysin, myogenin, and desmine; and the Ki-67 proliferation index was 80%; diagnosed as malignant spindle cell mesenchymal tumour (Figure 3). Afterwards, the mass was excised subtotally. In the excised specimen, a partially encapsulated nodular mass with a firm consistency was observed on gross examination. Microscopically, the neoplasm was highly cellular and composed of spindled to immature round cells. Necrosis and calcification were observed. ETV6-NTRK3 gene fusion was found as a result of molecular analysis in the excisional biopsy. Adjuvant chemotherapy with vincristine and actinomycin D according to EpSSG infantile fibrosarcoma IRS group III was started for residual disease. After 10 weeks of chemotherapy, progression occurred. Re-surgery was performed, and the mass was removed with near-total resection. After 4 cycles of Ifosfamide-Doxorubicin as second-line treatment, the disease was stable. Then, the NTRK inhibitor (Larotrectinib) was started. No side effects were observed. Following a 9-month Larotrectinib treatment, control MRI showed no residue. Informed consent to be published for this case report was obtained from the parents of the patient. Infantile fibrosarcomas are rare tumours with a high survival rate. Despite their morbidity, the gold standard way of treatment is still surgery [7]. When radical surgery is not feasible, neo-adjuvant chemotherapies including vincristine, actinomycin, and cyclophosphamide are used as first-line treatment options [2, 7]. Adjuvant chemotherapy can be used in patients with positive surgical margins or residual disease after surgical excision [6]. Our patient also had residual disease after surgical excision, so she was given adjuvant chemotherapy according to EpSSG infantile fibrosarcoma IRS group III. Because of progression during chemotherapy, she underwent surgery during which subtotal resection could be achieved Then, an NTRK inhibitor was started. NTRK inhibitors are new, oral, highly selective, and potent options for the treatment of infantile fibrosarcoma [5]. They provide a rapid, complete, and sustained response to chemotherapy, especially in infantile fibrosarcoma patients with ETV6-NTRK positivity [2]. Besides, they are also used as neoadjuvant therapy with acceptable toxicity in inoperable tumours [8, 9]; they are currently used for patients whose lesions cannot be surgically removed, who do not respond to conventional chemotherapy, or who have metastatic disease, as well [2]. Our patient also achieved full remission with Larotrectinib, and no residual lesion was seen after 9 months of treatment. Because the neurotrophin tropomyosin receptor kinases (TRKA, TRKB and TRKC) play a role in neuronal development, differentiation, and function and also have a role in sensation, movement, and regulation of behaviour and cognition, it is important to monitor the long-term neurophysiological and neuropsychological development of the patients treated with NTRK inhibitors [3, 10]. Although the 9-month follow-up period for the presented case here is short, she had good neuromotor development compatible with her age and her peers. In conclusion, infantile fibrosarcoma is one of the rare tumours of childhood with locally aggressive behaviour but a favourable prognosis. In terms of the side effects of chemotherapy and radiotherapy in the short and long term, Larotrectinib is a promising targeted drug with a less invasive and manageable side effect profile. With this case, it stands out that targeted treatments are a promising form of treatment, especially in selected cases. The authors have nothing to report. Ethics and informed consent were taken from the patient's parents. The authors declare no conflicts of interest.