Metastatic pediatric sclerosing epithelioid fibrosarcoma

Abstract

Sclerosing epithelioid fibrosarcoma (SEF) is a rare and aggressive soft-tissue sarcoma thought to originate in fibroblasts of the tissues comprising tendons, ligaments, and muscles. Minimally responsive to conventional cytotoxic chemotherapies, >50% of SEF patients experience local recurrence and/or metastatic disease. SEF is most commonly discovered in middle-aged and elderly adults, but also rarely in children. A common gene fusion occurring between the EWSR1 and CREB3L1 genes has been observed in 80%-90% of SEF cases. We describe here the youngest SEF patient reported to date (a 3-yr-old Caucasian male) who presented with numerous bony and lung metastases. Additionally, we perform a comprehensive literature review of all SEF-related articles published since the disease was first characterized. Finally, we describe the generation of an SEF primary cell line, the first such culture to be reported. The patient described here experienced persistent disease progression despite aggressive treatment including multiple resections, radiotherapy, and numerous chemotherapies and targeted therapeutics. Untreated and locally recurrent tumor and metastatic tissue were sequenced by whole-genome, whole-exome, and deep-transcriptome next-generation sequencing with comparison to a patient-matched normal blood sample. Consistent across all sequencing analyses was the disease-defining EWSR1-CREB3L1 fusion as a single feature consensus. We provide an analysis of our genomic findings and discuss potential therapeutic strategies for SEF.

Keywords: renal sarcoma.

Figure 1.

(A) Morphological diagnostic immunochemistry image with hematoxylin and eosin (H&E) staining of the right posterior upper lung nodule biopsy. Circumscribed tumor adjacent to normal tissue (top left corner) showing spindle to sclerotic tumor. The round spaces are thought to be entrapped/residual alveolar spaces. Scale bar, 300 µM. (B) H&E close-up showing spindle to sclerotic tumor. Scale bar, 200 µM. (C) Immunohistochemistry (IHC) staining for CD24. Scale bar, 300 µM. (D) IHC staining for cleaved NOTCH1. Scale bar, 100 µM. (E) IHC staining for JAGGED1 (upstream of NOTCH). Scale bar, 300 µM. (F) IHC staining for HEY1 (downstream from NOTCH). Scale bar, 100 µM.

Figure 2.

Radiology images showing progression of lung and numerous skeletal metastases over a 16 wk period while enrolled on clinical trial ADVL1615 (pevonedistat, irinotecan, and temozolomide). Left panel images represent metastatic sites at the time of trial enrollment. Right panel images show disease progression at all sites after four treatment cycles. (A) Progression of rib, pelvic, femur, and tibia metastases. (B) Progression of the right femur metastasis. (C) Growth in the skull lesion. (D) Progression of the lung metastases.

Figure 3.

Locations of primary and metastatic SEF tumors. Altogether, 230 cases reported in the literature from 1995 to 2021 were reviewed. (A) Eleven primary tumor sites were reported, the most common being the lower limb or limb girdle (28.3%) and the trunk (18.7%). (B) Eighty-eight patients reported metastasis to 12 sites, the most common being the lung (42.1%) and bone (28.6%).

Figure 4.

SEF cell culture EZ-PZ. (A) Brightfield confocal image of SEF cell culture EZ-PZ at 10× magnification. Scale bar, 100 µM. (B) Polymerase chain reaction (PCR) indicating the presence of a EWSR1–CREB3L1 gene fusion in the EZ-PZ cell culture. BJ5TA is a normal human fibroblast cell culture that shows an absence of the EWSR1–CREB3L1 fusion. Three primer sets captured the fusion breakpoint, the majority and the entirety of the gene fusion. (C) Baseline short tandem repeat (STR) analysis of the cell culture. Results did not match to any known cell lines. The cell culture was free of mycoplasma. (D) Drug screen results from the EZ-PZ and BJ5TA cell cultures. Heatmap indicates IC₅₀ values and shows a general increase in resistance and sensitivity of the SEF cell culture to TORC 1/2 inhibition.