Hydropic leiomyoma: a distinct variant of leiomyoma closely related to HMGA2 overexpression

Abstract

Hydropic leiomyoma (HLM) is a variant of uterine leiomyoma with characteristic features of zonal distributions of edema, increased vascularity, and tumor cells arranged in nodules or cords. Diagnostic difficulty and patient management are further complicated by a lack of studies and unknown cause of the disease. To study this tumor's nature, 24 HLM cases were selected for analysis of cytohistologic features, immunohistochemical profile (HMGA2, FH, CD34, pAKT, p16, ER, SMA, and Ki-67), and molecular alterations of HMGA2 by fluorescence in situ hybridization and MED12 mutations. HLM showed large tumor size (average 14.4 cm) and unique histology, characterized by edematous areas of tumor cells with mostly round-oval nuclei, arranged in cords and/or with perinodular growth around vessels, and increased thick-walled vessels (average 17 vessels/10× medium-power field). Immunohistochemistry revealed that 76% (18/24) of HLMs had HMGA2 overexpression, 32% (6/19) of which harbored HMGA2 rearrangement detected by fluorescence in situ hybridization. Thick-walled vessels in HLM were composed of mostly HMGA2-positive tumor cells, and HLM with HMGA2 overexpression also showed CD34-positive tumor vessel-supporting pericytes. In contrast to usual-type leiomyoma with a high frequency of MED12 mutations, no MED12 mutations were found in any HLM. HLM showed increased pAKT activity, indicating a strong contribution of AKT pathway signaling in HLM promoting tumor growth. Our findings suggest that HLM is a distinct variant of uterine smooth muscle tumor likely driven by HMGA2 overexpression.