EWSR1-SMAD3–rearranged Fibroblastic Tumor

Abstract

Three cases of superficial acral fibroblastic spindle cell neoplasms with EWSR1-SMAD3 fusion have been recently reported. Their differential diagnosis is broad, primarily comprising rare tumors from the fibroblastic/myofibroblastic category. The aim of this report is to present 4 new cases of this entity and to discuss the appropriate differential diagnosis. Also, as the ERG antibody seems to be a characteristic marker for these tumors, we analyzed ERG immunostaining characteristics in potential mimics of this entity. All cases in our cohort occurred in women aged 5 to 68 years (mean, 36.5 y). Two were located on the hand, 1 on foot, and the last case arose on the calf. The tumor size ranged from 1 to 1.5 cm in the greatest dimension, with a mean size of 1.2 cm. Except for one recent case, follow-up was available, ranging from 7 to 18 years (mean, 11.7 y), with a recurrence noted in 1 case after 10 years. All tumors were subcutaneous and showed 2 main components. One consisted of bland, spindled cells with elongated nuclei which were round when observed on the cross-section. These cells mostly grew in relatively hypercellular, well-organized, and intersecting fascicles. The second component was prominently hyalinized and paucicellular, but lacked calcifications. Both components showed either a distinct zonation pattern, or they were randomly intermingled with each other. In all 3 analyzable tumors, next-generation sequencing showed EWSR1-SMAD3 gene fusion in each case. By fluorescence in situ hybridization, one tested case also revealed unbalanced rearrangement of the EWSR1 gene. All 4 cases showed strong, diffuse nuclear expression of ERG, whereas none of the mimics stained with this antibody except for weak to moderate staining in calcifying aponeurotic fibromas (9/10 cases). Two tumors showed focal weak to moderate expression of SAT-B2. The 4 herein presented cases further broaden the clinicopathologic spectrum of tumors with EWSR1-SMAD3 gene fusion. They also confirm that they represent a novel entity for which we propose the name EWSR1-SMAD3-rearranged fibroblastic Tumor. Our study also proves that in the context of fibroblastic/myofibroblastic tumors, ERG immunohistochemistry is a relatively specific marker for these neoplasms.

Fibroblastic and myofibroblastic tumors of children: new genetic entities and new ancillary testing

“…12 and Michal et al . 13 as “ EWSRI-SMAD3 -rearranged fibroblastic tumor” (ESFT). These tumors have occurred in patients who are 1 to 68 years old; two occurred in young children (one and five years of age).…”

EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review

“…This recently defined tumor type was first described by Kao et al in 2018 [166]. Few reports have followed since then [167][168][169][170][171].…”

“…Arrangement around blood vessels as seen in myopericytomas is sometimes observed. Myxoid and collagenous areas with the latter reminiscent of collagen rosettes are rarely reported [167][168][169][170][171]. Immunohistochemically, the most reliable marker by now seems to be ERG demonstrating an homogeneous nuclear expression.…”

“…When a classical clinicopathologic constellation is present with expression of ERG, the diagnosis is straight forward. However fusion gene analysis may aid for the precise diagnosis, because benign and malignant lesions are in the differential diagnoses listed in Table 12 [167][168][169][170][171]. The clinical behavior appears to be benign, also when located in the bone, but lesions are prone to local recurrence even after 10 years [167][168][169][170][171].…”

The Recent Advances in Molecular Diagnosis of Soft Tissue Tumors

“…EWSR1 :: SMAD3 –positive fibroblastic tumor (ESFT) is a benign neoplasm defined by a fusion of exon 7 of EWSR1 with exon 5 of SMAD3 [ 287 , 288 , 289 ]. It is characterized by small dermal and subcutaneous acral nodules and histological zonation with an acellular hyalinized center and peripheral fascicular spindle cell growth [ 290 ].…”