Detection of MDM2 gene amplification or protein expression distinguishes sclerosing mesenteritis and retroperitoneal fibrosis from inflammatory well-differentiated liposarcoma

Abstract

Inflammatory liposarcoma is a variant of well-differentiated liposarcoma/atypical lipomatous tumor that consists of a mixture of lymphocytes, histiocytes, scattered atypical stromal cells, mature adipocytes, and rarely lipoblasts. When the inflammatory infiltrate predominates, the morphological features overlap with various fibroinflammatory disorders including sclerosing mesenteritis and retroperitoneal fibrosis, making the diagnosis difficult. Well-differentiated liposarcoma/atypical lipomatous tumor and dedifferentiated liposarcoma have characteristic molecular markers in the form of giant marker and ring chromosomes consisting of amplicons of 12q13-15, which includes MDM2. MDM2 immunohistochemistry (IHC) (Zymed; clone IF2) and dual color fluorescence in situ hybridization utilizing MDM2 (12q15) and chromosome 12 centromeric probes were performed on formalin-fixed and paraffin-embedded specimens from inflammatory well-differentiated liposarcoma (17 cases), sclerosing mesenteritis (14 cases), and idiopathic retroperitoneal fibrosis (10 cases). MDM2 expression as detected by IHC is a very sensitive tool in recognizing inflammatory well-differentiated liposarcoma (17 of 17); however, 21% (3 of 14) and 10% (1 of 10) of sclerosing mesenteritis and retroperitoneal fibrosis, respectively, displayed weak MDM2 immunoexpression. The MDM2 fluorescence in situ hybridization assay was very specific for inflammatory well-differentiated liposarcoma as 15 of 17 (88%) cases showed MDM2 amplification, whereas none of the cases of sclerosing mesenteritis or idiopathic retroperitoneal fibrosis showed amplification. Five cases of retroperitoneal fibrosis were noncontributory secondary to autofluorescence, potentially limiting the usefulness of the assay in certain situations such as inappropriate fixation. Increased MDM2 expression and/or MDM2 amplification can be employed to aid discrimination of inflammatory well-differentiated liposarcoma from fibroinflammatory mimics. MDM2 fluorescence in situ hybridization is a very specific method (100%), but less sensitive (88%), whereas MDM2 expression by IHC is very sensitive (100%), but less specific (83%). Therefore, a positive screen of difficult cases with MDM2 IHC would require confirmation by the fluorescence in situ hybridization. However, lack of MDM2 immunoexpression would rule out the possibility of inflammatory well-differentiated liposarcoma.

Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 (alpha 12 satellite sequences) signals in atypical lipomatous tumor

“…A total of 79 of 92 (86%) tumors classified histologically as atypical lipomatous tumors, revealed MDM2 amplification ( Figure 1c, Table 1) as assessed using the strict definition of amplification described above. Seven of the MDM2 amplification-positive atypical lipomatous tumors (9% of 79) had low-level copy number (defined as tumors harboring on average number 410 MDM2 signals per nucleus), 19 and these cases were indistinguishable morphologically from atypical lipomatous tumors with high copy number.…”

Can MDM2 analytical tests performed on core needle biopsy be relied upon to diagnose well-differentiated liposarcoma?

“…Detection of MDM2 protein expression by immunohistochemistry or MDM2 amplification by FISH as surrogates for the marker chromosomes characteristic of well-differentiated liposarcoma have been shown to be helpful adjunctive tools when performed on whole-tissue sections of well-characterized cases. 4,[9][10][11][12] However, distinguishing a benign lipomatous lesion from well-differentiated liposarcoma is most important at primary biopsy, more commonly being performed by computer topography-guided core needle biopsies, in which limited diagnostic material is obtained. It is in these instances wherein it is most important to understand the limitations of the adjunctive tests described above.…”

“…A brisk inflammatory component characteristic of the inflammatory variant of well-differentiated liposarcoma may also obscure the diagnostic findings. 4 Furthermore, morphological findings including pseudolipoblasts, pleomorphic cells, fat necrosis, and intermixed skeletal muscle fibers found in the various benign lipomatous mimickers such as intramuscular lipoma, pleomorphic lipoma, and hibernoma can lead to diagnostic confusion. Thus, the use of adjunctive, relatively objective analytical tools would be useful in these circumstances to help discriminate between these entities, especially in difficult cases or in which there is limited biopsy material such as core needle biopsy.…”

“…8 Detection of the resultant MDM2 amplification by fluorescence in situ hybridization (FISH) or the corresponding protein overexpression by immunohistochemistry have been shown to be both very sensitive and specific for the distinction of various well-differentiated liposarcoma subtypes from their morphological mimickers. 4,[9][10][11][12] However, both adjunctive tools have predominantly been evaluated retrospectively on whole-tissue sections from resection specimens. The utility of both the detection of MDM2 amplification by FISH and MDM2 protein overexpression by immunohistochemistry have not been studied or compared in limited biopsy material/core needle biopsies.…”

Sclerosing mesenteritis, a rare cause of a retroperitoneal tumor

“…Hodgkin and non-Hodgkin lymphoma, which may present with a prominent sclerotic/fibroblastic background reaction, should be especially considered, as well as an infl ammatory myofi broblastic tumor, a gastrointestinal stroma tumor, a mesenteric fi bromatosis and a well diff erentiated liposarcoma with a prominent infl ammatory infi ltrate. Th e tumor growth pattern and immunohistochemical stains for CD15, CD30, KIT and ß-catenin, as well as MDM-2 and CDK4, should facilitate the diagnosis of SM [2,20].…”