July 2025 Case

Patient in his late 80’s with a history of type 2 diabetes, hypertension, hypothyroidism, and recurrent small bowel obstructions, presented for evaluation of an ill-defined 3.0cm mass of his left foot which he first noticed 6 months ago. There is mild tenderness over the mass, rated 4/10. An initial ultrasound-guided biopsy was performed and a month later the mass was excised.

Histological examination demonstrated an infiltrative cellular proliferation of spindle and pleomorphic cells, with mild to moderate cytologic atypia and no necrosis (Fig 1). Mitotic figures were not seen.

Immunohistochemistry (IHC) was performed with results summarized in Table 1. Given the nonspecific morphological and immunophenotype, additional molecular testing was performed, including MDM2 fluorescent in-situ hybridization (FISH), in-house next-generation sequencing (NGS), and send-out to Cleveland Clinic for solid tumor gene fusion NGS.

Table 1: Summary of IHC results

Atypical spindle and pleomorphic cell proliferation, best interpreted as a low-grade sarcoma. On the excision specimen, the tumor measured 3.3 cm in greatest dimension and involved the dermis, adipose tissue, fascia, and was present at the surgical margins.

In-house NGS did not detect any clinically relevant molecular alterations and FISH did not identify any MDM2 gene amplification; however, the send-out fusion NGS detected a novel YAP1::FUS fusion protein. The fusion occurred between YAP1 exon 4 and FUS exon 2.

YAP1 is a crucial transcriptional regulator which provides downstream transcriptional regulation in the Hippo signaling pathway, which physiologically functions to regulate organ size and tissue repair.¹ Within this pathway, YAP1 promotes cell proliferation while suppressing apoptotic genes through interactions with a series of transcription factors, most notably through TEAD (transcriptional enhanced associate domain) transcription factors. As such, it is implicated in tumorigenesis, contributing to initiation, progression, and therapy resistance in numerous cancer types.²

While the exact pathogenic role of YAP1 is not fully understood, it does not appear able to independently drive malignant transformation, as simple overexpression of the protein did not lead to tumor formation. Additional inactivation of upstream Hippo tumor suppressors or multiple activating point mutations are usually required to initiate transformation.^3–5 Missense mutations have been reported in the serine residues which control regulation, with the most important being S127 and S397 which regulates nuclear exclusion and proteasomal degradation, respectively.

YAP1 fusions, on the other hand, have evidence showing they can independently function as tumor initiating events and oncogenic drivers.^5,7–10 These fusions lead to the production of a chimeric protein with the N-terminal domain of the YAP1 protein fused to the C-terminal domain of another protein. These fusion proteins preserve the TEAD-binding domain of the YAP1 protein but will lose the regulatory S397 residue, impairing degradation and leading to accumulation of YAP1 protein. Most of the YAP1 fusion partners possess putative transactivation or p300 interaction domains which are theorized to act as surrogate for lost YAP1 C-terminal transactivation domains.⁵ Reported fusion partners include MAMLD1, FAM118B, TFE3, and SS18. Of note, the YAP1::FUS fusion in this case has not yet been previously reported.

Due to the emerging role of YAP1 as an oncogenic driver, it is currently being evaluated as a potential biomarker for targeted therapy. Some of the most promising studies are looking into small molecule inhibitors that impede the YAP1-TEAD interactions, as this is a shared function in all studied fusion proteins thus far.^12–15