Management of Primary Well-differentiated Liposarcoma and Dedifferentiated Liposarcoma in the Extremity

Treatment strategies for WDLS/DDLS diagnosed in the extremity parallel those of STS in general ; however, diagnosis can often be made radiographically and not based on core biopsy. DDLS appears as an enhancing nodule in association with a lipomatous tumor (WDLS); the adipogenic component appears similar to fat on CT or MRI ( Fig. 1 A ). High-grade DDLS is managed primarily with surgical resection. The tumor is removed with margins of 1 cm of normal tissue or a major fascial barrier circumferentially. Encasement of a major neurovascular structure may require resection with arterial reconstruction. When the tumor abuts the neurovascular bundle or bone, then the neurovascular sheath, perineurium, or periosteum can be resected as closest margin. Adjuvant radiation is used to reduce risk of local recurrence in cases of high-grade DDLS of the extremity that is greater than 5 cm in diameter or after R1 resection that cannot be improved without causing major morbidity. Radiation planned in the neoadjuvant setting is an indication for preoperative biopsy as opposed to clinical diagnosis. Because DDLS is relatively chemoresistant, systemic therapies are rarely used for localized DDLS.

MRI T1 images showing cross-sectional evaluation of ( A ) DDLS in the hip and ( B ) WDLS in the thigh. Arrows show lipomatous components representing a well-differentiated component of the dedifferentiated tumor and the nodular high-grade component.

WDLS in the extremity is also termed atypical lipomatous tumor. As in the case of DDLS, diagnosis of WDLS can be suggested by preoperative imaging. WDLS appears as a lipomatous mass, with similar signal intensity as normal fat ( Fig. 1 B). The differential diagnosis for lipomatous mass in the extremity includes WDLS and lipoma. Final diagnosis is accurately determined only after pathologic evaluation of the surgically resected specimen, because core biopsy results are susceptible to sampling error, but WDLS may be suspected in deep lesions. WDLS tends to be larger than lipoma (>10 cm), diagnosed in older patients (≥55 years), and identified in the context of recurrence. MRI may show enhancing septae in WDLS. Outcomes for patients with WDLS of the extremity are good, with 5-year and 10-year local recurrence-free survival rates of 100% and 78%, respectively; the tumors have no metastatic potential unless they have a dedifferentiated component. The surgical approach can, therefore, be more conservative than that for DDLS. For example, WDLS that encases a neurovascular bundle may be bivalved to preserve the structures, and margins of less than 1 cm can be planned to optimize function and cosmesis. Similarly, radiation is generally deferred after resection of extremity WDLS, because even in the context of local recurrence, disease-related deaths are exceedingly rare.

An algorithm for the treatment of localized WDLS/DDLS of the extremity (and other LPSs) is shown in Fig. 2 .

Flow-diagram delineating basic treatment algorithm used for management of patients with localized LPS of the extremity. Dediff, dedifferentiated liposarcoma; RT, radiation therapy; Well diff, well-differentiated liposarcoma.

Management of Primary Well-differentiated Liposarcoma and Dedifferentiated Liposarcoma of the Retroperitoneum

WDLS/DDLS is the most common type of STS in the retroperitoneum. Like extremity WDLS/DDLS, WDLS/DDLS of the retroperitoneum can often be diagnosed based on imaging studies. Highly suggestive of WDLS/DDLS is cross-sectional imaging demonstrating a lipomatous lesion with pushing borders and enhancing septae, with or without solid nodules. Surgery can be planned without biopsy when imaging is reviewed by an experienced diagnostician. The primary goal of surgery for retroperitoneal WDLS/DDLS should be complete gross resection of all disease. For retroperitoneal sarcoma, R2 resection is associated with significantly poorer outcomes than R0 or R1 resection, and, in most series, patients with gross residual disease have outcomes as poor as patients who did not undergo any surgery. Whether R0 resections have better outcomes than R1 resections is unclear, because results have varied among the retrospective analyses of retroperitoneal sarcomas. Therefore, there is no clear consensus regarding the importance of obtaining an R0 versus R1 resection.

This controversy regarding the role of R0 resection underlies ongoing debate on extended compartmental resection for patients with primary retroperitoneal disease, particularly because retroperitoneal WDLS/DDLS often recurs locally, and death is often caused by unresectable local recurrence that compresses visceral organs as opposed to distant metastases. Retrospective series compared patients treated with excision of primary tumor, including surrounding fat and fascial planes (eg, kidney capsule) where feasible, with patients treated by extended compartmental resection, that is, removal of the tumor with surrounding organs where those organs would provide an additional 1-cm margin (eg, kidney, colon, pancreas, and spleen). Decreased rates of local recurrence were reported for the extended compartmental resection group, and, with longer follow-up, results suggested improvements in overall survival. Many major sarcoma centers, however, have not adopted this practice, for reasons delineated in depth in multiple reviews. Briefly, extended compartmental resection is criticized for high rates of postoperative morbidity and for the limited ability to optimize margins because most retroperitoneal lesions lie close to central vessels and unresectable organs (eg, liver and duodenum). Prior reports have also associated multivisceral organ resection with poorer outcomes for LPS, suggesting that the need for aggressive surgery to control disease may be a function of poor tumor biology. More recent data suggest that rates of local recurrence (in the absence synchronous distant metastases) are highest in grade II (French or Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC]) DDLS, so extended resections may be most appropriate for this subset.

Most STS specialists agree on the need for complete gross resection of retroperitoneal WDLS/DDLS, and, as in the extremity, adjuvant systemic therapy is rarely considered. Given poor rates of response, systemic therapy is generally reserved for unresectable disease, in some instances preoperatively for marginally resectable disease, or in the context of metastatic disease. The role for radiation is debatable; radiation is considered at many institutions because of high rates of local recurrence. When given, it is generally as neoadjuvant to prevent injury to surrounding normal tissues. Adjuvant radiation causes, for example, small bowel enteritis in up to 60% of patients. The efficacy of neoadjuvant radiation has been partially defined by 2 prospective series with a combined 72 patients, although only 40% of the patients had LPS and 25% had recurrent disease. Among the 54 radiation-treated patients who were able to undergo complete gross resection, 5-year local recurrence-free survival was 60% compared with nonirradiated historic controls, with 5-year local recurrence-free survivals of 30% to 60%. The benefit was not clear-cut, however, and the role of neoadjuvant radiation in primary retroperitoneal sarcoma is currently being examined in a phase III, randomized European Organisation for Research and Treatment of Cancer trial.

Management of Recurrent Disease

Local recurrence rates in the extremity are low, and follow-up can be performed with serial examinations or MRI yearly for WDLS (every 6 months for DDLS). Local recurrences of extremity disease are managed in much the same way as primary disease. If reoperation carries significant morbidity, WDLS recurrence can be observed with serial imaging, given its lack of metastatic potential. When surgery is required, all attempt is made to preserve the limb. Patients with DDLS should undergo chest imaging every 4 to 6 months, because distant recurrence of extremity DDLS is generally noted in the lung. Metastasectomy can be performed if technically favorable and if the patient has good prognostic indicators, such as a solitary site and long disease-free interval, with the caveat that these recommendations are generally based on studies covering a range of sarcoma histologies. For patients who had retroperitoneal WDLS/DDLS, distant recurrence is less often a problem although up to 22% of patients may develop metastatic disease in the lungs, but local recurrence is common. CT of the abdomen and pelvis is completed every 3 to 6 months in the first 2 years after surgery, then every 6 months for 2 years. Chest imaging is indicated for patients treated for DDLS.

Because of the relative resistance of WDLS/DDLS to systemic therapy, surgical re-resection has been the standard management for recurrent disease. Resection of recurrent disease is associated, however, with increased rates of complications, so careful patient selection is essential in determining who may benefit from alternative treatments. Recurrent disease is rarely curable, and surgery should be seen as a temporizing measure and reserved for instances in which significant disease control is anticipated. Recurrence after re-resection is least frequent in patients who had a long disease-free interval and whose recurrence is small and not multifocal, so these characteristics identify ideal surgical candidates. In a multivariate analysis of 393 patients with primary or recurrent disease, those with multifocal lesions had significantly poorer outcomes regardless of resectability. Patients with more than 7 lesions had 5-year overall survival of only 7%. This outcome was similar to that in patients undergoing incomplete gross resection. Both disease-free interval and size of recurrence were examined in a study of 61 patients with retroperitoneal LPS undergoing resection of a first local recurrence. Patients with tumors that grew faster than 0.9 cm per month since the prior complete gross resection had median disease-specific survival of only 13 months. Therefore, patients with rapid recurrence and multifocal disease are generally considered for systemic therapies, and operative intervention is reserved for palliation of symptoms.

Systemic Therapies for Well-differentiated Liposarcoma and Dedifferentiated Liposarcoma

Doxorubicin-based chemotherapy (either as a single agent or with ifosfamide) has been a standard treatment of recurrent STS for many years. In a retrospective review of 208 STS patients, the observed response rate to doxorubicin-based chemotherapy was 12% ; liposomal doxorubicin is also a reasonable option with comparable activity in STS. Unfortunately, few patients with LPS were included in clinical trials, so histology-specific rates of response are unclear although it is considered a first-line treatment in most patients. Ifosfamide also has some single-agent activity in WDLS/DDLS. Combination therapy with doxorubicin and ifosfamide in STS in general has been shown to improve response rates and progression-free survival (PFS) compared with doxorubicin alone but not to improve survival. Thus, single-agent therapy in the setting of recurrent disease is likely best for most patients unless the disease burden requires an urgent response to palliate symptoms. Dacarbazine shows some activity in second-line or third-line regimens, and the combination of gemcitabine and docetaxel is also widely used in advanced STS, although there are few data on response rates in WDLS/DDLS. A subgroup analysis of a randomized phase II trial of gemcitabine versus gemcitabine and docetaxel showed 75% of patients with WDLS/DDLS had some stabilization of disease, although this was only durable (≥24 weeks) in 2 of 12 patients.

Although a range of systemic options are available for patients with advanced WDLS/DDLS, they seem to have limited efficacy, at least compared with MLS and pleomorphic LPS. Therefore, significant effort has been made to identify targeted therapies for the disease by understanding the genetic events that drive tumorigenesis. As discussed previously, WDLS/DDLS almost universally has amplification of 12q13–15. A high-throughput small hairpin RNA screen of genes amplified on this chromosome identified more than 20 potential drivers of liposarcomagenesis. One of the most commonly amplified among these was CDK4, a cell-cycle regulator that promotes G1 to S phase transition by phosphorylating RB and inducing transcription of E2F targets. Palbociclib, an inhibitor of CDK4, was recently Food and Drug Administration (FDA) approved for treatment in breast cancer, and an initial phase II trial of palbociclib in WDLS/DDLS has been reported. In this report, examining 29 patients with unresectable WDLS/DDLS and disease progressing through prior treatments, PFS at 12 weeks was 66% and there was 1 partial response; median PFS was 4.7 months. Although these results do not approximate those for targeted therapy in other subtypes of STS (eg, imatinib in metastatic gastrointestinal stromal tumor), a small subset of patients had prolonged PFS of over a year. Ongoing research is aimed at discovering predictive markers for response to palbociclib.

Chromosome 12q13–15 also contains the MDM2 gene. MDM2 promotes degradation of p53 to prevent apoptosis and/or cell-cycle arrest and may have p53-independent effects on alternative tumor suppressors, such as p21 and regulators of the epithelial-to-mesenchymal transition. MDM2 inhibitors that prevent its binding to p53 (eg, Nutlin) have yielded promising results in vitro and in mouse xenografts. In patient trials, however, MDM2 inhibitors have been associated with significant adverse events (up to 40% of patients), which have precluded their chronic administration. Recent data suggest, however, that in vitro abrogation of MDM2 may exert cytostatic effects on the cell (senescence, an irreversible form of growth arrest) without altering cellular levels of p53. Specific targeting of the p53-independent activities of MDM2 may have therapeutic potential and minimize toxicity, a hypothesis that warrants further study.

Some additional 12q13–15 amplicon genes, such as YEATS4 , have been implicated in WDLS/DDLS, but research examining their oncogenic functions is limited, minimizing their impact on clinical therapeutics. Similarly, studies of dedifferentiation of WDLS have identified potential oncogenes and tumor suppressors that drive tumor progression, such as 11q23–25, 3p14–21, 3q29, and 19q13. Although integrated copy number and gene expression data have implicated the loss of tumor suppressors, such as CEBP-α in dedifferentiation, mechanisms for inducing re-expression of such proteins have been elusive. One possible mechanism is targeting the epigenetic modification that contributes to down-regulation of these tumor suppressors. For example, methylation of the CEBP-α gene was identified in 10 of 42 DDLS samples (24%). Treatment of DDLS cell lines with demethylating agents induced cellular apoptosis in increased expression of CEBP-α. Future studies are likely to examine these findings in greater depth as well as the findings of aberrant expression of receptor tyrosine kinases (eg, MET and AXL) and microRNAs (eg, mir-193b) in subsets of WDLS/DDLS.