After diagnosis of retroperitoneal sarcoma (RPS), detailed imaging and multidisciplinary discussion should guide treatment including surgical resection and in select cases, neoadjuvant therapy. Local recurrence is common in RPS and is associated with grade, histologic subtype, completeness of resection, and size. As guidelines to standardize RPS patient management emerge, expert pathologic assessment and management in centers of excellence are benchmarks of quality of care. The efficacy of current chemotherapy is limited and there is a critical need to understand the molecular basis of sarcoma so that new drug therapies are developed. Multicenter clinical trials are needed to limit opinion and controversy in this complex and challenging disease.
Key points
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Retroperitoneal sarcomas (RPS) are rare cancers whose work-up includes detailed radiologic assessment (CT scan of chest/abdomen/pelvis) and expert pathologic review.
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The overall goal of a primary RPS resection is gross resection of tumor with en bloc removal of closely associated/involved viscera and retroperitoneal musculature.
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Neoadjuvant chemotherapy and/or radiation may be key components of the therapeutic armamentarium in patients with RPS especially in chemosensitive subtypes or borderline resectable tumors.
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The predominant pattern of failure in RPS is local recurrence, which occurs in 25% to 50% of patients at 5 years and 35% to 60% at 10 years.
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Long-term surveillance should be in centers of expertise because the decision making for RPS recurrence is complex and warrants multidisciplinary input and access to clinical trials.
Fact
Soft tissue sarcomas (STS) are malignant neoplasms that arise predominately from mesenchymal tissues including fat, muscle, fibrous tissue, and blood vessels. Overall, 15% of STS arise in the retroperitoneum. Retroperitoneal sarcomas (RPS) are rare tumors with an incidence of 0.5 to 1 cases per 100,000. In general, RPS are sporadic cancers; however, there are several hereditary cancer syndromes associated with STS including Li-Fraumeni and neurofibromatosis type 1. Radiation-associated sarcomas are rare and can arise as a late complication of treatment with a median onset of 10 years.
Diagnostic Challenges of Retroperitoneal Sarcomas
One of the challenges in the management of patients with RPS is that most present with advanced disease yet are asymptomatic. It is essential in evaluating an undiagnosed retroperitoneal (RP) mass that other tumors are excluded in particular lymphoma, adenocarcinoma, germ cell tumor, and paraganglioma. After performing a through history and physical examination, obtaining tumor markers (ie, LDH, AFP, βHCG) may aid in making a diagnosis. Although endoscopy is not usually necessary, a percutaneous biopsy may be required for a definitive diagnosis. It is also critical that all patients with RP masses have diagnostic abdominal and pelvic computed tomography (CT) scans performed along with a staging CT chest when malignancy is suspected ( Fig. 1 ). MRI is used in cases where CT is contraindicated and/or when it may complement CT, whereas the use of ultrasound alone is discouraged. To date, there is limited utility in use of PET scans in patients with RPS; however, they may be useful in staging other RP tumors, such as lymphoma and adenocarcinoma.
In general, RPS grow by direct local extension into adjacent tissues and structures, often pushing them aside and less commonly invade fascial planes, joints, or bone. They are usually large in size (median size, 20 cm) at presentation. There are more than 80 different histologic subtypes of STS in the retroperitoneum. Liposarcoma (LPS) is the most common (63%), and is further divided into four different subtypes: (1) well-differentiated (WD LPS), (2) dedifferentiated (DD LPS), (3) myxoid round cell (MRC LPS), and (4) pleomorphic. The second most common subtype is leiomyosarcoma (LMS) (19%), which primarily consists of sarcoma of major veins, specifically the inferior vena cava, renal vein, and gonadal vessels. Less frequent RPS subtypes include solitary fibrous tumor (SFT), fibrosarcoma, and malignant peripheral nerve sheath tumor (MPNST). Pathologic diagnoses excluded in this review include benign conditions, such as lipoma, benign peripheral nerve sheath tumors, desmoid, and angiomyolipoma; and visceral sarcomas, such as gastrointestinal stromal tumor, uterine LMS, paratesticular/spermatic cord, or prostatic sarcoma. Histologies including extraosseous Ewing sarcoma, rhabdomyosarcoma, and primitive ectodermal tumors are less common but may be encountered in the retroperitoneum. These generally require special consideration including detailed pathologic assessment and multidisciplinary management strategies.
Some RPS subtypes have diagnostic signatures, however most do not ( Table 1 ). For example, malignant fibrous histiocytoma (MFH) is a historical diagnosis and been reclassified as undifferentiated pleomorphic sarcoma. Undifferentiated pleomorphic sarcoma has emerged as a less common subtype in the retroperitoneum because most high-grade poorly differentiated sarcomas are diagnosed as DD LPS based on positive MDM2 immunohistochemistry confirmed by fluorescent in situ hybridization. Expert pathologic review is essential in managing patients with sarcoma, which includes an extensive immunohistochemical panel plus access to standardized molecular diagnostic tests when applicable. Whether this assessment is done preoperatively with a percutaneous biopsy as a standard of care is still debated; however, this approach is endorsed in most but not all sarcoma expert centers (discussed in the opinion section). The use of intraoperative biopsy for an RP mass that is incidentally discovered or not fully worked up preoperatively is discouraged because this is often nondiagnostic and may involve disruption of tumor planes.
| Histology | Frequency (%) | Immunohistochemistry | Molecular |
|---|---|---|---|
| Liposarcoma | 63 | MDM2, CDK4, p16 | MDM2 amplification |
| Leiomyosarcoma | 19 | Smooth muscle actin, desmin, H-caldesmin | Not applicable |
| Solitary fibrous tumour | 6 | CD34, CD99, BCL2, STAT6 | NAB2-STAT6 fusion product |
| Malignant peripheral nerve sheath tumour | 3 | S100, SOX10, CD56, CD57, PGP9.5 | Not applicable |
| Undifferentiated pleomorphic sarcoma | 2 | Not applicable | Not applicable |
| Other | 7 | Diagnosis-dependent | Diagnosis-dependent |
The current staging for STS from the American Joint Committee on Cancer 7th edition incorporates histologic grade and TNM status. The most significant change to the 7th edition is the downstaging of nodal disease from stage IV to stage III, although lymph node involvement is uncommon in STS (5%–15%). TNM staging has limited use in patients with RPS because almost all RPS are greater than 5 cm in size and by definition are deep. An alternate means of prognosticating survival in resected RPS was derived by analyzing population-based data, which defined grade, invasion of adjacent structures, and histologic subtype as better predictors of outcome than American Joint Committee on Cancer staging, yet this has not been widely adapted. It is, however, universally accepted that grade is the most important prognostic factor in STS. The most widely used grading system is from the French three-tiered system, which is based on assigning a score for tumor differentiation (1–3), mitotic activity (1–3), and necrosis (0–2). Alternatively, sarcoma-specific nomograms have been developed and validated to predict postoperative survival and subtype-specific survival.
Management of Primary Retroperitoneal Sarcomas
The cornerstone of treatment in primary RPS is surgical resection. Although the use of neoadjuvant chemotherapy and radiation therapy (RT) is not universally agreed on because of lack of level one evidence (discussed in the controversies section), neoadjuvant therapies may be key components of the therapeutic armamentarium especially in chemosensitive subtypes or borderline resectable tumors ( Fig. 2 ). Thus, it has been advocated that patients with RPS be managed and treatment decisions rendered at expert sarcoma centers where the multidisciplinary team consists of dedicated sarcoma pathologists, diagnostic radiology, surgical oncology, medical oncology, and radiation oncology (discussed in the opinion section). Furthermore, the extensive surgical procedures performed in patients with RPS require advanced supportive care by anesthesia, intensive care, and/or interventional radiology.
The overall goal of a primary RPS resection is gross resection of tumor with en bloc removal of closely associated/involved viscera and RP musculature. Resection should also include complete removal of all ipsilateral RP fat in patients with LPS. The role of more extended RP resection has been advocated by several centers but remains controversial (discussed in the section on extended RPS resections). The anatomic constraints of the retroperitoneum render margin-negative excisions more technically challenging than for STS at other sites. Overall, grossly incomplete resection is discouraged, because it may not be beneficial. Preoperative planning may also include a differential renal scan to anticipate renal dysfunction postoperatively if a nephrectomy is likely. Additionally, assessment and optimization of the patient’s nutritional and performance status before surgery is important to mitigate perioperative complications because the large size of RPS can impair adequate nutritional intake and/or is associated with deconditioning.
The best chance of a curative outcome is at the primary resection; thus detailed surgical planning and expertise is required to perform multivisceral resections with reconstruction while minimizing microscopically positive margins. Viscera commonly resected in RPS include colon, kidney, pancreas, spleen, diaphragm, small bowel, duodenum, liver, bladder, with resection of psoas, iliacus musculature, and/or abdominal wall. Select cases require resection and reconstruction of major vascular structures (interior vena cava, aorta, and/or iliac vessels) and less commonly include vertebral or pelvic bony resection. Another complex surgical issue is extension of the RPS into other anatomic compartments, such as crossing the inguinal ligament into the scrotum or adductor compartment of the thigh or posterior extension out of the sciatic notch. These technically challenging cases therefore may require involvement of multidisciplinary surgical teams including uro-oncology, orthopedic oncology, vascular surgery, and/or plastic surgery. Generally accepted criteria for RPS unresectability include diffuse metastases, peritoneal implants, or extensive/circumferential involvement of the superior mesenteric artery (SMA) or superior mesenteric vein (SMV).
Given the large size of most RPS (>20 cm), the ability to achieve and accurately pathologically assess microscopically clear (R0) margins is limited. Although R0 resections have been reported to be associated with decreased abdominal recurrence and improved overall survival (OS) by multivariate analysis in a series by Bonvalot and colleagues, this has not been replicated in other series. Thus, most RPS centers of excellence report gross margin clearance (R0 and R1) compared with grossly incomplete resections (R2) ( Table 2 ).
| Author, Year | Number Resected | Margin (%) R0/R1 vs R2 | Median Follow-up (mo) | Local Recurrence (%) | Distant Recurrence (%) | Notes |
|---|---|---|---|---|---|---|
| Gronchi et al, 2016 | 1007 | 95 | 58 | 5-y 26 | 5-y 21 | 8 expert centers |
| 10-y 35 | 10-y 22 | |||||
| Tan et al, 2016 | 632 | 90 | 90 | 5-y 39 | 5-y 24 | Single expert center |
| Gronchi et al, 2015 | 377 | 96 | 44 | 5-y 24 | 5-y 22 | 2 expert centers |
| Smith et al, 2015 | 362 | 96 | 26 | 3-y LRFS | 5-y DRFS 46 | Single expert center |
| 98 WD LPS | 100 WD LPS | |||||
| 57 DD LPS | 86 DD LPS | |||||
| 80 LMS | 65 LMS | |||||
| Toulemonde et al, 2014 | 511 | 76 | 78 | 5-y LRFS 46 | — | 12 French sarcoma centers |
| Keung et al, 2014 | 119 | 80 | 74 | 5-y LRFS 15 | 5-y DRFS 33 | Single expert center DD LPS only |
| Bonvalot et al, 2010 | 249 | 93 | 37 | 5-y 22 | 5-y 24 | 2 expert centers |
| Gronchi et al, 2009 | 193 | 89 | 58 | 5-y LR | 5-y DR | Single expert center |
| Recent cohort 28 | Recent cohort 22 | |||||
| Early cohort 48 | Early cohort 13 | |||||
| Lewis et al, 1998 | 231 | 80 | 28 | 5-y LRFS 59 | 5-y DRFS 79 | Single expert center |
With the complexity of surgery undertaken in patients with RPS, the morbidity and mortality associated with these procedures with and without neoadjuvant therapies is increasingly recognized as an important index of quality of care. Although 30-day mortality in patients with RPS from single institutional series (1.4%–3.0%) or combined multicenter experience (1.9%) is consistent with outcomes in other major oncologic abdominal procedures, major perioperative morbidity is common. Specifically, the 30-day morbidity in 1007 primary RPS from the Multi-institutional Collaborative RPS Working Group, which combined the experience of eight international sarcoma centers, reported grade 3 events in 12.7% of patients, whereas grade 4 events occurred in 5.2% of patients as defined by Common Terminology Criteria for Adverse Events. Part of the controversy in performing extended resections is that these procedures are associated with increased morbidity including high reoperative rates (12%), which are usually performed for anastomotic leakage or postoperative bleeding. With extended resection, factors associated with increased morbidity include three or more organs resected, major vascular resection, gastrectomy, and/or duodenectomy. Finally, there are limited data to address the concern that preoperative RT is associated with increased perioperative morbidity. Thus, the morbidity and toxicity data being compiled in the ongoing phase III multicenter STRASS (Study of Preoperative Radiotherapy Plus Surgery Versus Surgery Alone for Patients with RPS) sponsored by the European Organization for Research and Treatment of Cancer ( NCT01344018 ) should be informative.
Outcomes and Recurrence in Retroperitoneal Sarcomas
OS rates for primary RPS treated with curative intent range from 39% to 70% at 5 years and 20% to 64% at 10 years from series with long-term follow-up ( Table 3 ). Predictive factors associated with survival include age, tumor size, completeness of resection, grade, and multifocality.
| Author, Year | Number Resected | Primary RPS (%) | Median Follow-up (mo) | Survival (%) | (Neo) Adjuvant Therapy (%) | |
|---|---|---|---|---|---|---|
| Chemotherapy | Radiation | |||||
| Gronchi et al, 2016 | 1007 | 100 | 58 | OS 5-y 67 | 18.2 | 32 |
| 10-y 46 | ||||||
| Tan et al, 2016 | 632 | 100 | 90 | DSD 5-y 31 | 18 | 8 |
| Gronchi et al, 2015 | 377 | 100 | 44 | OS 5-y 64 | 32 | 31 |
| Smith et al, 2015 | 362 | 100 | 26 | DSS 3-y 81 | 3 | 8 |
| Smith et al, 2014 | 40 | 73 | 73 | OS 5-y 70 | — | 100 |
| 10-y 64 | ||||||
| Toulemonde et al, 2014 | 511 | 100 | 78 | OS 5-y 66 | 17 | 29 |
| Keung et al, 2014 | 119 | 100 | 74 | OS 5-y 42 | 12.6 | 28 |
| Bonvalot et al, 2010 | 249 | 100 | 37 | OS 5-y 64 | 37 | 36 |
| Gronchi et al, 2009 | 288 | 67 | 58 | OS 10-y 36 | 32 | 31 |
| Bonvalot et al, 2009 | 374 | 100 | 52 | OS 5-y 57 | 34 | 32 |
| van Dalen et al, 2007 | 115 | 100 | 122 | OS 5-y 39 | 18 | 16 |
| Lewis et al, 1998 | 231 | 100 | 28 | OS 5-y 54 | — | — |
The predominant pattern of failure in RPS is local recurrence (LR), which occurs in 25% to 50% of patients at 5 years and 35% to 60% at 10 years (see Table 2 ). The median time to LR ranges from 24 to 41 months. Factors associated with LR include age, size, completeness of resection, grade, tumor rupture, multifocality, administration of RT, and histologic subtype. With long-term follow-up from prospective databases at single institutions and a recently established RPS consortium (Trans-Atlantic RPS Working Group), there is a better appreciation that histologic subtype directs patterns of failure. Specifically, in a study of 675 patients with primary RPS, DD LPS had a high LR rate of 58% at 5 years and 62% at 15 years compared with WD LPS and MRC LPS, which had 39% and 60% incidence of LR at 5 and 15 years, respectively. Furthermore, LR was uncommon in patients with SFT (8%) and, interestingly, all LR in MPNST patients occurred within 3 years.
The development of distant recurrence (DR) occurs in 21% to 24% patients at 5 years and 22% patients at 10 years (see Table 2 ). The median OS post-DR is 20 months. Predictive factors associated with DR include size, grade, multifocality, and subtype. Metastasis most commonly occurs in the lung (30%) and liver (5%–10%); other sites of RPS DR include bone, RP fat, mediastinum, and soft tissue. Although LR rates are low in LMS (10%–20% at 5 years), DR occurs in 58% of high-grade LMS at 10 years and is the main cause of sarcoma-specific death. Other STS associated with high DR rates at 10 years are SFT (41%) and DD LPS (28%), whereas MPNST and WD LPS have limited DR rates of 15% and 8%, respectively.
Patients with RPS should be surveyed for their lifetime because late recurrence (>20 years) occurs. Because the risk of recurrence is most highly associated with tumor grade, guidelines for RPS surveillance are stratified as follows: low-grade, CT chest/abdomen/pelvis every 6 months for first 2 to 3 years then yearly thereafter; and high-grade, CT chest/abdomen/pelvis every 4 months for first 2 to 3 years, then every 6 months for next 2 years and then annually. Ideally, long-term surveillance should be in centers of expertise because the decision making to manage recurrence is complex and ongoing clinical trials should be available. Furthermore, to better understand RPS outcomes, ongoing clinical assessment and data collection are critical in determining which interventions are beneficial to patients long-term.
Fact
Soft tissue sarcomas (STS) are malignant neoplasms that arise predominately from mesenchymal tissues including fat, muscle, fibrous tissue, and blood vessels. Overall, 15% of STS arise in the retroperitoneum. Retroperitoneal sarcomas (RPS) are rare tumors with an incidence of 0.5 to 1 cases per 100,000. In general, RPS are sporadic cancers; however, there are several hereditary cancer syndromes associated with STS including Li-Fraumeni and neurofibromatosis type 1. Radiation-associated sarcomas are rare and can arise as a late complication of treatment with a median onset of 10 years.
Diagnostic Challenges of Retroperitoneal Sarcomas
One of the challenges in the management of patients with RPS is that most present with advanced disease yet are asymptomatic. It is essential in evaluating an undiagnosed retroperitoneal (RP) mass that other tumors are excluded in particular lymphoma, adenocarcinoma, germ cell tumor, and paraganglioma. After performing a through history and physical examination, obtaining tumor markers (ie, LDH, AFP, βHCG) may aid in making a diagnosis. Although endoscopy is not usually necessary, a percutaneous biopsy may be required for a definitive diagnosis. It is also critical that all patients with RP masses have diagnostic abdominal and pelvic computed tomography (CT) scans performed along with a staging CT chest when malignancy is suspected ( Fig. 1 ). MRI is used in cases where CT is contraindicated and/or when it may complement CT, whereas the use of ultrasound alone is discouraged. To date, there is limited utility in use of PET scans in patients with RPS; however, they may be useful in staging other RP tumors, such as lymphoma and adenocarcinoma.
Related posts:
Contemporary Management and Controversies of Sarcoma
Refinements in Sarcoma Classification in the Current 2013 World Health Organization Classification of Tumours of Soft Tissue and Bone
Sarcomas 2016
Management of Sarcoma Metastases to the Lung
Combined Therapy of Gastrointestinal Stromal Tumors
Myxofibrosarcoma
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