Liposarcoma - WikiHQ

Liposarcomas are the most common subtype of soft tissue sarcomas, accounting for at least 20% of all sarcomas in adults. Soft tissue sarcomas are rare neoplasms with over 150 different histological subtypes or forms. Liposarcomas arise from the precursor lipoblasts of the adipocytes (i.e. fat cells) in adipose (i.e. fat) tissues. Adipose tissues are distributed throughout the body, including such sites as the deep and more superficial layers of subcutaneous tissues as well as in less surgically accessible sites like the retroperitoneum (i.e. space behind the abdominal cavity) and visceral fat inside the abdominal cavity.

All liposarcomas consist of at least some cells that bear a resemblance to fat cells when examined for their histopathologic appearances under a microscope. However, the liposarcomas do have several forms based on differences in their clinical presentations (e.g. ages, gender preferences, sites of tumors, signs, and symptoms), severities (i.e. potential to invade local tissues, recur after surgical removal, and metastasize to distal tissues), genetic abnormalities, prognoses, and preferred treatment regimens. The World Health Organization in 2020 reclassified liposarcomas into five more or less distinct forms: 1) atypical lipomatous tumor/well-differentiated liposarcoma (WD-LPS); 2) dedifferentiated liposarcoma (DD-LPS); 3) myxoid liposarcoma; 4) pleomorphic liposarcoma; and 5) myxoid pleomorphic liposarcoma. (Pleomorphic indicates the presence of cells that have abnormal and often large variations in their size and shape and/or the size and shape of their nuclei.)

While liposarcoma forms are classified as being aggressive and malignant or, in the case of the atypical lipomatous tumor/well-differentiated liposarcoma, as relatively non-aggressive and benign, all five liposarcoma forms can infiltrate locally to injure nearby tissues and organs, occur in surgically inaccessible sites adjacent to vital organs (e.g. the retroperitoneum), recur after surgical removal, and progress to life-threatening diseases. Studies to date find that all five liposarcoma forms, while usually treatable at least initially by surgical resection, are often only marginally responsive to currently used chemotherapy and radiotherapy regimens. The liposarcomas require a wide range of further studies to determine their responsiveness to various radiotherapy, chemotherapy, and more novel treatment regimens as used individually and in various combinations that would include, where possible, surgical removal. The very rare cases occurring in children and adolescents are diagnosed predominantly as being the myxoid liposarcoma form. 2) atypical spindle cell lipomas (i.e. benign tumors with mildly atypical spindle-shaped cells in a fibrous-to-myxoid stroma intermixed with vacuolated lipoblasts and variable-sized adipocytes with atypical nuclei; 3) pleomorphic lipomas (i.e. benign tumors characterized by giant cells with overlapping nuclei);). They rarely if ever metastasize and therefore are regarded as benign or premalignant tumors. However, they are locally invasive and may transform to a more aggressive and potentially metastasizing liposarcoma, i.e. a dedifferentiated liposarcoma. Furthermore, a surgically removed atypical lipomatous tumor/well-differentiated liposarcoma may recur as a dedifferentiated liposarcoma. This terminology has prognostic implications: less than 7% of ALT tumors convert to dedifferentiated liposarcomas within a median time of 7 years while 17% of WDL tumors convert to this more malignant liposarcoma within a median time of 8 years. and CDK4 (a gene that when overexpressed promotes the development of various tumors) located at band 14.1. The amplification (i.e. increased copies of a gene without a proportional increase in other genes) of these two genes is a highly sensitive and specific indicator that a liposarcoma is either an ALT/WDL or a dedifferentiated liposarcoma rather than any other liposarcoma or lipoma form. and/or highly specialized cytogenetic G banding analyses) strongly supports the diagnosis of ALT/WDL or dedifferentiated liposarcoma. The clinical presentation and histopathology differences between the latter two liposarcoma forms usually help distinguish between them.

Novel therapies

The novel therapies of ALT/WDL are the same as those listed in the Novel therapies section of Dedifferentiated liposarcoma.

Dedifferentiated liposarcoma

Dedifferentiated liposarcomas are malignant tumors which in ~10% of cases develop in an existing atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) tumor or at the site were an ALT/WPL tumor was surgically removed. Individuals with a de novo diagnosis of this tumor may have had an ALT/WDL that progressed to a dedifferentiated liposarcoma but went undetected because it developed asymptomatically in a highly sequestered site such as the retroperitoneum or abdominal cavity. Many of the dedifferentiated liposarcoma tumors' clinical and genetic features are similar to those found in ALT/WDL tumors. At presentation, DDL tumors typically are painless, large, may have been slowly and progressively enlarging for years, Less commonly, affected individuals have signs and/or symptoms due to their tumor's impingement on an organ (e.g. abdominal pain caused by blockage of the intestines or urinary tract obstruction caused by blockage of the urethra). Very rarely, individuals with DDL present with one or more signs or symptoms of chronic inflammation (see B symptoms) and/or one of the endrocrine, neurological, mucocutaneous, hematological, or other tissue-related paraneoplastic syndromes. The signs and symptoms of chronic inflammation and the various paraneoplastic syndromes are caused by the tumors' secretion of cytokines, hormones, prostaglandins, and/or other systemically acting agents; they completely disappear after the DDL is successfully treated.

Genetics

The neoplastic cells in both DDL and ALT/WDL carry similar small supernumerary marker chromosomes (sSMCs) and/or giant marker chromosomes that contain extra parts of chromosome 12's q arm at bands 13 through 15. This chromosomal area includes two genes associated with tumor development, the MDM2 and CDK4 genes. Other genes in the sMMC and giant marker chromosome that are also overexpressed in ALT/WDL and DDL neoplastic cells include HMGA2, CPM, YEATS4, and DDIT3. Compared to ALT/WDL neoplastic cells, however, DDL neoplastic cells: 1) express higher levels of the genes in the two abnormal chromosomes; this may contribute to the progression of ALT/WDL to DDL; and 2) higher levels of gene products on the long arm of chromosome 1 at band 32, the long arm of chromosome 6 at band 33, and, in ~25% of cases, the short arm of chromosome 1 at band 32.2 which contains the JUN gene (this gene is overexpressed in DDL but not ALT/WDL). Since the JUN gene's product, c-jun, inhibits cell death and promotes cell proliferation, its overproduction may contribute to the progression of ALT/WDL to DDL and/or the malignancy of DDL neoplastic cells. For these localized forms of DDL, perioperative radiotherapy following National Comprehensive Cancer Network guidelines may also be considered. The primary treatment option for retroperitoneal DDL is surgical resection. A phase III clinical trial found little difference in the results of radiation therapy followed by surgical resection compared to surgical resection alone in the treatment of retroperitoneal DDL. Further studies are needed to provide evidence on the efficacies of radiotherapy, chemotherapy, and novel therapies in all the varieties of DDL.

Novel therapies

Several novel therapy regimens for DDL and the more aggressive or otherwise problematic cases of ALT/WDL are currently undergoing clinical trials. A phase II clinical study investigating abemaciclib is underway in patients with pretreated or untreated DDL. Preliminary analysis showed that this inhibitor of the CDK4 and CDK6 genes' product Serine/threonine-specific protein kinase enzymes produced a prolonged median progression-free survival time of 30.4 weeks. in collaboration with Eli Lilly and Company. Ribociclib, also a CDK4 and CDK6 gene inhibitor, in combination with a mTOR inhibitor, everolimus is in a phase II clinical trial in individuals with advanced DDL or leiomyosarcoma. Another phase III clinical trial is investigating the MDM2 inhibitor milademetan versus trabectedin, a blocker of the oncogenic transcription factor FUS-CHOP, in MDM2-overexpressing ALT/WDL and DDL. Milademetan has shown manageable toxicity and some activity resulting in stable disease and/or a few partial responses in DDL. represents ~30% of all liposarcomas. It has a peak incidence in individuals' fourth and fifth decades with a male predominance in most studies. While uncommon in children and adolescents, MLS is the most common liposarcoma form diagnosed in these age groups. MLS typically presents as a large (1 to 39 cm; average 12 cm), mobile, well-circumscribed, painless mass that developed from 1 week to 15 years prior to diagnosis. MLS tumors are located in deep-seated soft tissues of the thighs (65–80% of cases), lower legs (10–15% of cases), retroperitoneum (8% of cases), and arms (5% of cases). In about one-third of cases, these tumors metastasize to other soft tissue sites (e.g. retroperitoneum, thorax, or other extremity), skeletal bone, and/or lung. Individuals may present with these metastasis, particularly those in bone; it has been recommended that patients should be tested at presentation for bone metastasis by medical imaging, including X-rays, CT scans, and/or magnetic resonance imaging.

Pathology

Histopathologic analyses of MLS (see Figs. 3 and 4 in the below Histopathology of liposarcomas section) reveals cells scattered throughout a myxoid matrix (i.e. a connective tissue background that appears more blue or purple than the red color of normal connective tissue when these tissues are properly prepared, H&E stained, and viewed microscopically). These cells are lipoblasts, some of which are signet ring-shaped (a shape suggesting that the cell may be neoplastic), oval-shaped, or round-shaped. at band 12 of chromosome 12's q arm and the site of the FUS gene at band 11 on chromosome 16's short arm (also termed the p arm). The fusion protein (also termed chimeric protein) product of this chimeric oncogene gene, FUS-DDIT3, is known to arrest fat cell maturation and promote neoplasia. The EWSR1-DDIT3 fusion gene (termed t(12;22)(q13;q12)) results from a translocation of the EWSR1 gene located at band 12.2 on chromosome 22's q arm with the DDIT2 gene. The fusion protein product of the EWSR1-DDIT3 gene, like the FUS-DDIT3 fusion protein, promotes neoplasia. In spite of these fusion gene relations, further studies are required to define their contribution to the development and/or maintenance of MLS tumors. However, further studies are needed to determine the value of radiotherapy in treating the various varieties of MLS. The round cell form of myxoid liposarcomas also appears to have a relatively poor prognosis: in various retrospective reviews, myxoid liposarcoma was usually found to be low-grade and therefore relatively responsive to chemotherapy whereas high grade (i.e. round cell) myxoid lipsarcoma had higher rates of metastasis, behaved more aggressively, and did not respond well to chemotherapy. was studied in a small phase I trial on individuals with various advanced-stage malignancies. The drug produced a markedly durable response in a person with MLS suggesting that PPAR-γ agonists would be useful for treating this disease. A stage II clinical trial conducted in Italy is examining the effects of a trabectedin plus pioglitazone (another PPAR-γ agonist) in individuals with stable MLS tumors. The study involves two sequential steps. The first step examines the response of patients treated for a minimum of 4 cycles with trabectedin alone. If stable disease is attained, the second step will examine the effects of further treating initially responding patients with a combination of trabectedin and pioglitazone. A stage II clinical trial is nearing completion to evaluate the efficacy of sirolimus (an inhibitor of MTOR; sirolimus is also known as rapamycin) plus cyclophosphamide (a chemotherapy drug) in metastatic or unresectable MLS. A phase II clinical trial is recruiting patients to evaluate sintilimab (a human IgG4 monoclonal antibody directed against the programmed cell death protein 1 located on the surface of cells) in combination with two chemotherapy drugs, doxorubicin and ifosfamide, as first-line treatment of soft tissue sarcomas including MLS.

T cells have been genetically engineered to target the MAGE-A4 antigen expressed on a HLA-A*02 MAGE-A4-containing peptide located on the surface of the neoplastic cells in certain types of tumors. These engineered cells (termed ADP-A2M4-T cells) attacked and killed various cultured human cancer cells bearing this antigen and, in a clinical stage 1 study, shrank various solid tumor types in patients whose tumors' contained neoplastic cells expressing this antigen. A phase II clinical study is has recruited individuals to investigate the efficacy and safety of ADP-A2M4 T cells (engineered from the recipient's own T cells) in HLA-A*02-positive patients with metastatic or inoperable, advanced-stage MSGE-4-positive MLS tumors.

Pleomorphic liposarcoma

Presentation

Pleomorphic liposarcomas (PLS), which account for 5% to 10% of all liposarcoma cases, are fast-growing, usually large (>5 cm), and painless but highly malignant adipocyte tumors. They occur primarily in individuals >50 years old chest wall, pelvic cavity, pulmonary pleurae, pericardium, and spine. mixed with areas containing undifferentiated cells. The undifferentiated component of these tumors most often consists of spindle-shaped cells, with 25% of cases showing cells with an epithelioid cell morphology. These tumors have at least some foci with a histopathology similar to high-grade myxofibrosarcoma type histiocytomas, a tumor formerly termed malignant myxoid fibrous histiocytoma.

Genetics

PLS neoplastic cells contain various gene and chromosome abnormalities: the TP53 gene is deleted or mutated in 17–60% of cases; the RB1 gene is deleted in 60% of cases; and the Neurofibromin 1 gene is lost by inactivating mutations in 8% of cases or in rarer cases by a deletion around its location in band 11.2 on the long arm of chromosome 12. These cells can also show gains in the genetic material around: bands 12–15 on the short arm of chromosome 5; band 21 on the short arm of chromosome 1; and band 22 on the long arm of chromosome 7. The alterations in gene copy numbers induced by these abnormalities are similar to those seen in the myxofibrosarcoma type of the histiocytomas. The role(s) of these changes in gene copy numbers in promoting PLS has not been defined. Thus, PLS is unlike other liposarcomas in that its neoplastic cells have a complex genome without characteristic genomic alterations or identifiable genes that drive the disease. Detection of alterations in the expression of the TP53, RB1, and neurofibromin 1 genes, as well as other, less commonly altered genes in PLS (e.g. PIK3CA, tyrosine-protein kinase SYK, PTK2B, EPHA5, and ERBB4), may help support but do not clearly define a tumor as being PLS.) was first described in a large 2009 study of the liposarcomas. While initially regarded as a possible variant of the myxoid liposarcomas with pleomorphic features, the World Health Organization (2020) classified it as a new and distinct form of the liposarcomas. This classification was based on findings that the myxoid pleomorphic liposarcomas, while having histopathological features that were similar to myxoid liposarcomas, had clinical and, most importantly, critical genetic and molecular features that differed from the myxoid as well as the other three liposarcoma forms.

Pathology

On histopathologic analyses, MPL tumors consist of areas resembling conventional myxoid liposarcoma; these areas, which represent 30–50% of the total tumor areas, have an abundant myxoid matrix, a well-developed capillary vasculature, bland cells that are round and/or slightly spindle-shaped, vacuolated lipoblasts, and multinucleated cells shaped like small flowers. However, these areas also contain a scattering of highly pleomorphic cells that show greater degrees of nuclear enlargement and irregularity than the cells seen myxoid liposarcoma tumors. Other areas of MPL tumors are more cellular and consist of rapidly growing and highly pleomorphic lipoblasts. a 2021 review found that there were no consensus recommendations for the standard of care for MPL with respect to radiation and chemotherapy regimens (when used either alone or combined with surgery) for treating these tumors.

In myxoid liposarcoma, it shows low signal intensity mass with high signal intensity foci on T1-weighted MRI images. The mass shows high signal intensity on T2-weighted images. This is because it contains predominantly mucoid substance (accounts for low signal intensity on T1) and small amount of mature fat (accounts for high signal intensity on T1). The mass is well-defined, lobulated, multiloculated, or oval in shape without any infiltration into surrounding structures.

Scrotal ultrasonography of liposarcoma mimicking a lipoma.jpg|Fig. 6 Ultrasonography of a liposarcoma mimicking a lipoma. This homogeneous high-echoic mass has the same appearance as a lipoma.