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Distinct mdm2/p53 expression patterns in liposarcoma subgroups: implications for different pathogenetic mechanisms.

Recent findings have indicated that TP53 inactivation in sarcomas may result from mutation and/or deletion of the TP53 gene or, alternatively, from binding to the MDM2 gene products. To investigate further a possible role of the two genes in sarcomas, 24 large and deep-seated lipomas and 74 liposarcomas of various subtypes were analysed for mdm2 and p53 overexpression by immunocytochemistry. Nineteen cases of the same series were also molecularly analysed for both MDM2 gene amplification and TP53 mutations, and a further ten cases for non-random chromosomal abnormalities. In the retroperitoneal well-differentiated-dedifferentiated (WD-DD) group, 15/16 WD and 8/8 DD liposarcomas displayed the mdm2+/p53+ phenotype, consistent with MDM2 gene amplification in the absence of TP53 mutations. In the non-retroperitoneal WD-DD group, 5/11 WD liposarcomas also retained the mdm2+/p53+ phenotype whereas all DD liposarcomas showed an immunophenotype and, when assessed, a genotype consistent with mutant TP53. Null mdm2 immunophenotype, coupled with evidence of a specific chromosome translocation t(12;16), was constantly observed in both the usual and the cellular subtypes of myxoid liposarcoma, three cases of which also showed TP53 alterations at the genetic or protein level. Neither mdm2 nor p53 overexpression was observed in the lipomas. The results show the existence of three main pathogenetically distinct groups of liposarcoma. The first retroperitoneal WD-DD group, which represents a novel class of tumours within a single histological category of sarcoma, where MDM2-mediated inactivation of p53 could be related to the pathogenetic mechanism. The second is the non-retroperitoneal WD-DD group, where the TP53 mutations appear to correlate with the dedifferentiation process. The third is the myxoid group, which is characterized by its own unique cytogenetic profile and never shows any involvement of TP53 or MDM2 genes. As for diagnostic significance, the absence of mdm2 and p53 reactivity in lipomas seems to represent a useful marker for differential diagnosis from lipoma-like WD liposarcomas.

Adolescent↗

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 p21Waf1 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 p21Waf1 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).

Cell Differentiation↗

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.

Blotting, Southern↗

Evaluation of MDM2 and CDK4 amplification by real-time PCR on paraffin wax-embedded material: a potential tool for the diagnosis of atypical lipomatous tumours/well-differentiated liposarcomas.

Atypical lipomatous tumours/well-differentiated liposarcomas and dedifferentiated liposarcomas are characterized by 12q13-15 region amplification. In contrast, this molecular event has not been reported in benign lipomas. Within the 12q13-15 chromosomal region, the MDM2, SAS, HMGA2, and CDK4 genes are the most frequent targets of amplification. A series of lipomas (36 cases) and liposarcomas (48 cases) was analysed for MDM2 and CDK4 gene amplification by real-time PCR. MDM2 and CDK4 gene amplification was detected in 2.8% and 5.6% of lipomas and 98.2% and 82.4% of liposarcomas, respectively. Moreover, co-amplification of the two genes as well as a higher-level amplification was observed more frequently in dedifferentiated liposarcomas than in atypical lipomatous tumours/well-differentiated liposarcomas. Real-time PCR proved to be a fast and reliable method to characterize lipomas and liposarcomas by quantification of MDM2 and CDK4 gene amplification. It is applicable to paraffin wax-embedded tissues and could be useful when histological diagnosis is difficult.

Abdominal Neoplasms↗

Septum-like structures in lipoma and liposarcoma: MR imaging and pathologic correlation.

OBJECTIVE: To investigate the septum-like structures in predominantly lipomatous tumors, by correlating fat-suppressed MR images with histopathologic findings. DESIGN AND PATIENTS: The MR findings of three cases of well-differentiated liposarcoma (atypical lipoma), one case of lipoma-like component of dedifferentiated liposarcoma, and nine cases of lipoma were analyzed. T1-, T2-, and fat-suppressed T1-weighted images after Gd-DTPA administration were obtained. Surgical specimens from five patients (four with liposarcoma and one with lipoma) were also scanned with a MR unit, and compared with the pathologic findings. RESULTS AND CONCLUSIONS: Enhancement features of lipoma and liposarcoma were well visualized on fat-suppressed T1-weighted images after Gd-DTPA administration. The septum-like structures of liposarcoma are thick and enhanced considerably, while septa of lipoma are thin and enhanced only slightly. Pathologically, the septum-like structures of liposarcoma contained muscle fibers and the septa of lipoma represented fibrous capsule. Identification of well-enhanced septa in a predominantly lipomatous tumor helps to differentiate malignant tumors from lipomas. As the septum-like structures of liposarcoma contain a skeletal muscle component the tumor might need more extensive surgical procedures including resection of adjacent muscles.

Aged↗

MDM2 amplification and loss of heterozygosity at Rb and p53 genes: no simultaneous alterations in the oncogenesis of liposarcomas.

PURPOSE: The present study aimed to investigate the status of alterations of the MDM2, Rb and p53 genes in a series of 45 liposarcomas. Furthermore, the possible correlation with histological and clinical parameters was studied. METHODS: MDM2 amplification was examined by non-radioactive Southern blot hybridization with a human MDM2 cDNA probe. Mutations in the p53 gene were screened by polymerase chain reaction/single-strand conformation polymorphism analysis and direct sequencing. To study loss of heterozygosity (LOH) at the tumor-suppressor genes Rb and p53, we used four polymorphic intragenic Rb markers (introns 1, 17, 20, and 25) and two p53 markers (intron 1 and exon 4). RESULTS: MDM2 amplification was found in 19 of 45 liposarcomas (42.2%). The frequency of LOH in Rb and p53 was nearly identical (22%). In 4 of 9 tumors (44.4%) with LOH, allelic loss was a concurrent event in both genes. Of 45 liposarcomas, 6 (13.3%) showed p53 mutations. Overall, alterations of the p53/MDM2/Rb pathway occurred in 30 of 45 liposarcomas (66.6%). In contrast to myxoid and pleomorphic variants, well-differentiated liposarcomas were characterized by a high frequency of MDM2 amplification, a lack of LOH of Rb and p53, and p53 mutations. CONCLUSIONS: Obviously MDM2 amplification and LOH at the Rh and p53 genes do not occur simultaneously in the oncogenesis of liposarcomas, as is the case for MDM2 amplification and p53 gene mutations (with one exception). We suggest that well-differentiated, myxoid and pleomorphic liposarcomas are characterized by a different pattern of molecular alterations.

Adult↗

Composition of fat in different types of liposarcomas in comparison with lipomas.

Different types of liposarcomas, and for comparison, lipomas were investigated for their lipid composition. Triglycerides were the main components of lipomas and lipoma-like liposarcomas. Myxoid liposarcomas had a high water content and contained considerable amounts of free cholesterol and phospholipids. One pleomorphic liposarcoma resembled a myxoid liposarcoma in its lipid composition and water content. In 4 liposarcomas of mixed type the lipid composition resembled the main subtype. A glycerol ether-like fraction was found in all lipoma-like (well differentiated) liposarcomas, in one myxoid type but not in the other types.

Chemical Fractionation↗

Magnetic resonance imaging of lipoma and liposarcoma: potential of short tau inversion recovery as a technique of fat suppression.

The present limited retrospective study was performed to assess MR imaging of lipomatous tumours of the musculoskeletal system and to evaluate the potential of the T2 short tau inversion-recovery (STIR) technique for differentiating lipomas from liposarcomas. Magnetic resonance imaging of 12 patients with lipomatous tumours of the musculoskeletal system (eight benign lipomas, three well-differentiated liposarcomas and one myxoid liposarcoma) were reviewed. Benign lipomas were usually superficial and showed homogeneity on T1- and T2-weighted spin echo sequences. Full suppression at T2 STIR was readily demonstrated. In contrast, the liposarcomas in the present series were all deep-seated. Two well-differentiated liposaromas showed homogeneity at long and short relaxation time (TR) but failed to show complete suppression at T2 STIR. One case of well-differentiated liposarcoma (dedifferentiated liposarcoma) and one of myxoid liposarcoma showed mild and moderate heterogeneity at T1 and T2, respectively, and posed no difficulty in being diagnosed correctly. In conclusion, short and long TR in combination with T2 STIR show promise in differentiating benign from malignant lipomatous tumours of the musculoskeletal system, when taken in combination with the position of the tumour.

Adolescent↗

Primary liposarcoma of the orbit: a clinicopathologic study of seven cases.

Liposarcoma, the most common soft tissue sarcoma in adults, will rarely involve the orbit, either primarily or as a metastasis. We describe seven primary orbital liposarcomas, representing the largest documented series of primary orbital liposarcoma to date. Affected patients were three males and four females ranging in age from 28 to 69 years (median, 51 years). Five patients presented with painless proptosis, one patient had painful proptosis, and no details of presenting symptoms are available in one case. The site distribution was retrobulbar (3 cases), lateral orbital wall (2 cases), medial wall (1 case), and unspecified (1 case). Radiologic impression included hemangioma, lipoma, and an inflammatory process. Lesional size ranged from 2.8 to 4 cm. Five liposarcomas were purely well-differentiated, one was dedifferentiated, and one was pleomorphic in type. The well-differentiated cases comprised the following subtypes: spindle cell (2 cases), adipocytic (2 cases), and combined adipocytic/sclerosing/inflammatory (1 case). Five patients underwent orbital exenteration (one followed by radiation) and two had marginal/partial excision of their tumors. Follow-up was available for five patients, ranging from 13 to 204 months (median 65 months). Four patients showed no evidence of recurrence, including the patient with pleomorphic liposarcoma who had a long, disease-free survival (65 months) following marginal excision. One patient has had multiple recurrences following initial partial excision. One patient died of an unrelated cause with no clinical evidence of recurrence. Despite the difficulty in obtaining wide surgical margins, the small tumor size at presentation and the apparent predominance of the well-differentiated type means that the prognosis for orbital liposarcoma is generally good. In view of the various morphologic patterns that may occur, liposarcoma should be considered in the differential diagnosis of any histologically unusual mesenchymal lesion in the orbit.

Adult↗

[Magnetic resonance tomography of liposarcoma].

PURPOSE: Liposarcoma is the most common soft tissue sarcoma in adults. The purpose of the study was to correlate MR imaging features with the four ICD subclasses. METHODS: 28 patients with liposarcoma were examined preoperatively on a 1.0 T MRI system, using spin echo sequences, gradient echo imaging and STIR sequences. In all patients, classification of the liposarcomas was made by histologic diagnosis (ICD-10-M-classification). RESULTS: Well differentiated liposarcomas (9 patients) showed a number of MRI features consistent with lipoma (well defined mass high signal intensity (SI) on T1 images, low signal on T2 images, no or only little signal increase of tumour tissue after contrast material application, no necrosis). Not well differentiated liposarcomas (myxoid 14 patients, pleomorphic three patients, round cell two patients) revealed the largest part of the mass to be of low SI on T1-weighted images. Only scattered fatty islands and septa (9 patients with myxoid liposarcoma had more SI in T1-weighted images. T2-weighted image showed most of the mass to be of intermediate to high SI are the fatty island of relatively low SI. The probability of tumor necrosis increased with lower tumour grading. CONCLUSION: MRI seems to be valuable to identify well differentiated liposarcomas.

Adult↗

Heterologous elements in the dedifferentiated component of dedifferentiated liposarcoma.

Five cases of dedifferentiated liposarcoma in which heterologous elements were present in the dedifferentiated component are presented. Two patients, men 54 and 66 years of age, had retroperitoneal atypical lipomatous tumors (well-differentiated liposarcomas) that recurred (after 2.5 and 12 years, respectively) as dedifferentiated liposarcomas with rhabdomyosarcomatous elements in the dedifferentiated components. The third patient, a 63-year-old woman, had a retroperitoneal dedifferentiated liposarcoma whose dedifferentiated component demonstrated focal osteoid formation. The fourth patient, a 36-year-old woman, had two seemingly separate retroperitoneal masses, one composed of atypical lipomatous tumor with foci of smooth muscle and the other of leiomyosarcoma; despite the apparent separation, it was thought more logical to consider this a dedifferentiated liposarcoma with leiomyosarcoma as the dedifferentiated component than two unrelated neoplasms. The fifth patient, a 45-year-old man, had a mediastinal dedifferentiated liposarcoma with angiosarcomatous areas in the dedifferentiated component. The relatively short follow-up thus far available on these cases has not demonstrated tumor behavior significantly different from that of dedifferentiated liposarcoma as a whole.

Adult↗

Upper aerodigestive tract liposarcoma: report on four cases and literature review.

OBJECTIVE: To report on the clinical behavior, histopathology, treatment, and prognosis of laryngeal, hypopharyngeal, and cervical esophageal liposarcomas. STUDY DESIGN: Retrospective reviews of pathology files and hospital records at a tertiary care hospital and a retrospective search of the English-language literature. METHODS: Cases of upper aerodigestive tract (UADT) liposarcoma with adequate histopathologic documentation and clinical information were included for review. RESULTS: Four cases of UADT liposarcomas were identified. The literature review revealed 26 cases of laryngeal liposarcomas, 7 cases of hypopharyngeal liposarcomas, and 6 cases of esophageal liposarcomas: the mean age at presentation was 55.8 years, the male:female ratio was 5:1, and 60% of the patients presented with dysphagia. Eighty-six percent of tumors had low-grade histologic findings. The recurrence rate after primary resection was 50%. Recurrence correlated with surgical procedure rather than with histologic subtype; 94.7% of recurrences happened after simple excision. Distant metastases occurred in three patients; two of them died of the disease. CONCLUSIONS: The literature supports that UADT liposarcomas are rare and usually of low-grade histologic type. The rate of metastatic disease and tumor-related mortality is low. However, high recurrence rates have been noted, particularly when less radical surgery is employed.

Adult↗

Biochemical uncovering of mdm2/p53 complexes in liposarcomas parallels their immunohistochemical detection.

Recent observations indicate the existence of pathogenetically distinct groups of well-differentiated (WD) dedifferentiated (DD) liposarcomas. In the retroperitoneal WD-DD liposarcomas, the predominant phenotype is represented by the aberrant (overexpressed) mdm2+/p53+ wild-type profile. At the nonretroperitoneal site, the WD liposarcomas present a wider association of MDM2/P53 gene expression; i.e., mdm2+/p53+, mdm2+/p53-, mdm2-/p53+ and mdm2-/p53-, and TP53 mutations seem to correlate with the dedifferentiation process. A biochemical study of mdm2-p53 association in 11 tumor samples characterized by the presence of different mdm2 and p53 immunophenotypes was performed. Immunoprecipitation assays using a p53-specific antibody were performed on tumor tissue and surrounding normal tissue; the immunoprecipitated material was then investigated for the presence of p53 (control) and of coimmunoprecipitated mdm2. This biochemical analysis showed that, in mdm2+/p53+/wild-type retroperitoneal liposarcomas, a band corresponded to mdm2 protein in the cellular lysates immunoprecipitated with a p53-directed antibody. In contrast, the mdm2+/p53- liposarcoma did not evidence the presence of mdm2 protein nor was p53 protein available to direct immunoprecipitation, as in the p53 mutant tumor samples with mdm2-/p53+ and mdm2-/p53- phenotypes. From the normal counterpart of retroperitoneal liposarcoma lysates, no p53 protein was immunoprecipitated. The findings in this study agree with the molecular data and they show the physical association of mdm2 and p53 in fresh liposarcoma surgical specimens.

Gene Amplification↗

Myxoid liposarcoma: appearance at MR imaging with histologic correlation.

Although myxoid liposarcoma is a subtype of liposarcoma, it may be difficult to establish the correct diagnosis with magnetic resonance (MR) imaging due to the lack of fat signal intensity. Without the administration of gadolinium contrast material, the tumor may even mimic a cystic tumor. A spectrum of MR imaging abnormalities occur in myxoid liposarcoma, depending on the amount of fat and myxoid material, the degree of cellularity and vascularity, and the presence of necrosis. Most myxoid liposarcomas have lacy or linear, amorphous foci of fat. Some myxoid liposarcomas appear to be cystic at nonenhanced MR imaging, although they enhance like other solid masses at contrast material-enhanced MR imaging. The enhancing areas within the tumor represent increased cellularity and vascularity; the nonenhancing areas represent necrosis, reduced cellularity, and accumulated mucinous material. Gadolinium-enhanced imaging is important in differentiating myxoid liposarcoma from benign cystic tumors. Characterization of the tumor with MR imaging plays an important role in the management of myxoid liposarcoma.

Adipose Tissue↗

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.

Aged↗

Liposarcomas of the larynx and hypopharynx: a clinicopathologic study of eight new cases and a review of the literature.

Laryngeal and hypopharyngeal liposarcomas were studied in seven men and one woman. Patient age ranged from 25 to 81 years, with a median of 64 years. Symptoms included dysphagia, airway obstruction, and the sensation of a foreign body in the back of the throat. Histologically, seven of the tumors were of the biologically favorable types, either representing well-differentiated (lipoma-like) liposarcomas or myxoid liposarcomas. One tumor was a pleomorphic liposarcoma. Six of the eight patients had one or more episodes of recurrent tumor. Surgery is the treatment of choice and can include conservative (organ-sparing) procedures. However, to eradicate the tumor completely and thereby prevent recurrent disease, open surgical approaches (i.e., lateral pharyngotomy), rather than endoscopic techniques should be employed. The morbidity rate for laryngeal and hypopharyngeal liposarcomas is high because these tumors tend to recur over extended periods of time. In this study, however, there were no instances of metastatic disease, and no deaths were attributed to liposarcoma. Prospectively, laryngeal and hypopharyngeal well-differentiated (lipoma-like) liposarcoma is a difficult clinical and histopathologic diagnosis to establish. Often, this diagnosis is made only after one or more episodes of recurrent disease.

Adult↗

Dedifferentiated liposarcoma of the extremities: imaging findings in four patients.

OBJECTIVE: The term "dedifferentiated" liposarcoma is used to describe a distinctive lesion in which a well-differentiated liposarcoma is juxtaposed with a high-grade nonlipogenic sarcoma. Dedifferentiated liposarcoma is probably the most common of all the dedifferentiated sarcomas, occurring almost exclusively in the mediastinum, the retroperitoneum, and the inguinal/paratesticular regions. We report the imaging findings in four cases of dedifferentiated liposarcoma of the lower extremities. MATERIALS AND METHODS: The radiologic images and clinical histories of four patients with histologically verified dedifferentiated liposarcoma were retrospectively studied. The mean age of the patients was 61 years (range, 33-79 years). All lesions occurred in the thigh. Spin-echo MR images were available for review in two cases and CT scans in the two remaining cases. Plain radiographs were available in all cases. RESULTS: All lesions were large, with a mean maximum size of 24 cm (range, 12-30 cm), and had a significant fatty component radiologically. Both MR and CT showed a well-delineated fatty component of the lesions and a closely apposed nonfatty region. Radiographs showed well-defined bone within one lesion, bone and amorphous calcification in another, and a single punctate calcification in a third. Two patients had a history of excision of a lipomatous lesion in the region of the mass. One patient had pulmonary metastases. CONCLUSION: The potential for deep well-differentiated fatty tumors of the extremities to dedifferentiate is not generally recognized. Although the different types of liposarcoma cannot be reliably distinguished with imaging studies, a well-defined nonlipomatous mass juxtaposed with a predominantly fatty tumor is suggestive of a dedifferentiated liposarcoma.

Adult↗

Prognostic relevance of p53 alterations and Mib-1 proliferation index in subgroups of primary liposarcomas.

For prognostic analyses of p53 alterations (p53 gene mutations + p53 immunopositivity) and Mib-1 proliferation index, we investigated 42 primary malignant lipomatous tumors for which complete clinical data and a long follow-up were available. p53 gene mutations were investigated by PCR-single strand conformation polymorphism-sequencing analysis, and immunohistochemistry was used to determine p53 protein expression and Mib-1 proliferation index. We found a mutation frequency of 14.3%. Nine liposarcomas (21%) were p53 immunopositive, and 11 (26.2%) had at least one p53 alteration. In myxoid liposarcomas, p53 alterations are not relevant to the presence or absence of round cell components. Pleomorphic liposarcomas showed a significantly higher proliferation index and more p53 alterations than myxoid or well-differentiated variants (P<0.001). When the Cox's regression analysis tumors of grade III histology (P = 0.005) was performed, the pleomorphic subtype (P = 0.016) and liposarcomas of retroperitoneal localization (P = 0.015) showed a significantly poorer prognosis. Moreover, we found that p53 alterations and high proliferation index correlated significantly with reduced overall survival. Their prognostic value seemed to be higher in myxoid than in pleomorphic liposarcomas. The metastasis-free survival was reduced in patients who had liposarcomas with p53 alterations (P = 0.171) or elevated proliferation index (P<0.016), reflecting a more aggressive behavior. In conclusion, the determination of p53 alterations and/or Mib-1 proliferation index is useful for assessing the prognosis of patients with liposarcomas and may especially be helpful in dividing different prognostic groups for patients with myxoid variants.

Adolescent↗