Recurrent RET fusions in fibrosarcoma‐like neoplasms in adult viscera: expanding the clinicopathological and genetic spectrum

Abstract

Aims: RET-fused mesenchymal neoplasms mostly affect the soft tissue of paediatric patients. Given their responsiveness to selective RET inhibitors, it remains critical to identify those extraordinary cases occurring in the visceral organs of adults. In this study, we report three RET-rearranged spindle-cell tumours occurring in the visceral organs of adults. Methods and Results: Clinicopathological features were assessed and partner agnostic targeted nextgeneration sequencing on clinically validated platforms were performed. The patients were 18, 53, and 55 years old and included one male and two females. The tumours were located in the kidney (case 1), small intestine (case 2), and ureter (case 3), with maximum diameters of 14, 5, and 1 cm, respectively. Histologically, all tumours displayed a morphological spectrum typical of fibrosarcoma, including moderately to highly cellular, nonpleomorphic, ovoid to spindle-shaped cells arranged in long fascicles or haphazardly within collagenised to myxohyaline stroma. Foci of irregular alveolar oedema-like structures and areas with microcystic and reticular arrangements were identified in the renal tumour. Staghorn-type vessels and foci of band-like stromal hyalinisation were observed in the small intestine tumour. Cases 1 and 2 were high-grade and pursed a highly aggressive clinical course, while case 3 was of intermediate grade with no tumour recurrence or metastasis 14 years after surgery. All three tumours expressed CD34, which was coexpressed with S100 protein in cases 2 and 3. Molecular genetic testing revealed PRKAR1A::RET, KIF5B::RET, and SPECC1L::RET inframe gene fusions. Conclusion: Our study expands the clinicopathological and genetic spectrum of mesenchymal neoplasms associated with RET fusions.

Kinase fusion positive intra‐osseous spindle cell tumors: A series of eight cases with review of the literature

“…In this case, the tumor showed a fast and durable response to the NTRK inhibitor entrectinib for 10 months 17 . The KIF5B::RET fusion found in a single myxoma‐like tumor (case #8) has also been reported as a molecular event in an adult FS‐like tumor arising in the small intestine 18 . In addition, this gene fusion represents a common driver alteration in non‐small cell lung cancer 19 .…”

“…has also been reported as a molecular event in an adult FS-like tumor arising in the small intestine. 18 In addition, this gene fusion represents a common driver alteration in non-small cell lung cancer. 19 Although the FNBP1::BRAF fusion detected in an adult FS-like tumor (case #6) has only been reported in a single case of a primary lung melanoma, 20 several cases of BRAF-rearranged spindle cell neoplasms with many other fusion partners and IFS-like or FS-like morphology have been published in the literature.…”