Genomic profiling reveals subsets of dedifferentiated liposarcoma to follow separate molecular pathways

With the aim to provide more insight into their biology, a series of 79 liposarcomas (LS) representative of all main subtypes was analysed for chromosomal imbalances using comparative genomic hybridization. Based on the genetic data, unsupervised hierarchical clustering unveiled two main LS clusters, each with two subclusters, one comprising three subsets. The first main cluster consisted of one larger subcluster, being characterised by gains/high-level amplifications of chromosomal subregions 12q13–q15, and exclusively included well-differentiated and dedifferentiated LS. A smaller subcluster was set apart on the basis of recurrent gains of 20q13 and 8q24, and mainly comprised pleomorphic and myxoid/round cell LS. The larger subcluster was subdivided into three subsets, one with nearly exclusive overrepresentations of 12q13–q15, the second with additional frequent gains of 1q21–q24, and the third with further recurrent overrepresentations of 6q22–q24, 20q13, and 12q24 and frequent losses of 13q14–q21 and 11q22–q23. While the first subset comprised both well-differentiated and dedifferentiated LS, the second and third subsets entirely included dedifferentiated LS. The second main cluster was characterised by recurrent overrepresentations of 5p13–p15, 1q21–q24, 1p12–p21, and 17p11.2–p12 and essentially comprised pleomorphic and myxoid/round cell LS. A separation of this second main cluster into two subclusters was based on additional gains on 22q13 and losses on 1q42–q43. Genomic profiling reveals genetically distinct subsets of dedifferentiated LS, which are clearly different from pleomorphic, myxoid/round cell, and, for some subsets, from well-differentiated LS. These data indicate that dedifferentiated LS follow separate tumourigenic pathways and that genetic analysis is important to unravel these differences.     

Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis

Almost all primary retroperitoneal liposarcomas can be classified as well-/dedifferentiated liposarcoma. Rarely, however, primary retroperitoneal liposarcoma is classified as myxoid/round cell liposarcoma, based on the presence of myxoid areas and vascular crow's feet pattern, which has resulted in a debate on the classification of liposarcoma in the retroperitoneum. Genetically, myxoid/round cell liposarcoma and well-/dedifferentiated liposarcoma are different diseases. Myxoid/round cell liposarcoma is characterized by a translocation causing FUS-CHOP or EWSR1-CHOP fusion, whereas well-/dedifferentiated liposarcoma is characterized by an amplification of the 12q13-15 region, including MDM2 and CDK4 genes. As myxoid/round cell liposarcoma is highly radio- and chemosensitive, differentiation between subtypes is important to optimize treatment. We studied whether primary retroperitoneal liposarcomas diagnosed as myxoid/round cell liposarcoma represent molecularly true myxoid/round cell liposarcoma or are histopathological mimics and represent well-/dedifferentiated liposarcoma. Primary retroperitoneal myxoid/round cell liposarcoma (n=16) were compared to primary extremity myxoid/round cell liposarcoma (n=20). Histopathological and immunohistochemical features were studied. Amplification status of the 12q13-15 region was studied using a multiplex ligation-dependent probe amplification analysis, and FUS-CHOP or EWS-CHOP translocations were studied using RT-PCR. In primary retroperitoneal myxoid/round cell liposarcoma, MDM2 and CDK4 staining was both positive in 12 of 15 cases. In primary extremity myxoid/round cell liposarcoma, MDM2 was negative in 18/20 and CDK4 was negative in all cases. Multiplex ligation-dependent probe amplification showed the amplification of 12q13-15 region in 16/16 primary retroperitoneal myxoid/round cell liposarcomas and in 1/20 primary extremity myxoid/round cell liposarcomas. Translocation was present in all (18/18) primary extremity myxoid/round cell liposarcomas, but absent in all primary retroperitoneal myxoid/round cell liposarcomas. On the basis of immunohistochemical and molecular characteristics, apparent primary retroperitoneal myxoid/round cell liposarcoma can be recognized as well-/dedifferentiated liposarcoma with morphological features mimicking myxoid/round cell liposarcoma. In these cases, treatment should probably be specifically designed as for well-/dedifferentiated liposarcoma. Moreover, finding of myxoid/round cell liposarcoma translocations in a retroperitoneal localization is highly suggestive of metastasis and should prompt search for a primary localization outside the retroperitoneum.     

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.     

Gains of 12q are the most frequent genomic imbalances in adult fibrosarcoma and are correlated with a poor outcome

Comparative genomic hybridization was used to analyze 41 adult fibrosarcomas from 34 patients. Thirty-one patients showed in their tumors DNA sequence copy number changes (mean 11, range 3-25). The minimal common regions for the most frequent gains were narrowed down to 12q21 (18 cases); 12q14-q15 and 14q22 (16 cases each); 4q22, 7q31, and 14q23-q24 (15 cases each); and 4q21, 4q23-q24, 8q22, and 12q22 (14 cases each). Twenty-five high-level amplifications were observed in 12 samples. 12q21 and 18p were affected three times each; and 1p21, 4q31.3, 7p21, 12q14-q15, Xp22.1-p22.2, and Xq22-q23 two times each. Losses were less frequent than gains. Early stages of adult fibrosarcomas were characterized by frequent gains of chromosomes 2, 4q, and 14q, whereas gains of chromosomes 7 and 8q were associated with progression. Gains of 12q were frequent in all of the developmental steps of this soft-tissue sarcoma. By investigation of several tumors of the same patient, a number of corresponding changes were always detected. Adult fibrosarcomas from patients who died during the observation time showed statistically significant more frequent gains of 8q, 12q, 13q, and 15q compared to the fibrosarcomas of patients who are alive. Gains and high-level amplifications of 12q14-q22, which were the most frequent genomic imbalances, partly reflected an MDM2 amplification, indicating the importance of this region in the tumorigenesis of sarcomas. In adult fibrosarcomas, a gain of 12q22 correlated significantly (P = 0.028) with a poor overall survival rate.     

LIPOSARCOMA

Fifty-two cases of liposarcoma were analyzed clinicopathologically, and were grouped into the following five types: myxoid (28 cases), well-differentiated (14 cases), pleomorphic (4 cases), round-cell (3 cases), and mixed (3 cases). Three of the 28 myxoid tumors showed a pleomorphic pattern resembling that of the myxoid variant of malignant fibrous histiocytoma, and one of the 3 round-cell tumors was considered to be a malignant counterpart of hibernoma. Ages ranged from 22 to 86 years with the average age of 49 years, the average patients with myxoid or round-cell liposarcoma being over 10 years younger than those with well-differentiated or pleomorphic liposarcoma. There was also a variation in the site of predilection of the cases: the great majority of myxoid type tumors occurred in the thigh, popliteal fossa and buttock (23 cases), while the majority of well-differentiated type tumors were seen in the retroperitoneum (10 cases). The rate of local recurrence of the tumor was 46%. Four of the 5 well-differentiated liposarcomas which recurred exhibited dedifferentiated pleomorphic components resembling those in malignant fibrous histiocytoma. The prognosis was more favorable in patients with ordinary myxoid tumors than in those with well-differentiated tumors. The overall relative five-year survival rate was 63%.     

Liposarcoma. A clinicopathologic subtyping of 52 cases

Fifty-two cases of liposarcoma were analyzed clinicopathologically, and were grouped into the following five types: myxoid (28 cases), well-differentiated (14 cases), pleomorphic (4 cases), round-cell (3 cases), and mixed (3 cases). Three of the 28 myxoid tumors showed a pleomorphic pattern resembling that of the myxoid variant of malignant fibrous histiocytoma, and one of the 3 round-cell tumors was considered to be a malignant counterpart of hibernoma. Ages ranged from 22 to 86 years with the average age of 49 years, the average patients with myxoid or round-cell liposarcoma being over 10 years younger than those with well-differentiated or pleomorphic liposarcoma. There was also a variation in the site of predilection of the cases: the great majority of myxoid type tumors occurred in the thigh, popliteal fossa and buttock (23 cases), while the majority of well-differentiated type tumors were seen in the retroperitoneum (10 cases). The rate of local recurrence of the tumor was 46%. Four of the 5 well-differentiated liposarcomas which recurred exhibited dedifferentiated pleomorphic components resembling those in malignant fibrous histiocytoma. The prognosis was more favorable in patients with ordinary myxoid tumors than in those with well-differentiated tumors. The overall relative five-year survival rate was 63%.     

The Ultrastructure of Liposarcomas with Attention to “Dedifferentiation”

Liposarcomas are among the most common soft tissue sarcomas. It is recognized that dedifferentiation can occur within a well-differentiated liposarcoma, but there is limited information concerning the ultrastructure of the dedifferentiated cells. A series of 8 cases has been studied by light and electron microscopy and compared with well-differentiated, myxoid, and pleomorphic liposarcomas. No definite evidence of lipoblastic differentiation could be found in the dedifferentiated cases. The tumor cells resembled atypical cells in the well-differentiated liposarcomas, supporting the close relationship between these two types of tumors. However, since no conclusive line of differentiation could be found in the dedifferentiated cases, this study supports the contention that these neoplasms are undifferentiated counterparts of well-differentiated liposarcomas.     

Crystalline inclusions in oligodendroglial cells

Liposarcomas are among the most common soft tissue sarcomas. It is recognized that dedifferentiation can occur within a well-differentiated liposarcoma, but there is limited information concerning the ultrastructure of the dedifferentiated cells. A series of 8 cases has been studied by light and electron microscopy and compared with well-differentiated, myxoid, and pleomorphic liposarcomas. No definite evidence of lipoblastic differentiation could be found in the dedifferentiated cases. The tumor cells resembled atypical cells in the well-differentiated liposarcomas, supporting the close relationship between these two types of tumors. However, since no conclusive line of differentiation could be found in the dedifferentiated cases, this study supports the contention that these neoplasms are undifferentiated counterparts of well-differentiated liposarcomas.     

Loss of chromosome 13 is the most frequent genomic imbalance in malignant fibrous histiocytomas. A comparative genomic hybridization analysis of a series of 30 cases.

Regional chromosome localizations of DNA copy number imbalances were studied by comparative genomic hybridization in 30 malignant fibrous histiocytomas: 13 primary tumors (2 myxoid, 9 storiform pleomorphic, and 2 with more undifferentiated phenotype) and 17 local recurrences (2 myxoid, 11 storiform pleomorphic, and 4 with more undifferentiated phenotype). Abnormal comparative genomic hybridization (CGH) profiles were observed in 25 tumors (83%). The most frequent gains (ratio > 1.2) corresponded, by order of frequency, to entire Xp, and bands 1q21, 19q13.1, 19p13, 5p13-p14, 1p31, 17p, 18p, 20q, 1p35, 17q23, and 22q12. High levels of gains (ratio > 1.5) were recurrently detected for Xp (10 cases), and in bands 1q21-q22 (8 cases), 3q27 (4 cases), 5p13-p14 (3 cases), 13q32-q34 (3 cases), 15q22-q26 (3 cases), and 17p11-p12 (3 cases). Losses of 13q12-q14 or 13q21 were observed in a large proportion of tumors (17 cases), suggesting that a gene localized in this region could act as a tumor suppressor gene. Losses of 11q23, 2q32, 11p13, 10p, 1q4, 9p2, 16q12, 4q3, 10q25, 3p23, 2p24, and 12p were also recurrently observed. Taken together, these results provide an overview of chromosome imbalances present in MFH, which could be of use for diagnostic purposes. They point to various chromosome regions which may harbor genes important for malignant fibrous histiocytomas (MFH) oncogenesis and progression.     

Focal divergent chondrosarcomatous differentiation in a primary pleomorphic liposarcoma and expression of transforming growth factor beta

A rare case of primary pleomorphic liposarcoma of the thigh with a myxoid component, in which divergent differentiation to a well-differentiated chondrosarcoma was focally present, is described. Presence of heterologous elements has mainly been recognized in the context of dedifferentiated liposarcomas. Few cases of benign mesenchymal tissue have also been reported in well-differentiated and myxoid liposarcomas, while divergent sarcomatous differentiation in liposarcomas appears to be also rare in the absence of dedifferentiation. Positive immunostaining of transforming growth factor-beta, which seems to play a role in the formation of bone and cartilage, was demonstrated in our case. Review of the existing literature on the subject has been carried out.     

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.     

Myxoid malignant fibrous histiocytoma and pleomorphic liposarcoma share very similar genomic imbalances

Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma. Nevertheless, the validity of this heterogeneous pathological entity has been recurrently questioned by pathologists. Recently, analyses by comparative genomic hybridization (CGH) of a large series of MFHs suggested that MFHs consist of morphologic modulation of other poorly differentiated sarcomas like leiomyosarcomas (LMS) or dedifferentiated liposarcomas (DLPS). We report here an analysis by CGH of 22 myxoid MFHs (mMFH), one of the five histological subtypes of MFH, and of nine pleomorphic liposarcomas (pLPS), a rare poorly differentiated LPS. The chromosome imbalances encountered in the series of mMFH were very similar to those observed in the series of pLPS studied in the laboratory and in the series of 14 pLPS published in the literature. The most frequent gains involved chromosome subregions: pericentromeric regions of 1, 5p, 19p, 19q and 20q. Losses found in the chromosomal arms 1q, 2q, 3p, 4q, 10q, 11q and 13q were also recurrent. The use of a clustering software did not separate the two pathological groups (mMFH and pLPS) on the basis of genomic data. Moreover, pLPS-mMFH represented, according to the clustering software results, an entity clearly distinguished from other soft tissue sarcomas, LMS in particular, with which they share common genetic aberrations. Additional studies are needed to identify genes targeted by these genomic aberrations, and implicated in the oncogenesis of these tumor subtypes. The characterization of common gene alterations in both tumor groups would suggest a closer relationship between these two types of soft tissue sarcomas.     

Genomic imbalances of 7p and 17q in malignant peripheral nerve sheath tumors are clinically relevant.

We investigated 31 malignant peripheral nerve sheath tumors (MPNSTs) from 23 patients by means of comparative genomic hybridization (CGH) in order to study quantitative genomic aberrations of these tumors. Twenty-one of the 23 patients revealed changes, with a mean value of 11 aberrations per sample (range 2-29). The minimal common regions of the most frequent gains were 8q23-q24.1 (12 cases), 5p14 (11 cases), and 6p22-pter, 7p15-p21, 7q32-q35, 8q21.1-q22, 8q24.2-qter, and 17q22-qter (10 cases each). Seventeen high-level amplifications were detected in eight of the 21 samples. In three cases, the high-level amplifications involved 8q24.1-qter, and in two cases each the high-level amplifications involved regions 5p14, 7p14-pter, 8q21.1-q23, and 13q32-q33. The minimal common region of frequent losses was 14q24.3-qter (five cases). The gain of 8q as a single common change in the primary tumor, the recurrence, and the metastasis from the same patient suggests that this aberration is an early change in the tumorigenesis of MPNSTs. Comparable aberrations were observed in separate tumors of the same patients affected by Recklinghausen's disease, indicating a limited number of accidental secondary changes. In sporadic MPNSTs, the most frequent gains were narrowed down predominantly to 5p, 6, 8q, and 20q, whereas in MPNSTs from patients with Recklinghausen's disease, there was most often a gain in 7q, 8q, 15q, and 17q. The occurrence of gain of both 7p15-p21 and 17q22-qter was associated with a statistically significant poor overall survival rate (P = 0.0096).     

Liposarcoma of the oral and salivary gland region: a clinicopathologic study of 18 cases with emphasis on specific sites, morphologic subtypes, and clinical outcome.

Liposarcoma is rare in the oral and salivary gland region (OSG), previously described in only case reports and two small series. Clinicopathologic features of a large series of these tumors were studied. Cases coded as "liposarcoma or lipoma" from 1970 to 2000 were searched for in our files. Inclusion required an OSG location and diagnosis by established soft tissue criteria. Dermal, other soft tissue, and intraosseous liposarcomas were excluded. Clinical and pathologic material was reviewed and follow-up obtained. Eighteen liposarcomas were included: 10 from males and 8 from females. The median patient age was 51 years (range, 30-70 years). Specific anatomic locations included buccal mucosa (n = 7), tongue (n = 4), parotid gland (n = 3), soft tissue overlying the mandible (n = 2), and one each of palate and submandibular gland. The average tumor size was 4.2 cm (range, 1.5 to 6.0 cm). Histologically, most tumors were well differentiated, including one atypical lipoma (n = 10), followed by myxoid (n = 5) and dedifferentiated (n = 3). OSG liposarcomas of all subtypes had increased numbers of lipoblasts. All patients were treated with surgical excision alone. Follow-up on 15 patients (83%) over a mean of 16.5 years (range, 2 to 53 years) revealed that three patients had between one and six local recurrences over periods of 18 months to 6 years. Twelve patients were without recurrence, with a mean follow-up of 12.8 years (range, 2-23 years). No patients, including those with dedifferentiated liposarcoma, had metastases or died of disease. OSG liposarcomas are rare tumors of adults, occurring most commonly in the buccal mucosa, tongue, and then parotid gland. There were no pleomorphic liposarcomas in this series; well-differentiated liposarcoma was the most common subtype, which can locally recur but, even with high-grade dedifferentiation, does not necessarily predict poor outcome. Therefore, OSG liposarcomas have better prognosis than liposarcoma in other soft-tissue locations, perhaps based on smaller size at presentation. Complete local excision and careful patient follow-up, without adjuvant therapy, appears to be the best treatment for OSG liposarcoma.     

Liposarcoma: new entities and evolving concepts

Liposarcoma is the most common soft tissue sarcoma and accounts for approximately 20% of all mesenchymal malignancies. In the last decade, the results of several studies have led to the delineation of new variants as well as to the introduction of new concepts, mainly as a result of the fruitful interactions between genetics and pathology. Spindle cell liposarcoma represents an uncommon variant of well-differentiated liposarcoma. It tends to occur in adults and often involves the subcutaneous soft tissue. However, from the observation of a larger number of cases, the anatomic distribution of spindle cell liposarcoma seems to be comparable to that of the other well-differentiated liposarcoma subtypes. Spindle cell liposarcoma tends to recur locally and may dedifferentiate. Morphologically it is composed of a fairly bland neural-like spindle cell proliferation set in a fibrous and/or myxoid background and is associated with an atypical lipomatous component. Great debate has been generated by the introduction of the term atypical lipoma to emphasize the fact that well-differentiated liposarcoma shows risk of local recurrence but no potential for metastasis. In our opinion well-differentiated liposarcoma and atypical lipoma should be considered synonyms that describe lesions identical both morphologically and kayotypically. Dedifferentiated liposarcoma is a distinct type of liposarcoma in which transition from low-grade to high-grade nonlipogenic morphology within a well-differentiated liposarcoma is observed. The transition usually occurs in an abrupt fashion; however, in rare cases it can be more gradual. Recently, it also has been proposed that dedifferentiated liposarcoma should be further classified into low and high grade. Dedifferentiated liposarcoma rarely exhibits heterologous (most often myoid) differentiation. A peculiar "neural-like whorling pattern" of dedifferentiation also has been described recently. Surprisingly, the clinical outcome of dedifferentiated liposarcoma is less aggressive that in other high-grade pleomorphic sarcomas but genetic as well as molecular data exist that may partiallyjustify such a discrepancy. Myxoid and round cell liposarcoma, even if still classified by the World Health Organization as two distinct subtypes, share both clinical and morphologic features. Lesions combining both patterns are very frequent and wide agreement exists in considering round cell liposarcoma as the high-grade counterpart of myxoid liposarcoma. Furthermore, myxoid and round cell liposarcoma share the same characteristic chromosome change. Albeit rare, it has been recently shown that liposarcoma indeed can occur as a primary skin lesion. It often presents clinically as a dome-shaped or polypoid lesion that, histologically, most frequently shows high-grade morphologic features but carries a comparatively good prognosis. Considering currently available data, the most logical classification of liposarcoma is into three main groups: (1) well-differentiated liposarcoma (including adipocytic, sclerosing, inflammatory, spindle-cell, and dedifferentiated variants), characterized by ring or long markers chromosomes derived from the long arm of chromosome 12; (2) myxoid and round cell (poorly differentiated myxoid) liposarcoma, characterized in most cases by a reciprocal translocation t(12;16)(q13;p11); and (3) pleomorphic liposarcoma, characterized by complex karyotypes.     

The ultrastructure of liposarcoma. A study of 10 cases.

An ultrastructural study of 10 liposarcomas is reported. Four of the liposarcomas were wholly or predominantly of well-differentiated, lipoma-like or fibrosing type, 3 of myxoid type, 2 of round cell type and 1 pleomorphic type. The well-differentiated, lipoma-like liposarcomas showed cells with a few, large lipid droplets, few organelles and a peripherally located, fairly large nucleus, The well-differentiated liposarcomas of fibrosing type revealed mostly spindle-shaped, fibroblast-like cells, with abundant rough endoplasmic reticulum and inconspicuous lipid inclusions, surrounded by collagen. One well-differentiated liposarcoma contained an area which was similar to brown adipose tissue and hibernoma. The spindle and stellate shaped cells of the myxoid liposarcomas showed abundant rough endoplasmic reticulum and large smooth-membraned vacuoles filled with moderately dense amorphous material, which appeared to be extruded extracellularly by rupture of the vacuoles. Cytoplasmic lipid droplets were seen in most cells but were much less prominent than in the well-differentiated lipoma-like liposarcomas. Ultrastructurally there were many similarities between the myxoid and round cell liposarcoma, indicating a close relationship between the two types. The pleomorphic liposarcoma revealed cells with one or more large, irregular nuclei, numerous large vacuoles after dissolved lipids, abundant dilated cisternae of rough endoplasmic reticulum and rounded, electron-dense bodies corresponding to PAS-positive hyalin globules seen in the light microscope. The ultrastructural study suggests that the variegated cellular appearance of the different subtypes of liposarcoma reflects the wide cellular spectrum seen during the differentiation of adipose tissue and supports the view that all liposarcomas histogenetically represent a single entity.     

Novel genomic imbalances in B-cell splenic marginal zone lymphomas revealed by comparative genomic hybridization and cytogenetics

Splenic marginal zone lymphoma (SMZL) has recently been recognized in the World Health Organization classification of hematological diseases as distinct type of non-Hodgkin's lymphoma. In contrast to the well-established chromosomal changes associated with other B-cell non-Hodgkin's lymphoma, few genetic alterations have been found associated with SMZL. The aim of our study was to analyze by comparative genomic hybridization (CGH) the chromosomal imbalances in 29 patients with SMZL and to correlate these findings with clinical and biological characteristics and patient outcome. In 21 cases, cytogenetic studies were simultaneously performed. Most of the patients (83%) displayed genomic imbalances. A total of 111 DNA copy number changes were detected with a median of four abnormalities per case (range, 1 to 12). Gains (n = 92) were more frequent than losses (n = 16), while three high-level amplifications (3q26-q29, 5p11-p15, and 17q22-q25) were observed. The most frequent gains involved 3q (31%), 5q (28%), 12q and 20q (24% each), 9q (21%), and 4q (17%). Losses were observed in 7q (14%) and 17p (10%). SMZL patients with genetic losses had a shorter survival than the remaining SMZL patients (P < 0.05). In summary, chromosomal imbalances in regions 3q, 4q, 5q, 7q, 9q, 12q, and 20q have been detected by CGH in SMZL. Patients with SMZL displaying genetic losses by CGH had a short survival.     

Do DNA copy number changes differentiate uterine from non-uterine leiomyosarcomas and predict metastasis?

DNA copy number changes were investigated in 51 (19 uterine and 32 nonuterine) primary leiomyosarcomas by comparative genomic hybridization. The aim was to evaluate whether true biological differences exist between uterine and nonuterine leiomyosarcoma and whether changes revealed by comparative genomic hybridization have prognostic value. Genomic imbalances were found in 48 (94%) cases. The most frequent DNA copy number changes were losses in 10q (35%), 13q (57%), and 16q (41%), gains in 1q (41%), and gains and high-level amplifications in 17p (39%). Gains were nearly as frequent as losses in both uterine and nonuterine leiomyosarcoma. Correlation-based tree modeling revealed two clusters that segregated significantly a group of uterine (gains at 1q11-q24) and a group of nonuterine (losses at 13q14-q34, 16q11.1-q24, and 10q21-q26) cases. The nonuterine cluster was associated with subcutaneous origin and a trend toward increased metastasis-free survival. Further explorative analyses identified aberrations associated with shorter metastasis-free survival time, including losses at 2q32.1-q37 and gains at 8q24.1-q24.3, whereas the cases with losses at 6cen-p25 showed longer metastasis-free survival time.     

Dedifferentiated myxoid liposarcoma: a clinicopathological study suggesting a closer relationship between myxoid and well-differentiated liposarcoma

Myxoid/round cell liposarcoma is arguably the commonest type of liposarcoma occurring in the extremities and may show gradual progression from low-grade, pure myxoid liposarcoma to high-grade round cell liposarcoma. Rarely myxoid/round cell liposarcoma is associated with areas of well-differentiated or pleomorphic liposarcoma (mixed liposarcoma). We describe the clinicopathological features of three unusual myxoid/round cell liposarcomas which showed morphological features of de novo dedifferentiation. All patients were male and were aged 66, 70 and 76 years, respectively. One lesion each arose in the retroperitoneum, inguinal region and peritoneal cavity. Histologically, in one case the myxoid/round cell component was juxtaposed to a high-grade non-lipogenic component resembling non-pleomorphic storiform 'malignant fibrous histiocytoma' ('MFH'), one case showed a combination of myxoid liposarcoma and a high-grade myxofibrosarcoma-like component (so-called myxoid 'MFH'), and in the third case, a well-differentiated myxoid liposarcoma with a discontinuous micronodular pattern of dedifferentiation was seen. Follow-up information of 30, 28 and 26 months revealed two recurrences each in two patients. These patients died of postoperative pulmonary embolism and abdominal haemorrhage, respectively; systemic metastases were not noted. These cases demonstrate that myxoid/round cell liposarcoma can show, albeit very rarely, histological features of dedifferentiation. Cases like these, combined with the occurrence of mixed-type liposarcoma (well-differentiated/myxoid liposarcoma) and the vicinity of chromosomal regions involved by specific karyotypic aberrations in these tumours, suggest that myxoid/round cell liposarcoma and well-differentiated liposarcoma (including its dedifferentiated variant) are more closely related in biological terms than is generally believed.     

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.