DDIT3 Immunohistochemistry Is a Useful Tool for the Diagnosis of Myxoid Liposarcoma

Abstract

Myxoid liposarcoma is a malignant adipogenic neoplasm characterized by prominent arborizing capillaries, occasional lipoblasts, and primitive-appearing spindle cells in a myxoid background. A recurrent translocation in myxoid liposarcoma results in an oncoprotein consisting of full-length DDIT3 (CHOP) fused to an N-terminal segment of either FUS (TLS) or, less often, EWSR1. Here, we explore the diagnostic significance of DDIT3 expression in myxoid liposarcoma using a mouse monoclonal antibody recognizing an epitope in the N-terminal region. Studying a total of 300 tumors, we find diffuse, moderate-to-strong nuclear-localized anti-DDIT3 immunoreactivity in all 46 cases of myxoid liposarcoma representing 36 unique tumors, including 6 cases with high-grade (round cell) morphology. DDIT3 immunohistochemistry also highlighted a distinctive vasculocentric growth pattern in 7 myxoid liposarcomas treated with neoadjuvant radiation. In contrast, the vast majority of other examined lipomatous and myxoid neoplasms exhibited no DDIT3 expression; limited, weak immunoreactivity in <10% of cells was infrequently observed in dedifferentiated liposarcoma (6/39, 15%), solitary fibrous tumor (3/12, 25%), pleomorphic liposarcoma (1/15, 7%), and high-grade myxofibrosarcoma (2/17, 12%). Although this minimal DDIT3 expression did not correlate with DDIT3 amplification or myxoid liposarcoma–like morphology in dedifferentiated liposarcoma, there was evidence among sarcomas (excluding myxoid liposarcoma) of a relationship between expression and exposure to neoadjuvant radiation or cytotoxic chemotherapy. The constellation of findings indicates that DDIT3 immunohistochemistry may have utility in the evaluation of myxoid and lipomatous neoplasms to support the diagnosis of myxoid liposarcoma.

DNA damage‐inducible transcript 3 immunohistochemistry is highly sensitive for the diagnosis of myxoid liposarcoma but care is required in interpreting the significance of focal expression

“…Our findings strongly support the conclusions of Scapa et al 20 . that diffuse nuclear DDIT3 expression can be clinically very useful to definitively confirm the diagnosis of MLPS, whereas negative staining can be used to argue strongly against MLPS.…”

“…One key issue in the optimisation of antibodies for diagnostic use is the need to develop criteria for positive and negative staining that are both reproducible and optimise the balance between sensitivity and specificity. When they used a cut‐off of >50% cells being positive in a mixed TMA and whole section cohort, Scapa et al 20 . found a sensitivity of 100% (46 of 46 tumours from 36 patients), as compared with our sensitivity of 96%, and a specificity of 100% (254 of 254 patients), the same as our specificity of 100%.…”

“…IHC was performed with the same mouse monoclonal antibody directed against the N‐terminus of DDIT3 that had been used in the study of Scapa et al 20 . (clone 9C8; cat.…”

“…A clinically validated IHC marker, particularly if it were sensitive and specific enough to obviate the need for FISH or molecular testing, would be helpful. Recently Scapa et al 20 . reported that IHC for DDIT3, with a novel mouse monoclonal antibody directed against the N‐terminal region of the protein (clone 9C8), holds promise as a diagnostic marker of MLPS.…”

Diagnostic Immunohistochemistry of Soft Tissue and Bone Tumors: An Update on Biomarkers That Correlate with Molecular Alterations

“…Very recently, immunohistochemistry for DDIT3 (DNA Damage-Inducible Transcript 3) has emerged as a useful surrogate for molecular testing. Scapa et al reported DDIT3 positivity in 46/46 cases of myxoid liposarcoma and only limited weak expression in other tumors [56]. Minimal staining was observed in cases of dedifferentiated liposarcoma (15%) and solitary fibrous tumor (25%), possibly due to the proximity of DDIT3, MDM2 and STAT6 on chromosome 12.…”