Liposarcoma

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Background

Liposarcoma is a malignancy of fat cells (see Pediatric Liposarcoma and Liposarcoma Imaging). In adults, it is the most common soft tissue sarcoma. Liposarcoma normally appears as a slowly enlarging, painless, nonulcerated submucosal mass in a middle-aged person, but some lesions grow rapidly and become ulcerated early. Virchow first described liposarcoma in the 1860s.

The development of a liposarcoma from a preexisting benign lipoma is rare. Most cases arise de novo. Liposarcomas most frequently arise from the deep-seated stroma rather than the submucosal or subcutaneous fat. Dermal lesions are rare and may resemble pleomorphic fibroma.[1]

The most recent World Health Organization classification of soft tissue tumors recognizes 5 categories of liposarcomas: (1) well differentiated, which includes the adipocytic, sclerosing, and inflammatory subtypes; (2) dedifferentiated; (3) myxoid; (4) round cell; and (5) pleomorphic.

A spindle-cell variant of well-differentiated liposarcoma is also described. The concept that round-cell liposarcoma represents the high-grade counterpart of myxoid liposarcoma is generally accepted. Spindle-cell liposarcoma is a rare variant of an atypical lipomatous tumor (ie, well-differentiated liposarcoma), and it must be distinguished from a dedifferentiated liposarcoma with metastatic potential and a benign spindle-cell lipoma. The advent of cytogenetic and molecular investigations has contributed to better categorization of this subset of mesenchymal neoplasms. Not only have they provided new insights into the biology of these tumors, but they have also validated the current classification schemes based on conventional morphologic observations.[2, 3, 4, 5]

Liposarcoma occurs in three main biologic forms: (1) well-differentiated liposarcoma; (2) myxoid and/or round cell; and (3) pleomorphic. The latter is a rare high-grade type with a high recurrence rate and poor prognosis.[6] Exceptionally, there may be a combination of morphologic types; these are classified as combined or mixed-type liposarcomas.

The anatomical distribution of liposarcoma appears to be partly related to the histologic type. Well-differentiated liposarcoma tends to occur in deep soft tissues of both the limbs and the retroperitoneum. Myxoid and/or round-cell liposarcomas and pleomorphic liposarcomas have a striking predilection for the limbs, and dedifferentiated liposarcoma occurs predominantly in the retroperitoneum. Although any liposarcoma subtype occasionally arises in the subcutis, involvement of the dermis appears to be exceedingly rare.

Pathophysiology

Liposarcoma is a lipogenic tumor of large deep-seated connective tissue spaces. Fusion proteins created by chromosomal abnormalities are key components of mesenchymal cancer development. An abnormality of band 12q13 has been associated with the development of liposarcomas. The most common chromosomal translocation is the FUS-CHOP fusion gene, which encodes a transcription factor necessary for adipocyte differentiation. These and other distinct genetic aberrations may aid in the diagnosis of particular liposarcoma subtypes, and they can potentially be targets that can be exploited therapeutically.[7]

Etiology

No well-established causative factor has been identified, although trauma has been implicated.

Epidemiology

Frequency

United States

Soft tissue sarcomas occur in approximately 5000 patients in the United States per year. Overall, liposarcomas account for less than 20% of all soft tissue sarcomas, and the average patient age at presentation is 50 years. However, in children, liposarcomas account for less than 5% of all soft tissue sarcomas; fewer than 60 cases in children have been reported.

International

With an annual incidence of 2.5 cases per million population, liposarcoma is the most common soft tissue sarcoma, accounting for approximately 17% of all soft tissue sarcomas and 3% of all liposarcomas in the head and neck region (usually the neck and the cheek). Oral involvement is rare; as of the year 2000, fewer than 50 oral cases had been reported. The trunk and the lower extremities are the most likely sites of tumor development.

Race

No association with race or geography is known.

Sex

Liposarcomas are slightly more common in males than in females.

Age

The mean patient age at onset is 50 years. Although liposarcomas account for about 17% of all soft tissue sarcomas, they are involved in only 4% of childhood soft tissue sarcomas. Cases of liposarcoma are reported in young adults and teenagers, but cases in children are rare.[8]

Prognosis

The prognosis is affected by the type of liposarcoma present. In general, survival for extremity tumors is favorable.[9] The histologic grade of localized liposarcomas of the extremities may be the most important prognostic factor.[10]

The well-differentiated type and most myxoid types have favorable prognoses, with 100% and 88% 5-year survival rates, respectively.[11] However, these tumors are poorly circumscribed and locally recur after incomplete excision. Although they rarely metastasize, repeated local recurrences may cause the tumor to evolve into a higher grade of sarcoma or to dedifferentiate, in which case metastasis is possible. Between 1973 and 2015, 1756 patients with extremity myxoid liposarcomas were evaluated. The 5- and 10-year overall survival rates of the entire cohort were 86.4% and 75.9%, respectively.[12]

The form that a dermatologist is most likely to examine at biopsy is 1 of the 3 subtypes of a well-differentiated liposarcoma, that is, the lipomalike liposarcoma or atypical lipoma; the other 2, inflammatory and sclerosing, are less likely. The clinical outcome of this subtype is best predicted by the anatomical location. In the subcutis, lipomalike liposarcomas are often cured with local excision. Lipomalike liposarcomas rarely recur, and they do not metastasize. Use of the term atypical lipomatous tumor, a less serious designation for atypical lipoma, has been suggested.

Round-cell and poorly differentiated types have a poor prognosis. Each has a 5-year survival rate of about 50% because they recur locally and tend to metastasize quickly and widely, especially in poorly differentiated liposarcomas. The lungs and the liver are the most common sites of metastasis. .

Despite high-grade morphology, cutaneous liposarcomas have a favorable clinical prognosis.

For soft tissue sarcoma involving the popliteal fossa, despite a high rate of microscopically positive margins, the local recurrence rate reported is only 7%.[13]

Cutaneous and subcutaneous pleomorphic liposarcomas have a more favorable outcome compared with their deep-seated counterparts, a fact attributable to their small size and superficial location.[14]

History

Liposarcomas are most commonly found in the extremities; in the retroperitoneum; and, less often, in the head and neck area. These tumors are most likely to arise from deep-seated, well-vascularized structures than from submucosal or subcutaneous fat. Myxoid liposarcoma is usually evident as a deep-seated mass in the lower extremity of adults, but it may be less commonly be first evident as a primary subcutaneous mass.[15]

Liposarcomas of all subtypes can occur in the cutis and the subcutis; however, their primary occurrence in the skin is rare. Clinically, all cases of liposarcomas in the skin tend to grow in an exophytic manner, presenting as either dome-shaped or polypoid lesions. In all patients, the neoplasm is centered in the dermis, and it has a minimal tendency to grow downward into the underlying subcutaneous adipose tissue.

Most patients with liposarcoma have no symptoms until the tumor is large and impinges on neighboring structures, causing tenderness, pain, or functional disturbances. In the retroperitoneal area, where liposarcoma is detected at a late stage, the tumor may grow to a substantial size, weighing several pounds at the time of diagnosis. In general, liposarcoma grows silently, and the patient's estimation of the clinical duration is often unreliable. The patient eventually becomes aware of a swelling or a mass and reports this finding to the physician.

Patients may report the following:

Physical Examination

The three most common locations of involvement are the thighs, the retroperitoneum, and the inguinal region.

Liposarcoma usually appears as a well-circumscribed palpable mass as large as 10 cm in diameter. The mass tends to grow slowly over time. The lesion is commonly not tender on palpation. Diffuse abdominal enlargement may be observed in patients with retroperitoneal disease. Liposarcoma that resembles a skin tag has been reported but is an exceptionally rare event.[16]

Fascial compartmentalization may cause liposarcomas to have awkward discoid and fusiform shapes rather than smooth, round forms. Thus, liposarcoma can appear with an array of clinical morphologies and manifestations. Other aspects to note on physical examination are neurologic involvement and lymphadenopathy.

Pleomorphic liposarcoma is both uncommon and rarely occurs in the skin and subcutis.[14] They are most often located on an extremity, trunk, and head and neck and more often involve the subcutaneous, less so the subcutis or dermis. It may be evident as a painless pedunculated pink papulonodule.[17]

Complications

A case report describes liposarcoma complicating pregnancy.[18] A myxoid liposarcoma was described in a psoriatic patient on adalimumab.[19] A tumor-to-tumor metastasis of a prostatic adenocarcinoma metastasizing to a myxoid liposarcoma has been described, a most unusual coincidence.[20]

Laboratory Studies

Cytogenetics may be of value when diagnosing lipomatous tumors because different tumor types have different more or less specific chromosomal abnormalities.[28] The lipoblastoma, for example, often exhibits rearrangements of bands 8q11-13, and the gene PLAG1 has been implicated as the target of these chromosomal changes.

Imaging Studies

CT scanning (see image below) is superior to MRI in detailing cortical bone erosion and tumor mineralization, whereas MRI is useful in providing views of the long axis of the limb and in depicting the fatty nature of the tumor.



View Image

Computed tomography (CT) scan of a left thigh shows a huge mass (arrows) with predominant fat attenuation. The central soft-tissue component (asterisk....

Most liposarcomas have well-defined and mostly lobulated margins. The well-differentiated liposarcomas are composed of mainly fat with septa or nodules. These tumors are hyperintense on T2-weighted images, and they demonstrate faint enhancement or no enhancement after the intravenous administration of contrast material.

Myxoid liposarcomas are homogeneous or mildly heterogeneous, and a pseudocapsule can be present. Pleomorphic types have a markedly heterogeneous internal structure. Both myxoid and pleomorphic lesions have moderate or marked heterogeneous enhancement after the administration of contrast material. Well-differentiated liposarcomas may be distinguished from the other types by their largely lipomatous appearance. The malignancy grade increases with the degree of tumor heterogeneity and contrast enhancement.

Angiography may demonstrate tumor malignancy on the basis of prominent vascularity; thus, angiography may be of value in planning surgical resection.

Chest radiography may be used as an initial screening for pulmonary metastases; however, the definitive test for detection of pulmonary metastases is chest CT scanning.

An early-phase bone scan may show a marked increase of radioisotopic uptake.

Risk assessment in liposarcoma patients can be based on [(18)F]fluorodeoxyglucose (FDG) PET imaging.[29] Although tumor grade and subtype are considered standard parameters for risk assessment in patients with liposarcoma, pretherapy tumor standardized uptake values obtained by FDG PET imaging was found to be a more useful parameter for risk assessment in liposarcoma compared with tumor grade or subtype. A maximum standardized uptake value of more than 3.6 was associated with significantly reduced disease-free survival and identified patients at high risk for developing early local recurrences or metastatic disease.

Also see Liposarcoma Imaging.

Procedures

Preoperative biopsy is important in planning therapy.[30] The diagnostic procedure of choice for liposarcoma is open biopsy. With superficial, small, fatty tumors, excisional biopsy is recommended for diagnosis. In large (>3 cm) and deep tumors, diagnosis and treatment may involve open incisional biopsy followed by definitive resection.

Fine-needle aspiration or biopsy should be followed by histologic and immunohistochemical examination. Adjunctive tests for MDM2 (murine double minute 2) may be helpful to distinguish liposarcoma from benign fatty neoplasms, but cutaneous and subcutaneous pleomorphic liposarcoma is less likely to demonstrate amplification.[31, 32] Immunohistochemical examination aids in excluding other sarcomas. Lipid staining may be helpful, although Sudan black or oil red O stains are generally insufficient for diagnosis. Helpful stains include the following:

Histologic Findings

The recognition of lipoblasts is the key finding in the diagnosis of liposarcoma. A lipoblast has the ability to produce and accumulate non–membrane-bound lipid within its cytoplasm. The key morphologic features are well-demarcated cytoplasmic lipid that shifts, causes indentations in an irregular hyperchromatic nucleus, and creates a characteristic scalloping of the nuclear membrane.

The stage and further differentiation into 1 of the 4 major types affect the prognosis.

Well-differentiated liposarcomas usually contain a predominance of mature fat cells with relatively few, widely scattered lipoblasts. A misdiagnosis of lipoma can result from inadequate sampling. In the sclerosing subtype of a well-differentiated liposarcoma, collagen fibrils that encircle fat cells and lipoblasts make up a prominent part of the matrix.

Myxoid liposarcoma, the most common type, is diagnosed by the observation of a delicate plexiform capillary network that is associated with both primitive mesenchymelike cells and a variable number of lipoblasts. The stroma contains a large proportion of myxoid ground substance (ie, hyaluronic acid), in which numerous microcysts may form.

In the round-cell type, lipoblasts are interspersed among sheets of poorly differentiated round cells.

Poorly differentiated pleomorphic liposarcoma is recognized by a mixture of bizarre, often multivacuolated lipoblasts and atypical stromal cells, many of which contain highly abnormal mitotic figures. Hemorrhagic and necrotic areas are common. Lipoblasts are present.

Staging

The Enneking oncologic staging system defines the biologic behavior of primary tumors. This system has proven to be effective in planning surgery for limb lesions (eg, intralesional, marginal, wide, radical) and in evaluating its results. Note the following:

Surgical staging is appropriate only after the diagnosis is established and the oncologic stage is determined.

Medical Care

Liposarcoma has a number of different subtypes (ie, well differentiated, dedifferentiated, myxoid/round cell, pleomorphic), and their response to chemotherapy is not well documented.[34] Thus, the response rates to chemotherapy of the different histological subtypes and overall and progression free survival were investigated; survival according to histological grade was also assessed. This retrospective analysis suggested that myxoid liposarcoma is relatively chemosensitive in comparison to a combination of other liposarcomas, in particular dedifferentiated and well-differentiated tumors.

In the case of well-differentiated liposarcoma, grade provides no incremental information over other histological subtypes in terms of response to therapy. In myxoid/round cell liposarcoma, the presence of a round cell component may be an adverse prognostic sign. Tumor site, a high proliferative fraction noted with MIB-1 labeling, and TP53 missense mutations are also adverse prognostic factors in myxoid/round cell tumors.[35]

For liposarcomas, radiation therapy may be a valuable adjunct to surgery, especially in those of the myxoid variant.

The use of chemotherapy in liposarcomas remains experimental.

Although surgical resection is the mainstay of curative treatment, patients with large high-grade liposarcomas may benefit from multimodality treatment with chemotherapy and radiation.[36]

Treatment of an atypical lipoma using liposuction has been described.[37]

Trabectedin (Yondelis) was approved in November 2015 in the United States for unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen. It is an alkylating drug that binds guanine residues in the minor groove of DNA. Approval was based on a phase 3 trial (n=518) that showed a statistically significant improvement in progression-free survival compared with dacarbazine (4.2 mo vs 1.5 mo; P< .0001). No improvement in overall survival was observed.[38]

In January 2016, eribulin (Halaven), a microtubule inhibitor,[39]  was approved by the US Food and Drug Administration (FDA) for unresectable or metastatic liposarcoma in patients who received a prior anthracycline-containing regimen. The FDA approval is based on the results from the subgroup of 143 patients with liposarcoma. In this subgroup, the results show a 7-month improvement in survival (15.6 months with eribulin compared with 8.4 months with dacarbazine). The median progression-free survival, a secondary endpoint, was 2.9 months with eribulin compared with 1.7 months with dacarbazine. However, eribulin was more toxic than dacarbazine. Treatment-emergent adverse events included neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%), and alopecia (35% vs 3%) for eribulin compared with dacarbazine, respectively.[40]

Comprehensive genomic profiling may facilitate targeted therapy for individual liposarcomas in the future.[41]

Surgical Care

The rationale for wide surgical excision of atypical lipomatous tumors is the prevention of recurrence and dedifferentiation.

Wide and deep surgical excision, along with local radiation and/or chemotherapy, may be necessary for high-grade lesions.

Given the favorable outcome with wide surgical excision alone, regardless of the histologic type of the tumor, some authors believe that adjuvant radiation therapy is unjustified.

Consultations

Consultation with the following specialists may be warranted:

Trabectedin (Yondelis)

Clinical Context:  Trabectedin is an alkylating drug that binds guanine residues in the minor groove of DNA. It is indicated for unresectable or metastatic liposarcoma or leiomyosarcoma in patients who have received a prior anthracycline-containing regimen.

Class Summary

Treatment with trabectedin may be considered in patients who have already received an anthracycline.

Eribulin (Halaven)

Clinical Context:  Eribulin is a microtubule inhibitor. It inhibits the growth phase of microtubules, leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death. It is indicated for adults with unresectable or metastatic liposarcoma in patients who have received a prior anthracycline-containing regimen.

Class Summary

These agents inhibit the growth phase of microtubules, leading to cell death.

What is liposarcoma?How is liposarcoma classified?What are the biologic forms of liposarcoma?What is the pathophysiology of liposarcoma?What causes liposarcoma?What is the prevalence of liposarcoma in the US?What is the global prevalence of liposarcoma?What is the racial predilection of liposarcoma?What is the sexual predilection of liposarcoma?Which age groups have the highest prevalence of liposarcoma?What is the prognosis of liposarcoma?Which clinical history findings are characteristic of liposarcoma?What are the signs and symptoms of liposarcoma?Which physical findings are characteristic of liposarcoma?Which conditions should be included in the differential diagnoses of liposarcoma?What are the differential diagnoses for Liposarcoma?What is the role of lab testing in the workup of liposarcoma?What is the role of imaging studies in the workup of liposarcoma?What is the role of biopsy in the diagnosis of liposarcoma?Which histologic findings are characteristic of liposarcoma?How is liposarcoma staged?How is liposarcoma treated?What is the role of trabectedin (Yondelis) in the treatment of liposarcoma?What is the role of eribulin (Halaven) in the treatment of liposarcoma?What is the role of surgery in the treatment of liposarcoma?Which specialist consultations are beneficial to patients with liposarcoma?Which medications in the drug class Antineoplastics, Antimicrotubular are used in the treatment of Liposarcoma?Which medications in the drug class Antineoplastics, Alkylating are used in the treatment of Liposarcoma?

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Santiago A Centurion, MD, Dermatologist, Dermatology Associates of Central NJ

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Disclosure: Received honoraria from UpToDate for author/editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Jacek C Szepietowski, MD, PhD, Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland

Disclosure: Received consulting fee from Orfagen for consulting; Received consulting fee from Maruho for consulting; Received consulting fee from Astellas for consulting; Received consulting fee from Abbott for consulting; Received consulting fee from Leo Pharma for consulting; Received consulting fee from Biogenoma for consulting; Received honoraria from Janssen for speaking and teaching; Received honoraria from Medac for speaking and teaching; Received consulting fee from Dignity Sciences for consulting; .

Acknowledgements

Matthew J Trovato, MD Fellow, Division of Plastic Surgery, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

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Computed tomography (CT) scan of a left thigh shows a huge mass (arrows) with predominant fat attenuation. The central soft-tissue component (asterisk) and thick, internal septations are consistent with liposarcoma.

Computed tomography (CT) scan of a left thigh shows a huge mass (arrows) with predominant fat attenuation. The central soft-tissue component (asterisk) and thick, internal septations are consistent with liposarcoma.