Whole exome sequencing of well-differentiated liposarcoma and dedifferentiated liposarcoma in older woman: a case report
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Background Common kinds of soft tissue sarcomas (STS) include well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). In this case, we present a comprehensive clinical profile of a patient who underwent multiple recurrences during the progression from WDLPS to DDLPS. Case presentation A 62-year-old Asian female underwent retroperitoneal resection of a large tumor 11 years ago, the initial pathology revealed a fibrolipoma-like lesion. Over the next six years, the patient underwent three resections for recurrence of abdominal tumors. Postoperative histology shows mature adipose tissue with scattered “adipoblast”-like cells with moderate-to-severe heterogeneous spindle cells, pleomorphic cells, or tumor giant cells. Immunohistochemistry (IHC) demonstrated positive staining for MDM2 and CDK4, confirming that the abdominal tumor was WDLPS and gradually progressing to DDLPS. Post-operative targeted sequencing and IHC confirmed the POC1B::ROS1 fusion gene in DDLPS. Whole-exome sequencing (WES) revealed that WDLPS and DDLPS shared similar somatic mutations and copy number variations (CNVs), whereas DDLPS had more mutated genes and a higher and more concentrated amplification of the chromosome 12q region. Furthermore, somatic mutations in DDLPS were significantly reduced after treatment with CDK4 inhibitors, while CNVs remained elevated. Conclusion Due to the high likelihood of recurrence of liposarcoma, various effective treatments should be taken into consideration even if surgery is the primary treatment for recurrent liposarcoma. To effectively control the course of the disease following surgery, combination targeted therapy may be a viable alternative to chemotherapy and radiotherapy in the treatment of liposarcoma.Keywords:
Myxoid liposarcoma
Myxoid pleomorphic liposarcoma is an exceptionally discerned, aggressive variant of liposarcoma predominantly incriminating young individuals. The preponderantly hybrid tumefaction demonstrates an amalgamation of morphological features of myxoid liposarcoma and pleomorphic liposarcoma. Additionally designated as pleomorphic myxoid liposarcoma, myxoid pleomorphic liposarcoma is a soft tissue tumour delineating an aggressive clinical course and inferior overall survival. Commonly, tumefaction is devoid of FUS/EWSR1-DDIT3 genetic fusions or MDM2 genomic amplification. Commonly, myxoid pleomorphic liposarcoma incriminates young subjects < 30 years. However, few lesions may occur within older adults. A specific gender predilection is absent. Nevertheless, a mild female preponderance or an equivalent gender predisposition may be encountered
Myxoid liposarcoma
Undifferentiated Pleomorphic Sarcoma
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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.
Myxoid liposarcoma
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Myxoid liposarcoma is a malignant soft tissue tumor with a relatively indolent natural history. It commonly occurs in the extremities with extrapulmonary metastatic potential. Round cell liposarcoma, recently, is widely agreed to be the aggressive counterpart of the myxoid liposarcoma, mostly arising in adverse, local recurrence, and metastatic lesions. Metastatic liposarcoma with pure myxoid element is unusual. The authors report an extremely rare case of a 47-year-old Thai male patient having a metastatic pure myxoid liposarcoma to the thoracic vertebrae, one year after primary tumor documented on the left thigh. Histology of the primary and metastatic sites shows only myxoid pattern. Round cell feature was not documented. To the best of the authors' knowledge, this is the second case report of metastatic myxoid liposarcoma without round cell morphology.
Myxoid liposarcoma
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Liposarcoma rarely occurs in the mediastinum, and most reports predate the current genetically based classification system. We report the clinicopathologic and molecular genetic features of a series of thoracic liposarcomas identified over a 60-year period. Twenty-four confirmed cases were reclassified using the most recent World Health Organization classification. Fluorescent in situ hybridization for CPM amplification and/or DDIT3 rearrangement was performed on selected cases. The 24 cases occurred in 13 men and 11 women (mean age, 53 y; range, 15 to 73 y) and arose in all mediastinal compartments. All subtypes were encountered with 8 well-differentiated liposarcomas, 6 dedifferentiated liposarcomas (3 of 6 confirmed CPM+), 7 pleomorphic liposarcomas (2 of 7 confirmed CPM-, 1 of 7 confirmed DDIT3-), 2 myxoid liposarcomas, and 1 unclassifiable liposarcoma (CPM- and DDIT3-). Unusual histologic features included myxoid well-differentiated liposarcoma mimicking myxoid liposarcoma (2 cases), lipoleiomyosarcoma (1 case), dedifferentiated liposarcoma with "meningothelial"-like dedifferentiation, differentiated myxoid liposarcoma mimicking well-differentiated liposarcoma (CPM-), and pleomorphic liposarcoma with epithelioid and myxoid change. Follow-up information was available for 19 patients (mean, 55 mo; range, 8 to 252 mo). Outcome was strongly associated with histologic subtype, with death from disease occurring in 1 of 6 well-differentiated, 1 of 4 dedifferentiated, 5 of 7 pleomorphic, and 2 of 2 myxoid liposarcomas. The mediastinum shows a preponderance of uncommon subtypes and unusual morphologic variants. Correct classification has important implications, with most patients with well-differentiated/dedifferentiated liposarcoma having a protracted clinical course, in contrast to the more rapid disease progression seen in patients with myxoid and pleomorphic liposarcoma.
Myxoid liposarcoma
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Myxoid liposarcoma is a malignant adipogenic neoplasm characterized by prominent arborizing capillaries, occasional lipoblasts, and primitive-appearing spindle cells in a myxoid background. A recurrent translocation in myxoid liposarcoma results in an oncoprotein consisting of full-length DDIT3 (CHOP) fused to an N-terminal segment of either FUS (TLS) or, less often, EWSR1. Here, we explore the diagnostic significance of DDIT3 expression in myxoid liposarcoma using a mouse monoclonal antibody recognizing an epitope in the N-terminal region. Studying a total of 300 tumors, we find diffuse, moderate-to-strong nuclear-localized anti-DDIT3 immunoreactivity in all 46 cases of myxoid liposarcoma representing 36 unique tumors, including 6 cases with high-grade (round cell) morphology. DDIT3 immunohistochemistry also highlighted a distinctive vasculocentric growth pattern in 7 myxoid liposarcomas treated with neoadjuvant radiation. In contrast, the vast majority of other examined lipomatous and myxoid neoplasms exhibited no DDIT3 expression; limited, weak immunoreactivity in <10% of cells was infrequently observed in dedifferentiated liposarcoma (6/39, 15%), solitary fibrous tumor (3/12, 25%), pleomorphic liposarcoma (1/15, 7%), and high-grade myxofibrosarcoma (2/17, 12%). Although this minimal DDIT3 expression did not correlate with DDIT3 amplification or myxoid liposarcoma-like morphology in dedifferentiated liposarcoma, there was evidence among sarcomas (excluding myxoid liposarcoma) of a relationship between expression and exposure to neoadjuvant radiation or cytotoxic chemotherapy. The constellation of findings indicates that DDIT3 immunohistochemistry may have utility in the evaluation of myxoid and lipomatous neoplasms to support the diagnosis of myxoid liposarcoma.
Myxoid liposarcoma
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Liposarcoma is a common malignant soft tissue tumor, accounting for 10% to 16% of all sarcomas. Multicentric myxoid liposarcoma is an uncommon condition. Differentiation between several primary tumors and metastasis of a single liposarcoma represents the main difficulty in diagnosis. A 47-years old woman presented with right thigh myxoid liposarcoma and underwent wide margin tumor resection. Other investigations like CXR, abdominal and pelvic CT-scans were negative. After 18 months another myxoid liposarma was found in her ipsi-lateral breast without any evidence of other organs metastasis. Second lesion location, time between two presentation and cytogenetic differences are accepted criteria to site a sarcoma in multicentric category, but in myxoid liposarcoma these can be explained by the special features inherent to this tumor.
Myxoid liposarcoma
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Round cell liposarcoma, a high-grade sarcoma, is a poorly differentiated form of myxoid liposarcoma, which is low grade. It is not known, however, how much of a round cell component within an otherwise typical myxoid liposarcoma results in a neoplasm that behaves as a high-grade sarcoma. Twenty-nine cases of myxoid liposarcoma of the extremities with or without a component of round cell liposarcoma were studied to semiquantitate the amount of round cell component needed to adversely affect prognosis. An estimate of the percent of necrosis, round cell liposarcoma, myxoid liposarcoma, and transitional areas was obtained for each slide on all cases. Transitional areas were defined as those that displayed an increased cellularity compared with typical myxoid liposarcoma, but in which the cells remained spindled, did not have overlapping nuclear borders, and retained an easily discernible plexiform vascular pattern. The amount of necrosis was subtracted from the total material available for evaluation, and a composite estimate of the percent of round cell, myxoid and transitional areas was obtained. Two tumors were located on the upper extremity, 27 on the lower extremity; tumor size ranged from 3 to 30 cm (median, 14 cm). All 29 tumors had a myxoid component, with a range from 12 to 100% (median, 73%). The range of transitional component for all 29 tumors was 0 to 88% (median, 11%). Twenty-one tumors had transitional areas (range, 4-88%). The range of round cell component for all 29 tumors was 0 to 58% (median, 0%). Twelve tumors had round cell areas (range, 1-58%). Seventeen patients are either alive without disease, or died from unrelated causes at 24-202 months (median, 96 months). Twelve patients are either alive with metastases or died of disease at 10 to 180 months (median, 53 months). Patients with >5% round cell component in their initial tumor had a statistically significant higher rate of metastasis or death due to disease than those with ≤5% round cell liposarcoma (p = 0.05). In addition, patients with myxoid liposarcoma with transitional areas did not fare worse than those with myxoid liposarcoma alone. In conclusion, we found that a round cell component of >5% portends a higher risk of metastasis or death from disease. Furthermore, transitional areas alone do not appear to alter the prognosis of myxoid liposarcoma. Thus, only those areas that are unequivocally round cell liposarcoma should be designated as high grade.
Myxoid liposarcoma
Clear-cell sarcoma
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Myxoid pleomorphic liposarcoma is characterized by pathological features of both pleomorphic liposarcoma and myxoid liposarcoma, as the name suggests. In this case, a myxoid pleomorphic liposarcoma was observed in a 5-year-old male African pygmy hedgehog. It consisted of ~60% of the myxoid substance area with proliferating round cells and ~30% of pleomorphic neoplastic cells. The subject presented with extrapulmonary metastasis, but a good prognosis during 6 months of follow-up, which is similar to the characteristics of myxoid liposarcoma. The histopathological features of myxoid pleomorphic liposarcoma may reflect the features of either myxoid liposarcoma or pleomorphic liposarcoma depending on the proportion of each histopathological feature. The proportion of the pleomorphic area and the myxoid area may offer information on the prognosis and metastasis of myxoid pleomorphic liposarcoma, which will be helpful for setting up a treatment plan. Thus, analyzing the proportion of pleomorphic area and myxoid area could be suggested as one of the ways to predict clinical outcomes. In addition to the fact that this is the first case of a myxoid pleomorphic liposarcoma in hedgehogs, this case is meaningful, considering the unique histopathological characteristics and rare incidence of myxoid pleomorphic liposarcoma that could be important in humans as well.
Myxoid liposarcoma
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Fifty-five cases of liposarcoma were reviewed. The cases were classified on the basis of histopathologic findings as follows: myxoid, 29 cases; well-differentiated, 11 cases; dedifferentiated, eight cases; pleomorphic, four cases; combined well-differentiated and pleomorphic, two cases; and unclassified, one case. The term “dedifferentiated liposarcoma” is proposed for tumors containing distinct areas of well-differentiated liposarcoma and cellular nonlipogenic spindle-cell or plemorphic sarcoma. All patients except one were adults. Myxoid and plemorphic liposarcoma predominantly involved the thigh, while well-differentiated, dedifferentiated, and combined well-differentiated-plemorphic liposarcoma showed a marked preference for the retroperitoneum. The survival of patients with pleomorphic and dedifferentiated liposarcoma was significantly poorer than that of those with the myxoid and well-differentiated varieties. There was a marked tendency toward local recurrence in all types. Recurrent myxoid and pleomorphic liposarcomas were often controlled by additional therapy, whereas recurrences of other types usually were not; this difference was considered largely a result of locational factors. Metastasis was observed in 10 cases of myxoid liposarcoma, three of plemorphic liposarcoma, and two of dedifferentiated liposarcoma. In myxoid liposarcoma, initial treatment consisting of excision followed by radiation resulted in a significantly reduced rate of local recurrence as compared with excision alone, and more extensive as compared with excision alone, and more extensive hypercellular zones were associated with increased metastatic potential. “Round cell” liposarcoma was not found to be an independent type; all cases for which this designation might have been considered could be better classified as myxoid liposarcoma with cellular areas (usually) or plemorphic liposarcoma with rounded cells (rarely). The resemblance of portions of some dedifferentiated and plemorphi liposarcomas to “malignat fibrous histocytoma” was sufficient to deny the specificity of the histologic pattern of the latter.
Myxoid liposarcoma
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Myxoid liposarcoma
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