Journal of Biomedicine and BiotechnologyVolume 2011 (2011), Article ID 524067, 9 pagesdoi:10.1155/2011/524067

Review Article

Contributions of Cytogenetics and Molecular Cytogenetics to the Diagnosis of Adipocytic Tumors

Jun Nishio

Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Received 5 September 2010; Accepted 15 December 2010

Academic Editor: Brynn Levy

Copyright © 2011 Jun Nishio. Jun Nishio. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Over the last 20 years, a number of tumor-specific chromosomal translocations and associated fusion genes have been identified for mesenchymal neoplasms including adipocytic tumors. The addition of molecular cytogenetic techniques, especially fluorescence in situ hybridization (FISH), has further enhanced the sensitivity and accuracy of detecting nonrandom chromosomal translocations and/or other rearrangements in adipocytic tumors. Indeed, most resent molecular cytogenetic analysis has demonstrated a translocation t(11;16)(q13;p13) that produces a C11orf95-MKL2 fusion gene in chondroid lipoma. Additionally, it is well recognized that supernumerary ring and/or giant rod chromosomes are characteristic for atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma, and amplification of 12q13–15 involving the MDM2, CDK4, and CPM genes is shown by FISH in these tumors. Moreover, myxoid/round cell liposarcoma is characterized by a translocation t(12;16)(q13;p11) that fuses the DDIT3 and FUS genes. This paper provides an overview of the role of conventional cytogenetics and molecular cytogenetics in the diagnosis of adipocytic tumors.

1. Introduction

Adipocytic tumors represent the largest group of soft tissue tumors that have been studied by cytogenetic analysis. In 1986, the first consistent karyotypic abnormality was discovered in adipocytic tumors [1–3]. The current World Health Organization (WHO) classification of adipocytic tumors includes eleven benign, one intermediate, and five malignant subtypes [4].

The diagnosis of adipocytic tumors is primarily based on clinical features and histologic patterns. However, atypical lipomatous tumor/well-differentiated liposarcoma dedifferentiated liposarcoma are often difficult to distinguish morphologically from benign adipocytic tumors and other high-grade sarcomas, respectively. Immunohistochemistry plays little role in the differential diagnosis of adipocytic tumors [4]. Moreover, the use of minimally invasive biopsies to diagnose adipocytic tumors has become increasingly common, and this shift has created additional challenges. In such instances, molecular genetic testing can serve as a useful diagnostic adjunct for adipocytic tumors.

Most types of adipocytic tumor have distinctive cytogenetic aberrations which can be of considerable help in diagnosis. This paper reviews the cytogenetic and molecular cytogenetic characteristics of adipocytic tumors as well as their clinicopathologic features. The consistent chromosomal alterations are summarized in Table 1.

Table 1: Chromosomal aberrations and associated molecular events in adipocytic tumors.

Tumor type
Chromosomal aberration
Molecular event

Benign

    Lipoma
t(3;12)(q27-28;q13–15)
HMGA2-LPP

t(9;12)(p22;q13–15)
HMGA2-NFIB

t(2;12)(q37;q13–15)
HMGA2-CXCR7

t(5;12)(q32-33;q13–15)
HMGA2-EBF1

t(12;13)(q13–15;q12)
HMGA2-LHFP

6p21–23 rearrangement
HMGA1 rearrangement

13q deletion
Not known

    Chondroid lipoma
t(11;16)(q13;p13)
C11of95-MKL2

    Spindle cell/pleomorphic lipoma
13q and/or 16q deletions
Not known

    Hibernoma
11q13 rearrangement
MEN1, PPP1A deletion

    Lipoblastoma
8q11–13 rearrangement
PLAG1 rearrangement

Intermediate (locally aggressive)

    Atypical lipomatous tumor/
Ring/giant marker chromosome
MDM2, CDK4, CPM,

    well differentiated liposarcoma
(12q13–15 amplification)
HMGA2 amplification

Malignant

    Dedifferentiated liposarcoma
Ring/giant marker chromosome*
MDM2, CDK4, CPM,

(12q13–15 amplification)
HMGA2 amplification

    Myxoid/round cell liposarcoma
t(12;16)(q13;p11)
FUS-DDIT3

t(12;22)(q13;q12)
EWSR1-DDIT3

    Pleomorphic liposarcoma
Complex karyotype
Not known

Dedifferentiated liposarcoma may contain complex aberrations in addition to ring or giant marker chromosomes.

2. Methods of Cytogenetic and Molecular Cytogenetic Analyses

A soft tissue sample submitted for conventional cytogenetic analysis must be fresh and should be representative of the neoplastic process. Also, necrotic tissue should be dissected from the sample. Generally, a 1-2 cm³ fresh sample is provided for cytogenetics [5]. The basic process of cell culturing is the same for all adipocytic lesions. Briefly, sterile tumor tissue is minced with scissors and then disaggregated with collagenase. The isolated cells are washed, diluted in culture medium, and seeded in culture flaks or chamber slides. The cultures are incubated in a 5% CO₂ atmosphere at 37°C. A short-term culturing usually results in a sufficient number of mitoses within 5–10 days. Then, dividing cells are arrested in metaphase by the addition of a mitotic-spindle inhibitor such as colcemid. The cells are fixed with methanol/glacial acetic acid (3 : 1) and stained using a trypsin-Giemsa method to produce characteristic banding patterns. Ideally, 20 metaphase cells are analyzed for each specimen.

During the last two decades, the ability to identify chromosomal abnormalities has been markedly improved by the development of molecular cytogenetic technologies such as fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). FISH is a technique that involves detection of specific DNA sequences by hybridization with complimentary DNA probes. A major advantage of FISH is that nondividing (interphase) nuclei from fresh, frozen, or formalin-fixed samples can be evaluated. It has been realized that FISH is an effective adjunct in the diagnosis of soft tissue tumors including adipocytic tumors [6]. On the other hand, FISH cannot detect smaller genetic alterations such as point mutations. Recently, multicolor FISH (M-FISH) can be used to detect cryptic rearrangements or decipher the origin of marker chromosomes in complex karyotypes [7]. The combination of chromosome banding analysis with M-FISH has the potential to identify and describe most karyotypic changes of sarcoma cells. CGH is a technique for the analysis of DNA sequence copy number changes across the genome in a single hybridization experiment [8]. Briefly, tumor (test) and reference (control) DNAs are differentially labeled with green or red fluorescence dyes, mixed in a 1 : 1 ratio in the presence of human Cot-1 DNA (to block repetitive sequences), and cohybridized to normal metaphase chromosome spreads. Metaphase spreads are captured using a high resolution or cooled charge-coupled device camera, and the images are analyzed with the CGH software. The sensitivity of CGH is restricted by purity of the cell population and depends on the level and size of the copy number changes. In addition, CGH cannot detect rearrangements such as inversions or balanced translocations. Recently, a higher resolution version of CGH, so-called array CGH, has been made available [9]. In this novel technique, test and reference DNAs are differentially labeled and competitively hybridized to glass slides (chips) containing multiple DNA fragments. A distinct advantage of array CGH is the ability to directly map the copy number changes to the genome sequence. Moreover, low copy number gains and losses can be detected by array CGH at a resolution about 100 kb.

3. Benign Adipocytic Tumors

3.1. Lipoma

Ordinary lipoma is the most common soft tissue tumor and may appear at any site. It occurs mainly in the fifth to seventh decades of life, frequently in obese individuals. Lipomas are rare in children. Approximately 5% of patients have multiple lipomas [4]. Ordinary lipomas present as painless, slowly growing soft tissue masses and can arise within subcutaneous tissue or deep soft tissue. Deep-seated lipomas (e.g., intramuscular or intermuscular lipomas) are larger and grossly less well-defined than their subcutaneous counterparts and can mimic atypical lipomatous tumor/well differentiated liposarcoma. Histologically, the tumor is composed of lobules of mature fat cells which vary slightly in size and shape.

Clonal cytogenetic aberrations have been identified in nearly 60% of ordinary lipomas [4, 10–12]. The 12q13–15 region is the most commonly involved in such aberrations, followed by 6p21–23 and 13q [10, 13, 14]. This chromosomal region recombines with a large variety of other chromosome bands through translocations. The most frequent translocation is t(3;12)(q27-28;q13–15) that fuses the HMGA2 and LPP genes [15]. HMGA2 has also been reported to form fusion genes with CXCR7 (at 2q37), EBF1 (at 5q33), NFIB (at 9p22), and LHFP (at 13q12) [16–20]. Rearrangements of HMGA2 can be identified by FISH analysis [14, 17, 21, 22], but these probes are not widely available. About 15%–20% of ordinary lipomas show rearrangements or deletions of the long arm of chromosome 13, in particular 13q12–22 [14, 23]. Moreover, FISH analysis has revealed that chromosome 13 is involved in a variety of rearrangements and deletions that cover a limited segment (~2.5 Mb) of chromosome band 13q14, distal to the RB1 gene [23]. Rearrangements of 6p21–23 involving the HMGA1 gene has been described in ordinary lipomas without 12q13–15 aberrations [10, 14]. Recently, Wang et al. [24] detected the presence of an HMGA1-LPP/TPRG1 gene fusion in an ordinary lipoma with t(3;6)(q27;p21). A CGH study has indicated that no copy number changes are found in ordinary lipomas, and this technique may help in the differential diagnosis of intermediate adipocytic tumors [25].

3.2. Chondroid Lipoma

Chondroid lipoma is a distinctive tumor composed of strands and nests of lipoblasts and mature fat cells in a variably myxoid or myxochondroid matrix. This tumor occurs predominantly in the proximal extremities and limb girdles of middle-aged adults. Chondroid lipoma may be mistaken for several other benign and malignant soft tissue tumors such as myxoid liposarcoma or extraskeletal myxoid chondrosarcoma [12].

A reciprocal translocation t(11;16)(q13;p13) has been found in six chondroid lipoma cases [26–29]. Most recently, Huang et al. [29] reported that this chromosomal translocation results in a fusion of C11orf95 and MKL2. The presence of the t(11;16) or the C11orf95-MKL2 fusion transcript is highly specific for chondroid lipoma, and is absent in any other related tumors. Therefore, an analysis of C11orf95 or MKL2 rearrangement using FISH is useful for the differential diagnosis of chondroid lipoma and its histologic mimickers.

3.3. Spindle Cell Lipoma/Pleomorphic Lipoma

Spindle cell and pleomorphic lipomas are histologic ends of a spectrum of a single clinicopathologic entity and supported by cytogenetic evidence [4]. These tumors present as circumscribed subcutaneous lesions occurring typically on the neck and upper back, particularly older males. Histologically, spindle cell lipoma is composed of a mixture of mature fat cells and small spindle cells associated with a myxoid matrix and collagen bundles. In the other end of the spectrum, pleomorphic lipoma is characterized by the presence of multinucleated floret-like giant cells. Immunohistochemically, the spindle cells in both spindle cell and pleomorphic lipomas are strongly positive for CD34 [4].

Spindle cell and pleomorphic lipomas show similar cytogenetic aberrations which are usually more complex than ordinary lipomas. The karyotypes of these tumors are frequently hypodiploid with multiple partial deletions and few balanced rearrangements. The recurrent cytogenetic aberrations appear to be deletion of 16q13-qter, monosomy for chromosome 13, or partial deletion of 13q [30–32]. However, it should be kept in mind that deletions and structural rearrangements of 13q have been described in other adipocytic tumors [23].

3.4. Hibernoma

Hibernoma is rare, benign adipocytic tumor composed of brown fat cells with granular, multivacuolated cytoplasm. The tumor occurs primarily in the thigh and scapular and interscapular regions of young adults. In cases with numerous univacuolated cells, histologic distinction from ordinary lipoma may be difficult. Also, hibernoma may be misdiagnosed as well differentiated or myxoid liposarcoma because of the paucity of diagnostic brown fat cells in the lipoma-like or myxoid variant [12].

Hibernomas have near or pseudodiploid karyotypes which are frequently somewhat more complex than ordinary lipomas. They are characterized by structural rearrangements involving the long arm of chromosome 11, in particular 11q13. No chromosomal band has been involved more than once as a translocation partner [4]. Metaphase FISH analyses have demonstrated that homozygous deletion of the MEN1 tumor suppressor gene (at 11q13.1) and heterozygous deletion of PPP1CA (distal to MEN1 at 11q13) are found in hibernomas [33]. Recently, Maire et al. [34] reported that the altered region at 11q13 is larger than previously reported and rearrangements of GARP (at 11q13.5) or a neighboring gene may be important in the pathogenesis of hibernomas.

3.5. Lipoblastoma

Lipoblastoma occurs predominantly in children younger than 3 years of age. It presents as a localized (lipoblastoma) or diffuse (lipoblastomatosis) tumor, resembling fetal white adipose tissue. The extremities are the most common site, but many other locations can be involved [4]. Histologically, lipoblastoma shows a lobular appearance and is composed of an admixture of mature adipocytes and lipoblasts in different stages of development. The matrix can be myxoid with plexiform vascular pattern. Lipoblastoma can be confused with intermediate and malignant adipocytic tumors, including atypical lipomatous tumor/well differentiated liposarcoma and myxoid liposarcoma [12].

Lipoblastomas usually have simple, pseudodiploid karyotypes with structural chromosomal alterations. They are characterized by rearrangements of 8q11–13 involving the PLAG1 gene [35–38]. Excess copies of chromosome 8 may be found in cases with or without 8q11–13 rearrangements [10, 39]. Among the several chromosomal aberrations targeting PLAG1, two partner genes have been indentified: HAS2 at 8q24 and COL1A2 at 7q22 [40]. Interestingly, PLAG1 rearrangement can be demonstrated by FISH analysis [36, 37, 41–43]. These findings provide a useful distinguishing feature from the cytogenetic and molecular cytogenetic aberrations found in myxoid liposarcoma and other adipocytic tumors.

3.6. Miscellaneous Types of Lipoma

Angiolipoma occurs chiefly as a subcutaneous painful nodule in young adults. The forearm is the most common site, followed by the trunk and upper arm. Multiple angiolipomas are much more common than solitary ones. Histologically, angiolipoma is composed of mature fat cells separated by a branching network of small vessels. There has been only a single case report of an angiolipoma with a t(X;12)(p22;p12) [44].

Angiomyolipoma is an uncommon mesenchymal tumor composed of a variable mixture of mature fat cells, spindle and epithelioid smooth muscle cells, and abnormal thick-walled blood vessels. Although most commonly presenting in the kidney, angiomyolipomas may also occur in the extrarenal sites. Approximately one-third of patients with angiomyolipoma present with manifestations of the tuberous sclerosis [12]. Immunohistochemically, angiomyolipomas are characterized by a coexpression of the melanocytic marker HMB-45 and smooth muscle markers such as smooth muscle action and muscle-specific action. Cytogenetic studies in renal angiomyolipomas have shown chromosomal aberrations involving trisomy for chromosomes 7 and/or 8 and rearrangements of the long arm of chromosome 12 [45–49]. A CGH study has indicated that chromosomal imbalances are common and the 5q33-34 region may contain a tumor suppressor gene significant in the pathogenesis of some renal angiomyolipomas [50].

Myelolipoma, most common in the adrenal grand, is a rare, benign tumor or tumor-like lesion composed of mature fat cells and haematopoietic elements comprising myeloid and erythroid cells as well as megakaryocytes. It can also occur in extra-adrenal soft tissue. There has been only a single case report of an adrenal myelolipoma with a t(3;21)(q25;p11) [51].

4. Intermediate and Malignant Adipocytic Tumors

4.1. Atypical Lipomatous Tumor/Well Differentiated Liposarcoma

In the current WHO classification, atypical lipomatous tumor and well differentiated liposarcoma have been grouped under the “intermediate (locally aggressive) malignancy” label [4]. It has been suggested to use the term “atypical lipomatous tumor” only for the superficial or subcutaneous locations. Atypical lipomatous tumor/well differentiated liposarcoma accounts for about 40%–45% of all liposarcomas and occurs most frequently in the thigh, retroperitoneum, and paratesticular/inguinal region of middle-aged and older individuals [4]. It usually presents as a painless, slowly growing mass that can attain a very large size. Histologically, the tumor is composed entirely or partially of a mature adipocytic proliferation showing significant variation in cell size and at least focal nuclear atypia in both adipocytes and stromal cells. Four main subtypes of atypical lipomatous tumor/well differentiated liposarcoma are recognized in the current WHO classification: adipocytic (lipoma-like), sclerosing, inflammatory, and spindle cell [4]. The presence of more than one histologic pattern in the same lesion is common. In some situations, atypical lipomatous tumor/well differentiated liposarcoma may be indistinguishable from benign adipocytic tumors at the histologic level, and inadequate samples can lead to misdiagnosis.

Cytogetically, atypical lipomatous tumor/well differentiated liposarcoma is characterized by the presence of supernumerary ring and/or giant marker chromosomes, lacking alpha-satellite centromeric sequences. These ring and giant marker chromosomes have been observed as the sole change or concomitant with a few other numerical or structural aberrations in mostly near-diploid karyotypes. Random and nonrandom telomeric associations can be found [52]. FISH and CGH studies have shown that ring and giant marker chromosomes are composed mainly of amplified sequences from the 12q13–15 region, including the MDM2, CDK4, HMGA2, and SAS genes [53–61]. Recently, Erickson-Johnson et al. [62] demonstrated that CPM (at 12q15) is coamplified with MDM2 in atypical lipomatous tumors/well differentiated liposarcomas. Coamplification of 1q21–23 involving the COAS genes has also been reported [63]. This 12q13–15 amplification is not observed in benign adipocytic tumors, and its detection can therefore be used as an ancillary diagnostic technique for the diagnosis of atypical lipomatous tumor/well differentiated liposarcoma [64, 65]. More importantly, FISH for MDM2 amplification can be performed on nondividing cells from limited tissue samples and is a more sensitive and specific adjunctive tool than MDM2 immunohistochemistry [66].

4.2. Dedifferentiated Liposarcoma

Dedifferentiated liposarcoma is a malignant adipocytic tumor showing transition from atypical lipomatous tumor/well differentiated liposarcoma to a nonlipogenic sarcoma of variable histologic grade. Dedifferentiation is thought to be a time-dependent phenomenon that occurs in up to 10% of atypical lipomatous tumor/well differentiated liposarcoma. About 90% of dedifferentiated liposarcomas arise “de novo,” while 10% occur in recurrences [4]. The risk of dedifferentiation appears to be higher in deep-seated lesions. Dedifferentiated liposarcoma occurs typically in the retroperitoneum of elderly individuals and can also affect the extremities. It usually presents as a painless, large mass, which may be found by chance. In contrast to atypical lipomatous tumor/well differentiated liposarcoma, dedifferentiated liposarcoma has a 15%–20% metastatic rate [67]. Histologically, dedifferentiated liposarcoma is traditionally defined by the association of atypical lipomatous tumor/well differentiated liposarcoma areas and a nonlipogenic component, most often in an abrupt fashion. In about 90% of cases, the dedifferentiated components have the appearance of a high-grade poorly differentiated sarcoma [12]. Recently, the concept of low-grade dedifferentiation has increasingly been recognized [68]. Due to the histologic complexity of dedifferentiated liposarcoma, many differential diagnoses may be raised on the morphologic aspect alone.

Similar to atypical lipomatous tumor/well differentiated liposarcoma, dedifferentiated liposarcoma is characterized by the presence of ring or giant marker chromosomes and double minutes. A peculiarity of dedifferentiated liposarcoma might be the presence of multiple abnormal clones [4]. FISH and CGH studies have demonstrated that ring and giant marker chromosomes are composed, exclusively or partly, of amplified 12q13–15 material, involving MDM2, CDK4, and HMGA2 [56, 69]. In a previous analysis, we established the first human dedifferentiated liposarcoma cell line (FU-DDLS-1) and showed that giant marker chromosomes were composed partly of chromosome 12 material [70]. In addition to the 12q13–15 amplification, 1p32 and 6q23 amplifications have been detected by CGH in dedifferentiated liposarcomas [71–73]. Array CGH analyses have shown that the target genes are JUN in the 1p32 band [74] and ASK1 in the 6q23 band [75]. Interestingly, co-amplifications of 1p32 and 6q23 are absent in atypical lipomatous tumor/well differentiated liposarcoma, suggesting that CGH is a helpful diagnostic adjunct in the discrimination between dedifferentiated liposarcoma and atypical lipomatous tumor/well differentiated liposarcoma.

4.3. Myxoid Liposarcoma/Round Cell Liposarcoma

The WHO Committee combined myxoid and round cell liposarcomas (previously two distinct subtypes) under the umbrella of myxoid liposarcoma [4]. Myxoid liposarcoma, the second most common subtype of liposarcoma, occurs predominantly in the extremities of young to middle-aged adults and has a tendency to recur locally or to metastasize to unusual sites such as the retroperitoneum, opposite extremity, and bone. Histologically, the tumor is composed of a mixture of uniform round- to oval- shaped primitive mesenchymal cells and a variable number of small lipoblasts in a prominent myxoid stroma. The presence of round cell component is associated with a poor prognosis. Pure myxoid liposarcoma must be differentiated from a number of benign and malignant soft tissue lesions characterized by a myxoid stroma, such as lipoblastoma, myxoma, myxofibrosarcoma, low-grade fibromyxoid sarcoma, and extraskeletal myxoid chondrosarcoma.

Myxoid/round cell liposarcoma is generally associated with a chromosome number in the diploid range, with only rare cases being hyperdiploid or near-triploid [76]. It is characterized by a translocation t(12;16)(q13;p11) in more than 90% of cases, resulting in an FUS-DDIT3 fusion gene [77–80]. A variant translocation t(12;22)(q13;q12) has also been described, resulting in an EWR1-DDIT3 fusion gene [81–83]. In addition, several nonrandom secondary aberrations have been identified, including del(6q), i(7)(q10), +8, and der(16)t(1;16) [84–86]. The presence of these translocations and molecular alterations is highly sensitive and specific for myxoid/round cell liposarcoma and is absent in other liposarcoma subtypes or in other myxoid soft tissue tumors. Therefore, cytogenetics is an excellent analytic method for the initial workup of a suspected myxoid/round cell liposarcoma. Moreover, dual color, break apart rearrangement probes spanning the genomic regions of DDIT3 (12q13), FUS (16p11), and EWSR1 (22q12) (Abbott Molecular/Vysis, Des Plaines, IL) are readily available, and FISH can be used to provide support for the diagnosis of myxoid/round cell liposarcoma [6, 87]. Conventional and array CGH studies have shown that genomic imbalances frequently include gains of 8p21–23, 8q, and 13q in myxoid/round cell liposarcomas [88–90].

4.4. Pleomorphic Liposarcoma

Pleomorphic liposarcoma is a rare, high-grade sarcoma with at least focal adipocytic differentiation in the form of pleomorphic lipoblasts. It occurs predominantly in the extremities of elderly patients (>50 years) and is usually deep-seated but may be superficial. In general, pleomorphic liposarcoma has an aggressive behavior with a 30%–50% metastatic rate and an overall tumor-associated mortality of 40%–50% [4]. Histologically, the tumor is composed of pleomorphic multivacuolated lipoblasts admixed with pleomorphic spindle cells and multinucleated giant cells. In some cases of pleomorphic liposarcoma, a small round cell area indistinguishing from myxoid/round cell liposarcoma is observed with a varying number of pleomorphic lipoblasts [12].

Pleomorphic liposarcomas are generally associated with highly complex karyotypes lacking specific structural or numerical aberrations [76, 78, 91]. The presence of rings, large markers, or double minute chromosomes has been reported [4]. Recently, Sugita et al. [92] demonstrated that the number of DDIT3 split signals in pleomorphic liposarcomas is extremely scarce compared with that of myxoid/round cell liposarcoma. Therefore, FISH for DDIT3 rearrangement can play a role in distinguishing between these two liposarcoma subtypes. Conventional and array CGH analyses have shown gains of 1p21, 1q21-22, 5p13–15, 7q22, 9q22-qter, 13q, 17p11.2–12, 20q13, and 22q and losses of 2q, 3p, 4q, 10q, 11q, 12p13, 13q21, and 14q23-24 [72, 88, 89, 93, 94]. Interestingly, amplification of the 12q13–15 region and the MDM2 gene does not occur consistently in pleomorphic liposarcomas, suggesting that CGH can be performed to distinguish pleomorphic liposarcoma from high grade dedifferentiated liposarcoma.

4.5. Mixed-Type Liposarcoma

Mixed-type liposarcoma represents the rarest subtype of liposarcoma and is still considered a controversial entity. It is defined as a liposarcoma showing a mixture of features of at least two main subtypes by histologic examination [4]. The tumor occurs predominantly in retroperitoneal or intra-abdominal locations of elderly patients. Most recently, de Vreeze et al. [95] proposed that mixed-type liposarcomas should not be regarded as collision tumors, but as an extreme variant of the morphologic spectrum within a single biologic entity.

Cytogenetic aberrations in mixed-type liposarcomas usually reflect at least one of the histologic components of the tumor. The presence of ring or giant marker chromosomes has been observed as the sole anomaly or in association with complex rearrangements [31, 69, 96]. Interestingly, Mentzel et al. [97] have reported that amplification of the MDM2 and CDK4 genes and rearrangements of the DDIT3 and FUS genes were detected by FISH analysis in the atypical lipomatous tumor/well differentiated liposarcoma and myxoid/round cell liposarcoma components, respectively.

5. Molecular Diagnostic Algorithm for Adipocytic Tumors

Molecular genetic testing can be used to distinguish between (1) lipoma and atypical lipomatous tumor/well differentiated liposarcoma; (2) myxoid liposarcoma and a variety of myxoid soft tissue tumors including lipoblastoma; and (3) dedifferentiated liposarcoma and pleomorphic liposarcoma when histologic diagnosis is difficult. In addition, molecular genetic testing should be considered for recurrent lipomas, large adipocytic tumors (>15 cm) with minimal or no cytologic atypia [98], lesions arising in rare anatomic locations or unusual age groups, or small biopsy specimens.

6. Conclusions and Future Directions

Cytogenetics is the most comprehensive laboratory method for spotting the various translocations and other structural alterations that characterize adipocytic tumors. In addition, dramatic advances in molecular cytogenetic technologies have greatly improved diagnostic accuracy in adipocytic tumors. In our experience, FISH is very useful in the diagnosis of adipocytic tumors, which harbor consistent molecular alterations including nonrandom translocations and amplification of gene regions. Hopefully in the future, clinical decisions will increasingly be based on a combination of histologic criteria and specific molecular/cytogenetic aberrations. Better understanding of the molecular biology of adipocytic tumors will undoubtedly lead to the development of novel therapeutic strategies.

Acknowledgments

This paper was supported in part by Kaibara Morikazu Medical Science Promotion Foundation, Japan Orthopaedics and Traumatology Foundation, Fukuoka Cancer Society, Clinical Research Foundation, and a Grant-in-Aid for Young Scientists (B) (21791424) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

References

A. A. Sandberg, Z. Gibas, and E. Saren, “Chromosome abnormalities in two benign adipose tumors,” Cancer Genetics and Cytogenetics, vol. 22, no. 1, pp. 55–61, 1986.

C. Turc-Carel, P. Dal Cin, and U. Rao, “Cytogenetic studies of adipose tissue tumors. I. A benign lipoma with reciprocal translocation t(3;12) (q28;q14),” Cancer Genetics and Cytogenetics, vol. 23, no. 4, pp. 283–289, 1986.

S. Heim, N. Mandahl, and U. Kristoffersson, “Reciprocal translocation t(3;12) (q27;q13) in lipoma,” Cancer Genetics and Cytogenetics, vol. 23, no. 4, pp. 301–304, 1986.

C. D. M. Fletcher, K. K. Unni, and F. Mertens, Pathology and Genetics of Tumours of Soft Tissue and Bone, World Health Organization Classification of Tumours, IARC Press, Lyon, France, 2002.

J. A. Bridge, “Advantages and limitations of cytogenetic, molecular cytogenetic, and molecular diagnostic testing in mesenchymal neoplasms,” Journal of Orthopaedic Science, vol. 13, no. 3, pp. 273–282, 2008.

M. R. Tanas and J. R. Goldblum, “Fluorescence in situ hybridization in the diagnosis of soft tissue neoplasms: a review,” Advances in Anatomic Pathology, vol. 16, no. 6, pp. 383–391, 2009.

L. Kearney, “Multiplex-FISH (M-FISH): technique, developments and applications,” Cytogenetic and Genome Research, vol. 114, no. 3-4, pp. 189–198, 2006.

A. Kallioniemi, O. P. Kallioniemi, D. Sudar, D. Rutovitz, J. W. Gray, F. Waldman, and D. Pinkel, “Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors,” Science, vol. 258, no. 5083, pp. 818–821, 1992.

D. Pinkel, R. Segraves, D. Sudar, S. Clark, I. Poole, D. Kowbel, C. Collins, W. L. Kuo, C. Chen, YE. Zhai, S. H. Dairkee, B. M. Ljung, J. W. Gray, and D. G. Albertson, “High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays,” Nature Genetics, vol. 20, no. 2, pp. 207–211, 1998.

A. A. Sandberg, “Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: lipoma,” Cancer Genetics and Cytogenetics, vol. 150, no. 2, pp. 93–115, 2004.

M. Hameed, “Pathology and genetics of adipocytic tumors,” Cytogenetic and Genome Research, vol. 118, no. 2-4, pp. 138–147, 2007.

S. W. Weiss and J. R. Goldblum, Enzinger and Weiss's Soft Tissue Tumors, Mosby, Philadelphia, Pa, USA, 15th edition, 2008.

H. Willén, M. Åkerman, P. Dal Cin, I. De Wever, C. D. M. Fletcher, N. Mandahl, F. Mertens, F. Mitelman, J. Rosai, A. Rydholm, R. Sciot, G. Tallini, H. Van Den Berghe, and R. Vanni, “Comparison of chromosomal patterns with clinical features in 165 lipomas: a report of the CHAMP study group,” Cancer Genetics and Cytogenetics, vol. 102, no. 1, pp. 46–49, 1998.

H. Bartuma, K. H. Hallor, I. Panagopoulos, A. Collin, A. Rydholm, P. Gustafson, H. C. F. Bauer, O. Brosjö, H. A. Domanski, N. Mandahl, and F. Mertens, “Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype,” Genes Chromosomes and Cancer, vol. 46, no. 6, pp. 594–606, 2007.

M. M. R. Petit, R. Mols, E. F. P. M. Schoenmakers, N. Mandahl, and W. J. M. Van De Ven, “LPP, the preferred fusion partner gene of HMGIC in lipomas, is a novel member of the LIM protein gene family,” Genomics, vol. 36, no. 1, pp. 118–129, 1996.

K. Broberg, M. Zhang, B. Strömbeck, M. Isaksson, M. Nilsson, F. Mertens, N. Mandahl, and I. Panagopoulos, “Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15,” International Journal of Oncology, vol. 21, no. 2, pp. 321–326, 2002.

M. Nilsson, F. Mertens, M. Höglund, N. Mandahl, and I. Panagopoulos, “Truncation and fusion of HMGA2 in lipomas with rearrangements of 5q32→q33 and 12q14→q15,” Cytogenetic and Genome Research, vol. 112, no. 1-2, pp. 60–66, 2006.

M. Nilsson, I. Panagopoulos, F. Mertens, and N. Mandahl, “Fusion of the HMGA2 and NFIB genes in lipoma,” Virchows Archiv, vol. 447, no. 5, pp. 855–858, 2005.

A. Italiano, N. Ebran, R. Attias, A. Chevallier, I. Monticelli, C. Mainguené, D. Benchimol, and F. Pedeutour, “NFIB rearrangement in superficial, retroperitoneal, and colonic lipomas with aberrations involving chromosome band 9p22,” Genes Chromosomes and Cancer, vol. 47, no. 11, pp. 971–977, 2008.

M. M. R. Petit, E. F. P. M. Schoenmakers, C. Huysmans, J. M. W. Geurts, N. Mandahl, and W. J. M. Van De Ven, “LHFP, a novel translocation partner gene of HMGIC in a lipoma, is a member of a new family of LHFP-like genes,” Genomics, vol. 57, no. 3, pp. 438–441, 1999.

H. Bartuma, I. Panagopoulos, A. Collin, D. Trombetta, H. A. Domanski, N. Mandahl, and F. Mertens, “Expression levels of HMGA2 in adipocytic tumors correlate with morphologic and cytogenetic subgroups,” Molecular Cancer, vol. 8, article 36, 2009.

X. Wang, R. L. Hulshizer, M. R. Erickson-Johnson, H. C. Flynn, R. B. Jenkins, R. V. Lloyd, and A. M. Oliveira, “Identification of novel HMGA2 fusion sequences in lipoma: evidence that deletion of let-7 miRNA consensus binding site 1 in the HMGA2 3′ UTR is not critical for HMGA2 transcriptional upregulation,” Genes Chromosomes and Cancer, vol. 48, no. 8, pp. 673–678, 2009.

A. Dahlén, M. Debiec-Rychter, F. Pedeutour, H. A. Domanski, M. Höglund, H. C. F. Bauer, A. Rydholm, R. Sciot, N. Mandahl, and F. Mertens, “Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous tumors,” International Journal of Cancer, vol. 103, no. 5, pp. 616–623, 2003.

X. Wang, R. Q. Zamolyi, H. Zhang, V. L. Pannain, F. Medeiros, M. Erickson-Johnson, R. B. Jenkins, and A. M. Oliveira, “Fusion of HMGA1 to the LPP/TPRG1 intergenic region in a lipoma identified by mapping paraffin-embedded tissues,” Cancer Genetics and Cytogenetics, vol. 196, no. 1, pp. 64–67, 2010.

J. Szymanska, M. Virolainen, M. Tarkkanen, T. Wiklund, S. Asko-Seljavaara, E. Tukiainen, I. Elomaa, C. Blomqvist, and S. Knuutila, “Overrepresentation of 1q21-23 and 12q13-21 in lipoma-like liposarcomas but not in benign lipomas: a comparative genomic hybridization study,” Cancer Genetics and Cytogenetics, vol. 99, no. 1, pp. 14–18, 1997.

D. Gisselsson, H. A. Domanski, M. Höglund, B. Carlén, F. Mertens, H. Willén, and N. Mandahl, “Unique cytological features and chromosome aberrations in chondroid lipoma: a case report based on fine-needle aspiration cytology, histopathology, electron microscopy, chromosome banding, and molecular cytogenetics,” American Journal of Surgical Pathology, vol. 23, no. 10, pp. 1300–1304, 1999.

T. A. Thomson, D. Horsman, and T. C. Bainbridge, “Cytogenetic and cytologic features of chondroid lipoma of soft tissue,” Modern Pathology, vol. 12, no. 1, pp. 88–91, 1999.

F. Ballaux, M. Debiec-Rychter, I. De Wever, and R. Sciot, “Chondroid lipoma is characterized by t(11;16)(q13;p12-13),” Virchows Archiv, vol. 444, no. 2, pp. 208–210, 2004.

D. Huang, J. Sumegi, P. D. Cin, J. D. Reith, T. Yasuda, M. Nelson, D. Muirhead, and J. A. Bridge, “C11orf95-MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma,” Genes Chromosomes and Cancer, vol. 49, no. 9, pp. 810–818, 2010.

N. Mandahl, F. Mertens, H. Willen, A. Rydholm, O. Brosjo, and F. Mitelman, “A new cytogenetic subgroup in lipomas: loss of chromosome 16 material in spindle cell and pleomorphic lipomas,” Journal of Cancer Research and Clinical Oncology, vol. 120, no. 12, pp. 707–711, 1994.

C. D. M. Fletcher, M. Akerman, P. Dal Cin, I. De Wever, N. Mandahl, F. Mertens, F. Mitelman, J. Rosai, A. Rydholm, R. Sciot, G. Tallini, H. D. Van Berghe, W. D. Van Ven, R. Vanni, and H. Willen, “Correlation between clinicopathological features and karyotype in lipomatous tumors: a report of 178 cases from the Chromosomes and Morphology (CHAMP) Collaborative Study Group,” American Journal of Pathology, vol. 148, no. 2, pp. 623–630, 1996.

P. D. Cin, R. Sciot, P. Polito, M. Stas, I. De Wever, A. Cornelis, and H. Van Den Berghe, “Lesions of 13q may occur independently of deletion of 16q in spindle cell/pleomorphic lipomas,” Histopathology, vol. 31, no. 3, pp. 222–225, 1997.

D. Gisselsson, M. Höglund, F. Mertens, P. Dal Cin, and N. Mandahl, “Hibernomas are characterized by homozygous deletions in the multiple endocrine neoplasia type region: metaphase fluorescence in situ hybridization reveals complex rearrangements not detected by conventional cytogenetics,” American Journal of Pathology, vol. 155, no. 1, pp. 61–66, 1999.

G. Maire, A. Forus, C. Foa, B. Bjerkehagen, C. Mainguené, S. H. Kresse, O. Myklebost, and F. Pedeutour, “11q13 alterations in two cases of hibernoma: large heterozygous deletions and rearrangement breakpoints near GARP in 11q13.5,” Genes Chromosomes and Cancer, vol. 37, no. 4, pp. 389–395, 2003.

D. Gisselsson, M. K. Hibbard, P. Dal Cin, R. Sciot, B. L. Hsi, H. P. Kozakewich, and J. A. Fletcher, “PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms,” American Journal of Pathology, vol. 159, no. 3, pp. 955–962, 2001.

P. Brandal, B. Bjerkehagen, and S. Heim, “Rearrangement of chromosomal region 8q11-13 in lipomatous tumours: correlation with lipoblastoma morphology,” Journal of Pathology, vol. 208, no. 3, pp. 388–394, 2006.

H. Bartuma, H. A. Domanski, F. V. Von Steyern, C. M. Kullendorff, N. Mandahl, and F. Mertens, “Cytogenetic and molecular cytogenetic findings in lipoblastoma,” Cancer Genetics and Cytogenetics, vol. 183, no. 1, pp. 60–63, 2008.

C. M. Coffin, A. Lowichik, and A. Putnam, “Lipoblastoma (LPB): a clinicopathologic and immunohistochemical analysis of 59 cases,” American Journal of Surgical Pathology, vol. 33, no. 11, pp. 1705–1712, 2009.

A. M. Meloni-Ehrig, L. Riggott, N. C. Christacos, P. N. Mowrey, and J. Johal, “A case of lipoblastoma with seven copies of chromosome 8,” Cancer Genetics and Cytogenetics, vol. 190, no. 1, pp. 49–51, 2009.

M. K. Hibbard, H. P. Kozakewich, P. Dal Cin, R. Sciot, X. Tan, S. Xiao, and J. A. Fletcher, “PLAG1 fusion oncogenes in lipoblastoma,” Cancer Research, vol. 60, no. 17, pp. 4869–4872, 2000.

R. Sciot, I. De Wever, and M. Debiec-Rychter, “Lipoblastoma in a 23-year-old male: distinction from atypical lipomatous tumor using cytogenetic and fluorescence in-situ hybridization analysis,” Virchows Archiv, vol. 442, no. 5, pp. 468–471, 2003.

A. Röpke, T. Kalinski, U. Kluba, U. Von Falkenhausen, P. F. Wieacker, and M. Röpke, “PLAG1 activation in lipoblastoma coinciding with low-level amplification of a derivative chromosome 8 with a deletion del(8)(q13q21.2),” Cytogenetic and Genome Research, vol. 119, no. 1-2, pp. 33–38, 2007.

N. De Saint Aubain Somerhausen, J. M. Coindre, M. Debiec-Rychter, J. Delplace, and R. Sciot, “Lipoblastoma in adolescents and young adults: report of six cases with FISH analysis,” Histopathology, vol. 52, no. 3, pp. 294–298, 2008.

R. Sciot, M. Akerman, P. Dal Cin, I. De Wever, C. D. M. Fletcher, N. Mandahl, F. Mertens, F. Mitelman, J. Rosai, A. Rydholm, G. Tallini, H. Van Den Berghe, R. Vanni, and H. Willen, “Cytogenetic analysis of subcutaneous angiolipoma: further evidence supporting its difference from ordinary pure lipomas: a report of the CHAMP study group,” American Journal of Surgical Pathology, vol. 21, no. 4, pp. 441–444, 1997.

B. De Jong, S. M. M. J. Castedo, J. W. Oosterhuis, and A. Dam, “Trisomy 7 in a case of angiomyolipoma,” Cancer Genetics and Cytogenetics, vol. 34, no. 2, pp. 219–222, 1988.

M. Debiec-Rychter, H. Saryusz-Wolska, and M. Salagierski, “Cytogenetic analysis of renal angiomyolipoma,” Genes Chromosomes and Cancer, vol. 4, no. 1, pp. 101–103, 1992.

B. Wullich, W. Henn, S. Siemer, G. Seitz, A. Freiler, and K. D. Zang, “Clonal chromosome aberrations in three of five sporadic angiomyolipomas of the kidney,” Cancer Genetics and Cytogenetics, vol. 96, no. 1, pp. 42–45, 1997.

P. Dal Cin, R. Sciot, H. Van Poppel, L. Baert, B. Van Damme, and H. Van Den Berghe, “Chromosome analysis in angiomyolipoma,” Cancer Genetics and Cytogenetics, vol. 99, no. 2, pp. 132–134, 1997.

P. Dal Cin, N. C. Gutierrez, J. M. Hernandez, and H. Van Den Berghe, “Molecular cytogenetics in angiomyolipomas,” Cancer Genetics and Cytogenetics, vol. 106, no. 2, p. 182, 1998.

M. M. Kattar, D. J. Grignon, J. N. Eble, P. M. Hurley, P. E. Lewis, W. E. Sakr, and M. L. Cher, “Chromosomal analysis of renal angiomyolipoma by comparative genomic hybridization: evidence for clonal origin,” Human Pathology, vol. 30, no. 3, pp. 295–299, 1999.

K. C. Chang, P. I. Chen, Z. H. Huang, Y. M. Lin, and P. L. Kuo, “Adrenal myelolipoma with translocation (3;21)(q25;p11),” Cancer Genetics and Cytogenetics, vol. 134, no. 1, pp. 77–80, 2002.

N. Mandahl, F. Mertens, H. Willén, A. Rydholm, A. Kreicbergs, and F. Mitelman, “Nonrandom pattern of telomeric associations in atypical lipomatous tumors with ring and giant marker chromosomes,” Cancer Genetics and Cytogenetics, vol. 103, no. 1, pp. 25–34, 1998.

P. D. Cin, P. Kools, R. Sciot, I. De Wever, B. Van Damme, W. Van de Ven, and H. Van den Berghe, “Cytogenetic and fluorescence in situ hybridization investigation of ring chromosomes characterizing a specific pathologic subgroup of adipose tissue tumors,” Cancer Genetics and Cytogenetics, vol. 68, no. 2, pp. 85–90, 1993.

F. Pedeutour, R. F. Suijkerbuijk, J. Van Gaal, W. Van de Klundert, J. M. Coindre -, A. Van Haelst, F. Collin, K. Huffermann, and C. Turc-Carel, “Chromosome 12 origin in rings and giant markers in well-differentiated liposarcoma,” Cancer Genetics and Cytogenetics, vol. 66, no. 2, pp. 133–134, 1993.

F. Pedeutour, R. F. Suijkerbuijk, A. Forus, J. Van Gaal, W. Van de Klundert, J. M. Coindre, G. Nicolo, F. Collin, U. Van Haelst, K. Huffermann, and C. Turc-Carel, “Complex composition and co-amplification of SAS and MDM2 in ring and giant rod marker chromosomes in well-differentiated liposarcoma,” Genes Chromosomes and Cancer, vol. 10, no. 2, pp. 85–94, 1994.

J. Szymanska, M. Tarkkanen, T. Wiklund, M. Virolainen, C. Blomqvist, S. Asko-Seljavaara, E. Tukiainen, I. Elomaa, and S. Knuutila, “Gains and losses of DNA sequences in liposarcomas evaluated by comparative genomic hybridization,” Genes Chromosomes and Cancer, vol. 15, no. 2, pp. 89–94, 1996.

F. Pedeutour, A. Forus, J. M. Coindre, J. M. Berner, G. Nicolo, J. F. Michiels, P. Terrier, D. Ranchere-Vince, F. Collin, O. Myklebost, and C. Turc-Carel, “Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors,” Genes Chromosomes and Cancer, vol. 24, no. 1, pp. 30–41, 1999.

A. P. Dei Tos, C. Doglioni, S. Piccinin, R. Sciot, A. Furlanetto, M. Boiocchi, P. Dal Cin, R. Maestro, C. D. M. Fletcher, and G. Tallini, “Coordinated expression and amplification of the MDM2, CDK4, and HMGI-C genes in atypical lipomatous tumours,” Journal of Pathology, vol. 190, no. 5, pp. 531–536, 2000.

F. Micci, M. R. Teixeira, B. Bjerkehagen, and S. Heim, “Characterization of supernumerary rings and giant marker chromosomes in well-differentiated lipomatous tumors by a combination of G-banding, CGH, M-FISH, and chromosome- and locus-specific FISH,” Cytogenetic and Genome Research, vol. 97, no. 1-2, pp. 13–19, 2002.

A. Italiano, L. Bianchini, F. Keslair, S. Bonnafous, N. Cardot-Leccia, J. M. Coindre, J. M. Dumollard, P. Hofman, A. Leroux, C. Mainguené, I. Peyrottes, D. Ranchere-Vince, P. Terrier, A. Tran, P. Gual, and F. Pedeutour, “HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon,” International Journal of Cancer, vol. 122, no. 10, pp. 2233–2241, 2008.

D. Trombetta, F. Mertens, A. Lonoce, P. D'Addabbo, K. Rennstam, N. Mandahl, and C. T. Storlazzi, “Characterization of a hotspot region on chromosome 12 for amplification in ring chromosomes in atypical lipomatous tumors,” Genes Chromosomes and Cancer, vol. 48, no. 11, pp. 993–1001, 2009.

M. R. Erickson-Johnson, A. R. Seys, C. W. Roth, A. A. King, R. L. Hulshizer, X. Wang, Y. W. Asmann, R. V. Lloyd, E. K. Jacob, and A. M. Oliveira, “Carboxypeptidase M: a biomarker for the discrimination of well-differentiated liposarcoma from lipoma,” Modern Pathology, vol. 22, no. 12, pp. 1541–1547, 2009.

M. Nilsson, L. A. Meza-Zepeda, F. Mertens, A. Forus, O. Myklebost, and N. Mandahl, “Amplification of chromosome 1 sequences in lipomatous tumors and other sarcomas,” International Journal of Cancer, vol. 109, no. 3, pp. 363–369, 2004.

N. Sirvent, J. M. Coindre, G. Maire, I. Hostein, F. Keslair, L. Guillou, D. Ranchere-Vince, P. Terrier, and F. Pedeutour, “Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR,” American Journal of Surgical Pathology, vol. 31, no. 10, pp. 1476–1489, 2007.

J. Weaver, E. Downs-Kelly, J. R. Goldblum, S. Turner, S. Kulkarni, R. R. Tubbs, B. P. Rubin, and M. Skacel, “Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms,” Modern Pathology, vol. 21, no. 8, pp. 943–949, 2008.

J. Weaver, P. Rao, J. R. Goldblum, M. J. Joyce, S. L. Turner, A. J. Lazar, D. López-Terada, R. R. Tubbs, and B. P. Rubin, “Can MDM2 analytical tests performed on core needle biopsy be relied upon to diagnose well-differentiated liposarcoma?” Modern Pathology, vol. 23, no. 10, pp. 1301–1306, 2010.

W. H. Henricks, Y. C. Chu, J. R. Goldblum, and S. W. Weiss, “Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation,” American Journal of Surgical Pathology, vol. 21, no. 3, pp. 271–281, 1997.

F. Elgar and J. R. Goldblum, “Well-differentiated liposarcoma of the retroperitoneum: a clinicopathologic analysis of 20 cases, with particular attention to the extent of low-grade dedifferentiation,” Modern Pathology, vol. 10, no. 2, pp. 113–120, 1997.

D. Gisselsson, M. Höglund, F. Mertens, B. Johansson, P. Dal Cin, H. Van Den Berghe, W. C. Earnshaw, F. Mitelman, and N. Mandahl, “The structure and dynamics of ring chromosomes in human neoplastic and non-neoplastic cells,” Human Genetics, vol. 104, no. 4, pp. 315–325, 1999.

J. Nishio, H. Iwasaki, M. Ishiguro, Y. Ohjimi, C. Fujita, H. Ikegami, A. Ariyoshi, M. Naito, Y. Kaneko, and M. Kikuchi, “Establishment of a novel human dedifferentiated liposarcoma cell line, FU-DDLS-1: conventional and molecular cytogenetic characterization,” International Journal of Oncology, vol. 22, no. 3, pp. 535–542, 2003.

F. Chibon, O. Mariani, J. Derré, S. Malinge, J. M. Coindre, L. Guillou, R. Lagacé, and A. Aurias, “A subgroup of malignant fibrous histiocytomas is associated with genetic changes similar to those of well-differentiated liposarcomas,” Cancer Genetics and Cytogenetics, vol. 139, no. 1, pp. 24–29, 2002.

R. J. Rieker, S. Joos, C. Bartsch, F. Willeke, M. Schwarzbach, M. Otaño-Joos, S. Ohl, J. Högel, T. Lehnert, P. Lichter, H. F. Otto, and G. Mechtersheimer, “Distinct chromosomal imbalances in pleomorphic and in high-grade dedifferentiated liposarcomas,” International Journal of Cancer, vol. 99, no. 1, pp. 68–73, 2002.

I. Hostein, J. M. Coindre, J. Derré, O. Mariani, F. Chibon, and A. Aurias, “Comparative genomic hybridization study of paraffin-embedded dedifferentiated liposarcoma fixed with Holland Bouin's fluid,” Diagnostic Molecular Pathology, vol. 12, no. 3, pp. 166–173, 2003.

O. Mariani, C. Brennetot, J. M. Coindre, N. Gruel, C. Ganem, O. Delattre, M. H. Stern, and A. Aurias, “JUN oncogene amplification and overexpression block adipocytic differentiation in highly aggressive sarcomas,” Cancer Cell, vol. 11, no. 4, pp. 361–374, 2007.

F. Chibon, O. Mariani, J. Derré, A. Mairal, J. M. Coindre, L. Guillou, X. Sastre, F. Pédeutour, and A. Aurias, “ASK1 (MAP3K5) as a potential therapeutic target in malignant fibrous histiocytomas with 12q14q-q15 and 6q23 amplifications,” Genes Chromosomes and Cancer, vol. 40, no. 1, pp. 32–37, 2004.

A. A. Sandberg, “Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma,” Cancer Genetics and Cytogenetics, vol. 155, no. 1, pp. 1–24, 2004.

C. Turc-Carel, J. Limon, and P. Dal Cin, “Cytogenetic studies of adipose tissue tumors. II. Recurrent reciprocal translocation t(12;16) (q13;p11) in myxoid liposarcomas,” Cancer Genetics and Cytogenetics, vol. 23, no. 4, pp. 291–299, 1986.

C. Sreekantaiah, C. P. Karakousis, S. P. L. Leong, and A. A. Sandberg, “Cytogenetic findings in liposarcoma correlate with histopathologic subtypes,” Cancer, vol. 69, no. 10, pp. 2484–2495, 1992.

B. P. Rubin and P. Dal Cin, “The genetics of lipomatous tumors,” Seminars in Diagnostic Pathology, vol. 18, no. 4, pp. 286–293, 2001.

H. Iwasaki, K. Nabeshima, J. Nishio, S. Jimi, M. Aoki, K. Koga, M. Hamasaki, H. Hayashi, and AI. Mogi, “Pathology of soft-tissue tumors: daily diagnosis, molecular cytogenetics and experimental approach,” Pathology International, vol. 59, no. 8, pp. 501–521, 2009.

I. Panagopoulos, M. Höglund, F. Mertens, N. Mandahl, F. Mitelman, and P. Åman, “Fusion of the EWS and CHOP genes in myxoid liposarcoma,” Oncogene, vol. 12, no. 3, pp. 489–494, 1996.

I. Panagopoulos, C. Lassen, M. Isaksson, F. Mitelman, N. Mandahl, and P. Åman, “Characteristics sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia,” Oncogene, vol. 15, no. 11, pp. 1357–1362, 1997.

P. Dal Cin, R. Sciot, I. Panagopoulos, P. Åman, I. Samson, N. Mandahl, F. Mitelman, H. Van Den Berghe, and C. D. M. Fletcher, “Additional evidence of a variant translocation t(12;22) with EWS/CHOP fusion in myxoid liposarcoma: clinicopathological features,” Journal of Pathology, vol. 182, no. 4, pp. 437–441, 1997.

K. Mrozek and C. D. Bloomfield, “Der(16)t(1;16) is a secondary chromosome aberration in at least eighteen different types of human cancer,” Genes Chromosomes and Cancer, vol. 23, no. 1, pp. 78–80, 1998.

Z. Gibas, M. Miettinen, J. Limon, B. Nedoszytko, K. Mrozek, A. Roszkiewicz, J. Rys, A. Niezabitowski, and M. Debiec-Rychter, “Cytogenetic and immunohistochemical profile of myxoid liposarcoma,” American Journal of Clinical Pathology, vol. 103, no. 1, pp. 20–26, 1995.

N. C. Birch, C. R. Antonescu, M. Nelson, L. Sarran, J. R. Neff, T. Seemayer, and J. A. Bridge, “Inconspicuous insertion 22;12 in myxoid/round cell liposarcoma accompanied by the secondary structural abnormality der(16)t(1;16),” Journal of Molecular Diagnostics, vol. 5, no. 3, pp. 191–194, 2003.

E. Downs-Kelly, J. R. Goldblum, R. M. Patel, S. W. Weiss, A. L. Folpe, F. Mertens, M. Hartke, R. R. Tubbs, and M. Skacel, “The utility of fluorescence in situ hybridization (FISH) in the diagnosis of myxoid soft tissue neoplasms,” American Journal of Surgical Pathology, vol. 32, no. 1, pp. 8–13, 2008.

F. Parente, J. Grosgeorge, J. M. Coindre, P. Terrier, O. Vilain, and C. Turc-Carel, “Comparative genomic hybridization reveals novel chromosome deletions in 90 primary soft tissue tumors,” Cancer Genetics and Cytogenetics, vol. 115, no. 2, pp. 89–95, 1999.

H. Schmidt, F. Bartel, M. Kappler, P. Würl, H. Lange, M. Bache, H. J. Holzhausen, and H. Taubert, “Gains of 13q are correlated with a poor prognosis in liposarcoma,” Modern Pathology, vol. 18, no. 5, pp. 638–644, 2005.

T. Ohguri, M. Hisaoka, S. Kawauchi, K. Sasaki, T. Aoki, S. Kanemitsu, A. Matsuyama, Y. Korogi, and H. Hashimoto, “Cytogenetic analysis of myxoid liposarcoma and myxofibrosarcoma by array-based comparative genomic hybridisation,” Journal of Clinical Pathology, vol. 59, no. 9, pp. 978–983, 2006.

F. Mertens, C. D. M. Fletcher, P. Dal Cin, I. De Wever, N. Mandahl, F. Mitelman, J. Rosai, A. Rydholm, R. Sciot, G. Tallini, H. Van Den Berghe, R. Vanni, and H. Willén, “Cytogenetic analysis of 46 pleomorphic soft tissue sarcomas and correlation with morphologic and clinical features: a report of the champ study group,” Genes Chromosomes and Cancer, vol. 22, no. 1, pp. 16–25, 1998.

S. Sugita, K. Seki, K. Yokozawa, N. Tochigi, K. Furuta, M. Hisaoka, H. Hashimoto, T. Shimoda, and T. Hasegawa, “Analysis of CHOP rearrangement in pleomorphic liposarcomas using fluorescence in situ hybridization,” Cancer Science, vol. 100, no. 1, pp. 82–87, 2009.

A. Forus, D. O. Weghuis, D. Smeets, O. Fodstad, O. Myklebost, and A. G. Van Kessel, “Comparative genomic hybridization analysis of human sarcomas: I. Occurrence of genomic imbalances and identification of a novel major amplicon at 1q21-q22 in soft tissue sarcomas,” Genes Chromosomes and Cancer, vol. 14, no. 1, pp. 8–14, 1995.

P. Popov, M. Virolainen, E. Tukiainen, S. Asko-Scljavaara, R. Huuhtanen, S. Knuutila, and M. Tarkkanen, “Primary soft tissue sarcoma and its local recurrence: genetic changes studied by comparative genomic hybridization,” Modern Pathology, vol. 14, no. 10, pp. 978–984, 2001.

R. S. de Vreeze, D. de Jong, W. Koops, et al., “Oncogenesis and classification of mixed-type liposarcoma: a radiological, histopathological and molecular biological analysis,” International Journal of Cancer, vol. 128, no. 4, pp. 778–786, 2011.

R. Schneider-Stock, H. Walter, K. Radig, J. Rys, A. Bosse, C. Kuhnen, C. Hoang-Vu, and A. Roessner, “MDM2 amplification and loss of heterozygosity at Rb and p53 genes: no simultaneous alterations in the oncogenesis of liposarcomas,” Journal of Cancer Research and Clinical Oncology, vol. 124, no. 10, pp. 532–540, 1998.

T. Mentzel, G. Palmedo, M. Hantschke, J. Woziwodzki, and C. Beck, “Mixed-type liposarcoma: clinicopathological, immunohistochemical, and molecular analysis of a case arising in deep soft tissues of the lower extremity,” Virchows Archiv, vol. 453, no. 2, pp. 197–201, 2008.

H. Zhang, M. Erickson-Johnson, X. Wang, J. L. Oliveira, A. G. Nascimento, F. H. Sim, D. E. Wenger, R. Q. Zamolyi, V. L. Pannain, and A. M. Oliveira, “Molecular testing for lipomatous tumors: critical analysis and test recommendations based on the analysis of 405 extremity-based tumors,” American Journal of Surgical Pathology, vol. 34, no. 9, pp. 1304–1311, 2010.