Background

Liposarcoma is a malignancy of fat cells (see Liposarcoma in the Pediatric Medicine section of eMedicine and Liposarcoma, Soft Tissue in the Radiology section of eMedicine). 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. 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, welldifferentiated 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.1,2,3,4 Liposarcoma occurs in 3 main biologic forms: (1) well-differentiated liposarcoma; (2) myxoid and/or round cell; and (3) pleomorphic. In rare circumstances, lesions can have 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.

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.

Mortality/Morbidity
The overall 5-year survival rate of patients with deep high-grade liposarcoma is less than 50%. Metastases are common, especially in poorly differentiated liposarcomas. The lungs and the liver are the most common sites of metastasis. Primary cutaneous liposarcoma has an indolent course.

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.5

Clinical
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, wellvascularized structures than from submucosal or subcutaneous fat. 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:

Associated episode of trauma to the region containing the mass Painful swelling (occurs in one third of cases for as long as 6 mo) Decreased function (ie, range of motion) Numbness Enlargement of varicose veins Fatigue Abdominal pain Weight loss Nausea Vomiting

Physical
The 3 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. 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.

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

Differential Diagnoses

Lipomas Neurofibromatosis

Other Problems to Be Considered

Cellular angiofibroma Solitary fibrous tumor Cutaneous neurofibroma Malignant schwannoma Rhabdomyosarcoma Leiomyosarcoma Fibrous histiocytoma Benign lipoblastoma in infants and children Late granulomatous reactions from silicone may appear in a site different from that of the injection and may cause an incorrect diagnosis of liposarcoma.6 Silicone implants for chin augmentation may create a tissue reaction that mimics a low-grade liposarcoma.7 Myxofibrosarcoma, one of the most common soft tissue sarcomas of elderly patients, may histologically resemble pleomorphic liposarcoma.8 Primary liposarcoma may be evident as metastatic liposarcoma to the head and neck region, including the gingival mucosa.9,10 Spindle cell lipomas are benign lipomatous tumors that may require histological distinction from liposarcoma. These lipomas are typically seen in the posterior neck, shoulder, or upper back of older males.11

Workup
Laboratory Studies
Cytogenetics may be of value when diagnosing lipomatous tumors because different tumor types have different more or less specific chromosomal abnormalities.12 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 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. 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.13 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, Soft Tissue in eMedicine Radiology.

Procedures
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.14 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:

S-100 - Positive results in fat cells and lipoblasts Alpha-1-antitrypsin - Positive results in malignant fibrous histiocytomas Desmin - Positive results in leiomyosarcomas Myoglobin - Positive results in rhabdomyosarcomas

Histologic Findings

The recognition of lipoblasts is the key finding in the diagnosis of liposarcoma. A lipoblast has the ability to produce and accumulate nonmembrane-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:

The Enneking staging system divides benign tumors into 3 stages: S1, S2, and S3. Localized malignant tumors are divided into 4 stages: IA, IB, IIA, and IIB. Two other stages include metastatic high-grade intracompartmental tumors, or stage IIIA tumors, and extracompartmental malignant tumors, or stage IIIB tumors. This classification scheme was formerly used to describe long-bone tumors. This staging system is based on a complete preoperative workup that includes an assessment of the clinical features; the radiographic pattern and CT and MRI data regarding the extension of the tumor; the peculiar imaging features of the tumor and its relationship to the neighboring tissues; the findings from isotopic scanning, which provides information about local aggression and systemic diffusion; and the histologic findings obtained at biopsy.

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

Treatment
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.15 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.16 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.17 Treatment of an atypical lipoma using liposuction has been described.18

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:

Oncologist: When malignancy is strongly suspected or when previous incisional biopsy reveals liposarcoma, consultation with an oncologist prior to the definitive surgical procedure is recommended. Radiation oncologist: Adjuvant therapy may be indicated in cases in which excision is incomplete. In such cases, consultation with a radiation oncologist is recommended.

Follow-up
Prognosis
The prognosis is affected by the type of liposarcoma present. The well-differentiated type and most myxoid types have favorable prognoses, with 100% and 88% 5-year survival rates, respectively.19 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. The form that a dermatologist is most likely to examine at biopsy is 1 of the 3 subtypes of a welldifferentiated 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. The lungs are particularly affected. 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%.20

Miscellaneous
Medicolegal Pitfalls
The misdiagnosis of a liposarcoma as a lipoma or another benign condition is a pitfall.

Special Concerns
Because cutaneous liposarcoma is extremely rare, the physician must rule out a metastatic lesion. A case report describes liposarcoma complicating pregnancy.21