Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: Histological review, genomic profile, and MDM2 and CDK4 status favour a single entity
Université Victor Segalen Bordeaux 2, Burdeos, Aquitaine, France The Journal of Pathology
(Impact Factor: 7.43).
07/2004; 203(3):822-30. DOI: 10.1002/path.1579
Inflammatory malignant fibrous histiocytoma (inflammatory MFH) is a very rare tumour that occurs most often in the retroperitoneum. So far, it has been considered to be a special subtype of MFH. As it is now widely accepted that most retroperitoneal pleomorphic MFHs are dedifferentiated liposarcomas, the present study compared histological features, genomic profile (CGH analysis), and MDM2 and CDK4 status (immunohistochemistry, FISH, and quantitative PCR) in inflammatory MFHs from 12 patients and dedifferentiated liposarcomas that had an inflammatory MFH component from eight patients. Metaphase cytogenetic and FISH analyses were also performed on one inflammatory MFH. Histological review showed areas of well-differentiated liposarcoma in nine inflammatory MFHs. CGH analysis showed 12q13-15 amplification or gain in six of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas. Immunohistochemistry showed positivity of tumour cells for MDM2 in every tumour in both groups and for CDK4 in ten and seven inflammatory MFHs and dedifferentiated liposarcomas, respectively. Metaphase cytogenetic and FISH analysis performed on one inflammatory MFH showed the presence of a supernumerary large marker chromosome and ring chromosome with high-level amplification of both MDM2 and CDK4 genes. FISH analysis on paraffin wax-embedded sections showed amplifications of MDM2 and CDK4 in seven of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas. Quantitative PCR showed amplification of MDM2 in six and of CDK4 in seven of nine inflammatory MFHs. In conclusion, this study strongly suggests that most so-called inflammatory MFHs are dedifferentiated liposarcomas.
Available from: Tadashi Kondo
- "Comprehensive studies at DNA and mRNA levels have provided several valuable findings. For example, studies of changes in gene copy number using array-based CGH have demonstrated relationships among malignant fibrous histiocytoma (MFH), leiomyosarcoma, and liposarcoma [4, 5]. Expression profiling of 5520 genes at the mRNA level using microarrays has revealed distinct molecular signatures for 41 sarcomas, thereby providing new markers with potential diagnostic value . "
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ABSTRACT: Soft tissue sarcomas are rare and account for less than 1% of all malignant cancers. Other than development of intensive therapies, the clinical outcome of patients with soft tissue sarcoma remains very poor, particularly when diagnosed at a late stage. Unique mutations have been associated with certain soft tissue sarcomas, but their etiologies remain unknown. The proteome is a functional translation of a genome, which directly regulates the malignant features of tumors. Thus, proteomics is a promising approach for investigating soft tissue sarcomas. Various proteomic approaches and clinical materials have been used to address clinical and biological issues, including biomarker development, molecular target identification, and study of disease mechanisms. Several cancer-associated proteins have been identified using conventional technologies such as 2D-PAGE, mass spectrometry, and array technology. The functional backgrounds of proteins identified were assessed extensively using in vitro experiments, thus supporting expression analysis. These observations demonstrate the applicability of proteomics to soft tissue sarcoma studies. However, the sample size in each study was insufficient to allow conclusive results. Given the low frequency of soft tissue sarcomas, multi-institutional collaborations are required to validate the results of proteomic approaches.
- "Thus, MDM2 may be more helpful in deciding if a lesion is malignant, and may not be as helpful in specifically subtyping a neoplasm as a LPS. However, when looking at mesenchymal malignancies, it is uncertain whether the MDM2 amplification truly occurs in a subset of pleomorphic sarcomas other than LPS, or whether this group simply represents dedifferentiated LPS that were under-sampled. For example, one study looked at a series of malignant fibrous histiocytomas diagnosed in the retroperitoneum and most of these were reclassified as dedifferentiated LPS after careful analysis, including examination for MDM2 and CDK4 amplification by IHC and CGH. "
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ABSTRACT: Lipomatous mesenchymal tumors constitute the most common type of soft tissue tumors. Well-differentiated liposarcoma (WDLS) can undergo dedifferentiation to a nonlipogenic sarcoma of variable histologic grade. In the recent literature, amplification of the murine double minute 2 (MDM2) oncogene, which has a role in cell cycle control, has been successful in distinguishing WDLS from benign lesions. We present a case of dedifferentiated liposarcoma diagnosed by fine-needle aspiration (FNA), using cytomorphology and ancillary studies (immunocytochemistry and fluorescent in-situ hybridization). An 85-year old female presented to our institution with a firm soft tissue mass of the right buttock. The FNA showed atypical spindle cells, osteoclast-like giant cells and extracellular dense matrix material. The cell block showed cellular groups of highly atypical spindle cells with osteoid and adipose tissue. Fluorescence in situ hybridization (FISH) studies performed on the cell block demonstrated amplification of the MDM2 gene. In addition, the findings were morphologically compatible with the previously resected retroperitoneal dedifferentiated liposarcoma with areas of osteosarcoma. This rare case illustrates the usefulness of FNA and ancillary studies in the diagnosis and subclassification of soft tissue tumors. To the best of our knowledge, this is the first report of MDM2 FISH positivity in a liposarcoma diagnosed by FNA.
Available from: Maria Zielenska
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ABSTRACT: Osteosarcoma (OS) is an aggressive bone tumor with complex abnormal karyotypes and a highly unstable ge- nome, exhibiting both numerical- and structural-chromosomal instability (N- and S-CIN). Chromosomal rearrange- ments and genomic imbalances affecting 8q24 are frequent in OS. RECQL4 gene maps to this cytoband and encodes a putative helicase involved in the fidelity of DNA replication and repair. This protective genomic function of the protein is relevant because often patients with Rothmund-Thomson syndrome have constitutional mutations of RECQL4 and carry a very high risk of developing OS. To determine the relative level of expression of RECQL4 in OS, 18 sporadic tumors were studied by reverse transcription-polymerase chain reaction. All tumors over- expressed RECQL4 in comparison to control osteoblasts, and fluorescence in situ hybridization analysis of tumor DNA showed that expression levels were strongly copy number-dependent. Relative N- and S-CIN levels were determined by classifying copy number transitions within array comparative genomic hybridization profiles and by enumerating the frequency of break-apart fluorescence in situ hybridization within 8q24 using region-specific and control probes. Although there was no evidence that disruption of 8q24 in OS led to an elevated expression of RECQL4, there was a marked association between increased overall levels of S-CIN, determined by copy number transition frequency and higher levels of RECQL4.
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