Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: histological review, genomic profile, and MDM2 and CDK4 status favour a single entity

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.     

Gene expression analysis of soft tissue sarcomas: characterization and reclassification of malignant fibrous histiocytoma.

In soft tissue sarcomas, the diagnosis of malignant fibrous histiocytoma (MFH) has been a very controversial issue, and MFH is now considered to be reclassified into pleomorphic subtypes of other sarcomas. To characterize MFH genetically, we used an oligonucleotide microarray to analyze gene expression in 105 samples from 10 types of soft tissue tumors. Spindle cell and pleomorphic sarcomas, such as dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST), fibrosarcoma and MFH, showed similar gene expression patterns compared to other tumors. Samples from those five sarcoma types could be classified into respective clusters based on gene expression by excluding MFH samples. We calculated distances between MFH samples and other five sarcoma types (dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, MPNST and fibrosarcoma) based on differentially expressed genes and evaluated similarities. Three of the 21 MFH samples showed marked similarities to one of the five sarcoma types, which were supported by histological findings. Although most of the remaining 18 MFH samples showed little or no histological resemblance to one of the five sarcoma types, 12 of them showed moderate similarities in terms of gene expression. These results explain the heterogeneity of MFH and show that the majority of MFHs could be reclassified into pleomorphic subtypes of other sarcomas. Taken together, gene expression profiling could be a useful tool to unveil the difference in the underlying molecular backgrounds, which leads to a rational taxonomy and diagnosis of a diverse group of soft tissue sarcomas.     

Gains of 13q are correlated with a poor prognosis in liposarcoma.

Liposarcomas are a phenotypical heterogeneous group of tumors divided into four main subtypes: well-differentiated, dedifferentiated, myxoid/round cell, and pleomorphic. The aim of this study was to compare DNA sequence copy number changes of these subtypes as investigated by comparative genomic hybridization in 36 patients. Comparative genomic hybridization revealed genomic imbalances in tumors of 27 patients (mean 5.6 imbalances per tumor). The most frequent gains were within single regions of 1q, 12q, and 13q. We found a significant correlation of poor overall survival and gain of 13q21 (P=0.0221), 13q22 (P=0.0341), 13q31 (P=0.0410), and 13q32 (P=0.0074). The univariate Cox regression analysis revealed an increased risk of tumor-related death for patients whose liposarcomas possess with gains of 13q21 and 13q32 simultaneously (P=0.010; RR=7.1; 95% CI 1.6-31.7). Furthermore, 12 high-level amplifications were found in tumors of seven patients. In four cases 12q14-q15 and in two cases 13q32-q33 were amplified. We identified in different liposarcoma subtypes characteristic genomic changes: Gains and high-level amplifications of 12q occurred in all 11 investigated well-differentiated liposarcomas, and these changes were often present simultaneously with gains of 1q (mean 5.5 changes). In the two dedifferentiated liposarcomas, gains of 1q in both liposarcomas, and a high-level amplification of 13q were striking. Only eight of the 17 patients with myxoid/round cell liposarcomas showed changes in DNA copy number (mean 3.4 imbalances). In four of these eight cases gains of 13q occurred. The six pleomorphic liposarcomas possessed the most frequent genomic imbalances (mean number 16.3) of all liposarcoma subtypes investigated. These imbalances were in almost all chromosomal regions detected predominantly as over-representations of chromosomes 1, 5p, 13q, and 22q. Summarizing, all subtypes but well-differentiated liposarcomas showed gains of 13q, which were associated with a poor prognosis.     

Alterations of the RB1 gene in dedifferentiated liposarcoma.

Dedifferentiated liposarcoma is a malignant adipocytic neoplasm containing a non-lipogenic sarcoma of variable histological grade that arises against the background of a pre-existing well-differentiated liposarcoma. The phenomenon of dedifferentiation is considered to be time-dependent, but the mechanism is not well known. The retinoblastoma protein, encoded by the RB1 gene located at 13q14, is a key regulator of proliferation, development, and differentiation of certain cell types, including adipocytes. In the current study, we investigated the genetic alterations of the RB1 gene, such as mutation (the essential promoter region and the protein-binding pocket domain; exons 20-24) and methylation of the promoter region, in addition to pRB expression and loss of heterozygosity (LOH) status, in two morphologically distinct areas (non-lipogenic dedifferentiated and well-differentiated components) in 27 patients. As a control, 11 undifferentiated high-grade pleomorphic sarcoma/pleomorphic malignant fibrous histiocytoma samples and 11 well-differentiated liposarcoma samples were also evaluated. Dedifferentiated components showed LOH (15/25; 60%) and abnormal retinoblastoma protein expression (18/27; 66.7%) more frequently than noted in the well-differentiated components (3/24; 12.5% and 9/27; 33.3%, respectively). Five and four out of the 27 dedifferentiated components harbored mutations and promoter methylation, respectively, whereas none of these alterations were seen in the well-differentiated components. These results suggest that retinoblastoma protein has a major role to play in dedifferentiation and that a 'two-hit' mechanism is involved in the altered retinoblastoma protein expression in dedifferentiated liposarcoma.     

Beta-catenin accumulation and gene mutation in exon 3 in dedifferentiated liposarcoma and malignant fibrous histiocytoma

CONTEXT: beta-Catenin is an adhesion molecule that also plays a role in the Wnt signaling pathway. Objective.-To analyze beta-catenin mutation and accumulation in a series of liposarcomas and malignant fibrous histiocytomas. DESIGN: beta-Catenin mutation in exon 3 was studied using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing analysis in 30 formalin-fixed, paraffin-embedded liposarcomas. The tumors included 12 dedifferentiated liposarcomas, characterized by both high-grade anaplastic components and well-differentiated liposarcoma components, plus 18 well-differentiated liposarcomas (10 lipoma-like and 8 sclerosing-type cases). The 2 components of dedifferentiated liposarcomas were analyzed independently. beta-Catenin accumulation in the nuclei or cytoplasm and Ki-67 expression (cell-proliferation marker, MIB-1 labeling index) were examined immunohistochemically. Nine storiform-pleomorphic-type malignant fibrous histiocytomas were also studied. RESULTS: Dedifferentiated liposarcomas showed mutation in 2 cases (17%) and accumulation in 5 cases (42%). One of the 2 cases that showed mutations had a mutation in the well-differentiated component; this mutation was silent. The other case had mutations that differed between the 2 components. In well-differentiated liposarcomas, mutation was not seen in any of the cases (0/18; 0%); however, accumulation was seen frequently in the sclerosing-type cases (5/8; 63%), but not in the lipoma-like cases (0/10; 0%). Malignant fibrous histiocytomas showed mutation and accumulation in 5 (56%) and 4 (44%) cases, respectively, without any exact correlation between the cases. Cases with accumulation had a higher MIB-1 labeling index than those without, among both the sclerosing-type well-differentiated liposarcomas (P <.05) and the malignant fibrous histiocytomas. CONCLUSIONS: Our results suggest the possible involvement of beta-catenin activation caused by beta-catenin mutation in liposarcoma and malignant fibrous histiocytoma, but the contribution would seem to be different, depending on the tumor type. beta-Catenin accumulation is also thought to be related to cell proliferation in some of the cases.     

Dedifferentiated liposarcoma with rhabdomyoblastic differentiation

Dedifferentiated areas of dedifferentiated liposarcoma (DDL) usually show malignant fibrous histiocytoma (MFH)- or fibrosarcoma-like features and lack any histologic signs of specific differentiation. However, some reports have demonstrated specific differentiation in these areas, with histologic features resembling those of rhabdomyosarcoma, leiomyosarcoma, and osteosarcoma. We report here a pathologic and genetic analysis of three cases of DDLs with rhabdomyosarcomatous areas. MFH- or fibrosarcoma-like areas of one primary DDL and two recurrent DDLs contained various amounts of rhabdomyoblasts, which were immunoreactive for desmin, myoglobin, muscle actin (HHF-35), and myogenin. An ultrastructural examination demonstrated rhabdomyoblasts with abundant cytoplasm containing thin and thick filaments and Z-bands. By real-time PCR, amplification of mdm2 and cdk4 was confirmed in both well-differentiated and dedifferentiated areas with rhabdomyoblasts of all cases. To our knowledge, only seven cases of DDLs with rhabdomyosarcomatous components have been reported, and furthermore, the genetic profiles of the rhabdomyosarcomatous components in DDLs have not been investigated. This study demonstrates that DDLs with rhabdomyosarcomatous areas have genetic alterations that are common to well-differentiated/dedifferentiated liposarcomas.     

MOLECULAR ABNORMALITIES OF THE p53 PATHWAY IN DEDIFFERENTIATED LIPOSARCOMA

Dedifferentiated liposarcoma represents a distinct subtype of liposarcoma and is characterized by the presence of abrupt transition from well-differentiated liposarcoma to high-grade pleomorphic sarcoma (mostly MFH-like). A key role for p53 in tumour progression of this subset of liposarcomas has been suggested on the basis of p53 immunopositivity. A series of 14 dedifferentiated liposarcomas has been investigated by analysing the p53 gene and protein together with the p53-related molecules p21^Waf1 and mdm2, to verify whether the p53 pathway is involved in the development and progression of this tumour type. The results indicate that the p53 gene is rarely involved in dedifferentiated liposarcoma (7 per cent of cases analysed) and that low percentages of p53 immunopositivity are still compatible with integrity of the p53 gene. This concept is also supported by the observed preservation of p21^Waf1 immunoreactivity in all but the p53-mutated cases. By contrast, mdm2 overexpression emerges as the most frequent abnormality in dedifferentiated liposarcoma (57 and 78 per cent of cases in well-differentiated and high-grade areas, respectively). © 1997 by John Wiley & Sons, Ltd.     

Molecular abnormalities in liposarcoma: role of MDM2 and CDK4-containing amplicons at 12q13–22

It has recently been shown that mdm2 overexpression with stabilization of p53 represents a characteristic of retroperitoneal well-differentiated-dedifferentiated, here renamed evolved (WD-E), liposarcomas at the immunocytochemical, molecular, and cytogenetic level. This make-up appears to be confined to half the cases in non-retroperitoneal well-differentiated liposarcomas. Since in different tumours MDM2 amplification involves amplicons encompassing flanking genes, such as CDK4, the possibility was investigated that in these tumours, CDK4 could act as an alternative or additional gene involved in the transformation mechanism. Forty-one retroperitoneal (R)/non-retroperitoneal (NR) well-differentiated-dedifferentiated (WD-DD) and 33 myxoid/round cell liposarcomas were reanalysed by immunocytochemical, molecular (nine cases) and fluorescence in situ hybridization (FISH) (one case) techniques. The results showed that all but one R WD-E cases carried the mdm2+, p53+, cdk4+ immunophenotype. In NR-WD liposarcomas, this immunophenotype was shared in five cases and the remainder showed mdm2+, p53−, cdk4+ in four and mdm2−, p53−, cdk4+ in one case, showing ring chromosomes by FISH analysis. TP53 mutations are confirmed to be closely correlated with NR-DD liposarcomas and no CDK4 involvement was found in the myxoid/round cell liposarcoma group. As well as confirming the synergistic effect of MDM2 and CDK4, these results are consistent with the concept that amplicon(s) excluding MDM2 may contribute to transformation and support a role of CDK4 in opposing p53 function, particularly in NR WD liposarcoma. © 1998 John Wiley & Sons, Ltd.     

Dedifferentiated liposarcoma of the pyriform sinus: report of a case and review of the literature

Laryngeal and hypopharyngeal liposarcomas are extraordinarily infrequent tumors. To the best of our knowledge there are fewer than 40 well-documented cases reported to date. Almost all of them are well-differentiated liposarcomas, with only 2 laryngeal-hypopharyngeal dedifferentiated liposarcomas. Dedifferentiated liposarcoma is defined as a well-differentiated liposarcoma with areas of high-grade spindle cell nonlipogenic sarcoma. The well-differentiated areas may be of a lipoma-like, sclerosing, or mixed type, and the dedifferentiated areas most frequently are of malignant fibrous hystiocytoma-like type. Despite its commonly pleomorphic histology, dedifferentiated liposarcoma does not behave as aggressively as most pleomorphic sarcomas of adulthood; however, it has the capacity to metastasize, in contrast to its well-differentiated counterpart. We present a case of dedifferentiated liposarcoma arising in the pyriform sinus, an event only twice reported previously in the literature.     

Distinction between lipoma and liposarcoma by MDM2 alterations: a case report of simultaneously occurring tumors and review of the literature

We investigated a lipoma and a well-differentiated/dedifferentiated liposarcoma (WD/DDL), occurring simultaneously in one patient for the possible role of p53 and mdm2 in the molecular oncogenesis of liposarcoma and tumor progression. The hypothesis tested was if there is a continuum in the development from lipoma to liposarcoma. Lipoma was characterized by a lack of p53 mutation, p53 LOH and p53 protein expression, as well as by mdm2 amplification and mdm2 protein expression. p53 mutation and p53 LOH were found neither in the well-differentiated nor in the dedifferentiated parts of the liposarcoma. In contrast, mdm2 amplification and an increase in mdm2 protein expression were found to be associated with malignancy and dedifferentiation, whereas p53 protein expression was only slightly increased. These findings indicate that mdm2 constitutes one of the most common targets for molecular aberration in WD/DDL. We suggest that mdm2 is a marker distinguishing between ordinary lipoma and well-differentiated liposarcoma, and that the genesis of these tumors is different.     

A subgroup of malignant fibrous histiocytomas is associated with genetic changes similar to those of well-differentiated liposarcomas

Increasing clinical and pathological evidence suggests that malignant fibrous histiocytomas (MFH) comprise a heterogeneous tumor group. In a series of 108 MFH tested by comparative genomic hybridization, we found in 22 tumors high-level coamplification of the 12q14 approximately q15 chromosome region with other loci, a genetics strongly reminiscent of what has been observed for well-differentiated liposarcomas. Nevertheless, these MFH differ from liposarcomas by a high recurrence of coamplified partners because coamplified loci were seen at 1p32 in nine cases, 6q23 in seven cases, and 12q24 in six cases. The same recurrence was observed in a series of dedifferentiated liposarcomas, but not in a series of well-differentiated liposarcomas. These observations demonstrate that a subgroup of MFH share a genetic partner very similar to that observed in liposarcomas, and suggest that the undifferentiated status of these tumors is closely related to the amplifications of specific chromosome loci.     

Dedifferentiated liposarcoma.

Dedifferentiated liposarcoma is a high-grade nonlipogenic sarcoma that arises in a background of a preexisting well-differentiated liposarcoma. The phenomenon of dedifferentiation is time dependent, and primary or de novo tumors exceed secondary neoplasms in a ratio of 9:1. The tumor occurs most frequently in adults beyond the 6th decade of life, slightly predominates in men, and involves the abdominal cavity most often. Pleomorphic malignant fibrous histiocytoma-like histologic features are the most commonly observed phenotype, although other sarcomatous phenotypes have been described less frequently. Surgical treatment is the main form of therapy for dedifferentiated liposarcoma, which is associated with a reported local recurrence rate of 41% to 52%, 15% distant metastatic rate, and 30% disease-related mortality rate. On a chromosomal level, dedifferentiated liposarcoma frequently displays the same chromosomal abnormality associated with well-differentiated liposarcomas--ie, the presence of a supernumerary ring or giant chromosome derived from the 12q(13-15) region.     

H-ras oncogene mutation in dedifferentiated liposarcoma. Polymerase chain reaction-restriction fragment length polymorphism analysis

Point mutations of the ras gene family (K-ras, H-ras, and N-ras) are thought to be involved in the development of a variety of human tumors. Dedifferentiated liposarcoma is characterized by the coexistence of well-differentiated (WD) and high-grade anaplastic (HG) components. The presence of point mutations at codons 12 and 13 of the H-ras gene was studied in 34 liposarcomas, comprising 15 well-differentiated liposarcomas and 19 dedifferentiated liposarcomas, and in 8 storiform-pleomorphic type malignant fibrous histiocytomas (MFHs) using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing analysis. The 2 components of dedifferentiated liposarcoma were analyzed independently. H-ras mutations were seen only in dedifferentiated liposarcomas (4/19 [21%]), 1 in WD components and 3 in HG components. The mutation was not seen in any of 15 cases of well-differentiated liposarcoma. MFHs showed an H-ras mutation in 1 (12%) of 8 cases. Our results seem to suggest that the H-ras mutation is a relatively uncommon event in dedifferentiated liposarcoma, which may demonstrate an epiphenomenon of dedifferentiation in dedifferentiated liposarcoma.     

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

This study assessed whether analysis of MDM2 copy number by fluorescence in situ hybridization (FISH) would help distinguish lipomas from atypical lipomatous tumors, otherwise referred to as well-differentiated liposarcomas, using a commercially available MDM2 FISH kit. 227 lipomatous and 201 non-lipomatous tumors were analyzed to assess its sensitivity and specificity. Of 178 mature lipomatous tumors, 86 were classified histologically as lipoma and 92 as atypical lipomatous tumor. Two of the lipomas harboring MDM2 amplification were reclassified as atypical lipomatous tumors. Overall, 13 atypical lipomatous tumors did not reveal MDM2 or CDK4 amplification, although this was reduced to 12 following analysis of multiple slides. Three of these cases revealed very occasional tumor cells harboring high-level MDM2 amplification, two had a dedifferentiated component, and MDM2 amplification was detected when one tumor recurred. The remaining six cases exhibited reactive/inflammatory features and were reclassified as lipomas. The findings indicate that MDM2 amplification is 93.5% sensitive for diagnosing atypical lipomatous tumor. A total of 2 of the 20 dedifferentiated liposarcomas failed to reveal MDM2 amplification. All atypical lipomatous tumors measured >10?cm, two dedifferentiated liposarcoma presented de novo at <10?cm, and ～50% of lipomas measured >10?cm. Spindle cell lipomas, lipoblastomas, hibernomas and pleomorphic liposarcomas did not reveal MDM2 amplification. Of 201 non-lipomatous tumors, eight revealed MDM2 amplification or multiple faint alphoid 12 signals and were reclassified as dedifferentiated liposarcoma. Multiple faint alphoid 12 signals were observed in nine tumors from seven patients, an observation not previously reported on paraffin sections: these included four atypical lipomatous tumors, and three dedifferentiated liposarcomas, one previously diagnosed as a myxofibrosarcoma, all of which also revealed amplification of CDK4, although two lacked MDM2 amplification. MDM2 FISH test is a useful adjunct to histology for distinguishing lipoma from atypical lipomatous tumor. The limitations of molecular genetic tests must be known before introducing them into a clinical service.     

Dedifferentiated liposarcoma with an inflammatory malignant fibrous histiocytoma-like component presenting a leukemoid reaction

A rare case of dedifferentiated llposarcoma (well-differentiated llposarcoma with an inflammatory mallgnant fibrous histiocytoma (MFH)-like anaplastlc component) occurrtng in a 69-year-old male is presented. The patient had noticed a dull pain in his left loin and thigh for about 1 month. Computed tomography examination revealed a low-density mass lesion, measuring about 6 cm In diameter, in the left lliopsoas muscie, and It was surgically removed. Grossly, the lesion was composed of an encapsulated, soft, whitish mass and an adjacent, well-demarcated, yellowish hard nodule, measuring about 2.5 cm In diameter. Microscopically, both lesions showed features of an inflammatory variant of MFH and a sclerosing type of well-differentiated liposarcoma, respectively. To our knowledge, only two cases of dedifferentiated liposarcoma combined with inflammatory MFH as a dedifferentiated component have been recorded in the literature. The salient feature of the present case is a systemic inflammatory reaction, as shown by prominent leukocytosis (up to 73 900/mm³) and the elevated serum value of C reactive protein (up to 26.0 mg/dL), which were transiently reduced after surgery. The Inflammatory reaction was suggested to be induced by cytokines, such as granulocyte colony-stimulating factor and interleukin-6, which were probably produced by the tumor cells in the present case, because the elevated serum values of those cytokines were decreased after surgery.     

Molecular aberrations of the G1-S checkpoint in myxoid and round cell liposarcoma.

Myxoid and round cell liposarcoma represents a morphological spectrum in which tumor progression from low-grade myxoid to high-grade round cell areas is frequently observed. A distinctive t(12;16)(q13;p11) reciprocal translocation rearranges the CHOP gene localized to 12q13 in most cases. Data concerning the occurrence of cell cycle aberrations in this subset of mesenchymal malignancies are very limited. Therefore, we analyzed a histologically homogeneous series of 21 cases of myxoid and round cell liposarcoma. The p53 pathway was studied by investigating the TP53 gene and protein, mdm2 protein, and p21Waf1 protein. The Rb-cyclin D pathway was analyzed by studying the pRb protein, the p16MTS1 gene, cyclin D1, cyclin D3, p27Kip1, cdk4, and cdk6 proteins. In contrast with the rare involvement of the TP53 gene in well differentiated liposarcoma, aberrations of the TP53 gene were observed in approximately 30% of cases of myxoid and round cell liposarcoma. Notably, mdm2 overexpression was seen in 56% of cases and correlated with histological grade, therefore indicating a possible role in tumor progression. Abnormalities involving the Rb-cyclin D pathway were observed in more than 90% of cases. pRb loss was present in one-third of cases and, at variance with that observed in other subsets of sarcoma, overexpression of cyclin Ds represented a rare event. Interestingly, upregulation of either cdk4 or cdk6 was demonstrated in 85% of cases.     

Retroperitoneal dedifferentiated liposarcoma with osteosarcomatous components: a case report

We report a rare case of recurrent retroperitoneal dedifferentiated liposarcoma with osteosarcomatous components. An 82-year-old male diagnosed with recurrent retroperitoneal liposarcoma underwent a tumor resection. Histologically, osseous matrix with osteoid and mature hyaline cartilaginous tissues with high cellularity were observed in a fibrous background through most of the tumor, and scattered MDM2- and CDK4-positive atypical hyperchromatic stromal cells were detected surrounding the dedifferentiated areas. Dedifferentiation occurs in up to 10% of well-differentiated liposarcomas, frequently resembling a malignant fibrous histiocytoma-like pleomorphic sarcoma. In contrast, divergent differentiation with osteosarcomatous components is considered to be extremely rare.     

Distinction Between Lipoma and Liposarcoma by MDM2 Alterations: A Case Report of Simultaneously Occurring Tumors and Review of the Literature

We investigated a lipoma and a well-differentiated/dedifferentiated liposarcoma (WD/DDL), occurring simultaneously in one patient for the possible role of p53 and mdm2 in the molecular oncogenesis of liposarcoma and tumor progression. The hypothesis tested was if there is a continuum in the development from lipoma to liposarcoma. Lipoma was characterized by a lack of p53 mutation, p53 LOH and p53 protein expression, as well as by mdm2 amplification and mdm2 protein expression. p53 mutation and p53 LOH were found neither in the well-differentiated nor in the dedifferentiated parts of the liposarcoma. In contrast, mdm2 amplification and an increase in mdm2 protein expression were found to be associated with malignancy and dedifferentiation, whereas p53 protein expression was only slightly increased. These findings indicate that mdm2 constitutes one of the most common targets for molecular aberration in WD/DDL. We suggest that mdm2 is a marker distinguishing between ordinary lipoma and well-differentiated liposarcoma, and that the genesis of these tumors is different.     

Primary cardiac dedifferentiated liposarcoma with homologous and heterologous differentiation: a case report

Liposarcoma originating in the heart is extraordinarily rare. Herein, we report a dedifferentiated liposarcoma arising from the left atrium in a 59-year-old Chinese man. Histologically, the neoplasm predominantly consisted of undifferentiated pleomorphic sarcoma. In addition, the neoplasm exhibited lipoblastic differentiation and osteo-/chondrosarcomatous components. Immunohistochemically, the neoplastic cells were strongly positive for p16, MDM2, and CDK4. Fluorescence in situ hybridization showed MDM2 gene amplification in all of the tumor components. To the best of our knowledge, this is the first published example of cardiac dedifferentiated liposarcoma exhibiting homologous and heterologous differentiation without a well-differentiated liposarcoma component.     

Well‐differentiated and dedifferentiated liposarcomas with prominent myxoid stroma: analysis of 56 cases

Aims: Occasional cases of well‐differentiated and dedifferentiated liposarcoma (LPS) contain myxoid stroma, leading to confusion with other sarcomas. The aim of this study was to analyse the clinicopathological and genetic features of well‐differentiated/dedifferentiated LPS with prominent myxoid stroma. Methods and results: Fifty‐six cases of LPS (22 well‐differentiated; 34 dedifferentiated) with prominent myxoid stroma were evaluated. Most arose in the retroperitoneum, abdominal cavity, or spermatic cord. The mean size was 170 mm. Myxoid LPS‐like plexiform vessels were conspicuous in 11 cases of well‐differentiated LPS. In 22 cases of dedifferentiated LPS, myxofibrosarcoma‐like curvilinear vessels were prominent. In other cases, the myxoid component had variably bland or pleomorphic morphology. By immunohistochemistry, staining for MDM2 was positive in 95% of cases, and CDK4 in 78%. Cytogenetics in 13 cases showed ring and giant marker chromosomes. Fluorescence in‐situ hybridization showed amplification of 12q13–15 in six cases evaluated. Of 30 patients with follow‐up, all but one had local recurrences (up to four), but only one has so far had distant metastases. Conclusions: Well‐differentiated/dedifferentiated LPS with prominent myxoid stroma can closely resemble other sarcoma types, especially myxoid LPS and myxofibrosarcoma. The clinical presentation (large retroperitoneal or abdominal tumour) is a clue to the correct diagnosis; the degree of nuclear atypia helps to exclude myxoid LPS. Immunohistochemistry for MDM2 and CDK4 and genetic analysis can be useful to confirm the diagnosis.