Infantile Fibrosarcoma

Not clinically relevant

IFS is driven by oncogenic activation of kinase signaling, mostly as a result of in-frame fusions upstream of the kinase domains and in rare cases due to complex activating mutations. Most cases harbor the canonical ETV6-NTRK3 fusion resulting from t(12;15)(p13;q25), although rare cases involving other partners, such as EML4-NTRK3, have been reported. In addition, alternative fusions involving other kinases have been reported in a subset of cases, including NTRK1, NTRK2, BRAF, and MET. NTRK1 fusion gene partners include TPM3, LMNA, TPR, SQSTM1, and MIR584F1. BRAF fusions and complex deletions have been described, which probably result in the loss of the negative regulatory RAS-binding domain, resulting in constitutive activation of BRAF. A single case with TFG-MET fusion has been reported. The genetic abnormalities of cellular congenital mesoblastic nephroma share substantial overlap, in keeping with a common pathogenesis. Secretory carcinomas of the breast and salivary gland also harbor the ETV6-NTRK3 fusion.

Tumors vary in size but can be quite large (median size: 5–6 cm; range: 1 to > 15 cm). Grossly, they are typically poorly circumscribed, with infiltrative borders into surrounding structures; some tumors may have a thin pseudocapsule.

Histologically, IFS can display a broad morphological spectrum. Most commonly, it is a cellular neoplasm composed of monomorphic spindled to ovoid cells with scant cytoplasm and slightly angulated nuclei. The cells may be arranged in randomly oriented compact sheets or in herringbone fascicles. The background stroma can range from collagenous to myxoid. A prominent haemangiopericytoma-like vascular pattern is often present. tumors with decreased cellularity and prominent collagen resembling fibromatosis or myofibromatosis can also be seen. A rich mixed chronic inflammatory infiltrate may be present. Infiltrative growth into and entrapping adipose tissue, skeletal muscle, and other structures is common. Mitoses range from infrequent to numerous, without prognostic significance; no atypical mitoses are seen. Patchy necrosis may be present. The immunohistochemical profile is nonspecific, with variable expression of SMA, CD34, S100, and desmin. IFSs with NTRK gene rearrangements are often positive by immunohistochemistry using a pan-TRK antibody.

Not clinically relevant

IFS is locally aggressive but with relatively infrequent metastases and an overall favorable outcome. The overall 10-year survival rate for IFS with standard treatment regimens (various combinations of surgery and/or standard chemotherapy) is about 90%. Reported local recurrence rates are 25–40%, with recurrence highly associated with incomplete resection. However, for many tumors, complete surgical resection would result in substantial morbidity and is therefore not the ideal management. The rate of metastasis is 8–15%. Rare cases of spontaneous tumor regression have been observed. The advent of targeted tyrosine kinase inhibitors may alter the prognosis and clinical management of this disease in advanced or intractable disease.

ETV6-NTRK3 or other gene fusions/rearrangements can be demonstrated by a variety of molecular approaches.

Essential: the majority of patients are aged < 2 years; spindle to primitive ovoid/round cell tumor; often arranged in a fascicular/herringbone pattern; staghorn vasculature and mixed inflammation. Desirable: ETV6-NTRK3 fusion or other rearrangements involving NTRK1, BRAF, and MET.