What is liposarcoma?

Liposarcoma is a rare cancer of connective tissues that resemble fat cells under a microscope. It accounts for up to 18% of all soft tissue sarcomas. Liposarcoma can occur in almost any part of the body, but more than half of liposarcoma cases involve the thigh, and up to a third involve the abdominal cavity.

Liposarcoma tends to affects adults between the ages of 40 and 60. When it does occur in children, it is usually during the teenage years.

There are four types of liposarcoma, each with its own unique characteristics and behaviors.

1. Well-differentiated liposarcoma is the most common subtype and usually starts as a low grade tumor. Low grade tumor cells look much like normal fat cells under the microscope and tend to grow and change slowly.

2. Myxoid liposarcoma is an intermediate to high grade tumor. Its cells look less normal under the microscope and may have a high grade component.

3. Pleomorphic liposarcoma is the rarest subtype and is a high grade tumor with cells that look very different from normal cells.

4. Dedifferentiated liposarcoma occurs when a low grade tumor changes, and the newer cells in the tumor are high grade.

The risk of recurrence and metastasis with liposarcoma increases with higher grade.

Well Differentiated

Represents 40-45% of all liposarcoma.

Commonly occurs in the retroperitoneum or the limbs and rarely in the spermatic cord and the mediastinum.

The alternative terms 'atypical lipoma' and 'atypical lipomatous tumour' have been suggested by different authors.

The behaviour of these lesions is substantially different depending on the location of the tumour.

Tumour in somatic soft tissue may recur but is incapable of distant metastasis and there is no tumour related death.

Tumour in retroperitoneum have a high incidence of recurrence.

The recurrent tumours may have 'dedifferentiated' appearance. Some of these patients die as a result.

Subtypes according to histopathological features:

1. Adipocytic (lipoma like)
2. Sclerosing
3. Inflammatory
4. Spindle cell

1. Adipocytic (Lipoma like ) -

Large well cicumscribed and coarsely lobulated tumour.

Microscopically, there are mature adipocytes showing variation in cell size. Focally nuclear atypia is evident.

In areas individual nuclei are compressed to crescentic shape.

Some hyperchromatic stromal cells are present. Lipoblasts may or may not be present.

Note: Presence of lipoblasts is not diagnostic of liposarcoma.

Lipoblasts are noted in benign adipocytic tumours. Example:chondroid lipoma, lipoblastoma, pleomorphic lipoma .



2. Sclerosing -

These are relatively pale and firm lesions occur most frequently in the retroperitoneum and the paratesticular region.

Microscopically, there are scattered hyperchromatic stromal cells, multivacuolated lipoblasts set in a collagenous backround.

Foci of atypical lipomatous elements are noted.

3. Inflammatory-


There is a dense chronic inflammatory infiltrate almost obscuring the lipogenic areas.

Prominent aggregates of lymphoid cells and plasma cells are noted simulating inflammatory pseudotumour.

4. Spindle cell-

There is proliferation of bland spindle cells in a fibrous or myxoid backround together with atypical lipomatous component including lipoblasts.

The differential diagnosis include: malignant peripheral nerve sheath tumour, spindle cell lipoma , neurofibroma (S100 positive),dermatofibrosarcoma protuberans (diffuse CD34 positive) , well differeniated sclerosing liposarcoma and low grade fibromyxoid sarcoma.

Cytogenetics- Ring or long marker chromosome derived from q13-15 region of chromosome 12.

Pleomorphic

Rare form of liposarcoma (5% of liposarcomas) usually located in the limbs of older adults.

These are aggressive tumours showing distant metastasis and about 40% mortality rate.

Microscopic appearances:

- A high grade pleomorphic MFH-like sarcoma containing few, scattered multivacuolated lipoblasts.

Careful sampling is necessary to identify these cells.

- A cellular pleomorphic or spindle cell neoplasm containing sheets of large bizarre lipoblasts.

Numerous intracytoplasmic eosinophilic globules may be present.

- Sometimes a heavy neutrophilic infiltrate is present. This lesion may cause diagnostic confusion with well differentiated inflammatory liposarcoma.

- A new variant of pleomorphic liposarcoma characterised by sheets of epithelioid cells and focal adipocytic differentiation.

Myxoid and Round Cell Represents 30-35% of all liposarcomas. Myxoid and round cell liposarcomas commonly occur in the limbs usually between third and fifth decade. Microscopic appearances- "Chicken-Wire Pattern" described in a Soft Tissue Tumour - 1) Purely Myxoid Liposarcoma (Low Grade Tumour)- Purely myxoid liposarcoma (low grade tumour) is characterised by hypocellular bland spindle cells in a myxoid backround. Univacuolated lipoblasts are noted around the vessels. Multivacuolated lipoblasts are present in the peripheral subcapsular zone. There arethin walled branching vessels arranged in aplexiform pattern ('crow's feet' or 'chicken wire pattern' ) Mitotic figures are extremely scarce. 2) Myxoid / Round Cell Liposarcoma- Myxoid/round cell liposarcoma is characterised by hypercellular areas with undifferentiated round cells. These cells are larger with hyperchromatic and more rounded configuration, in contrast to the spindle cells in the myxoid variant. Mitotic figures are more frequent. These tumours have an aggressive behaviour. Transition to hypercellular (round cell) areas are noted in myxoid liposarcoma. 3) Pure Round Cell Liposarcoma- Pure round cell liposarcoma is rare (more than 80% round cells). More than 10% round cell areas - increased potential for metastasis. More than 25% round cell areas - High grade tumour. Differential diagnosis- Myxoid Tumours of Soft Tissue Myxoid liposarcoma - Differential diagnosis: Intramuscular myxoma, Myxofibrosarcoma (myxoid MFH), lipoblastoma, extraskeletal chondrosarcoma, myxolipoma, well differentiated liposarcoma. Round cell liposarcoma - Differential diagnosis: Metastatic carcinoma, lymphoma, melanoma, Ewing's sarcoma. Immunohistochemistry- Undifferentiated round cells and bland spindle cells in myxoid and round cells display cytoplasmic and nuclearpositivity with S100 protein. The lipoblasts stain positively with S100 protein. Plexiform vascular areas may be demonstrated by CD31 and CD34 immuno- stains. Cytogenetics- t(12;16) (q13;p11) with rearrangement of the CHOP gene.



Dedifferentiated Dedifferentiated liposarcoma is characterised by abrupt transition from low grade to high grade non lipogenic morphology within a well differentiated liposarcoma. The transition is usually abrupt in nature. 90% cases occur in primary tumour. 10% cases occur in recurrent tumour. Microscopic appearances: - Dedifferentiated areas are characterised by spindle and pleomorphic cells resembling storiform-pleomorphic MFH or myxofibrosarcoma. -May exhibit heterologous differentiation (myogenic, osteochondrosarcomatous or angiosarcomatous). -New variant has been described exhibiting neural-like or meningothelial-like whorls of spindle cells. Rarely paraganglioma-like histologic pattern has been observed. - Sometimes the tumour exhibits fascicles of bland spindle cells these are described as low-grade areas. - Spindle cell liposarcoma which represents lipogenic lesion,must be distinguished fromlow grade dedifferentiated liposarcoma which isnon lipogenic in nature and has a relatively better prognosis. - High grade dedifferentiated liposarcoma (non lipogenic) must be differentiated from pleomorphic liposarcoma. - There is no difference in biological behaviour of low and high grade dedifferentiated liposarcomas. These are associated with 20-25% metastasis. Recurrence rate is usually high.
Soft Tissue Tumors: Liposarcoma: Well-differentiated liposarcoma
Other names Atypical lipoma
Atypical lipomatous tumors
Adipocytic liposarcoma
Note The fact that WD liposarcomas show no potential for metastasis unless they undergo dedifferentiation led in the late 1970s to the introduction of terms such as atypical lipoma or atypical lipomatous tumor (ALT), particularly for lesions arising at surgically amenable locations in the limbs and trunk. Currently, atypical lipomatous tumors and well-differentiated liposarcomas are synonyms describing lesions which are identical morphologically, karyotypically and in terms of biologic behavior. Use of each term is determined principally by the tumor's location; the term "well-differentiated liposarcoma" is used almost exclusively for lesions in the retroperitoneum, while the term "atypical lipomatous tumor" is used for lesions arising elsewhere.
Figure 1: Axial T1-weighted MR imaging of the thigh of a 41-year-old man with an anterior thigh mass. The lesion has a signal intensity similar to fat, and fine internal septations with scarce contrast enhancement. Needle biopsy showed lipoma-like well-differentiated liposarcoma. Figure 2: Axial T1-weighted with fat saturation MR imaging of the thigh. The lesion shows signal suppression as per normal adipose tissue.

Clinics and Pathology

Epidemiology Well-differentiated liposarcomas account for 40-45% of all liposarcomas and are usually diagnosed after the fifth decade of life; slight male predominance has been reported. Well-differentiated liposarcomas in childhood are extremely rare.
Clinics Pathogenesis is unknown. It is not known to develop from benign lipomas; trauma has been implicated. 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. Well-differentiated liposarcomas are most commonly found in the extremities and the retroperitoneum, and, less often, in the head and neck area. The tumors usually arise from deep-seated, well-vascularized structures, and rarely from submucosal or subcutaneous fat. Patients usually note a deep seated, slow growing mass in their soft tissue. Only when the tumor is very large do symptoms of pain or functional disturbances occur. Retroperitoneal tumors may present with signs of weight loss and abdominal pain, or mass effect to the kidney or ureter leading to kidney failure. Imaging - Radiography: May show a faint soft tissue mass or swelling; areas of calcification or bony erosion may be related to dedifferentiation or higher tumor grade. Chest radiography and computed tomography may be used as screening for pulmonary metastases. - Sonography: Ultrasonography shows a well-circumscribed uniformly hyperechoic mass. - Computed tomography: Usually shows a lobulated, well-circumscribed mass with multiple septations and variable contrast enhancement. Computed tomography is superior to MR imaging in detailing cortical bone erosion and tumor mineralization. - MR imaging: Well-differentiated liposarcomas have well-defined and mostly lobulated margins. The tumors are encapsulated and composed of mainly fat with septa or nodules. Their signal intensity is intermediate between subcutaneous fat and muscle; well-differentiated liposarcomas are hyperintense on T2-weighted images, and they demonstrate faint enhancement or no enhancement after the intravenous administration of contrast material, and linear septations. Diffuse enhancement is usually observed following gadolinium administration. There may be incomplete fat suppression because of the nature and amount of lipids. - Scintigraphy: An early-phase bone scan may show a marked increase of radioisotopic uptake.
Figure 3: Adipocytic or Lipoma-like well-differentiated liposarcoma. Low power photomicrograph shows scattered bizarre stromal cells with marked nuclear hyperchromasia (stain, hematoxylin and eosin; original magnification, 10x). Figure 4: Adipocytic or Lipoma-like well-differentiated liposarcoma. High power photomicrograph shows scattered bizarre stromal cells with marked nuclear hyperchromasia (stain, hematoxylin and eosin; original magnification, 20x).
Pathology Gross pathology: Well circumscribed, lobulated, soft, greasy to rubbery mass (see figure 5). In the retroperitoneum there may be multiple discontinuous masses. The cut surface varies from yellow to white (and firm) depending on the proportion of adipocytic, fibrous and/or myxoid areas. Areas of fat necrosis are common in larger lesions. Rarely an infiltrative growth pattern may be encountered. Microscopically: Light microscopy typically shows mature adipocytic cells, atypical stromal cells and limited number of scattered lipoblasts. Four sybtypes have been distinguished: - Adipocytic or Lipoma-like: the most common form; it is composed of a relatively mature adipocytic proliferation in which, in contrast to benign lipoma, significant variation in cell size, focal adipocytic nuclear atypia and hyperchromasia, and scattered hyperchromatic as well as multinucleate stromal cells are often identified (see figure 3 and 4). - Sclerosing: the second in frequency, most often seen in retroperitoneal or paratesticular lesions. It is characterized by the presence of scattered bizarre stromal cells, marked nuclear hyperchromasia and rare multivacuolated lipoblasts set in an extensive fibrillary collagenous stroma. Occasionally, the fibrous component may represent the majority of the neoplasm. - Inflammatory: rare variant, most often seen in the retroperitoneum. A chronic inflammatory infiltrate predominates to the extent that the adipocytic nature of the neoplasm can be obscured. - Spindle cell: it is composed of a fairly bland neural-like spindle cell proliferation set in a fibrous and/or myxoid stroma, and an atypical lipomatous component which usually includes lipoblasts. Interpretative difficulties arise when atypical lipomatous tumors contain fibrous or myxoid areas whose cellularity and mitotic rate are higher than in the typical tumors but lower than in the typical dedifferentiated component of dedifferentiated liposarcoma. Many studies pointed out that the cut-off portion of myxoid and fibrous areas with higher mitotic rate and cellularity is uncertain. This portion has been regarded 1 cm (up to 3 cm in large tumors) and considered as a sign of low-grade dedifferentiation from the very beginning. Similarity to large deep-seated lipomas is also a diagnostic problem. Several authors proposed a positivity in over-expression of MDM2, HMGA2 and CDK4 as a reliable hallmark to distinguish between these two entities, and genetic differences between low and higher grade liposarcomas. Others reported that CDK4 in ALT/WD liposarcomas is expressed inconsistently and is associated with adverse prognosis compared to the MDM2/CDK4 genotype. Differential diagnosis: Lipoma; lipoblastoma; hibernoma; neurofibroma. Cytogenetics may be of value when diagnosing lipomatous tumors because different tumor types have different more or less specific chromosomal abnormalities.
Figure 5: Tumor specimen of a lipoma-like well-differentiated liposarcoma. Figure 6: Complete en bloc excision of a lipoma-like well-differentiated liposarcoma of the anterior thigh.
Cytogenetics On cytogenetic grounds, approximately 80% of well-differentiated liposarcomas are characterized by the presence of a supernumerary ring and/or long marker chromosomes. The chromosomal region 12q-13-15 is the amplified component within these marker chromosomes.
Genes The 12q-13-15 chromosomal component contains several genes that are amplified or re-arranged in well-differentiated liposarcomas, including the CDK4 (cyclin-dependent kinases) and the MDM2 (murine double minutes) families. Both CDK4 and MDM2 are proto-oncogenes that permit over-ride of the block operated by the G1-S cell cycle checkpoint on cell proliferation. The mdm2 protein is known to inhibit transactivation of p53, a tumor suppressor gene product, which in turn results in cell proliferation. Recently, immunostaining of cdk4 and mdm2 proteins has been recognized as a valuable method for the differentiation of benign lipoma from well-differentiated liposarcoma. Furthermore, ki-67 expression is associated with progression of soft tissue sarcomas.
Treatment Complete, preferably wide-margin surgical resection is the treatment of choice (see figure 6). The rationale for wide surgical excision of atypical lipomatous tumors is the prevention of recurrence and dedifferentiation. 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. However, in patients with large high-grade liposarcomas may benefit from multimodality treatment with chemotherapy and radiation. Radiation therapy may be a valuable adjunct to surgery, especially if other than wide margins of resection. The use of chemotherapy in liposarcomas remains experimental. The grade of well-differentiated liposarcomas provides no incremental information over other histological subtypes in terms of response to therapy.
Prognosis The most important prognostic factor for well-differentiated liposarcoma is anatomical location. Lesions located in surgically amenable soft tissue do not recur following complete excision. In contrast, in retroperitoneum and mediastinum location it is often impossible to obtain a wide surgical excision; well-differentiated liposarcomas in these locations have been associated with adverse prognosis and a higher rate of local recurrence, and dedifferentiation of recurrent tumors. The ultimate risk of dedifferentiation varies according to site and lesional duration and is probably >20% in the retroperitoneum but <2% in the limbs. The rates of 10 to 20-year mortality range from essentially 0% for tumors of the extremities to more than 80% for those occurring in the retroperitoneum. Patients with a history of previous local recurrence seem to be more prone to further local recurrence; in our experience, all patients referred and treated for recurrence, experienced a 52% rate of local re-recurrence after re-excision, even if with wide margins. Recurrences my occur as late as 140 months after primary surgery. The increased rate of local re-recurrence may reflect that these tumors although low grade have a high local morbidity if not followed at long-term (at least 6 years).


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