Liposarcoma: A Detailed Review
Introduction
The term "liposarcoma" refers to a spectrum of neoplastic processes ranging from lesions that are essentially benign to those that are malignant, more aggressive, and likely to recur and/or metastasize (spread). Decisions regarding the treatment and aftercare of liposarcomas are guided by the known characteristics and behavior patterns of the various subtypes. While many of the principles governing the evaluation and management of other soft tissue sarcomas certainly apply to liposarcoma, there are many features unique to it that deserve special consideration. Management of these tumors requires a multidisciplinary team approach, and should be rendered in centers experienced in the many facets of care of sarcoma patients.
Background
In relation to other types of cancer, soft tissue sarcomas are relatively rare. Approximately 11,000 new cases of soft tissue sarcoma are diagnosed each year in the United States (ACS 2012) representing about 1% of all newly diagnosed human neoplasms (Lewis 1996). Liposarcoma itself constitutes about 9.8% to 18% of soft tissue sarcomas, its incidence second only to that of Malignant Fibrous Histiocytoma (MFH), (Peterson 2003, Enzinger 1995).
Liposarcoma is a tumor derived from primitive cells that undergo adipose differentiation. It is largely a disease of adults, its incidence peaking between the ages of 40 and 60 years, and it shows a slight predominance toward men (Enzinger 1995). When liposarcomas do occur in the pediatric population, they tend to present in the second decade of life (Coffin 1997). In either event, the deep soft tissues of the extremities, particularly those of the thigh, are the most common location, accounting for more than 50% of liposarcomas (Coffin 1997, Pisters 1996). Its presentation in this location is most commonly that of a slow growing, painless mass. Often these tumors are first noticed after the patient has sustained a minor trauma to the area. Having noted a hard lump that doesn’t go away with time often is what prompts the patient with a sarcoma to first seek medical attention. Unfortunately, since patients with sarcomas don’t initially feel "sick", their diagnosis, and thus their treatment, is often delayed.
Liposarcoma was originally described by R. Virchow in 1857. In 1944, Arthur Purdy Stout wrote "surely, one of the most bizarre and fantastic chapters in the story of oncology is furnished by the tumors of fat-forming cells. The strange way in which they grow, their astounding size…and many other peculiar features ... make them of great interest." [See R. Virchow, "Ein fall von Bosartigen zum Theil in der form des Neurons auftretenden Fettgeschwulsten," Arch A Pathol Anat Phys, 1857, 11: pp 281-288 and "Liposarcoma—the malignant tumor of lipoblasts", A. P. Stout, Annals of Surgery, 1944; 119( 1): pp 86-107.]
One unique feature of liposarcoma is its tendency to occur in visceral spaces, particularly that of the retroperitoneum. Up to 1/3 may occur in this location (Peterson 2003). The presentation of liposarcoma in this scenario may be quite different. While a mass may be appreciated, it tends to be found much later, since the retroperitoneal space can accommodate a much larger change in volume than can the thigh, for instance. Also, obstructive urinary and bowel symptoms may predominate as the mass impinges on these structures. The management of liposarcoma in this location can be particularly difficult.
A Paradigm for Histology-Specific Multimodality Therapy
Introduction
Soft tissue sarcoma represent less than 1% of all human neoplasms with approximately 7,000 new cases diagnosed in the USA per year.1 Despite sharing a common embryologic origin from mesodermal tissue, these tumors encompass a histologically and anatomically diverse group of neoplasms. Liposarcomas are the most common histologic subtype of soft tissue sarcoma and are subdivided into five well recognized subgroups based on morphology and cytogenetic abnormalities:2
- Well-differentiated (WD)
- Myxoid
- Round cell
- Pleomorphic
- Dedifferentiated liposarcoma (DD)
Initiated in 1962, the modern liposarcoma histological classification schema has included the category of well-differentiated liposarcoma. Well-differentiated and dedifferentiated liposarcoma comprise the vast majority (approximately 90%) of liposarcoma subtypes while myxoid, round cell and pleomorphic account for less than 10% of liposarcomas.7
Mesoderm comprises the middle germ cell layer and gives rise to cells that comprise cardiac and skeletal muscle, hematopoitic cells and cells producing bone, cartilage and connective tissue throughout the body. In addition this germ cell layer ultimately gives rise to the cells that make up the genitourinary system.
Figures 1A-1C...
The term "ALT" for atypical lipomatous tumor was introduced in 1974.3 The recent World Health Organization classification of soft tissue and bone tumors grouped these lesions into one category, "atypical lipomatous tumor/well differentiated liposarcoma." Well-differentiated (WD) liposarcomas are composed of mature adipocytes with significant variation in cell size and focal nuclear atypia. They typically show scattered atypical stromal cells with hyperchromatic nuclei embedded within mature adipose tissue. Fibrous septae are often present. These divide the tumor into irregular lobules infiltrated by atypical stromal cells, and are a feature especially characteristic of the Sclerosing variant of well-differentiated liposarcoma (Figure 1).4
The term dedifferentiated (DD) liposarcoma was advanced by Evans in 1979 to describe liposarcoma that consists of a combination of atypical lipomatous tumor (ALT) components and also cellular, non-lipogenic sarcomatous areas that have significant mitotic activity.5 Grossly, dedifferentiated liposarcoma has the appearance of multinodular yellow masses representing ALT or WD within which discrete solid areas of dedifferentiated liposarcoma can be appreciated by their distinctive fleshy, tan-gray non-lipomatous appearance. It is unclear whether WD and DD originate from two different cellular clones or if there is a process of progressive evolution from WD to DD. However, it is unequivocally established that DD constitutes a high grade lesion with increased cellularity that is prone to disseminate and is associated with a much worse prognosis than WD which has minimal metastatic potential.6 Many sarcoma centers do not report grade when describing liposarcoma in that WD tumors are generally considered to be low grade where as DD tumors are typically high grade. Moreover, grade is frequently not included in multivariate liposarcoma models that include histologic subtype.7
Liposarcomas of the extremity and trunk enjoy significantly lower rates of local recurrence (10-16%) compared to the rate of local recurrence (43%) from liposarcomas arising within the retroperitoneum.8-10 Liposarcomas arising from within the retroperitoneum typically grow to be quite large before associated symptoms are manifest.
Retroperitoneum: The retroperitoneuma is the anatomical space behind (retro) the abdominal cavity. It has no specific delineating anatomical structures. Organs are retroperitoneal if they only have peritoneum on their anterior side. Retroperitoneal organs: ureter, bladder kidneys, duodenum, colon, pancreas and adrenal glands.
Although different liposarcoma histologic subtypes can be observed in soft tissue sarcomas that arise in the retroperitoneum, histologic subtype per se is usually not incorporated into retroperitoneal disease management strategies. Complete surgical resection is a difficult challenge as these large tumors are often surrounded by a thin fibrous capsule which is frequently indistinguishable from surrounding retroperitoneal adipose tissue. Critical structures in the retroperitoneum can also pose a challenge to resectability. Accordingly, it is often difficult to obtain a margin of normal tissue around the tumor. The importance of complete macroscopic resection is well established and resection of contiguous organs in the hope of decreasing the rate of local failure is a common practice. However, evidence that a more extensive resection impacts survival is very limited. Among the factors that significantly influence clinical outcome, histologic subtype is recognized as an independent predictor of local recurrence (LR), distant metastasis (DM) and disease specific survival (DSS).7
A Treatment Strategy According to DD and WD Histology
At the University of Texas MD Anderson Cancer Center (MDACC) we have adopted a strategy of performing less-aggressive surgery for patients based upon the specific liposarcoma histologic subtype. Tumors without a component of dedifferentiation, referred to as either atypical lipomatous tumors or well-differentiated liposarcoma (WD), are associated with a less aggressive clinical course. WD tumors are characterized by repetitive local recurrence without the potential for metastasis. In contrast, dedifferentiated tumors (DD) also recur at a high rate, but have the potential to metastasize and represent an aggressive clinical phenotype. Accordingly, at MDACC we recognize these tumors as distinct with differing tumor biology and clinical outcome. Utilizing this general strategy for patients with WD tumors has resulted in less aggressive surgery without the addition of chemotherapy or radiotherapy. For patients with retroperitoneal liposarcomas with evidence of dedifferentiation, we adopt a more involved treatment approach that begins with neoadjuvant chemo-radiotherapy followed by aggressive surgical resection. In this review we present the rationale for this approach and discuss our clinical results vis-à-vis those centers that do not alter treatment approaches to retroperitoneal liposarcoma based on histologic subtype.
To date, the largest reported series of retroperitoneal liposarcoma resections is from Memorial Sloan-Kettering Cancer Center (MSKCC). In this experience, completeness of resection significantly impacted clinical outcome: the three year disease specific survival for patients with a margin negative resection was 87% compared with 43% for patients resected with grossly positive margins. In this series and others from the MSKCC group an aggressive surgical approach was applied based on the demonstrated prognostic significance of a complete macroscopic resection.7,10-11 Moreover, retroperitoneal liposarcoma histologic subtype did not influence decisions about neoadjuvant or adjuvant chemotherapy in that none of the patients in this series received such systemic treatment. Unlike extremity liposarcoma where tumor size is known to significantly affect outcome the size of retroperitoneal liposarcomas is typically much larger; in this series the mean tumor maximum dimension was 26 cm. As an indication of aggressive surgical resection, over two-thirds of patients in this series underwent resection of contiguous organs, including nephrectomy. Interestingly, contiguous organ resection was associated with a two fold increased risk of death compared to patients not undergoing contiguous organ resection after adjusting for other prognostic factors (p=0.05).7 In the MSKCC series, the local recurrence rate and rate of distant metastasis was 50% and 11% respectively. On multivariate analysis of prognostic factors associated with local recurrence, distant metastasis, and disease-specific survival, only the presence of contiguous organ resection and the DD histologic subtype were significant adverse factors. It is possible that the patients receiving contiguous organ resection simply had more extensive tumor burden rather than worse biology per se. Underlying tumor biology, rather than extensive surgical resection appears to be more important determinant of clinical outcome. We hypothesize that the histologic subtype of retroperitoneal sarcomas may serve as a surrogate for tumor biology and will affect clinical outcome more than extent of initial resection if a gross total excision is performed.
The MDACC Experience
Taking into account the markedly different biologic behaviors of WD compared to DD, our therapeutic approach at MDACC is tailored to reflect these differences. The treatment strategy for a retroperitoneal liposarcoma patient presenting to the MDACC Sarcoma Center is formulated upon multidisciplinary consensus review prior to initiation of therapy. This approach is in contrast to traditional tumor board review of patients who typically undergo resection and are then considered by the multidisciplinary review panel to determine the utility of adjuvant therapy based on final review of the resected specimen pathology. Our practice is to utilize validated diagnostic imaging criteria and selective image guided biopsy of suspected foci of DD to make a preoperative diagnosis of WD versus DD in patients presenting with retroperitoneal liposarcoma. WD patients generally undergo less aggressive surgery avoiding resection of contiguous organs if possible, while patients with DD are treated with neoadjuvant chemotherapy and radiation therapy followed by aggressive surgical resection.
Using this approach, patients may realize benefits from neoadjuvant therapies that would otherwise not be demonstrable were resection performed as the initial treatment strategy. The major theoretical benefits to neoadjuvant chemotherapy are to identify patients who respond to the systemic therapy as measured by the pathologic response, and to initiate treatment of possible occult metastatic disease at the earliest possible time after diagnosis. These potential advantages are offset by several disadvantages of neoadjuvant therapy, namely that definitive resection is delayed and wound healing may be compromised. However, there is evidence to suggest that response to front line sarcoma chemotherapeutic agents may be dependent on histologic liposarcoma subtype, with DD having greater response rates than WD.12
We have recently reviewed our experience utilizing this approach to patients with retroperitoneal sarcoma, demonstrating that WD patients usually benefit from a less aggressive surgical approach that avoids unnecessarily extensive resection. This strategy was developed based on initial anecdotal observations of the generally indolent clinical behavior of WD tumors in contrast to the metastasis prone phenotype of DD tumors. This approach to WD tumors stands in contrast to our traditional aggressive surgical management of other retroperitoneal histologies. The treatment variables and patient outcomes of the 127 patients presenting with primary or locally recurrent resectable retroperitoneal liposarcomas are depicted in Table 1.
Well-differentiated |
Dedifferentiated |
|||
N=54 |
N=73 |
|||
| Treatment Characteristics | No. |
% |
No. |
% |
| Neoadjuvant chemotherapy | 1 |
1.7 |
27 |
35.1 |
| Neoadjuvant radiation | 9 |
15.5 |
15 |
19.7 |
| Gross (RO) Resection | 50 |
86.2 |
66 |
85.7 |
| Positive microscopic margins | 23 |
40.4 |
33 |
43.4 |
| Multiple contiguous organ resection | 27 |
50 |
55 |
75 |
| Patient Outcomes | \ | |||
| Local Recurrence | 25 |
46 |
52 |
71 |
| Distant Metastases | 2 |
4 |
33 |
45 |
| Median time to recurrence (months) | 55.5 |
13.5 |
||
| 5-year recurrence free survival (RFS) | 41.9 |
7.8 |
||
| 5-year overall survival (OS) | 92.1 |
36.5 |
||
The incidence of local recurrence was 46% for WD patients and 71% for DD patients while the incidence of distant metastases was 3.7% for WD and 45.2% for DD patients.13 The median overall survival at 5 years was 92.1% for WD patients and 36.5% for DD patients. On multivariate analysis, presentation status (recurrent vs. primary), multifocal disease, and pelvic location were factors significantly associated with recurrence free survival (RFS). While it is difficult to compare outcomes between published single institutional series, our outcomes are comparable to those reported by the MSKCC group in which treatment decisions are apparently not as influenced by the presence of dedifferentiation. In the MSKCC series the incidence of local recurrence was 31% for WD patients and 83% for DD patients while the incidence of distant metastasis was 1% for WD patients and 30% for DD patients at three years of follow up. The 5-year disease specific survival for tumors with WD histology was 83% compared with 20% for tumors with dedifferentiated histology.7
In our series, the tumor burden as measured by tumor size was comparable between WD and DD tumors with the median size of the tumors measuring 20 cm and 17 cm respectively. Over 65% of the WD tumors measured >15cm compared to 55% of the DD tumors which is similar to the median tumor burden reported in the MSKCC series. Despite the comparable sizes of the WD and DD tumors, our apparently less aggressive surgical approach to WD patients resulted in only 46.6% of the WD patients undergoing resection of contiguous organs whereas over 70% of DD patients in our series underwent contiguous organ resection. Interestingly, we achieved equivalent rates of complete tumor resection while using this organ sparing strategy (WD: 86.2%; DD: 85.7%).16 In the MSKCC series, the incidence of contiguous organ resection was not stratified by histologic subtype, rendering further inter-series comparisons problematic.
Preoperative Diagnosis of WD and DD Retroperitoneal Liposarcoma
The success of this less-aggressive treatment approach requires accurate preoperative determination of WD versus DD retroperitoneal liposarcoma histology. At MDACC we utilize radiographic correlates of dedifferentiation to enhance the likelihood of obtaining informative tissue for diagnosis at the time of the CT scan guided biopsy of suspected DD regions. Since retroperitoneal liposarcomas are frequently large and heterogeneous, a random biopsy specimen retrieved from a limited area within the tumor may be very inaccurate; therefore, other diagnostic tools are also needed as adjuncts to unequivocally establish the DD diagnosis. CT scanning has been particularly useful in helping to identify areas of WD and DD within a given retroperitoneal liposarcoma in that retroperitoneal liposarcomas characteristically have an overall fatty appearance with areas of "streakiness" due to the presence of cellular stromal elements within the tumor.14 As a general paradigm, the more well-differentiated the tumor, the more its imaging appearance will resemble that of adipose tissue, whereas foci of DD have a CT appearance more consistent with that of high grade tumor.
Computed tomography (CT) is a medical imaging method employing tomography. Digital geometry processing is used to generate a three-dimensional image of the inside of an object from a large series of two-dimensional X-ray images taken around a single axis of rotation. The word "tomography" is derived from the Greek tomos (slice) and graphein (to write).
To establish radiographic markers of DD we examined a series of 78 patients (45 with DD and 33 with WD). Features previously reported as possible discriminators between low and high grade tumors were evaluated. One feature, the presence of focal nodular/water density, was identified as a radiographic surrogate marker for discriminating between the two differing histologies. Focal nodular/water density describes an area of nodularity within the tumor that has a density similar to muscle is depicted in Figure 2.
Forty-four out of 45 patients (97.8%) with postoperative pathologic diagnosis of DD were radiologically identified as DD by the study radiologist based on the presence of focal nodular/water density; however 16 patients with WD were diagnosed as DD based on this imaging criterion. In contrast, all 17 tumors that lacked areas of focal nodular/water density were confirmed to by WD on pathologic analysis of the resected specimen. The positive predictive value (PPV) of focal nodular/water density to predict DD histology therefore was 73.3% while the negative predictive value (NPV) was 100%. Taken together, these data suggest that preoperative CT imaging is very sensitive to detect DD histology based the presence of focal nodular/water density; however, its specificity is relative low. Moreover, as the negative predictive value (NPV) of this marker was 100% it appears that the diagnosis of WD can be based on CT scanning alone.
Predictive Values: The positive predictive value (PPV), or precision rate, is the proportion of patients with positive test results who are correctly diagnosed. It is the most important measure of a diagnostic method as it reflects the probability that a positive test reflects the underlying condition being tested for. Its value does however depend on the prevalence of the disease, which may vary. The negative predictive value (NPV) is the proportion of patients with negative test results who are correctly diagnosed.
In this series 72% of patients had pre-referral CT-guided biopsies and in only 22 cases (28%) a CT guided biopsy was performed at MDACC. All the 17 tumors identified as WD based on preoperative CT imaging criteria and confirmed on postoperative pathologic assessment to be WD were also diagnosed as WD on preoperative biopsy. In such patients a preoperative biopsy may therefore not be needed as the diagnosis of WD can be made by CT imaging criteria alone. Out of the 60 tumors that were radiographically identified as DD based on the presence of focal nodular/water density, preoperative biopsy showed DD in 34 (56.7%) cases and WD in 26 (43.4%). In Thirteen patients out of the 26 cases (50%) diagnosed as WD based on preoperative biopsy were found to be DD on postoperative pathologic assessment. The majority of biopsies performed in this series were obtained prior to evaluation at MDACC. It is unlikely that such pre-referral biopsies were taken from areas within the tumor suspicious for DD. Accordingly, we analyzed the 22 CT guided biopsies performed at MDACC. Twelve were taken from suspicious areas from within the tumor identified by the presence of focal/nodular water density by preoperative CT imaging. Of these, all six biopsies confirmed on final pathology as DD were also identified as DD on preoperative CT-guided biopsy. Conversely, 9 CT-guided biopsies taken from non-suspicious areas (fatty or ground glass opacities) were interpreted as WD and 5, nearly 50%, were diagnosed as DD on final postoperative pathologic assessment.
Taken together, these data suggest that a preoperative CT scan-guided biopsy is highly sensitive and specific for DD when taken from suspicious areas of focal/nodular water density. Our approach to a patient who presents with a retroperitoneal liposarcoma is as follows: CT scan to identify and localize areas of a focal nodular/water density as ascertained by the radiologist; if no focal/nodular water density areas are found the tumor is considered to be WD and a biopsy is unnecessary. If areas of a focal nodular/water density are detected then a CT-guided biopsy of these suspicious areas is needed to differentiate between DD and WD. Patients diagnosed as DD by CT-guided biopsy may therefore be considered for neoadjuvant systemic chemotherapy while WD patients generally undergo less aggressive surgery up-front with an aim to avoid resection of contiguous organs if possible.
Future Studies
Recently, the ability of fluorodeoxyglucose (FDG) PET imaging to assess clinically relevant liposarcoma parameters was evaluated in 54 patients prior to therapy. Sarcomas with the most metabolically active areas may have more aggressive tumor biology. In this study significant differences were found for the maximum standardized uptake value (SUVmax) between histologic subtype; tumor SUVmax was found to be a significant correlate of disease-free survival and time to relapse. The mean tumor SUV max was 2.3 for WD, 4.8 for DD and 5.6 for the pleomorphic histologic subtype. Patients with SUVmax >3.6 had a significantly shorter disease-free survival of 21 months compared with 44 months in patients with a SUVmax <3.6.15 In the future, PET-CT may provide even more accurate assessment of retroperitoneal liposarcoma histological subtype, and this possibility merits prospective evaluation.
Positron emission tomography (PET) is a nuclear medicine imaging technique that produces a three-dimensional image of functional processes in the body. The system detects pairs of gamma-rays emitted indirectly by a positron-emitting radioisotope (tracer), which is introduced into the body on a biologically active molecule. If the biologically active molecule chosen for PET is FDG (a derivative of glucose), the concentrations of tracer imaged then give tissue metabolic activity, in terms of glucose uptake.
In our series, DD patients had a five-year overall survival rate of 36.5% despite an aggressive surgical approach combined with high dose systemic chemotherapy. Clearly novel systemic therapies are needed to treat this and other histologic subtypes that are resistant to current multimodality approaches. The ability to identify and therapeutically exploit a unifying molecular abnormality that is associated with a specific histologic subtype is best exemplified by the dramatic success of imatinib mesylate (Gleevec or STI-571) for gastrointestinal stromal tumors (GISTs). Differential gene, RNA, and protein expression patterns identified by high throughput techniques such as cDNA and miRNA arrays as well as tissue microarray and/or proteomic profiling may offer insight into previously unappreciated sarcomagenesis pathways.
A unique characteristic (and the basis for the definition of dedifferentiated liposarcoma) is the presence of dedifferentiated areas within a sarcoma that consists of predominantly well-differentiated histology. This phenomenon begs the question of whether the dedifferentiated component represents an area of WD that has regressed to resemble an earlier stage of developmental cellular maturation as reflected by a dedifferentiated phenotype. Alternatively, areas of dedifferentiation may represent differing stages of maturity in the original sarcoma progenitor cells, also referred to as mesenchymal stem cells. The latter hypothesis is reminiscent of the accepted progression of leukemogenesis in which a lymphoid stem cell type arrests at differing stages of normal lymphoid stem cell maturation, then acquires potential for the transformed phenotype of a cell type specific leukemia or lymphoma.16
Recently, Matushansky et al. proposed a developmental model of sarcomagenesis to define the differentiation-based classification of liposarcomas.17 Using RNA isolated from human mesenchymal stem cells (hMSC) growing in adipocyte conditioned media, gene expression profiling was performed at predetermined days of hMSC-adipocytic differentiation to identify groups of adipocyte differentiation-specific genes. In parallel, to identify genes specific to the sarcomagenesis process that are not involved in the maturation process, a list of genes differentially expressed between normal fat tissue and each liposarcoma histologic subtype were generated from tumor tissue. Genes corresponding to the stage of normal differentiation were analyzed by comparing the two groups of gene sets.
Mesenchymal Stem Cell (MSC): Mesenchyme is embryonic connective tissue that is derived from the mesoderm and that differentiates into hematopoietic and connective tissue, whereas MSCs do not differentiate into hematopoietic cells. Mesenchymal stem cells are multipotent stem cells that differentiate into a variety of cell types such as: osteoblasts, chondrocytes, myocytes, adipocytes and beta-pancreatic islet cells.
Hierarchical clustering analysis of the adipocyte maturation gene set revealed that dedifferentiated and pleomorphic liposarcomas were associated with early maturation time points, whereas myxoid/round cell and well-differentiated were associated with late time points in a maturation process that more closely resembled that of normal fat. Each tumor subtype was compared to its corresponding normal cell stage of differentiation. Using differential gene expression analysis, two distinct gene sets were identified: genes overexpressed in liposarcomas that mark the stage of differentiation arrest, and a distinct set of genes overexpressed in liposarcomas that are not found in the corresponding stage of differentiation which could be enriched for genes critical to sarcomagenesis.17 In the future it is likely that sarcomas will be classified by their molecular pathologic characteristics that both defines the histologic subtype and are also prognostic of the metastatic phenotype.
Conclusions
In conclusion, the biologic behaviors of well-differentiated and dedifferentiated liposarcomas are significantly different. Using two distinct surgical and multidisciplinary approaches we propose that these tumors may be optimally managed as separate disease entities. We have established radiographic criteria that correlate with the presence of the dedifferentiated retroperitoneal liposarcoma components useful in maximizing the accuracy of pre-therapy image-directed diagnostic biopsy. In the future, the characterization of molecular pathways critical to liposarcomagenesis will hopefully facilitate development of individualized treatment strategies based on specific tumor biology, thereby enhancing multidisciplinary therapy for this challenging group of diseases.
It is worth mentioning that, in addition to the previously described locations, liposarcoma may occur in many other locations. Those occurring in the head and neck represent about 5%, while the upper extremity accounts for 10%. Other unusual locations may include the spermatic cord, peritoneal cavity, axilla, vulva and even the breast. While most liposarcomas are believed to arise de novo, those in the breast may arise from a preexisting cystosarcoma phyllodes (Donegan 1979, Austin 1986). Liposarcomas are not known to arise from benign lipomas.
History and Physical Exam
Most patients with liposarcomas will present to a clinician with complaint of a mass. Often they are painless unless some sort of trauma has occurred. As stated previously, liposarcomas can become quite large, depending on the site of involvement. Their character can be soft and fleshy or notably firm to palpation. This largely depends on how much the tumor resembles mature fat, or how well-differentiated the lesion is. It is important early on to distinguish large benign lipomas from liposarcoma. Factors that tend to suggest malignancy are masses > 5 cm (about 2 inches) in size and lesions that are deep-seated, firm and fixed to underlying structures (Sim 1994). As with the evaluation of any mass, a thorough physical examination is a must, and careful attention should be directed toward the chest, abdomen and pelvis in addition to the extremity of interest.
The Imaging of Liposarcomas
After a careful history and physical exam has been performed, imaging studies are obtained. For extremity lesions, this begins with standard X-Rays (Sim 1994). These will help elucidate whether or not the bone is involved. Next, an MRI is usually obtained, both with and without contrast enhancement. The MRI findings in liposarcoma can be quite distinct, and suggest the diagnosis even before biopsy is performed. This largely depends on how closely the tumor resembles normal fat (i.e. how "well-differentiated" it is); see Figure 1.
Liposarcomas tend to appear well-circumscribed and lobulated on MRI (Arkun 1997). Contrast enhancement depends on the level of differentiation. Little enhancement is noted in well-differentiated liposarcomas, and more is seen with the more aggressive round cell, pleomorphic and dedifferentiated subtypes. Myxoid liposarcoma, an intermediate variant, shows corresponding heterogeneity with regards to contrast enhancement (Arkun 1997). Other findings characteristic of liposarcoma are thick fibrous septae, nodularity and contrast enhancement on fat-suppressed sequences (Peterson 2003). Additionally, foci of hemorrhage and necrosis may be seen; see Figure 2.
Staging and Biopsy of Liposarcoma
Once a sarcoma is suspected by exam and imaging, staging and biopsy must be performed. This basically helps determine the nature of the lesion and to what extent, if any, the tumor has spread. Imaging of the tumor as described above is a critical part of the staging process. Additionally, since the lungs are the most common site of metastasis, radiography and CT scanning of the chest is routinely undertaken. With liposarcoma, CT of the abdomen is also recommended due to the relatively common involvement of retroperitoneal and visceral spaces. Laboratory studies including CBC, sedimentation rate and chemistries should be obtained. These tests provide insight into the systemic response elicited by the tumor, and provide a baseline by which therapy may be monitored.
Biopsy is critical, as it is the means by which tissue is acquired in order to make a definitive diagnosis. The histology (or the way it looks under the microscope) of the tumor gives the first clues to its behavior. The requisite tissue can be obtained via needle aspiration or through open incisional or excisional biopsy methods. Open techniques constitute surgery and are performed in the operating room. These provide the most tissue for review by the pathologist, however are often not necessary, or even appropriate. Because many soft tissue sarcomas are readily palpable, needle biopsy is often all that is necessary. This is frequently performed by a radiologist under CT guidance. Incisional biopsy sometimes is necessary to attain an adequate sample of tissue. This involves making an incision in the skin, and obtaining some pieces of the tumor for evaluation. Except for the rarest of instances, excisional biopsy (removing the entire tumor as a biopsy) should be avoided with suspected sarcomas as a well-planned, definitive resection after appropriate staging and tissue diagnosis is preferred.
Liposarcoma Pathology
Once tissue from a biopsy or resection is obtained, it is examined under the microscope to determine its histology. There are many special kinds of tests that may be run to aid the pathologist in making a diagnosis from the provided specimen. For this reason, biopsy results may take several days or sometimes even weeks to be finalized.
The World Health Organization currently recognizes four subtypes of liposarcoma: well-differentiated (or atypical lipoma), myxoid, pleomorphic and dedifferentiated (Christopher 2002). While these categories represent various points on a spectrum of disease, each of these entities displays its own unique character. Table I provides a simplified description of each of the aforementioned subtypes. Also, See Figure 3 and Figure 4.
| Well-differentiated | Includes atypical lipoma Most common subtype (50% of liposarcomas) Low grade (doesn’t metastasize, but may recur locally) Risk of dedifferentiation |
| Myxoid | Intermediate grade Includes round-cell variant as its high-grade counterpart Most common type in pediatric age group Metastatic risk especially in round-cell variant |
| Pleomorphic | Rarest type (5-10% of liposarcomas) High grade May mimic MFH or even carcinoma or melanoma High risk of local recurrence and metastasis |
| Dedifferentiated | High grade sarcoma arising in association with well-differentiated liposarcoma (MFH, fibrosarcoma) Most common with retroperitoneal lesions Risk of metastasis |
Table 1 compiled from Peterson 2003, Dei Tos 2000, Coffin 1997, Enzinger 1995 and Weiss 1992
A number of cytogenetic correlations also have been made with liposarcoma. Well-differentiated liposarcomas have been found to be associated with abnormalities derived from the q13-15 region of chromosome 12 (Rubin 1997). Such abnormalities also are found in dedifferentiated liposarcoma. Perhaps the best characterized genetic association is that found with myxoid liposarcoma. This represents a translocation, or sharing of genetic material between two chromosomes. In myxoid liposarcoma, the translocation is between chromosome 12 and 16. The result is a gene called TLS-CHOP which is an oncogene, or gene that when expressed can lead to the formation of cancer. This particular translocation and its products are found only in myxoid liposarcoma and therefore are diagnostic of this tumor (Rubin 1997).
The online Atlas of Genetics and Cytogenetics in Oncology and Haematology contains a webpage summarizing classification and other information about Liposarcoma. In particular, see the "Bibliography" section of this webpage which contains an extensive set of references. An introduction to DNA, RNA and proteins can be found on the Nobel website. After clicking on the above hyperlink, make sure to read the section "Learn how to navigate in the document" to take full advantage of this tutorial.
Once the tumor has been characterized, the staging is complete and an appropriate course of treatment can be planned. Table II demonstrates the commonly used staging system for bone and soft tissue sarcomas used by Musculoskeletal Oncologists (adapted from Enneking 1980).
| Stage | Grade | Site |
| IA | Low | Intracompartmental (in bone or muscle compartment of origin) |
| IB | Low | Extracompartmental |
| IIA | High | Intracompartmental |
| IIB | High | Extracompartmental |
| III | Any + Mets | Any + Mets |
Table II adapted from Enneking, 1980.
The Treatment of Liposarcoma
Liposarcoma is, like other soft tissue sarcomas, primarily a surgical disease. The main goal of surgery is to remove the tumor entirely and prevent recurrence. This is most reliably achieved with a wide or radical resection; see Table III.
Although amputation historically was the surgical option of choice for these tumors, today most are amenable to limb-sparing surgery. This is due in large part to advances in the understanding of sarcoma behavior, and in principles of radiation therapy. Such advances have led to a decrease in the frequency of amputations for primary soft tissue sarcomas from more than 50% to about 5% (Spiro 1997).
If a limb-sparing procedure is performed however, it must not compromise the main oncologic goal of tumor removal, and should preserve an extremity that serves the patient better than could a post-amputation prosthesis. It is important to note that even with limb-sparing procedures, functional deficits may be encountered. These may vary significantly depending on the size and location of the individual tumor, and are due to the removal of tissues associated with the tumor (i.e. muscles, tendons, nerves, etc). Reconstruction of post resection deficits can in some instances be performed to minimize these effects; see Figure 5.
| Intralesional | Curettage Partial tumor removal |
| Marginal | May leave microscopic tumor behind |
| Wide | Remove tumor and surrounding cuff of normal tissue |
| Radical | Remove entire compartment Includes amputation |
Table III adapted from Enneking 1980.
Radiation Therapy and Chemotherapy for Liposarcoma
Although local control rates of 85-90% have been achieved with combination therapy consisting of surgery and radiation (Spiro 1997), discussion is ongoing as to the timing of radiation, whether it should be given before or after surgery. Preoperative radiation has the advantage of allowing for smaller doses of radiation applied to a smaller field. Additionally, the tumor may actually shrink in size, making the surgery technically more feasible. The downside is that surgical complications, particularly those related to the wound, are increased. Pollack et al (1998) reported wound healing complications in 25% in patients radiated preoperatively versus 6% in those receiving postoperative treatment. It has been suggested that the improved oncologic outcomes and decreased incidence of more permanent late complications justify the use of preoperative radiation despite the increased complication rate (Virkus 2002). The role of chemotherapy in the treatment of liposarcoma also remains controversial, and is best addressed on a case-by-case basis.
What is commonly accepted regarding liposarcoma is that the behavior of a specific tumor is ultimately dependent on its histological subtype (see above). When treated with surgery and perioperative radiation therapy, well-differentiated liposarcomas exhibit a <10% local recurrence rate and a virtually 0% rate of metastasis (Zagars 1996). In contrast, pleomorphic liposarcomas recur in about 1/3 of cases and spread in about 40%. Five and ten year survival rates for patients with liposarcomas have been reported as 100% and 87% for well-differentiated, 88% and 76% for myxoid variants and 56% and 39% in the pleomorphic subtype (Zagars 1996, Chang 1989).
Local recurrence largely depends on margin status at the time of surgery, with margins positive for the presence of tumor conferring a higher recurrence rate (Sadoski 1993) and thus, less satisfactory outcomes (Spiro 1997). In some scenarios, amputation may still be the procedure of choice for a given patient with a sarcoma. While the goal of amputation is removal of the sarcoma, it does not address metastatic disease and is not fully protective against local recurrence. If amputation is required, the patient often will elect to use a post-amputation prosthesis. This depends largely on the level of the amputation. In short, the more native joints the patient is able to safely retain, the better his/her function tends to be. Essential elements of a successful transition to use of a prosthetic limb are the involvement of a knowledgeable prosthetist, a diligent program of hysical therapy including appropriate post-operative stump care and gait training, and most-importantly, a patient that is truly committed to the process.
Surveillance
Once the tumor has been excised and adjuvant therapy completed, continued surveillance is required to promptly detect any evidence of local recurrence or distant metastasis. This typically involves careful physical examination, x-rays of the afflicted limb and serial imaging of the chest and abdomen (usually CT) and pelvis if indicated. Such follow-up is continued in some fashion for the remainder of the patient’s life. If such disease is detected, treatment is rendered accordingly.
An entity which can sometimes occur after radiation therapy is radiation-induced sarcoma. By definition this arises in previously irradiated tissues that were documented to be "normal" prior to radiation (Arlen 1971). They tend to occur at least 2-3 years after treatment, and may appear up to 30 years later. The most common histology is that of malignant fibrous histiocytoma (70%), and is typically high grade (Enzinger 1995). Survival rates of 5-26% have been reported with regards to these tumors (Robinson 1988, Laskin 1988).
Conclusion
The term "liposarcoma" refers to an array of cancerous tumors. The behavior of any liposarcoma is dependent on its histological subtype. The treatment principles, however, are essentially identical to those of other soft tissue sarcomas. Largely, this includes some combination of radiation therapy and surgery, with or without chemotherapy. It is important for the patient to be serially evaluated for any signs of recurrence or metastasis, and any new complaints should be addressed promptly. This is particularly true in the setting of liposarcoma, which may exhibit unusual patterns of spread and recurrence (Vassilopoulos 2001, Linehan 2000, Pearlstone 1999).
