A unique case of hybrid sclerosing epithelioid fibrosarcoma low‐grade fibromyxoid sarcoma with EWSR1–CREB3L1 fusion in an 11 year‐old treated with robotic‐assisted bronchoscopy

摘要

To the Editor: Primary lung malignancies in the pediatric population are rare at 0.049 per 100,000 individuals, with a histological distribution unique to the pediatric population.1, 2 Here, we present a novel case of a child who presented with hemoptysis, who safely underwent robotic assisted flexible bronchoscopy and was diagnosed with a tumor not previously reported in the literature with the lung as primary site: a hybrid sclerosing epithelioid fibrosarcoma (SEF)–low-grade fibromyxoid sarcoma (LGFMS), with Ewing sarcoma breakpoint region 1 (EWSR1)/cAMP-responsive element binding protein 3-like 1 (CREB3L1) fusion mutation. EWSR1–CREB3L1 are the most frequent fusion mutations in SEF, composing 80%–90% of cases, while Fused in Sarcoma (FUS)–CREB3L1 and FUS–CREB3L2 gene fusions are more common in hybrid or LGFMS.8 EWSR1 is an RNA binding protein that functions in maintenance of genomic integrity, and CREB3L1 is a transcription factor implicated in cancer cell migration and invasion.3, 4 EWSR1 belongs to the same family of RNA binding proteins as FUS gene, and mutations in both drive soft tissue tumors, though mutation frequency varies by sarcoma type.3 SEF is associated with a more aggressive clinical course than LGFMS, though differences in clinical presentation between patients with EWSR1–CREB3L1 fusions and FUS-CREB3L1 fusions remain an active area of research. SEF, LGFMS, and hybrid tumors are all rare in the pediatric population.5 An 11-year-old female with no significant medical history presented to the emergency department with cough, shortness of breath, and three episodes of bright red hemoptysis for 1 day. A chest x-ray showed a round, well-demarcated 4.1 cm mass in the right lower lung (Figure 1). A computed tomography (CT) chest revealed a 4.9 × 3.0 cm mass in the right lower lobe (RLL) with coarse calcification (Figure 2), suggestive of a pulmonary hamartoma. The patient underwent flexible bronchoscopy with transbronchial needle aspiration guided by radial ultrasound. Rapid on-site evaluation (ROSE) did not show adequate specimens. The case was converted to robotic-guided bronchoscopy; transbronchial needle aspiration and transbronchial biopsies of the RLL mass were successfully obtained. Surgical pathology showed fragments of fibromyxoid stroma possibly consistent with hamartoma but not conclusive. Patient then underwent an RLL lobectomy, and pathology revealed a hybrid SEF–LGFMS, with genetic sequencing (Sema4 whole-exome sequencing [WES]/whole transcriptome sequencing [WTS]) demonstrating an EWSR1–CREB3L1 fusion gene. Background lung demonstrated emphysema and hemorrhage; bronchial and vascular markers were negative for tumor. The patient underwent staging scans, which negative for metastasis. Pulmonary function testing demonstrated low diffusing capacity for carbon monoxide (DLCO), yet normal DLCO/alveolar volume (VA) and total lung capacity. After surgical resection, the patient has been in complete remission for 12 months. To this date, this hybrid SEF–LGFMS tumor with an EWSR1–CREB3L1 fusion has not been described in the literature as a primary lung neoplasm. Only one other EWSR1–CREB3L1 hybrid SEF–LGMS tumor has been reported, a 10-year-old primary renal tumor.7 The patient presented with widespread metastases, underwent biopsy and subsequent palliative chemotherapy; the patient died of metastatic disease 12 months after the diagnosis. In contrast, the EWSR1–CREB3L1 gene fusion has been observed in 80%–90% of SEF (a rare soft tissue sarcoma) cases.8 The youngest patient reported with SEF and an EWSR1–CREB3L1 mutation was a 3-year old, who presented with numerous lung and bone metastases.8 In a case series of four pediatric patients with SEF in deep soft tissues of the trunk harboring EWSR1–CREB3L1 mutations, one patient did not receive further treatment and died 17 months after diagnosis, two remained disease-free post surgery, and one remained disease-free 22 months following radiation and multiple chemot