REVIEW ARTICLE
Retroperitoneal Liposarcoma A Comprehensive Review Adarsh Vijay, MBBS* and Lakshmi Ram, MBBSw
Abstract: Retroperitoneal liposarcomas are rare mesenchymal tumors of the retroperitoneum that typically present with advanced disease and often carry a poor prognosis. Because of their rarity and anatomic location, these malignant tumors can cause a diagnostic dilemma and present several therapeutic challenges. They are usually associated with a high rate of recurrence despite grossly complete resection, thus requiring long-term and often indefinite follow-up. Relevant data on this topic was procured and synthesized with the aid of a comprehensive Medline search in addition to oncologic, pathologic, urologic, radiologic, and surgical literature review on retroperitoneal sarcomas. This article provides an in-depth review into the natural history, pathology, clinical manifestations, and prognostic features of retroperitoneal liposarcomas. It also discusses the reliability of diagnostic procedures and novel curative approaches that are currently being evaluated for the disease. Key Words: retroperitoneal, liposarcoma, sarcoma, tumor, malignant
(Am J Clin Oncol 2015;38:213–219)
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etroperitoneal sarcomas are rare malignant tumors that account for approximately 15% of all sarcomas and have an overall incidence of 0.3% to 0.4% per 100,000 of the population.1 Liposarcomas (41%) comprise the most common type of sarcoma arising in the retroperitoneum, followed by leiomyosarcoma and malignant fibrous histiocytoma.2 Retroperitoneal liposarcomas alone encompass 0.07% to 0.2% of all neoplasias.3 Liposarcomas may occur wherever fat is present. Between 12% and 40% occur in the retroperitoneum, where about 35% originate in the perirenal fat.5 The rarity of retroperitoneal liposarcomas, combined with the varying clinical courses of the various histologic subtypes, has complicated our understanding of these tumors and impeded the development of effective therapies.
NATURAL HISTORY AND PATHOPHYSIOLOGY On the basis of morphologic features and cytogenetic aberrations, liposarcomas are classified into 5 types.6 These are (1) well-differentiated liposarcoma (WDLPS); (2) dedifferentiated liposarcoma (DDLPS); (3) myxoid/round cell liposarcoma (MLPS); (4) pleomorphic liposarcoma (PLPS); and (5) mixed liposarcoma. WDLPS is also classified into 3 subtypes: lipomatous, sclerotic, and inflammatory liposarcoma. From the Departments of *General Surgery; and wAnaesthesiology, Hamad Medical Corporation, Doha, Qatar. The authors declare no conflicts of interest. Reprint: Adarsh Vijay, MBBS, General Surgery Department, Hamad Medical Corporation, PO Box 3050, Doha, Qatar. E-mail: dradarsh [email protected]. Copyright r 2013 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/3802-0213 DOI: 10.1097/COC.0b013e31829b5667
American Journal of Clinical Oncology
WDLPS and DDLPS comprise the most common liposarcomas arising in the retroperitoneum. The natural history of WDLPS is one of a slow-growing tumor that often recurs locally but has minimum metastatic potential. Some amount of dedifferentiation or transdifferentiation can account for the transformation of a quarter of the WDLPS cases into higher grade tumors.7 DDLPS may be primary or may develop in a preexisting WDLPS and are usually associated with a superior growth and metastatic rate. MLPSs pursue an aggressive clinical course and also have a marked propensity for metastasis, often to unusual sites like bone and skin. PLPSs typically occur in the elderly and are very aggressive tumors with a high metastatic potential. Mixed liposarcoma constitute the rarest type, and show morphologic features of MLPS, PLPS, and/or WDLPS/DDLPS.6 They usually have a poor prognosis. Cytogenetically, WDLPS and DDLPS are characterized by supernumerary circular (ring) and giant rod chromosomes with amplification of the 12q13-15 region.8 Several tumor associated genes located at 12q, MDM2, CDK4, SAS, and HMGA2 have been implicated in the pathogenesis of WDLPS.9 Coamplification of MDM2 and CDK4 which are colocated on chromosome 12 can inactivate the p53 and pRb tumor suppressor pathways. Although the process of dedifferentiation of WDLPS is not well understood, it has been associated with mutations in p53 and overexpression of proto-oncogene JUN.10 The consistent cytogenetic abnormality in MLPS is translocation t(12;16)(q13;p11.2) that involves fusion between transcription factor gene CHOP on chromosome 12 and FUS gene on chromosome 16.11 Rarely, CHOP may fuse with the EWS gene on chromosome 22 in translocation t(12;22)(q13;q12). PLPSs usually have complex cytogenetic abnormalities without any acknowledged characteristic aberrations.
PRESENTATION AND EVALUATION Although retroperitoneal liposarcomas can occur in any age group, their peak incidence is in the sixth and seventh decades with no clear sex or racial predilection.4 Most of these are malignant from their inception, with only a few exceptions originating from benign lipomas.5 The rate at which these neoplasms grow varies greatly from case to case and even in the same individual. Usually, they grow slowly, at times rapidly, and occasionally they remain inert for a period of time and then develop an aggravation of growth rate.5 Because of the large potential spaces of the retroperitoneum, liposarcomas in this area tend to grow to very large sizes before they produce symptoms. On an average, half of the retroperitoneal sarcomas are >20 cm when diagnosed.4 Moreover, when symptoms do occur, they are nonspecific and include abdominal pain/fullness, flank pain, early satiety, lower extremity swelling, or pain. Local invasion or compression of the retroperitoneal structures may present as neurological, musculoskeletal, and obstructive urinary/bowel symptoms. Nevertheless, the majority
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present as an asymptomatic abdominal mass found incidentally on abdominal examination. A retroperitoneal liposarcoma has to be distinguished from other possible entities such as adrenal/renal/pancreatic tumors, advanced gastrointestinal (GI) carcinomas, benign peripheral nerve sheath tumors, testicular/germ cell tumors, lymphomas, lymphangiomas, retroperitoneal fibrosis, and metastatic carcinomas. Serum markers may be used to rule out germ cell tumors. Immunostains and flow cytometry may be used to exclude lymphomas. Upper GI endoscopy with biopsy may be diagnostic in tumors that appear to have arisen from the stomach, pancreas, or duodenum. Likewise, colonoscopy with biopsy can be useful in diagnosing tumors arising from the colon. Once these diagnoses are ruled out or are considered of low probability, sarcoma is the most likely diagnosis. Currently, no consensus exists in the literature regarding the need for a pretreatment percutaneous biopsy of a suspected retroperitoneal sarcoma (RPS). In the retroperitoneum, neoplasms are so much more likely to be liposarcomas than benign lipomas that it is best to assume malignancy and proceed with surgical excision without preliminary biopsy.5 Biopsy should be reserved for patients who are being considered for preoperative radiotherapy and/or chemotherapy, patients who have unresectable tumors, and patients with hematogenous metastases. Tissue may be obtained through fine-needle aspiration or core-needle biopsy, with the later being preferred because a pathologic diagnosis commonly relies on tissue architecture. Open biopsy should be used only if repeated percutaneous biopsies have failed and the management would change based on a definitive RPS diagnosis.
ROLE OF IMAGING Most sarcomas cannot be characterized to cell type with imaging, with an exception being liposarcoma. The presence of macroscopic fat ascertains the diagnosis of a liposarcoma. Nevertheless in instances where these tumors are composed mostly of soft tissue and fluid components, differentiating a liposarcoma from other types of sarcomas become unfeasible.12 Imaging can also be reliably used to predict the grade and prognosis of liposarcomas. Low-grade liposarcomas are usually associated with mostly fat and very little soft tissue giving them a radiolucent appearance on computed tomography (CT). However, large amount of soft tissue with little or no macroscopic fat may indicate either a low-grade, intermediate-grade, or high-grade liposarcoma. Intermediate-grade tumors appear relatively lucent with transverse septations. High-grade tumors appear dense and heterogenous and enhances with intravenous contrast. WDLPSs tend to have smooth margins, a lobular contour, and a predominate attenuation of fat with no visible calcification.13 Internal nodular septations of soft tissue attenuation that demonstrate mild to moderate enhancement help distinguish them from benign lipomas.14 DDLPSs are visualized as a predominant nonlipomatous mass within, adjacent to or encompassing a fatty mass.15 Calcification within the mass is associated with a poor prognosis. MLPSs tend to have attenuation less than that of muscle and a unique enhancement pattern consisting of gradual, heterogenous, and often incomplete enhancement.13 Some myxoid tumors may appear cystic on noncontrast images, but demonstrate internal enhancement after the administration of contrast agents. PLPSs have predominant attenuation similar to muscle with a varying degree of contrast enhancement.16 CT is the most commonly used modality for the diagnosis, staging, and preoperative evaluation of retroperitoneal liposarcomas.17 These tumors usually have a typical
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appearance on CT. The kidney is usually rotated and displaced to the periphery of the mass but may be encased in it. On intravenous contrast, the kidney usually maintains its normal internal architecture although there might be a degree of pelviureteric obstruction depending on the tumor size and degree of displacement. Imaging the abdomen and pelvis aid in evaluating the primary site, and provides valuable information regarding intraperitoneal seeding, regional lymph node involvement, and distant metastasis to liver. CT scanning of the chest can effectively rule out metastasis to the lungs. Although there are reports suggesting an equivalent efficacy of magnetic resonance imaging (MRI) in diagnosing retroperitoneal liposarcoma, large-scale comparisons of CT and MRI techniques in the setting of retroperitoneal liposarcomas are scarce.18 The use of MRI has been reserved to address questions regarding neurovascular and muscular invasion. MRI and ultrasound are useful compliments to CT in characterizing indeterminate liver lesions. Abdominal radiographs in patients with retroperitoneal liposarcomas are seldom diagnostic but may reveal a softtissue displacing, gas-filled structure and effacement of the normal fat planes. Rarely, calcification can be made out. Intravenous urography may reveal renal or ureteric displacement with or without hydronephrosis. Depending on the location of the tumor, contrast-enhanced studies of the GI tract may show displacement of the stomach, small bowel, or colon. On ultrasonography, liposarcomas are usually hyperechoic and helps confirm the presence of a mass. However, ultrasonography fails to distinguish poorly differentiated liposarcomas from other types of retroperitoneal masses. Ultrasound or CT scan may also aid percutaneous biopsies of the tumor. Owing to the possibility of tumor dissemination at the time of biopsy, histopathological study of the surgical sample remains the standard for diagnosis.19,20 More recently, nuclear imaging (positron emission tomography with 2-fluoro-deoxyglucose) is emerging as an important imaging modality in the management of patients with retroperitoneal liposarcoma.21 Its applications include tumor grading, staging, and evaluation for tumor recurrence.
PROGNOSTIC FACTORS Several prognostic factors have been identified for survival, as well as distant and local recurrence. The most consistent prognostic factor is the completeness of the surgical resection with negative margins. The inability to attain negative microscopic surgical margins due to anatomic constrains or local tumor invasion has been cited by several studies as a potent negative prognostic factor for disease-specific survival.22 Histologic grade, reflected in the extent of differentiation, remains a vital factor concerning clinical course and prognosis of patients with retroperitoneal liposarcoma. Sarcomas are designated as grade 1, G1 (well-differentiated), grade 2, G2 (moderately well-differentiated), or grade 3, G3 (poorly differentiated/undifferentiated) depending on the degree of cytologic atypia, number of mitoses, and presence and extent of necrosis. G1 comprises low-grade tumors as compared to G2 and G3 tumors which are considered high grade. The 5-year survival rates of low-grade myxoid (< 5% round cell component) and well-differentiated variants is about 90%. High-grade variants, such as pleomorphic, round cell (> 5% round cell component), and dedifferentiated tumors, have 5-year survival rates of 30% to 50%, 60%, and 75%, respectively.23 The metastatic potential of well-differentiated tumors is minimal, whereas that of dedifferentiated tumors is 10% to 15%.
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High-grade tumors are associated with high rates of local recurrence and distant metastasis. Furthermore, DDLPSs are 4 times more likely to cause local recurrence when compared with well-differentiated lesions.23 Not surprisingly, local disease accounts for most deaths associated with retroperitoneal liposarcomas.24 Other negative prognostic indicators include multifocal disease and invasion of adjacent structures, both of which restrict the possibility of a complete resection of all tumors.25 The current American Joint Committee on Cancer staging system used for soft-tissue sarcomas is better suited for extremity sarcomas. The American Joint Committee on Cancer system considers histologic grade, tumor size, tumor depth, and the presence or absence of lymph node and distant metastasis.26 It is not representative of patients with retroperitoneal liposarcomas and has limited discriminative power. The 5-cm threshold used in this system is of limited value for retroperitoneal liposarcomas as nearly all tumors are >5 cm and deep to the superficial fascia. Hence, localized retroperitoneal liposarcomas are nearly always classified as stage IIB or III, with the distinction between these 2 stages being made only on the basis of histologic grade. However, studies that used a higher threshold for tumor size have shown an improved predictive outcome.27 The importance of patient age as a prognostic variable has also been stressed in multiple studies.28 Thus, the situation demands an improved staging normogram specific for retroperitoneal liposarcomas which is capable of stratifying patients prognostically. One such normogram based on histologic subtype as opposed to tumor grade was put forward by Dalal et al.29 With a concordance index of 0.827 and high calibration accuracy, the authors claim this normogram to improve prediction of disease-specific survival and aid in more accurate identification of patients appropriate for adjuvant therapy.
MANAGEMENT Surgery The definitive treatment of primary retroperitoneal liposarcomas is complete surgical resection of the tumor with intent to obtain negative microscopic margins. A single-institutional study of 500 retroperitoneal sarcoma cases reported a median survival of 103 months for those who underwent complete resection with grossly negative margins in contrast to 18 months for those who underwent incomplete resection.30 However, the complete resection of these tumors is often very challenging (Table 1). Because of the large potential spaces of the retroperitoneum and local invasiveness of liposarcomas, these lesions are very large when diagnosed and often involve many adjacent organs and structures. The most common difficulties are gaining access behind the tumor to identify retroperitoneal structures to be preserved, or in obtaining control of the major vessels of organs to be removed. Furthermore, high degrees of adipocyte differentiation in the tumor can pose
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difficulty at distinguishing it from retroperitoneal fat. Thus, the determination of a safe margin for resection becomes difficult. The superior survival advantage conferred by a complete surgical resection often warrants an en-bloc local resection to include contiguous organs, such as kidneys, adrenals, or segments of small bowel/colon.36,37 An aggressive quasicompartmental approach to RPS resection has been advocated recently by several European centers. Authors advocate an improvement in local recurrence rates compared with historical controls. The basis for the European argument was that the rates of major complication (18%), early reoperation (12%), and postoperative mortality (3%) were comparable to reports by authors who use a more conventional, lessaggressive resection strategy.38 It was, however, noted that morbidity increased with increasing numbers of organs resected en bloc with the tumor. The aggressive surgical approach was rivaled by Strauss et al,33 who reported 5-year local recurrence-free and disease-specific survival rates of 55% and 75%, respectively. The management of tumors that involve unresectable vital structures or tumors whose removal would cause unacceptable morbidity is more complex. Options that follow a diagnostic biopsy include primary treatment with radiotherapy or chemotherapy to downstage tumors before resection.40 Observation is considered for asymptomatic patients. Unresectable tumors that become resectable after primary radiotherapy or chemotherapy should be surgically removed. Symptomatic patients with tumors that remain unresectable after primary treatment can be subjected to palliative surgery for symptom control. Infact, some studies also report prolonged survival in addition to symptom palliation following partial resection of liposarcomas as compared to those who only underwent biopsy.41 In patients with stage IV disease, resection should always be considered for resectable metastatic disease. Because of the tumor bulk and possible need for removing adjacent organs, open approach is generally preferred by most surgeons. However, the growing expertise in minimally invasive surgery has resulted in its improved application to retroperitoneal liposarcomas. Laparoscopy is a viable and valid alternative to open procedures in selected patients with retroperitoneal liposarcomas and can offer clinical outcomes comparable to open procedures in terms of disease control and better outcomes in terms of hospital stay, morbidity, cosmesis, and patient recovery.42
Role of Adjuvant/Neoadjuvant Therapy While the best outcomes are observed in patients with negative surgical margins, the highly aggressive nature of retroperitoneal liposarcomas and their propensity for local recurrence and distant metastasis in spite of obtaining clear surgical margins demand the need for complementary adjuvant/neoadjuvant therapy.
TABLE 1. Resection Margin Status in Retroperitoneal Sarcomas
References
No. Patients
Lee et al31 Strauss et al33 Bonvalot et al32 van Dalen et al34 Alldinger et al35 Erzen et al36
21 200 374 115 117 100
R0 (%) 11 55 176 78 20 55
(52.4) (28) (47) (68) (17) (55)
R1 (%)
R2 (%)
R Status Unknown
Comment
10 (47.6) 85 (42) 103 (28)
— 30 (15) 38 (10) 37 (32) 41 (35) 3 (2)
— 30 (15) 57 (15) — 2 (2) —
— — 8 biopsied only 8 explored only — 2 biopsied only
54 (46) 42 (42)
R0 indicates microscopically complete resection; R1, microscopically positive margins; R2, macroscopically incomplete resection.
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Copyright
— 48 — 23 — 59 — 29
EBRT indicates external beam radiotherapy; IORT, intraoperative radiotherapy; Sx, surgery; XRT, radiotherapy.
42 10 10 77 — — —
—
— 50 — — — 59 — 38 38 — — 20 — 17 —
—
— — 37.5 — 54.6 — 68.5 — 29 — — — — — 200
—
— 44
XRT + XRT
51.8 49 — —
XRT + XRT
27.5 — — 23
XRT + XRT
61.9 52 — — 31.5 29
XRT + XRT
41.4 47 — — — — — — 12 51 40 89 — — — 34
% Local Recurrence (5 y) % Local Control (5 y) % Diseasefree Survival (5 y) IORT + Adjuvant/ Median EBRT + IORT Neoadjuvant FollowIORT Only Chemotherapy up (mo) r
Lee et al48 Stoeckle et al28 Strauss et al33 Gieschen et al57 Petersen et al47
Studies evaluating the role of preoperative RT have shown to improve the probability of local control with minimum radiation-related toxicities.53,54 Preoperative radiation may be a safer alternative as the tumor bulk can displace adjacent normal tissue that could be dose limiting in the
References
Neoadjuvant Radiotherapy
Postoperative EBRT + Adjuvant/ Neoadjuvant Chemotherapy
Despite advances in delivery techniques and improved recurrence-free survival, postoperative radiation is clearly associated with significant risk of acute and late bowel toxicity.49 After the large tumor mass that had been displacing adjacent viscera is removed, the bowel tends to fall into the resection bed where it may become fixed by postoperative adhesions thereby making delivery of RT to the resection site more challenging. The time delay required between surgery and radiation has been criticized to promote multiplication of neoplastic cells in residual disease.
PrePostoperative operative Sx EBRT EBRT Only Alone Alone
Adjuvant Radiotherapy
TABLE 2. Radiation Therapy in Retroperitoneal Sarcomas
Retroperitoneal liposarcomas are radiosensitive tumors as compared to other retroperitoneal sarcoma subtypes. Because of the rarity of these tumors, combined with the varying clinical courses of the various histologic subtypes, randomized prospective studies evaluating the efficacy of radiotherapy in addition to surgery are hard to come by. Adjuvant radiation therapy (RT) in the preoperative setting is being evaluated in an ongoing European organisation research treatment cancer randomized trial. Outcomes of retrospective studies have been criticized due to the potential for selection/confounding bias. Despite these limitations, multiple studies have strongly suggested that RT can reduce the risk of local recurrence, and lengthens the recurrence-free interval.27,43 However, there is a paucity of data substantiating favorable impact with this therapy on overall patient survival.44,45 Besides, incomplete resections (margin positive) and nonoperable tumors warrant the use of radiotherapy to provide local tumor control and longer relapse free survival.46 RT for retroperitoneal liposarcoma patients is complex because it requires decisions not only on the “timing” of administration (eg, neoadjuvant, intraoperative, adjuvant), but also the “technique” of delivery (Table 2). However, the prime concern remains the increased risk of treatment-related toxicity to visceral structures that are highly radiosensitive, due to their rapidly proliferating mucosa and rich blood supply. The relatively low radiation tolerance for surrounding normal tissues (liver, kidney, GI tract, spinal cord) predisposes them to the risk of intestinal perforation, peritonitis, and peripheral neuropathy. Controversy exists on the effect of radiation dosage on local disease control. Earlier studies support the need of increased radiation doses for more effective local control, particularly in cases of microscopic residual disease.49 However, more recent studies report no advantage in local control associated with radiation dose-escalation with either external beam radiotherapy (EBRT) or intraoperative radiotherapy (IORT).50,51 The need to administer adequate radiation doses, without increasing the possibility of normal tissue toxicity has paved way for more refined delivery methods. Such techniques include intensity-modulated RT, 3-dimensional radiation therapy (3D-RT), helical tomotherapy, respiratory-guided therapy, image-guided RT, proton or heavy ion RT, and stereotactic RT. The use of intensity-modulated RT was found to yield superior treatment plans with respect to overall radiation dose conformality and good tolerance.52
% Overall Survival (5 y)
Radiotherapy
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postoperative setting. This approach also allows the target volume to be easily delineated for treatment planning, and treating the tumor before surgery theoretically diminishes the risk of peritoneal/locoregional seeding at the time of surgery. Tumor regression in response to therapy may also facilitate resection.
IORT This approach enables direct targeting of the resection bed with a high dose of radiation while nearby radiosensitive normal tissues are mechanically retracted out of the treatment field. IORT can be delivered using electrons or with brachytherapy catheters. The biological effectiveness of single-dose IORT is thought to be equivalent to 1.5 to 2.5 times the same total dose of fractionated EBRT.55 Nonrandomized studies of IORT in patients undergoing surgery suggest high recurrence-free survival rates.56,57 Peripheral neuropathy and ureteral injuries appear to be common morbidities associated with IORT. On the basis of existing data, it seems preoperative EBRT combined with surgical resection of the retroperitoneal liposarcoma is feasible and safe. Although data suggest that addition of IORT to EBRT improves local control compared with EBRT alone, dose-escalation attained with this combination adds further toxicity.57,58
Chemotherapy The role of adjuvant or neoadjuvant chemotherapy in the treatment of retroperitoneal liposarcomas remains controversial to date. The potential role for chemotherapy includes neoadjuvant cytoreductive therapy, sensitisizing the tumor to radiation, and as definitive therapy for unresectable tumors. Although randomized trials suggest benefit from adjuvant chemotherapy for extremity sarcomas, no trial shows a clear improvement in outcome for retroperitoneal liposarcomas. Recent data indicate a potential role for trabectedin in the treatment of MLPSs.59 Although early data from randomized trials suggested a poorer outcome for patients who received either preoperative or postoperative chemotherapy,30 the use of systemic therapy continues to be investigated.60 The effectiveness of intraoperative or postoperative hyperthermic total abdominal chemotherapeutic perfusion is also being scrutinized.61 Donahue and colleagues reported the histologically responding primary high-grade retroperitoneal sarcomas treated with chemotherapy to demonstrate significantly improved 5-year diseasespecific survival compared with the nomogram prediction for such patients.62 There is increasing interest in concurrent chemotherapy and RT as a treatment strategy for retroperitoneal liposarcomas. A handful of studies have shown such combination to be feasible and safe.60,63 Eilber et al64 from the University of California, Los Angeles reported 6 of 23 patients treated preoperatively with doxorubicin, ifosfamide, and cisplatin plus concurrent RT (28 Gy) to have no residual tumor in the resected specimen.
Retroperitoneal Liposarcoma
days.66 Karakousis et al67 reported 10-year survival rates of 57% for primary tumors versus 26% for locally recurrent tumors, thus indicating the low long-term salvage rate for recurrent retroperitoneal liposarcomas. Local recurrence is much more common than distant metastases and hence, complete excision of the lesion will account to a better outcome. Five-year local recurrence rates after complete gross resection are approximately 50% for welldifferentiated and 80% for dedifferentiated retroperitoneal liposarcomas.22 Recurrences that are diagnosed and operated early enjoy complete excision rates in about 90% of the patients.68 Five-year survival rates for reoperated patients were comparable to those with primary sarcoma, if a radical resection can be achieved.69 Sadly, many recurrences are diagnosed late in the course of the disease, leading to incomplete resection, which then leads to rerecurrence in about 50% of patients. Factors associated with a favorable outcome after reoperation include a long recurrence-free interval and complete resection.70 The addition of radiation or chemotherapy in the treatment of locally recurrent disease remains controversial. However, it should be considered strongly in patients presenting with recurrence, and had not received adjuvant/ neoadjuvant treatment after primary resection. Clinical follow-up is not promising as up to 50% of patients are asymptomatic, and if symptoms are present, they are usually nonspecific. As most recurrences are local, careful scrutiny of the resection site for subtle changes on follow-up imaging is essential. Local recurrences can often be misinterpreted as postoperative scarring/fibrosis. Also small, recurrent liposarcomas can be difficult to distinguish from normal retroperitoneal fat on imaging. Recurrent liposarcomas usually have imaging characteristics such as attenuation similar to that of the primary tumor, which along with the fact that, fat in a recurrent liposarcoma is of slightly higher CT attenuation when compared to normal retroperitoneal fat, aids in the diagnosis of a recurrence.66 The potential of retroperitoneal liposarcomas for locoregional recurrence/metastases warrants a thorough search of the draining nodes, peritoneal surfaces, and liver before evaluation for distant metastases. Follow-up imaging is usually performed with CT or MRI with the frequency of follow-up being often dictated by the completeness of the tumor resection, tumor type, and grade.71 The current guidelines from the National Comprehensive Cancer Network for the surveillance of soft-tissue sarcomas arising in the retroperitoneum recommend that patients with low-grade tumors who have been successfully resected should have a follow-up physical examination with imaging (chest/abdominal/pelvic CT) every 3 to 6 months for 2 to 3 years, then annually. For those with high-grade tumors that have been successfully resected should have a follow-up physical examination with imaging (chest/ abdominal/pelvic CT) every 3 to 6 months for 2 to 3 years, then every 6 months for the next 2 years, and then annually.72
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RECURRENCE AND FOLLOW-UP Retroperitoneal liposarcoma frequently recurs within 6 months to 2 years after the initial surgical resection. They tend to infiltrate adjacent tissues and structures with skip areas (satellites), thus explaining the occurrence of late and unexpected recurrences despite complete surgical resection with negative margins.65 They usually show a rapid growth pattern, with a mean tumor volume doubling time of around 100 Copyright
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of the French Cancer Center Federation Sarcoma Group. Cancer. 2001;92:359–368. Dalal KM, Kattan MW, Antonescu CR, et al. Subtype specific prognostic nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or trunk. Ann Surg. 2006;244:381–391. Lewis JJ, Leung D, Woodruff JM, et al. Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg. 1998;228:355–365, Review. Lee SY, Goh BK, Teo MC, et al. Retroperitoneal liposarcomas: the experience of a tertiary Asian center. World J Surg Oncol. 2011;9:12–17. Bonvalot S, Rivoire M, Castaing M, et al. Primary retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control. J Clin Oncol. 2009;27:31–37. Strauss D, Hayes A, Thway K, et al. Surgical management of primary retroperitoneal sarcoma. Br J Surg. 2010;97:698–706. van Dalen T, Plooij J, van Coevorden F, et al. Dutch Soft Tissue Sarcoma Group. Long-term prognosis of primary retroperitoneal soft tissue sarcoma. Eur J Surg Oncol. 2007;33:234–238. Alldinger I, Yang Q, Pilarsky C, et al. Retroperitoneal soft tissue sarcomas: prognosis and treatment of primary and recurrent disease in 117 patients. Anticancer Res. 2006;26(2B):1577–1581. Erzen D, Sencar M, Novak J. Retroperitoneal sarcoma: 25 years of experience with aggressive surgical treatment at the Institute of Oncology, Ljubljana. J Surg Oncol. 2005;91:1–9. Marinello P, Montresor E, Iacono C, et al. Long term results of aggressive surgical treatment of primary and recurrent retroperitoneal sarcomas. Chir Ital. 2001;53:149–157. Gronchi A, Lo Vullo S, Fiore M, et al. Aggressive surgical policies in a retrospectively reviewed single-institution case series of retroperitoneal soft tissue sarcoma patients. J Clin Oncol. 2009;27:24–30. Elias A, Ryan L, Sulkes A, et al. Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol. 1989;7:1208–1216. Shibata D, Lewis JJ, Leung DH, et al. Is there a role for incomplete resection in the management of retroperitoneal liposarcomas? J Am Coll Surg. 2001;193:373–379. Shalhav AL, Chan SW, Bercowsky E, et al. Laparoscopic exploration in the management of retroperitoneal masses. JSLS. 1999;3:209–214. Le Pe´choux C, Musat E, Baey C, et al. Should adjuvant radiotherapy be administered in addition to front-line aggressive surgery (FAS) in patients with primary retroperitoneal sarcoma? Ann Oncol. 2013;24:832–837. Choi AH, Barnholtz-Sloan JS, Kim JA. Effect of radiation therapy on survival in surgically resected retroperitoneal sarcoma: a propensity score-adjusted SEER analysis. Ann Oncol. 2012;23:2449–2457. Tseng W, Martinez S, Do L, et al. Lack of survival benefit following adjuvant radiation in patients with retroperitoneal sarcoma: a SEER analysis. J Surg Res. 2011;168:e173–e178. Azpiazu AP, Muro BI, De Frutos GA, et al. Tumores retroperitoneales. Liposarcoma mixoide retroperitoneal. Presentacio´n de un nuevo caso. Arch Esp de Urol. 2000;53:170–173. Petersen IA, Haddock MG, Donohue JH, et al. Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 2002;52:469–475. Lee HJ, Song SY, Kwon TW, et al. Treatment outcome of postoperative radiotherapy for retroperitoneal sarcoma. Radiat Oncol J. 2011;29:260–268. Fein DA, Corn BW, Lanciano RM, et al. Management of retroperitoneal liposarcomas: does dose escalation impact on locoregional control? Int J Radiat Oncol Biol Phys. 1995;31:129–134. Ballo M, Zagars G, Pollock R, et al. Retroperitoneal soft tissue sarcoma: an analysis of radiation and surgical treatment. Int J Radiat Oncol Biol Phys. 2007;67:158–163. Gilbeau L, Kantor G, Stoeckle E, et al. Surgical resection and radiotherapy for primary retroperitoneal soft tissue sarcoma. Radiother Oncol. 2002;65:133–136. Paumier A, Le Pechoux C, Beaudre A, et al. IMRT or conformal radiotherapy for adjuvant treatment of retroperitoneal sarcoma? Radiother Oncol. 2011;99:73–78.
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53. Pawlik TM, Pisters PW, Mikula L, et al. Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma. Ann Surg Oncol. 2006;13:508–517. 54. Tzeng CW, Fiveash JB, Popple RA, et al. Preoperative radiation therapy with selective dose escalation to the margin at risk for retroperitoneal sarcoma. Cancer. 2006;107:371–379. 55. Gunderson LL, Shipley WU, Suit HD, et al. Intraoperative irradiation: a pilot study combining external beam photons with “boost” dose intraoperative electrons. Cancer. 1982;49: 2259–2266. 56. Krempien R, Roeder F, Oertel S, et al. Intraoperative electronbeam therapy for primary and recurrent retroperitoneal soft-tissue sarcoma. Int J Radiat Oncol Biol Phys. 2006;65:773–779. 57. Gieschen HL, Spiro IJ, Suit HD, et al. Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys. 2001;50:127–131. 58. Dziewirski W, Rutkowski P, Nowecki ZI, et al. Surgery combined withintraoperative brachytherapy in the treatment of retroperitoneal sarcomas. Ann Surg Oncol. 2006;13:245–252. 59. Grosso F, Jones RL, Demetri GD, et al. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol. 2007;8:595–602. 60. Pisters PW, Ballo MT, Fenstermacher MJ, et al. Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J Clin Oncol. 2003;21:3092–3097. 61. Sugarbaker PH. Early postoperative intraperitoneal adriamycin as an adjuvant treatment for visceral and retroperitoneal sarcomas. Cancer Treat Res. 1996;81:7–14.
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62. Donahue TR, Kattan MW, Nelson SD, et al. Evaluation of neoadjuvant therapy and histopathologic response in primary, high-grade retroperitoneal sarcomas using the sarcoma nomogram. Cancer. 2010;116:3883–3891. 63. Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without ifosfamide for adult soft-tissue sarcoma. Am J Clin Oncol. 2002;25:468–473. 64. Eilber F, Eckardt J, Rosen G, et al. Preoperative therapy for soft tissue sarcoma. Hematol Oncol Clin North Am. 1995;9:817–823. 65. Goertz RS, Lenfers BH, Goertz GH. Huge liposarcoma of the left retroperitoneum. Am J Surg. 2009;197:e59–e60. 66. Kim EY, Kim SJ, Choi D, et al. Recurrence of retroperitoneal liposarcoma: imaging findings and growth rates at follow-up CT. AJR Am J Roentgenol. 2008;191:1841–1846. 67. Karakousis CP, Gerstenbluth R, Kontzglous K, et al. Retroperitoneal sarcomas and their management. Arch Surg. 1995;130: 1104–1109. 68. Hassan I, Park SZ, Donohue JH, et al. Operative management of primary retroperitoneal sarcomas: a reappraisal of an institutional experience. Ann Surg. 2004;239:244–250. 69. Ane SS, Jacob ML, Mette S, et al. Intraabdominal and retroperitoneal soft-tissue sarcomas—outcome of surgical treatment in primary and recurrent tumors. World J Surg Oncol. 2010;8:81. 70. Wang YN, Zhu WQ, Shen ZZ, et al. Treatment of locally recurrent soft tissue sarcomas of the retroperitoneum: report of 30 cases. J Surg Oncol. 1994;56:213–216. 71. Cormier JN, Pollock RE. Soft tissue sarcoma. CA Cancer J Clin. 2004;54:94–109. 72. NCCN Clinical Practice Guidelines in Oncology. Available at http://www.nccn.org/professionals/physician_gls/PDF/sarcoma.pdf. Accessed April 8, 2010.
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219
Retroperitoneal Liposarcoma A Comprehensive Review Adarsh Vijay, MBBS* and Lakshmi Ram, MBBSw
Abstract: Retroperitoneal liposarcomas are rare mesenchymal tumors of the retroperitoneum that typically present with advanced disease and often carry a poor prognosis. Because of their rarity and anatomic location, these malignant tumors can cause a diagnostic dilemma and present several therapeutic challenges. They are usually associated with a high rate of recurrence despite grossly complete resection, thus requiring long-term and often indefinite follow-up. Relevant data on this topic was procured and synthesized with the aid of a comprehensive Medline search in addition to oncologic, pathologic, urologic, radiologic, and surgical literature review on retroperitoneal sarcomas. This article provides an in-depth review into the natural history, pathology, clinical manifestations, and prognostic features of retroperitoneal liposarcomas. It also discusses the reliability of diagnostic procedures and novel curative approaches that are currently being evaluated for the disease. Key Words: retroperitoneal, liposarcoma, sarcoma, tumor, malignant
(Am J Clin Oncol 2015;38:213–219)
R
etroperitoneal sarcomas are rare malignant tumors that account for approximately 15% of all sarcomas and have an overall incidence of 0.3% to 0.4% per 100,000 of the population.1 Liposarcomas (41%) comprise the most common type of sarcoma arising in the retroperitoneum, followed by leiomyosarcoma and malignant fibrous histiocytoma.2 Retroperitoneal liposarcomas alone encompass 0.07% to 0.2% of all neoplasias.3 Liposarcomas may occur wherever fat is present. Between 12% and 40% occur in the retroperitoneum, where about 35% originate in the perirenal fat.5 The rarity of retroperitoneal liposarcomas, combined with the varying clinical courses of the various histologic subtypes, has complicated our understanding of these tumors and impeded the development of effective therapies.
NATURAL HISTORY AND PATHOPHYSIOLOGY On the basis of morphologic features and cytogenetic aberrations, liposarcomas are classified into 5 types.6 These are (1) well-differentiated liposarcoma (WDLPS); (2) dedifferentiated liposarcoma (DDLPS); (3) myxoid/round cell liposarcoma (MLPS); (4) pleomorphic liposarcoma (PLPS); and (5) mixed liposarcoma. WDLPS is also classified into 3 subtypes: lipomatous, sclerotic, and inflammatory liposarcoma. From the Departments of *General Surgery; and wAnaesthesiology, Hamad Medical Corporation, Doha, Qatar. The authors declare no conflicts of interest. Reprint: Adarsh Vijay, MBBS, General Surgery Department, Hamad Medical Corporation, PO Box 3050, Doha, Qatar. E-mail: dradarsh [email protected]. Copyright r 2013 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/15/3802-0213 DOI: 10.1097/COC.0b013e31829b5667
American Journal of Clinical Oncology
WDLPS and DDLPS comprise the most common liposarcomas arising in the retroperitoneum. The natural history of WDLPS is one of a slow-growing tumor that often recurs locally but has minimum metastatic potential. Some amount of dedifferentiation or transdifferentiation can account for the transformation of a quarter of the WDLPS cases into higher grade tumors.7 DDLPS may be primary or may develop in a preexisting WDLPS and are usually associated with a superior growth and metastatic rate. MLPSs pursue an aggressive clinical course and also have a marked propensity for metastasis, often to unusual sites like bone and skin. PLPSs typically occur in the elderly and are very aggressive tumors with a high metastatic potential. Mixed liposarcoma constitute the rarest type, and show morphologic features of MLPS, PLPS, and/or WDLPS/DDLPS.6 They usually have a poor prognosis. Cytogenetically, WDLPS and DDLPS are characterized by supernumerary circular (ring) and giant rod chromosomes with amplification of the 12q13-15 region.8 Several tumor associated genes located at 12q, MDM2, CDK4, SAS, and HMGA2 have been implicated in the pathogenesis of WDLPS.9 Coamplification of MDM2 and CDK4 which are colocated on chromosome 12 can inactivate the p53 and pRb tumor suppressor pathways. Although the process of dedifferentiation of WDLPS is not well understood, it has been associated with mutations in p53 and overexpression of proto-oncogene JUN.10 The consistent cytogenetic abnormality in MLPS is translocation t(12;16)(q13;p11.2) that involves fusion between transcription factor gene CHOP on chromosome 12 and FUS gene on chromosome 16.11 Rarely, CHOP may fuse with the EWS gene on chromosome 22 in translocation t(12;22)(q13;q12). PLPSs usually have complex cytogenetic abnormalities without any acknowledged characteristic aberrations.
PRESENTATION AND EVALUATION Although retroperitoneal liposarcomas can occur in any age group, their peak incidence is in the sixth and seventh decades with no clear sex or racial predilection.4 Most of these are malignant from their inception, with only a few exceptions originating from benign lipomas.5 The rate at which these neoplasms grow varies greatly from case to case and even in the same individual. Usually, they grow slowly, at times rapidly, and occasionally they remain inert for a period of time and then develop an aggravation of growth rate.5 Because of the large potential spaces of the retroperitoneum, liposarcomas in this area tend to grow to very large sizes before they produce symptoms. On an average, half of the retroperitoneal sarcomas are >20 cm when diagnosed.4 Moreover, when symptoms do occur, they are nonspecific and include abdominal pain/fullness, flank pain, early satiety, lower extremity swelling, or pain. Local invasion or compression of the retroperitoneal structures may present as neurological, musculoskeletal, and obstructive urinary/bowel symptoms. Nevertheless, the majority
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present as an asymptomatic abdominal mass found incidentally on abdominal examination. A retroperitoneal liposarcoma has to be distinguished from other possible entities such as adrenal/renal/pancreatic tumors, advanced gastrointestinal (GI) carcinomas, benign peripheral nerve sheath tumors, testicular/germ cell tumors, lymphomas, lymphangiomas, retroperitoneal fibrosis, and metastatic carcinomas. Serum markers may be used to rule out germ cell tumors. Immunostains and flow cytometry may be used to exclude lymphomas. Upper GI endoscopy with biopsy may be diagnostic in tumors that appear to have arisen from the stomach, pancreas, or duodenum. Likewise, colonoscopy with biopsy can be useful in diagnosing tumors arising from the colon. Once these diagnoses are ruled out or are considered of low probability, sarcoma is the most likely diagnosis. Currently, no consensus exists in the literature regarding the need for a pretreatment percutaneous biopsy of a suspected retroperitoneal sarcoma (RPS). In the retroperitoneum, neoplasms are so much more likely to be liposarcomas than benign lipomas that it is best to assume malignancy and proceed with surgical excision without preliminary biopsy.5 Biopsy should be reserved for patients who are being considered for preoperative radiotherapy and/or chemotherapy, patients who have unresectable tumors, and patients with hematogenous metastases. Tissue may be obtained through fine-needle aspiration or core-needle biopsy, with the later being preferred because a pathologic diagnosis commonly relies on tissue architecture. Open biopsy should be used only if repeated percutaneous biopsies have failed and the management would change based on a definitive RPS diagnosis.
ROLE OF IMAGING Most sarcomas cannot be characterized to cell type with imaging, with an exception being liposarcoma. The presence of macroscopic fat ascertains the diagnosis of a liposarcoma. Nevertheless in instances where these tumors are composed mostly of soft tissue and fluid components, differentiating a liposarcoma from other types of sarcomas become unfeasible.12 Imaging can also be reliably used to predict the grade and prognosis of liposarcomas. Low-grade liposarcomas are usually associated with mostly fat and very little soft tissue giving them a radiolucent appearance on computed tomography (CT). However, large amount of soft tissue with little or no macroscopic fat may indicate either a low-grade, intermediate-grade, or high-grade liposarcoma. Intermediate-grade tumors appear relatively lucent with transverse septations. High-grade tumors appear dense and heterogenous and enhances with intravenous contrast. WDLPSs tend to have smooth margins, a lobular contour, and a predominate attenuation of fat with no visible calcification.13 Internal nodular septations of soft tissue attenuation that demonstrate mild to moderate enhancement help distinguish them from benign lipomas.14 DDLPSs are visualized as a predominant nonlipomatous mass within, adjacent to or encompassing a fatty mass.15 Calcification within the mass is associated with a poor prognosis. MLPSs tend to have attenuation less than that of muscle and a unique enhancement pattern consisting of gradual, heterogenous, and often incomplete enhancement.13 Some myxoid tumors may appear cystic on noncontrast images, but demonstrate internal enhancement after the administration of contrast agents. PLPSs have predominant attenuation similar to muscle with a varying degree of contrast enhancement.16 CT is the most commonly used modality for the diagnosis, staging, and preoperative evaluation of retroperitoneal liposarcomas.17 These tumors usually have a typical
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appearance on CT. The kidney is usually rotated and displaced to the periphery of the mass but may be encased in it. On intravenous contrast, the kidney usually maintains its normal internal architecture although there might be a degree of pelviureteric obstruction depending on the tumor size and degree of displacement. Imaging the abdomen and pelvis aid in evaluating the primary site, and provides valuable information regarding intraperitoneal seeding, regional lymph node involvement, and distant metastasis to liver. CT scanning of the chest can effectively rule out metastasis to the lungs. Although there are reports suggesting an equivalent efficacy of magnetic resonance imaging (MRI) in diagnosing retroperitoneal liposarcoma, large-scale comparisons of CT and MRI techniques in the setting of retroperitoneal liposarcomas are scarce.18 The use of MRI has been reserved to address questions regarding neurovascular and muscular invasion. MRI and ultrasound are useful compliments to CT in characterizing indeterminate liver lesions. Abdominal radiographs in patients with retroperitoneal liposarcomas are seldom diagnostic but may reveal a softtissue displacing, gas-filled structure and effacement of the normal fat planes. Rarely, calcification can be made out. Intravenous urography may reveal renal or ureteric displacement with or without hydronephrosis. Depending on the location of the tumor, contrast-enhanced studies of the GI tract may show displacement of the stomach, small bowel, or colon. On ultrasonography, liposarcomas are usually hyperechoic and helps confirm the presence of a mass. However, ultrasonography fails to distinguish poorly differentiated liposarcomas from other types of retroperitoneal masses. Ultrasound or CT scan may also aid percutaneous biopsies of the tumor. Owing to the possibility of tumor dissemination at the time of biopsy, histopathological study of the surgical sample remains the standard for diagnosis.19,20 More recently, nuclear imaging (positron emission tomography with 2-fluoro-deoxyglucose) is emerging as an important imaging modality in the management of patients with retroperitoneal liposarcoma.21 Its applications include tumor grading, staging, and evaluation for tumor recurrence.
PROGNOSTIC FACTORS Several prognostic factors have been identified for survival, as well as distant and local recurrence. The most consistent prognostic factor is the completeness of the surgical resection with negative margins. The inability to attain negative microscopic surgical margins due to anatomic constrains or local tumor invasion has been cited by several studies as a potent negative prognostic factor for disease-specific survival.22 Histologic grade, reflected in the extent of differentiation, remains a vital factor concerning clinical course and prognosis of patients with retroperitoneal liposarcoma. Sarcomas are designated as grade 1, G1 (well-differentiated), grade 2, G2 (moderately well-differentiated), or grade 3, G3 (poorly differentiated/undifferentiated) depending on the degree of cytologic atypia, number of mitoses, and presence and extent of necrosis. G1 comprises low-grade tumors as compared to G2 and G3 tumors which are considered high grade. The 5-year survival rates of low-grade myxoid (< 5% round cell component) and well-differentiated variants is about 90%. High-grade variants, such as pleomorphic, round cell (> 5% round cell component), and dedifferentiated tumors, have 5-year survival rates of 30% to 50%, 60%, and 75%, respectively.23 The metastatic potential of well-differentiated tumors is minimal, whereas that of dedifferentiated tumors is 10% to 15%.
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High-grade tumors are associated with high rates of local recurrence and distant metastasis. Furthermore, DDLPSs are 4 times more likely to cause local recurrence when compared with well-differentiated lesions.23 Not surprisingly, local disease accounts for most deaths associated with retroperitoneal liposarcomas.24 Other negative prognostic indicators include multifocal disease and invasion of adjacent structures, both of which restrict the possibility of a complete resection of all tumors.25 The current American Joint Committee on Cancer staging system used for soft-tissue sarcomas is better suited for extremity sarcomas. The American Joint Committee on Cancer system considers histologic grade, tumor size, tumor depth, and the presence or absence of lymph node and distant metastasis.26 It is not representative of patients with retroperitoneal liposarcomas and has limited discriminative power. The 5-cm threshold used in this system is of limited value for retroperitoneal liposarcomas as nearly all tumors are >5 cm and deep to the superficial fascia. Hence, localized retroperitoneal liposarcomas are nearly always classified as stage IIB or III, with the distinction between these 2 stages being made only on the basis of histologic grade. However, studies that used a higher threshold for tumor size have shown an improved predictive outcome.27 The importance of patient age as a prognostic variable has also been stressed in multiple studies.28 Thus, the situation demands an improved staging normogram specific for retroperitoneal liposarcomas which is capable of stratifying patients prognostically. One such normogram based on histologic subtype as opposed to tumor grade was put forward by Dalal et al.29 With a concordance index of 0.827 and high calibration accuracy, the authors claim this normogram to improve prediction of disease-specific survival and aid in more accurate identification of patients appropriate for adjuvant therapy.
MANAGEMENT Surgery The definitive treatment of primary retroperitoneal liposarcomas is complete surgical resection of the tumor with intent to obtain negative microscopic margins. A single-institutional study of 500 retroperitoneal sarcoma cases reported a median survival of 103 months for those who underwent complete resection with grossly negative margins in contrast to 18 months for those who underwent incomplete resection.30 However, the complete resection of these tumors is often very challenging (Table 1). Because of the large potential spaces of the retroperitoneum and local invasiveness of liposarcomas, these lesions are very large when diagnosed and often involve many adjacent organs and structures. The most common difficulties are gaining access behind the tumor to identify retroperitoneal structures to be preserved, or in obtaining control of the major vessels of organs to be removed. Furthermore, high degrees of adipocyte differentiation in the tumor can pose
Retroperitoneal Liposarcoma
difficulty at distinguishing it from retroperitoneal fat. Thus, the determination of a safe margin for resection becomes difficult. The superior survival advantage conferred by a complete surgical resection often warrants an en-bloc local resection to include contiguous organs, such as kidneys, adrenals, or segments of small bowel/colon.36,37 An aggressive quasicompartmental approach to RPS resection has been advocated recently by several European centers. Authors advocate an improvement in local recurrence rates compared with historical controls. The basis for the European argument was that the rates of major complication (18%), early reoperation (12%), and postoperative mortality (3%) were comparable to reports by authors who use a more conventional, lessaggressive resection strategy.38 It was, however, noted that morbidity increased with increasing numbers of organs resected en bloc with the tumor. The aggressive surgical approach was rivaled by Strauss et al,33 who reported 5-year local recurrence-free and disease-specific survival rates of 55% and 75%, respectively. The management of tumors that involve unresectable vital structures or tumors whose removal would cause unacceptable morbidity is more complex. Options that follow a diagnostic biopsy include primary treatment with radiotherapy or chemotherapy to downstage tumors before resection.40 Observation is considered for asymptomatic patients. Unresectable tumors that become resectable after primary radiotherapy or chemotherapy should be surgically removed. Symptomatic patients with tumors that remain unresectable after primary treatment can be subjected to palliative surgery for symptom control. Infact, some studies also report prolonged survival in addition to symptom palliation following partial resection of liposarcomas as compared to those who only underwent biopsy.41 In patients with stage IV disease, resection should always be considered for resectable metastatic disease. Because of the tumor bulk and possible need for removing adjacent organs, open approach is generally preferred by most surgeons. However, the growing expertise in minimally invasive surgery has resulted in its improved application to retroperitoneal liposarcomas. Laparoscopy is a viable and valid alternative to open procedures in selected patients with retroperitoneal liposarcomas and can offer clinical outcomes comparable to open procedures in terms of disease control and better outcomes in terms of hospital stay, morbidity, cosmesis, and patient recovery.42
Role of Adjuvant/Neoadjuvant Therapy While the best outcomes are observed in patients with negative surgical margins, the highly aggressive nature of retroperitoneal liposarcomas and their propensity for local recurrence and distant metastasis in spite of obtaining clear surgical margins demand the need for complementary adjuvant/neoadjuvant therapy.
TABLE 1. Resection Margin Status in Retroperitoneal Sarcomas
References
No. Patients
Lee et al31 Strauss et al33 Bonvalot et al32 van Dalen et al34 Alldinger et al35 Erzen et al36
21 200 374 115 117 100
R0 (%) 11 55 176 78 20 55
(52.4) (28) (47) (68) (17) (55)
R1 (%)
R2 (%)
R Status Unknown
Comment
10 (47.6) 85 (42) 103 (28)
— 30 (15) 38 (10) 37 (32) 41 (35) 3 (2)
— 30 (15) 57 (15) — 2 (2) —
— — 8 biopsied only 8 explored only — 2 biopsied only
54 (46) 42 (42)
R0 indicates microscopically complete resection; R1, microscopically positive margins; R2, macroscopically incomplete resection.
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Copyright
— 48 — 23 — 59 — 29
EBRT indicates external beam radiotherapy; IORT, intraoperative radiotherapy; Sx, surgery; XRT, radiotherapy.
42 10 10 77 — — —
—
— 50 — — — 59 — 38 38 — — 20 — 17 —
—
— — 37.5 — 54.6 — 68.5 — 29 — — — — — 200
—
— 44
XRT + XRT
51.8 49 — —
XRT + XRT
27.5 — — 23
XRT + XRT
61.9 52 — — 31.5 29
XRT + XRT
41.4 47 — — — — — — 12 51 40 89 — — — 34
% Local Recurrence (5 y) % Local Control (5 y) % Diseasefree Survival (5 y) IORT + Adjuvant/ Median EBRT + IORT Neoadjuvant FollowIORT Only Chemotherapy up (mo) r
Lee et al48 Stoeckle et al28 Strauss et al33 Gieschen et al57 Petersen et al47
Studies evaluating the role of preoperative RT have shown to improve the probability of local control with minimum radiation-related toxicities.53,54 Preoperative radiation may be a safer alternative as the tumor bulk can displace adjacent normal tissue that could be dose limiting in the
References
Neoadjuvant Radiotherapy
Postoperative EBRT + Adjuvant/ Neoadjuvant Chemotherapy
Despite advances in delivery techniques and improved recurrence-free survival, postoperative radiation is clearly associated with significant risk of acute and late bowel toxicity.49 After the large tumor mass that had been displacing adjacent viscera is removed, the bowel tends to fall into the resection bed where it may become fixed by postoperative adhesions thereby making delivery of RT to the resection site more challenging. The time delay required between surgery and radiation has been criticized to promote multiplication of neoplastic cells in residual disease.
PrePostoperative operative Sx EBRT EBRT Only Alone Alone
Adjuvant Radiotherapy
TABLE 2. Radiation Therapy in Retroperitoneal Sarcomas
Retroperitoneal liposarcomas are radiosensitive tumors as compared to other retroperitoneal sarcoma subtypes. Because of the rarity of these tumors, combined with the varying clinical courses of the various histologic subtypes, randomized prospective studies evaluating the efficacy of radiotherapy in addition to surgery are hard to come by. Adjuvant radiation therapy (RT) in the preoperative setting is being evaluated in an ongoing European organisation research treatment cancer randomized trial. Outcomes of retrospective studies have been criticized due to the potential for selection/confounding bias. Despite these limitations, multiple studies have strongly suggested that RT can reduce the risk of local recurrence, and lengthens the recurrence-free interval.27,43 However, there is a paucity of data substantiating favorable impact with this therapy on overall patient survival.44,45 Besides, incomplete resections (margin positive) and nonoperable tumors warrant the use of radiotherapy to provide local tumor control and longer relapse free survival.46 RT for retroperitoneal liposarcoma patients is complex because it requires decisions not only on the “timing” of administration (eg, neoadjuvant, intraoperative, adjuvant), but also the “technique” of delivery (Table 2). However, the prime concern remains the increased risk of treatment-related toxicity to visceral structures that are highly radiosensitive, due to their rapidly proliferating mucosa and rich blood supply. The relatively low radiation tolerance for surrounding normal tissues (liver, kidney, GI tract, spinal cord) predisposes them to the risk of intestinal perforation, peritonitis, and peripheral neuropathy. Controversy exists on the effect of radiation dosage on local disease control. Earlier studies support the need of increased radiation doses for more effective local control, particularly in cases of microscopic residual disease.49 However, more recent studies report no advantage in local control associated with radiation dose-escalation with either external beam radiotherapy (EBRT) or intraoperative radiotherapy (IORT).50,51 The need to administer adequate radiation doses, without increasing the possibility of normal tissue toxicity has paved way for more refined delivery methods. Such techniques include intensity-modulated RT, 3-dimensional radiation therapy (3D-RT), helical tomotherapy, respiratory-guided therapy, image-guided RT, proton or heavy ion RT, and stereotactic RT. The use of intensity-modulated RT was found to yield superior treatment plans with respect to overall radiation dose conformality and good tolerance.52
% Overall Survival (5 y)
Radiotherapy
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postoperative setting. This approach also allows the target volume to be easily delineated for treatment planning, and treating the tumor before surgery theoretically diminishes the risk of peritoneal/locoregional seeding at the time of surgery. Tumor regression in response to therapy may also facilitate resection.
IORT This approach enables direct targeting of the resection bed with a high dose of radiation while nearby radiosensitive normal tissues are mechanically retracted out of the treatment field. IORT can be delivered using electrons or with brachytherapy catheters. The biological effectiveness of single-dose IORT is thought to be equivalent to 1.5 to 2.5 times the same total dose of fractionated EBRT.55 Nonrandomized studies of IORT in patients undergoing surgery suggest high recurrence-free survival rates.56,57 Peripheral neuropathy and ureteral injuries appear to be common morbidities associated with IORT. On the basis of existing data, it seems preoperative EBRT combined with surgical resection of the retroperitoneal liposarcoma is feasible and safe. Although data suggest that addition of IORT to EBRT improves local control compared with EBRT alone, dose-escalation attained with this combination adds further toxicity.57,58
Chemotherapy The role of adjuvant or neoadjuvant chemotherapy in the treatment of retroperitoneal liposarcomas remains controversial to date. The potential role for chemotherapy includes neoadjuvant cytoreductive therapy, sensitisizing the tumor to radiation, and as definitive therapy for unresectable tumors. Although randomized trials suggest benefit from adjuvant chemotherapy for extremity sarcomas, no trial shows a clear improvement in outcome for retroperitoneal liposarcomas. Recent data indicate a potential role for trabectedin in the treatment of MLPSs.59 Although early data from randomized trials suggested a poorer outcome for patients who received either preoperative or postoperative chemotherapy,30 the use of systemic therapy continues to be investigated.60 The effectiveness of intraoperative or postoperative hyperthermic total abdominal chemotherapeutic perfusion is also being scrutinized.61 Donahue and colleagues reported the histologically responding primary high-grade retroperitoneal sarcomas treated with chemotherapy to demonstrate significantly improved 5-year diseasespecific survival compared with the nomogram prediction for such patients.62 There is increasing interest in concurrent chemotherapy and RT as a treatment strategy for retroperitoneal liposarcomas. A handful of studies have shown such combination to be feasible and safe.60,63 Eilber et al64 from the University of California, Los Angeles reported 6 of 23 patients treated preoperatively with doxorubicin, ifosfamide, and cisplatin plus concurrent RT (28 Gy) to have no residual tumor in the resected specimen.
Retroperitoneal Liposarcoma
days.66 Karakousis et al67 reported 10-year survival rates of 57% for primary tumors versus 26% for locally recurrent tumors, thus indicating the low long-term salvage rate for recurrent retroperitoneal liposarcomas. Local recurrence is much more common than distant metastases and hence, complete excision of the lesion will account to a better outcome. Five-year local recurrence rates after complete gross resection are approximately 50% for welldifferentiated and 80% for dedifferentiated retroperitoneal liposarcomas.22 Recurrences that are diagnosed and operated early enjoy complete excision rates in about 90% of the patients.68 Five-year survival rates for reoperated patients were comparable to those with primary sarcoma, if a radical resection can be achieved.69 Sadly, many recurrences are diagnosed late in the course of the disease, leading to incomplete resection, which then leads to rerecurrence in about 50% of patients. Factors associated with a favorable outcome after reoperation include a long recurrence-free interval and complete resection.70 The addition of radiation or chemotherapy in the treatment of locally recurrent disease remains controversial. However, it should be considered strongly in patients presenting with recurrence, and had not received adjuvant/ neoadjuvant treatment after primary resection. Clinical follow-up is not promising as up to 50% of patients are asymptomatic, and if symptoms are present, they are usually nonspecific. As most recurrences are local, careful scrutiny of the resection site for subtle changes on follow-up imaging is essential. Local recurrences can often be misinterpreted as postoperative scarring/fibrosis. Also small, recurrent liposarcomas can be difficult to distinguish from normal retroperitoneal fat on imaging. Recurrent liposarcomas usually have imaging characteristics such as attenuation similar to that of the primary tumor, which along with the fact that, fat in a recurrent liposarcoma is of slightly higher CT attenuation when compared to normal retroperitoneal fat, aids in the diagnosis of a recurrence.66 The potential of retroperitoneal liposarcomas for locoregional recurrence/metastases warrants a thorough search of the draining nodes, peritoneal surfaces, and liver before evaluation for distant metastases. Follow-up imaging is usually performed with CT or MRI with the frequency of follow-up being often dictated by the completeness of the tumor resection, tumor type, and grade.71 The current guidelines from the National Comprehensive Cancer Network for the surveillance of soft-tissue sarcomas arising in the retroperitoneum recommend that patients with low-grade tumors who have been successfully resected should have a follow-up physical examination with imaging (chest/abdominal/pelvic CT) every 3 to 6 months for 2 to 3 years, then annually. For those with high-grade tumors that have been successfully resected should have a follow-up physical examination with imaging (chest/ abdominal/pelvic CT) every 3 to 6 months for 2 to 3 years, then every 6 months for the next 2 years, and then annually.72
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RECURRENCE AND FOLLOW-UP Retroperitoneal liposarcoma frequently recurs within 6 months to 2 years after the initial surgical resection. They tend to infiltrate adjacent tissues and structures with skip areas (satellites), thus explaining the occurrence of late and unexpected recurrences despite complete surgical resection with negative margins.65 They usually show a rapid growth pattern, with a mean tumor volume doubling time of around 100 Copyright
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