Novel EWSR1-SMAD3 Gene Fusions in a Group of Acral Fibroblastic Spindle Cell Neoplasms

Abstract

Benign/low-grade fibroblastic tumors encompass a broad spectrum of tumors with different morphologies and molecular genetic abnormalities. However, despite significant progress in recent genomic characterization, there are still tumors in this histologic spectrum that are difficult to classify, lacking known molecular characteristics. Triggered by a challenging congenital spindle cell neoplasm arising in the heel of a 1-year-old boy, we applied RNA sequencing for genetic discovery and identified a novel EWSR1-SMAD3 gene fusion. On the basis of the index case superficial acral location and fibroblastic appearance with a nonspecific immunophenotype, we searched our files for similar cases and screened them by fluorescence in situ hybridization for these abnormalities. Thus an identical EWSR1-SMAD3 fusion was identified in 2 additional spindle cell tumors with similar clinicopathologic features. Both cases occurred in the feet of adult women (58 and 61 y old) and were characterized by distinctive nodular growth with zonation pattern of peripheral hypercellular areas arranged in short fascicles, transitioning to hypocellular central areas of hyalinization and infarction. Focal stippled calcification in the collagenous area was present in 1 case. All 3 tumors had similar immunoprofiles, being negative for SMA, CD34, CD31, and S100, but showing consistent ERG positivity of uncertain significance. Follow-up information was available in 2 patients who developed local recurrences after incomplete initial excisions, at 5 and 14 months, respectively. None developed metastatic disease. In summary, we report a group of locally recurrent superficial acral tumors, characterized by bland spindle cell fascicular growth, occasional zonation pattern, ERG positivity, and recurrent EWSR1-SMAD3 gene fusions.

PRRX‐NCOA1/2 rearrangement characterizes a distinctive fibroblastic neoplasm

“…The identification of disease‐defining molecular alterations is gradually enabling more refined subclassification of these tumors, and this can be exploited for diagnostic purposes. This is exemplified by reports of NTRK ‐rearranged fibroblastic tumors, EWSR1‐SMAD3 ‐rearanged fibroblastic tumor, and PRDM10 ‐rearranged soft tissue tumor…”

“…purposes. This is exemplified by reports of NTRK-rearranged fibroblastic tumors, [2][3][4] EWSR1-SMAD3-rearanged fibroblastic tumor, 5,6 and PRDM10rearranged soft tissue tumor. 7 Our groups recently independently encountered a distinctive soft tissue neoplasm characterized by fusions involving PRRX1 and NCOA1.…”

New advances in the molecular classification of pediatric mesenchymal tumors

“…An EWSR1–SMAD3 fusion was recently identified as the genetic hallmark of a novel benign fibroblastic neoplasm with predilection for acral soft tissues . The index case occurred in the foot of an infant male, presenting as an ill‐defined dermal and subcutaneous nodule with an infiltrative border.…”

“…Unsupervised clustering of the whole transcriptome data showed that the EWSR1–SMAD3 fusion positive tumor clustered together with other fibroblastic tumors, including a CAF with FN1–EGF fusion, a LPF lacking genetic abnormalities, and a LPF‐NT with TPR–NTRK1 fusion. Interestingly, ERG mRNA was strongly upregulated, finding further supported by diffuse nuclear immunoexpression of ERG protein …”

“…CAF case from above harbored a FN1-EGF fusion by RNA sequencing, resulting in marked upregulation of EGF mRNA, compared to other soft tissue tumors (F). Infantile fibroblastic tumor displaying EWSR1-SMAD3 (G,H), resulting in ERG overexpression (I) EWSR1-SMAD3 fusion positive fibroblastic tumor with ERG positivity An EWSR1-SMAD3 fusion was recently identified as the genetic hallmark of a novel benign fibroblastic neoplasm with predilection for acral soft tissues 30. The index case occurred in the foot of an infant male, presenting as an ill-defined dermal and subcutaneous nodule with an infiltrative border.…”