Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases

Abstract

The high mobility group A (HMGA2) gene encodes a protein that alters chromatin structure and regulates the transcription of many genes; it is implicated in both benign and malignant neoplasias, but its rearrangements are a feature of development of several mesenchymal tumors. Given its implication in these tumors and particularly adipocytic tumors, and the availability of antibodies usable on paraffin-embedded tissues, we evaluated the immunohistochemical expression of this gene in a series of 1052 mesenchymal tumors. The objective was to define the value and limitations of HMGA2 immunohistochemical expression for histotyping, and compare with molecular data reported in the literature. We thus analyzed 880 cases on tissue microarray and 182 cases on whole sections (211 adipocytic tumors, 628 sarcomas, 213 benign mesenchymal tumors, and 10 normal adipose tissues). A nuclear immunostaining was detected in 86% of conventional and intramuscular lipomas, in 86% of well-differentiated liposarcomas and in 67% of dedifferentiated liposarcomas, as opposed to 16% of other benign adipose tumors and to 15% of non-well-differentiated liposarcoma/dedifferentiated liposarcoma sarcomas. Among benign mesenchymal tumors and lesions, it was detected in 90% of nodular fasciitis and in 88% of benign fibrous histiocytomas with respective specificities of 85 and 100%, and in 90% of aggressive angiomyxoma, contrary to other vulvovaginal tumor types, which expressed HMGA2 only rarely. The normal adipose tissue was always negative for HMGA2. Although not specific, immunohistochemical detection of the HMGA2 protein is helpful for the distinction of normal adipose tissue from well-differentiated lesions, particularly on biopsy or on re-excision. It is less sensitive than MDM2/CDK4 for dedifferentiated liposarcomas diagnosis, but it appears more specific to distinguish dedifferentiated liposarcomas from other poorly differentiated sarcomas. Finally, and may be more importantly, HMGA2 is useful for the diagnosis of benign fibrous histiocytoma, nodular fasciitis and vulvovaginal benign mesenchymal tumors.

Let‐7 MicroRNA and HMGA2 levels of expression are not inversely linked in adipocytic tumors: Analysis of 56 lipomas and liposarcomas with molecular cytogenetic data

“…Indeed, we found overexpression of HMGA2 mRNA in 100% of the WDLPS/DDLPS, in accordance with our genomic data that showed amplification of exons 1 and 2 of HMGA2 in 100% of cases as well as with data from other groups (Berner et al, 1997;Italiano et al, 2008a;Bartuma et al, 2009). Protein expression was found in 83% of cases, which is consistent with the results presented recently by Dreux et al (2010). Thus far, the cause of discrepancy between mRNA and protein expression levels is not known.…”

“…Indeed, most published data were partial, focusing separately either on the genomic or expression issues. Moreover, studies concerning HMGA2 protein in AT are scarce and need further development in regard to genomic and mRNA alterations (Tallini et al, 1997;Dei Tos et al, 2000;Tallini et al, 2000;Dreux et al, 2010).…”

“…Indeed, Hmga2 knock-out mice exhibit a pygmy phenotype corresponding to a drastic reduction of adipose tissue ; conversely, transgenic mice expressing activating mutations of HMGA2 develop gigantism and lipomatosis (Battista et al, 1999). In adipocytic tumors (AT), data about HMGA2 mRNA expression (Italiano et al, 2008a;Bartuma et al, 2009) and protein status (Tallini et al, 1997;Dreux et al, 2010) are scarce. Moreover, no analysis of the status of HMGA2 and of let-7 in AT has been performed thus far.…”

Aggressive Angiomyxoma

“…There was strong nuclear positivity in 90% of AAMs compared with weaker reactivity in 27% of fibroepithelial stromal polyps and no staining in angiomyofibroblastoma or cellular angiofibroma. 20 …”

“…19 These molecular data have led to the investigation of the role of HMGA2 immunohistochemistry in mesenchymal tumors. One recent study 20 characterized HMGA2 immunohistochemical expression in a variety of neoplasms and evaluated its utility as a discriminatory marker. There was strong nuclear positivity in 90% of AAMs compared with weaker reactivity in 27% of fibroepithelial stromal polyps and no staining in angiomyofibroblastoma or cellular angiofibroma.…”