Retroperitoneal Liposarcoma

Anahat Kaur; Stephen Leslie; Rodolfo  Garza Morales

Retroperitoneal Liposarcoma

Author: Anahat Kaur Author: Stephen W. Leslie Editor: Rodolfo Garza Morales Updated: 2/11/2025 7:48:25 PM

Introduction

Soft tissue sarcomas are rare tumors, with liposarcoma being the most common variant, accounting for 20% of cases.[1] The most prevalent locations for liposarcoma are the extremities (52%) and the retroperitoneum (19%).[2] Retroperitoneal liposarcomas are typically asymptomatic until they grow large enough to compress surrounding organs. The rarity and lack of symptoms often lead to delayed or incorrect diagnoses.[2] Compared to other subtypes of retroperitoneal sarcomas, retroperitoneal liposarcoma generally has a poor prognosis.

Complete surgical excision is the primary treatment for retroperitoneal liposarcoma. However, achieving clear margins is often challenging due to the tumor's large size and the frequent need for resection of surrounding organs, such as a kidney or a portion of the large intestine.[3]

Etiology

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Etiology

Distinct, recurrent genetic abnormalities are estimated to account for 30%–40% of sarcomas and have a role in their etiology.[4] CDK4 and MDM2 gene amplification is found in over 90% of well-differentiated and de-differentiated liposarcomas.[5]

Studies suggest that occupational exposure to dioxins or herbicides, such as Agent Orange, may increase the risk of sarcoma.[6] Please see StatPearl's companion resource, "Agent Orange Toxicity," for more information. Additionally, therapeutic radiation carries a small but measurable long-term risk of developing soft tissue sarcoma, estimated at well below 1% overall.[7]

Epidemiology

Rarity and Incidence

Retroperitoneal liposarcoma is a rare soft tissue sarcoma, constituting a small percentage of all soft tissue tumors. Incidence rates vary globally, with studies estimating that approximately 10% to 20% of all soft tissue sarcomas occur in the retroperitoneum, corresponding to an overall incidence of 0.3% to 0.4% per 100,000.[8]

Age and Gender

Retroperitoneal liposarcoma primarily affects adults, with a peak incidence occurring in the fifth to seventh decades of life.[9] The condition affects both genders equally.

Pathophysiology

Retroperitoneal liposarcoma develops through a complex interplay of genetic alterations, cellular differentiation, and tumor growth. The condition typically arises from the transformation of primitive mesenchymal cells, resulting in malignant lipomatous tumors within the retroperitoneal space.

The hallmark genetic aberration in these tumors is the amplification of the murine double minute-2 (MDM2) gene, leading to overexpression of the MDM2 protein. This overexpression inhibits the tumor suppressor p53, promoting cell cycle progression and preventing apoptosis.[5] The resulting dysregulation contributes to uncontrolled cellular proliferation and impacts overall survival.[10]

A research group performed exome sequencing involving 17 patients with retroperitoneal well-differentiated and de-differentiated liposarcomas. MDM2 and CDK4 are the 2 overlapping gene amplifications that were consistently detected in every sample.[11]

Histopathology

Liposarcoma is categorized into 4 main subtypes, as mentioned below, each presenting distinct histological features.[12]

Well-differentiated liposarcomas: These sarcomas are characterized by a background of mature adipocytes with interspersed lipoblasts, each containing a single abnormal nucleus surrounded by large intracytoplasmic vacuoles. These tumors typically present as slow-growing masses.[13]
De-differentiated liposarcoma: These sarcomas feature well-defined non-lipogenic sarcomatous tissue sections inside a well-differentiated tumor, leading to increased aggressiveness. These are usually high-grade tumors (grade 2 or grade 3) with higher rates of local recurrence and a greater propensity for metastasis compared to well-differentiated low-grade liposarcomas.[14]

Myxoid liposarcoma: These sarcomas exhibit a myxoid matrix and round to oval tumor cells, and they are usually associated with a favorable prognosis.

Pleomorphic liposarcoma: These sarcomas are a mixture of atypical lipoblasts and pleomorphic sarcoma cells, representing a more aggressive subtype.

Well-differentiated (low-grade) liposarcomas are the most prevalent type of liposarcoma seen in the retroperitoneum, followed by de-differentiated liposarcomas. Myxoid and pleomorphic liposarcomas are rare in the retroperitoneum.

History and Physical

Retroperitoneal liposarcoma presents a diagnostic challenge due to its often asymptomatic nature in the early stages. Patients may report vague abdominal discomfort, a palpable mass, or nonspecific gastrointestinal symptoms. Due to the expansive retroperitoneal space, these tumors can grow to significant sizes, typically 15 cm or more, before causing noticeable symptoms.

Physical examination may reveal a firm, non-tender abdominal mass, often deep-seated and challenging to palpate distinctly. Signs of compression on adjacent structures may also be present, potentially leading to vascular compromise or neurological symptoms. In male patients, a thorough scrotal examination is essential, as testicular malignancies can metastasize to retroperitoneal lymph nodes.

Symptoms of a possible retroperitoneal liposarcoma may include:

Ascites (from portal venous compression)
Edema in one or both of the lower extremities
Partial or complete bowel obstruction
Referred groin or leg pain from involvement or compression of retroperitoneal nerves
Unexplained weight loss

Metastases will be present in about 10% of patients initially diagnosed with the condition, with the lungs and liver being the most commonly involved organs.[15]

Evaluation

Imaging Techniques

Accurate diagnosis usually begins with imaging studies. Magnetic resonance imaging (MRI) is particularly valuable for detailed soft tissue visualization, helping to determine the tumor's location, size, and extent. Computed tomography (CT) scans, however, are more commonly used and provide a broader anatomical view, which can sometimes offer superior detail compared to MRI.[16][17]

The MRI signal intensity of liposarcomas is variable and heterogeneous, depending on the tumor's components and histological patterns. Myxoid liposarcomas appear with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Post-contrast images of myxoid liposarcoma reveal enhanced solid tissues and thickened septa. Well-differentiated liposarcomas exhibit high signal intensity on T1-weighted images, intermediate signal intensity on T2-weighted images, and signal drop-out on fat-suppressed MRI images. Post-contrast images show enhanced fine septa and solid tissues.[18]

Round-cell and pleomorphic liposarcomas exhibit soft-tissue tumor signal intensity without distinct fat signals. De-differentiated liposarcomas show small fatty components with a clear boundary between fat and non-fat solid tissue on MRI images.[18] Once retroperitoneal liposarcoma is diagnosed, a chest CT should be performed, as the lungs are the most common site of metastasis.

Currently, whole-body ¹⁸F-fluorodeoxyglucose (FDG)–positron emission tomography (PET)/CT scans are not currently considered standard for staging or prognosis in patients with this malignancy, although their potential role is being actively investigated.[19][20][21][22][23]

Biopsy

Although imaging provides valuable information, a definitive diagnosis is made through biopsy. Fine-needle aspiration or core needle biopsy, typically performed via a retroperitoneal approach with an 18-gauge (18G) needle, allows for histological examination to confirm liposarcoma, determine its histological type and grade, and rule out similar benign conditions.[19][24] Such biopsies should be obtained from areas of the tumor that do not appear necrotic, with at least 4 separate tissue cores recommended.[19][25] The incidence of needle tract seeding and other complications from these biopsies is extremely low.[19][26][27]

Incisional biopsies, whether open or minimally invasive, are discouraged due to the increased risk of tumor seeding and potential distortion of the tissue planes necessary for surgical resection.[19] Additionally, molecular and genetic testing, including analysis of MDM2 amplification, can further assist in confirming the diagnosis.[5][28][29]

Laboratory Studies

Lactate dehydrogenase (LDH) levels and a complete blood count with differential are typically obtained. Leukocytosis may be observed in patients with rapidly growing malignancies. When combined with lymphadenopathy, an isolated elevated LDH may also suggest lymphoma. Measurements of LDH, alpha-fetoprotein (AFP), and beta-human chorionic gonadotropin (beta-hCG) should be included in laboratory testing for patients in whom germ cell carcinoma is considered in the differential diagnosis. However, not all germ cell tumors will exhibit elevated tumor markers, and biopsy is ultimately required to confirm the diagnosis.

Treatment / Management

Multidisciplinary Approach

The management of retroperitoneal liposarcoma requires a collaborative approach involving general surgeons, vascular surgeons, urologists, oncologists, and radiation specialists. Surgical resection is the primary treatment, with the goal of complete tumor removal. However, the complex anatomical location often presents challenges, and achieving clear surgical margins can be challenging.

Better long-term survival and a reduced risk of local recurrence are associated with planned oncologic resections that remove the tumor intact with a margin of healthy tissue (R0 resections, i.e., negative surgical margins), compared to R1 resections (positive surgical margins).[19] Resections rated R2, which involve tumor rupture, grossly incomplete (partial) resection, or debulking, are linked to a much poorer prognosis.[19]

A more detailed description of the surgical approach can be found in the Surgical Oncology section below on Surgical Oncology below.

Adjuvant or Neoadjuvant Therapies

is generally not indicated when retroperitoneal liposarcoma is excised with clean or microscopically positive margins, as postoperative doses are typically insufficient to be tumoricidal due to dose limitations imposed by surrounding normal organs. For large or high-grade retroperitoneal liposarcomas, preoperative radiation therapy may be considered, as the tumor can act as a tissue expander, pushing normal abdominal structures, such as the colon, out of the radiation field. This anatomical feature can increase the likelihood of delivering a tumoricidal radiation dose to the tumor. However, neoadjuvant radiation therapy has not been shown to improve survival in this patient group definitively.[30](A1)

Patients who undergo both preoperative radiation therapy and surgery do not require additional adjuvant therapy and can proceed directly to posttreatment monitoring. The significance of chemotherapy in the preoperative or postoperative management of retroperitoneal liposarcoma remains uncertain. Patients should ideally enroll in clinical trials where available when considering this approach. Preliminary evidence suggests that preoperative chemotherapy is generally well-tolerated and may occasionally induce radiographic tumor responses.[31] These responses may help reduce tumor burden, potentially enabling the resection of tumors initially considered borderline resectable.[32]

Randomized studies, such as the STRASS-2 trial, are needed to assess the impact of this approach on long-term survival outcomes.[33]
Observational studies indicate that preoperative chemoradiation with concurrent doxorubicin or ifosfamide may decrease tumor burden and facilitate surgical resection in select patients; however, the long-term clinical outcomes and safety of neoadjuvant chemoradiation have not been confirmed through randomized trials.[34]

(A1)

Preoperative chemotherapy is not considered standard care but shows promise based on limited preliminary data, which suggests that it may reduce tumor burden and facilitate surgical resection.[32][35][36][37] Patients should be entered into clinical trials when possible. Preoperative chemoradiation with doxorubicin or ifosfamide may help reduce tumor burden and facilitate surgical resection in select patients.[34][35][38] However, randomized trials evaluating long-term outcomes for this approach are lacking.

Preoperative Therapy

Preoperative treatment for retroperitoneal liposarcoma may include regional externally delivered deep-wave hyperthermia combined with systemic chemotherapy. However, in randomized trials, this approach has not been directly compared to preoperative radiation therapy plus surgery. In a phase III trial (EORTC study 62961), 341 patients with recurrent, incompletely resected, or large primary soft tissue sarcomas were randomized to receive chemotherapy with or without regional hyperthermia, followed by local therapy and additional chemotherapy. Hyperthermia was associated with a higher objective response rate (29% versus 13%) and improved disease-free survival (32 versus 18 months) compared to chemotherapy alone.[39](A1)

For non-extremity sarcomas, hyperthermia significantly improved local progression-free survival (64% versus 45%), although overall survival remained similar (59% versus 57%).[39] Hyperthermia can notably affect the biological characteristics of retroperitoneal tumor cells by regulating the expression of ZO-1, GPX4, and tumor necrosis factor (TNF)-alpha. These effects seem to be synergistic when combined with cisplatin therapy, helping to inhibit the growth and proliferation of retroperitoneal liposarcoma.[40] (A1)

Treatment of Metastatic Disease

Ifosfamide and doxorubicin are the most effective single agents for the first-line treatment of metastatic liposarcomas.[41][42][43] These 2 medications provide additive rather than synergistic benefits. The combination of gemcitabine and docetaxel has demonstrated activity in advanced or metastatic liposarcomas.[44](A1)

Novel Therapies

Ongoing clinical trials explore novel therapeutic approaches, including immunotherapies and targeted treatments. Trabectedin has shown a favorable response in patients with liposarcoma who have previously received anthracycline therapy.[45] Similarly, the US Food and Drug Administration (FDA) has approved eribulin for advanced liposarcoma after anthracycline treatment.[46](A1)

In a phase 2 trial, patients with well-differentiated or de-differentiated liposarcoma treated with the CDK4 inhibitor palbociclib had a median progression-free survival of 18 weeks.[47] Another phase 2 trial showed promising results with abemaciclib in the treatment of de-differentiated liposarcomas. A phase 3 trial is currently underway to further evaluate its efficacy (ClinicalTrials.gov identifier: NCT04967521).

Differential Diagnosis

Most retroperitoneal neoplasms (about 80%) are malignant.

Possible differential diagnoses for retroperitoneal liposarcoma include primary germ cell tumors, metastatic testicular cancer, lymphoma, retroperitoneal lipoma (benign), solitary fibrous tumor, and retroperitoneal leiomyosarcoma. Imaging studies can help distinguish cancers originating from the pancreas, kidney, adrenal glands, duodenum, or other organs from retroperitoneal liposarcomas. Additionally, serum markers can be used to rule out germ cell cancers.

Midline retroperitoneal neoplasms adjacent to the vena cava or aorta could be paragangliomas or schwannomas.

Other possible diagnoses include angiofollicular lymph node hyperplasia (Castleman disease) and retroperitoneal fibrosis, both of which are benign. Please see StatPearls' companion resources, "Castleman Disease" and "Retroperitoneal Fibrosis," for more information.

Immunostains and flow cytometry can be used to rule out lymphomas.

Tumors suspected to originate from the stomach, pancreas, or duodenum can be evaluated through upper gastrointestinal endoscopy with biopsy.[48]

Surgical Oncology

Surgical Resection

Surgical resection is the most effective treatment for localized, primary retroperitoneal liposarcomas, with complete resection being a key determinant of survival. Given the rarity and complexity of these tumors, most surgeons have limited experience managing them. Referral to a tertiary care center with a fellowship-trained surgical oncologist experienced in retroperitoneal liposarcomas is strongly recommended to optimize patient outcomes.[19][49] Patient outcomes significantly improve when experienced specialists manage these rare and highly complex retroperitoneal neoplasms.[19][50][51][52][53] Although a minimum of 12 cases per year is suggested, high-volume centers often handle 24 or more annually.[19][51][53] However, this remains a topic of debate, as case volume alone does not adequately assess surgical expertise or allow for meaningful outcome comparisons.[19][50][54]

Surgeons with limited experience may inadvertently perform incomplete resections, often leaving behind low-grade, well-differentiated disease. They may also conduct unnecessary lymph node dissections, which provide no benefit in retroperitoneal liposarcomas and increase the risk of complications. Given these challenges, referral to a center of excellence with an experienced, fellowship-trained surgical oncologist is strongly recommended.[19]

The preoperative evaluation should include an assessment of renal function to identify potential renal failure and determine the patient's ability to tolerate a possible nephrectomy. Additionally, a nutritional evaluation is essential, as many patients may be malnourished.[19][55][56][57] The following factors may indicate unresectability:

Bilateral renal involvement
Diffuse and extensive peritoneal implants
Extensive involvement of the major vessels
Involvement of the hepatic hilum
Mesenteric root or celiac artery involvement
Spinal involvement

Surgical Approaches and Techniques for Retroperitoneal Liposarcoma Resection

A wide midline laparotomy incision is commonly used to ensure adequate exposure for these large tumors, with possible extensions as needed based on the specifics of the case. Although laparoscopic and robotic approaches have been explored, they are generally unsuitable due to the tumor's complexity and size.[58][59]

Organs and structures within the retroperitoneum that may be affected by a liposarcoma include the kidneys, ureters, adrenal glands, retroperitoneal fat, major arterial and venous vasculature (aorta, inferior vena cava, iliac vessels), and portions of the duodenum, pancreas, bladder, and colon. Involved organs may require partial or complete resection to achieve definitive surgical therapy. Please see StatPearls' companion resource, "Anatomy of the Abdomen and Pelvis, Retroperitoneum," for more information.

In cases requiring en bloc resection, adjacent organs or structures that cannot be separated from the tumor without leaving gross disease should be removed together, with imaging assisting in preoperative planning. Every effort should be made to achieve complete resection of all visible tumors. Repeat retroperitoneal surgery may be necessary, as well-differentiated liposarcoma can be challenging to distinguish from normal retroperitoneal fat. Lymph node dissection is not required, as retroperitoneal sarcomas rarely involve the retroperitoneal lymph nodes.[19]

The majority of these surgeries require a nephrectomy and a partial bowel resection (55%-57%).[19][60][61] Major vascular surgical procedures, such as resection of the inferior vena cava, are required less often (10%-15%).[19][60][61][62] These complex cases, particularly those involving major vascular structures, are best managed at specialized centers.[63][64][65][66] For left-sided tumors, a splenectomy and/or a distal pancreatectomy may also be required.[67] On the right side, a Whipple procedure (pancreaticoduodenectomy) may be considered but is rarely performed due to its high complication rate and limited efficacy in controlling malignancy.[68]

Surgical Resection Goals and Approaches in Retroperitoneal Liposarcoma Management

The primary goal of surgery for retroperitoneal liposarcoma is complete gross resection of the tumor, even if it necessitates a nephrectomy, bowel resection, revascularization, or other major procedures.[19]

Ideally, complete tumor removal with negative margins (R0 resection) is preferred. However, an R1 resection with microscopic residual disease is often acceptable, as achieving truly negative margins in large tumors is challenging, and follow-up outcomes are comparable.[19][69] Most surgical oncologists who treat retroperitoneal sarcomas differentiate between R0/R1 resections (no visible disease) and R2 resections (where gross tumor remains).[19] Evidence suggests that the prognosis for patients undergoing surgery with R2 resections is similar to that of patients who undergo only a biopsy without any surgery.[19][70][71][72]

The compartmental approach to retroperitoneal liposarcoma surgery has gained support primarily in Europe, particularly in France and Italy.[73][74] The concept involves removing all adjacent organs and structures that are not clearly involved, en bloc with the tumor, to maximize negative margins and improve outcomes. However, this approach remains controversial and is not widely accepted in the United States.[19][75] Although most patients tolerate nephrectomy and partial bowel resection well, extending the procedure to remove additional organs, structures, and surfaces can be more challenging unless there is clear evidence of direct involvement. Despite this, the reported local recurrence rate with compartmental resection is significantly lower (approximately three times less) than with standard surgery.[73][74]

Follow-up for patients who undergo complete macroscopic tumor resection (R0/R1) involves surveillance alone, as studies have not consistently shown a survival benefit for adjuvant radiotherapy or chemotherapy.[19] No distinction is made between R0 and R1 resections in terms of surveillance or further management, as microscopically positive margins (R1) are common due to the anatomical challenges of the disease.[76][77]

A preliminary study involving 81 patients demonstrated improved recurrence-free survival and overall survival in those who underwent total retroperitoneal lipectomy compared to standard surgical therapy.[78]
In highly selected cases, renal autotransplantation may be considered to minimize the risk of kidney failure.[79]

Re-resection for recurrent disease is often associated with better oncologic outcomes compared to nonsurgical management.[80][81] Factors that influence resectability include the disease-free interval, the degree and quality of prior resection, tumor grade (histology), age at the time of repeat resection, the presence of undifferentiated liposarcoma on histology, and whether the tumor is unifocal or multifocal.[19][82] High-grade tumors tend to have higher early recurrence rates, and liposarcomas, in general, are more prone to local recurrence.[19] A review from the Sloan-Kettering Cancer Center indicates that patients with recurrent tumors growing more than 1 centimeter per month may not benefit from resection and should consider enrolling in a clinical trial.[83]

The benefit of surgery for recurrent retroperitoneal sarcomas remains somewhat controversial; however, data support its use in select patients.[84][85][86] Therefore, decisions should be made through shared decision-making, involving the patient, their family, and the healthcare team in a multidisciplinary approach.[19]

Palliative surgery may be considered for symptom relief when a cure is no longer surgically feasible. This may involve tumor resection, including partial resection (eg, debulking), or procedures that do not remove the tumor, such as a diverting colostomy.[87]

Postoperative pain management is effectively managed with an epidural catheter. Early ambulation is encouraged, and the patient's diet is advanced as tolerated. Fluid management can be challenging, particularly in patients with a solitary kidney following nephrectomy. Hospital stays typically range from 5 to 10 days but may vary depending on complications, such as postoperative ileus. Older patients or those with comorbidities may require rehabilitation at a skilled nursing facility after discharge.

Radiation Oncology

Preoperative Radiation Therapy

Preoperative radiation therapy may be considered for patients with resectable retroperitoneal liposarcoma, particularly those with select histologies, such as well-differentiated and low-grade de-differentiated liposarcomas, that carry a high risk of local recurrence. Studies suggest that combining preoperative radiation with surgery reduces the risk of locoregional recurrence compared to surgery alone, although no consistent overall survival benefit has been demonstrated.[30][88]

A large population-based study from the SEER database involving 1700 liposarcoma patients showed no benefit from radiation in disease-specific survival.[88]
A multi-institutional, randomized phase III prospective trial in Europe and North America also showed no survival benefit to preoperative radiation therapy.[30]

Advocates of radiation therapy highlight the following:

About one-fourth of these negative trials had significant deviations in protocols, with 65% related to inadequate tumor volume delineation.[89]
Radiation therapy led to a greater than 50% reduction in local relapse in patients.[19]
Patients were not stratified by histology, but subgroup analysis showed that well-differentiated histology was associated with some benefit from radiation, a finding supported by another study.[19][90]

Potential and theoretical benefits of preoperative radiation therapy include:

Improved local control and reduced recurrence rates.
Tumor shrinkage, potentially making previously unresectable tumors amenable to surgical removal.
Reduced risk of intraperitoneal seeding during surgery.
Greater efficacy when used preoperatively.
Successful outlining of retroperitoneal sarcomas for radiation planning.
Displacement of intestinal contents away from the therapy zone, minimizing gastrointestinal toxicity.[91][92]

Data on adjuvant radiation therapy for retroperitoneal liposarcomas are conflicting, with some studies indicating a survival benefit while others do not.[93][94][95][96][97][98][99][100][101][102][103] Due to these inconsistent results and the known toxicity of postoperative radiation dosages, most oncology guidelines (including NCCN, ASTRO, European Society for Medical Oncology, and the Trans-Atlantic Retroperitoneal Sarcoma Working Group) currently do not recommend adjuvant radiation therapy for retroperitoneal sarcomas.[93][104][105][106]

The recommended preoperative radiation therapy dose is typically 50 to 50.4 Gy, delivered in 25 to 28 daily fractions over about 5.5 weeks. Surgery is usually scheduled 4 to 6 weeks after completing radiation therapy. Preoperative radiation is generally well-tolerated, with fewer acute toxicities than postoperative treatment, which carries higher risks due to the inclusion of surrounding normal tissues in the treatment field.[107]

Radiation treatment planning for preoperative therapy requires careful consideration and is typically conducted at specialized centers, often using techniques such as intensity-modulated radiation therapy (IMRT). No additional adjuvant therapy is recommended for patients receiving preoperative radiation and surgery, and posttreatment surveillance is advised. The standard preoperative radiation dose (50–50.4 Gy) aligns with American Society for Radiation Oncology guidelines, aiming to optimize tumor control while minimizing damage to surrounding healthy tissue.

The role of preoperative radiation therapy for primary retroperitoneal liposarcomas remains unproven, although it may have a potential role in palliative care. Further studies incorporating histological stratification are needed to clarify the potential role of radiation therapy in treating primary retroperitoneal liposarcoma.[19] The potential role of preoperative radiation therapy for patients undergoing compartmental en bloc surgery for retroperitoneal sarcoma has been studied. While recurrence-free survival improved, no significant difference in overall survival was observed.[108]

Palliative Radiotherapy

Palliative radiotherapy can provide symptomatic relief for approximately two-thirds of unresectable or metastatic liposarcoma patients with a favorable prognosis. In such cases, the symptomatic benefits of radiotherapy often outweigh the treatment's inconvenience, cost, and potential adverse effects.[109]

Treatment Planning

Complete resection is the only potential cure for patients with no evidence of distant metastasis on staging imaging. Therefore, all patients with localized retroperitoneal liposarcoma should be considered for surgery, unless preoperative imaging reveals diffuse peritoneal implants (sarcomatosis) or involvement of the mesenteric root, celiac artery, spine, liver hilum, or major vessels that would preclude surgical resection. Additionally, patient age and comorbidities should be considered when assessing the suitability for resection.[110]

For large or high-grade retroperitoneal liposarcomas, preoperative radiation therapy may be considered. When considering the use of chemotherapy in the preoperative or postoperative management of retroperitoneal liposarcoma, it is ideal for patients to participate in clinical trials when available. Additional clinical trials are needed to tailor treatment and optimize care for patients with this challenging malignancy.[25]

Medical Oncology

For patients with unresectable or metastatic retroperitoneal liposarcoma, systemic therapy is typically the treatment of choice and is guided by the tumor's histological subtype.

Certain subtypes of liposarcomas, including myxoid or round cell and pleomorphic variants, respond favorably to anthracycline-based chemotherapy. De-differentiated liposarcomas, although eligible for this treatment, demonstrate more variable response rates. First-line therapy for symptomatic or rapidly progressive disease often includes combination regimens such as doxorubicin plus ifosfamide, trabectedin, or olaratumab in specialized settings. The standard dosage of doxorubicin, a cornerstone drug in liposarcoma treatment, involves 75 mg/m² administered on day 1 of a 21-day cycle, with a maximum cumulative dosage of 450 to 500 mg/m² due to cumulative cardiotoxicity risks. Prophylaxis with dexrazoxane may be considered in patients with borderline cardiac function, although its routine use remains debated.

Efficacy and Toxicities of Combination Anthracycline-Based Therapy

Combination regimens, such as doxorubicin plus ifosfamide, demonstrate superior objective response rates (26% to 40%) compared to single-agent doxorubicin, especially in first-line treatment of high-grade sarcomas. However, these combinations do not significantly extend overall survival, with median progression-free survival typically ranging from 4 to 8 months.[41][111][112] Toxicities are substantial and include febrile neutropenia, fatigue, alopecia, mucositis, nephrotoxicity, and cumulative cardiotoxicity. Lower-toxicity anthracycline derivatives, such as epirubicin or pegylated liposomal doxorubicin, provide a safer profile, although their efficacy in liposarcomas is comparable or slightly lower than doxorubicin. Pegylated liposomal doxorubicin carries an increased risk of cutaneous toxicities, including palmar-plantar erythrodysesthesia.

Role of Gemcitabine-Based Regimens

Gemcitabine, especially combined with docetaxel or dacarbazine, is a viable option for patients with anthracycline-refractory disease or those unsuitable for intensive regimens. Gemcitabine or docetaxel regimens typically include gemcitabine at 900 to 1000 mg/m² on days 1 and 8, with docetaxel at 75 to 100 mg/m² on day 8, in a 21-day cycle.[44] Toxicities include fatigue, peripheral neuropathy, and significant myelosuppression.[44] For older or heavily pretreated patients, single-agent gemcitabine at a fixed dose rate of 10 mg/m²/min or as a continuous infusion offers an alternative.

Treatment Personalization and Quality of Life Considerations

The selection of chemotherapy regimens requires carefully balancing efficacy, toxicity, and individual patient factors, including performance status, comorbidities, and care goals. Combination anthracycline therapy remains the standard for eligible patients, while gemcitabine-based regimens offer essential options for second-line or refractory cases, particularly for older adults due to their manageable toxicity profiles. Low-dose gemcitabine or oral cyclophosphamide regimens are being explored for frail patients to optimize disease control with minimal adverse effects. These strategies highlight the importance of personalized treatment to maintain quality of life and maximize therapeutic outcomes in metastatic liposarcoma management.

Staging

The eighth edition of the Tumor, Node, Metastasis (TNM) system, established by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC), is used to stage retroperitoneal liposarcomas. This system includes distinct prognostic stage groupings that emphasize the importance of tumor grade included in the AJCC/UICC staging system, as noted in the Table below.

The latest guidelines classify tumors into 3 grades based on the degree of differentiation, mitotic activity, and necrosis.

Grade 1: Low-grade tumors
Grade 2: Intermediate to high-grade tumors
Grade 3: High-grade tumors [113]

Table. The Eighth Edition American Joint Committee on Cancer Cancer Staging for Retroperitoneal Sarcoma

T-Stage (Primary Tumor)	Description
TX T0 T1 T2 T3 T4	Primary tumors cannot be assessed No evidence of a primary tumor Tumor ≤5 cm in greatest dimension Tumor >5 cm and ≤10 cm in greatest dimension Tumor >10 cm and ≤15 cm in greatest dimension Tumor >15 cm in greatest dimension
N-Stage (Regional Lymph Nodes)	Description
N0 N1	No regional lymph node metastasis or unknown lymph node status Regional lymph node metastasis
M-Stage (Distant Metastases)	Description
M0 M1	No distant metastasis Distant metastasis
G-Stage (Tumor Grade)	Description
GX G1 G2 G3	Grade cannot be assessed Total differentiation; mitotic count and necrosis score of 2 or 3 Total differentiation; mitotic count and necrosis score of 4 or 5 Total differentiation; mitotic count and necrosis score of 6, 7, or 8

Prognostic Stage Groups
T-Stage	N-Stage	M-Stage	G-Stage	Stage Groups
T1	N0	M0	G1, GX	IA
T2, T3, T4	N0	M0	G1, GX	IB
T1	N0	M0	G2, G3	II
T2	N0	M0	G2, G3	IIIA
T3, T4	N0	M0	G2, G3	IIIB
Any T	N1	M0	Any G	IIIB
Any T	Any N	M1	Any G	IV

Reference for the Table.[113]

Prognosis

The prognosis for retroperitoneal liposarcomas is influenced by several factors. Compared to soft tissue sarcomas at other sites, such as the trunk or limbs, patients with retroperitoneal liposarcomas typically have a worse prognosis.[93] Other factors that affect prognosis include a lower histological tumor grade and stage, absence of positive surgical margins, smaller tumor size, no evidence of necrosis, lack of recurrence, absence of metastases, and younger patient age.[88][114][115] All of these factors significantly impact overall and progression-free survival, with smaller, lower-grade tumors and earlier stages in younger patients being associated with significantly improved outcomes.[88][114][115]

In addition to these, specific survival statistics and factors include:

The 3- and 5-year overall survival rates for tumors larger than 15 cm are 64.3% and 32.1%, respectively, compared to 59.1% and 45.5% for tumors smaller than 15 cm.[114]
A recent retrospective study showed that a negative surgical margin is a strong prognostic indicator for overall survival in patients with primary retroperitoneal liposarcoma.[114]
The 5-year survival rate for well-differentiated retroperitoneal liposarcomas is around 83%, while it is about 20% for de-differentiated tumors.[2]
Older patients (aged 80 or older) with retroperitoneal liposarcomas generally have a worse prognosis.[88]
Ki-67 label index and P53 status also affect prognosis.[115]
Among all prognostic factors, the most significant is the histological grade of the primary tumor.[116]

The most significant factors that negatively impact survival are higher histological grade, larger tumor size, tumor necrosis, and age of 80 or older.[88] The prognosis is considerably worse with R2 resections, so tumor rupture or leaving significant macroscopic disease should be avoided whenever possible.[19][73][117][118] Overall survival has improved gradually over time. In the 1990s, the 5-year overall survival rate was reported at 39%, whereas more recent studies indicate it has improved to approximately 70%.[60][61][119][120]

Complications

Complications associated with retroperitoneal liposarcoma stem from the tumor's expansive growth within the confined retroperitoneal space, which can impact adjacent structures. A major complication is the compression and infiltration of surrounding organs, which can lead to gastrointestinal symptoms, urinary obstruction, or vascular compromise. Neurological complications may also arise if the tumor compresses nerves, resulting in pain, weakness, or sensory deficits.

Surgical management of retroperitoneal liposarcomas presents a range of potential complications due to the complex anatomy of the retroperitoneum and the extensive nature of the resections. Common perioperative challenges include significant blood loss, as the tumor often involves major vessels or adjacent structures. Postoperative complications, such as wound infections, delayed healing, deep vein thrombosis, and ileus, are also frequently observed. Additionally, the extensive nature of the surgery can lead to longer recovery times.

Local recurrence is a relatively common occurrence following surgical resection, with rates ranging from 41% to 55% at 5 years and decreasing to 18% to 40% by 10 years.[121] Significant risk factors for local recurrence include larger tumor size (>15 cm), histological subtype, histopathological grade, and surgical margin status. Incomplete resection further increases the likelihood of recurrence, with patients who undergo macroscopically incomplete resection being 2.5 times more likely to experience local progression.[60]

For locally recurrent retroperitoneal liposarcoma, surgical resection remains the primary treatment approach if the recurrence is isolated and surgically resectable, offering a 5-year survival rate of up to 50%.[80] In cases of multifocal or unresectable recurrences, complete resection is often unachievable. Alternative treatments, such as preoperative radiation therapy, intraoperative radiation therapy (IORT), or regional hyperthermia combined with chemotherapy, may be considered. When surgical resection is not possible, palliative options, including surgical debulking, are sometimes used, although their long-term survival benefit is limited.[122] For widespread metastatic disease, systemic chemotherapy is typically the preferred treatment.

Surgical management of retroperitoneal sarcomas is challenging and associated with significant morbidity. In a large multi-institutional study, the 30-day reoperation rate was 10.5%, and the incidence of severe complications was 16.4%.[123] While a compartmental surgical approach can help reduce recurrence rates, it may lead to increased immediate surgical morbidity. The estimated rate of developing distant metastases ranges from 12% to 22%.[69]

Postoperative and Rehabilitation Care

A physical examination, along with CT imaging of the abdomen and pelvis and a chest CT, should be performed every 3 to 6 months for the first 2 to 3 years following a complete resection of retroperitoneal liposarcoma. Subsequently, imaging should be performed every 6 months for the next 2 years and then annually for at least 10 years.

Patients with retroperitoneal liposarcoma are at risk for late recurrences, necessitating a minimum of 10 years of long-term follow-up. This recommendation is in accordance with the NCCN guidelines.

Deterrence and Patient Education

The most common sign of retroperitoneal liposarcoma is an abdominal tumor that gradually enlarges over weeks to months. Additional symptoms may include leg swelling, weight loss, early satiety, and bloody stools, often accompanied by stomach pain. Patients with a persistent abdominal lump that increases in size over time should seek medical attention promptly.

Enhancing Healthcare Team Outcomes

Interprofessional healthcare providers, including physicians, advanced practice providers, nurses, and pharmacists, must collaborate to deliver patient-centered care for individuals with retroperitoneal liposarcoma. Healthcare providers must possess the necessary clinical expertise and knowledge to effectively diagnose, assess, and treat this condition. This includes being skilled in interpreting radiological and histological findings and maintaining a high level of suspicion when diagnosing this rare disease.

Consultations with general surgery, urology, nephrology, and vascular surgery may be necessary to plan tumor resection, depending on the size and location of the liposarcoma. For surgically unresectable or locally advanced or metastatic lesions, a tumor board discussion involving radiation oncology and medical oncology is recommended to develop an individualized care plan based on evidence-based guidelines. This collaborative approach enhances outcomes, ensures patient-centered treatment, reduces errors, minimizes delays, and improves patient safety. Referring the patient to a center of excellence with extensive experience in managing this rare malignancy should also be considered to optimize outcomes.

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