Retroperitoneal sarcoma (RPS) is a rare tumor whose diagnosis and management can be challenging and for which management requires a multidisciplinary team in a specialized center. An important part of the diagnosis-identification of the histologic subtype-depends on pathology; identifying the histologic subtype is important because this can affect prognosis and treatment options. Complete surgical resection with negative margins remains the cornerstone of treatment of nonmetastatic RPS and is the only chance for cure. In order to achieve negative margins, multivisceral en bloc resection is often necessary. Neoadjuvant therapies (chemotherapy, external beam radiation, or combination radiation and chemotherapy) are safe in well-selected patients and may be considered after careful review by a multidisciplinary sarcoma tumor board when the recurrence risk is high.
Introduction
Despite the advent of modern imaging, and the associated increase in incidental diagnoses, retroperitoneal soft-tissue sarcoma (RPS) remains a rare malignancy, occurring in 0.5 to 1.0 per 100,000 population.[1] The rarity of these tumors and the complexity of their treatment require multidisciplinary management in specialized centers to improve oncologic and clinical outcomes.[2] Moreover, sarcomas in the retroperitoneum have a worse prognosis than sarcomas in the extremities.[3] Surgery remains the only curative treatment for RPS. Unlike extremity sarcomas, however, RPS can expand massively in the confines of the retroperitoneum prior to detection and diagnosis, making these resections challenging.
Diagnosis and Staging
Often, RPS manifests with vague, indolent symptoms that present a diagnostic challenge or is discovered incidentally on imaging. Adequate, detailed imaging of the retroperitoneum with good visualization of the tumor and its relationship with adjacent organs and their potential involvement is critical. Contrast-enhanced CT of the abdomen and pelvis is often sufficient for the diagnosis of RPS. This imaging modality also provides a good indication of the nature of the tumor and is ideal for biopsy planning.[4] A CT scan of the chest is then sufficient to complete staging in most cases. Magnetic resonance imaging can be used in patients with allergies to intravenous contrast as well as in cases in which an assessment of spinal/vertebral foramina, nerves, and/or posterior muscles involvement is necessary.
RPS comprises a multitude of histopathologic subtypes that are difficult to distinguish based on imaging alone.[5] The Trans-Atlantic RPS Working Group (TARPSWG), a transatlantic collaboration of multiple specialized sarcoma centers, stress in their consensus guidelines the importance of tissue diagnosis prior to initiating treatment.[6] Although it was previously believed that biopsy of RPS could lead to inadvertent tumor tract seeding, a multi-institutional pooled analysis of four specialized centers demonstrated that the incidence of tumor tract seeding is negligible.[7-9] Image-guided, percutaneous core needle biopsy should be preferentially attempted in the most aggressive-looking portion of the RPS by a large core needle (14 or 16 gauge) with a coaxial technique and multiple cores obtained to maximize the quantity and quality of tissue examined. The biopsy should be performed via a posterior/lateral approach and never by a transperitoneal approach. Similarly, laparotomy or laparoscopic open biopsies should be avoided.
Of note, if at open or laparoscopic exploration for suspected adnexal mass, no abnormalities of the uterus, fallopian tubes, or ovaries are found but a retroperitoneal mass is detected, it is recommended that nothing further be done and that a coaxial core needle biopsy be performed after proper imaging. It is important to realize that there can be more than 70 histologic subtypes of RPS and that, along with grade, they have prognostic significance and guide treatment planning, including the extent of surgical resection.[10-12] A multi-institutional nomogram externally validated on multiple series has been constructed.[10,11] It is available on a free smartphone app (www.sarculator.com).
Surgery
The most critical component of the treatment of RPS remains the surgical excision, and the best chance for cure is at the time of primary surgery. Surgery should achieve a macroscopically complete excision of the tumor (R0 or R1), minimizing marginality, ideally through an en-bloc resection of all potentially involved structures as determined by careful preoperative imaging in combination with intraoperative findings.[6,13,14] However, despite ongoing efforts, no convincing method has been found to assess the quality of surgical margins, given the location and the size of these tumors and the lack of a standard protocol to process the specimen. An extended surgical approach leads to lower local recurrence rates than simple excisions, precisely because it reduces marginality/positive margins.[15,16]
Operative planning also includes the functional assessment of critical organs-eg, the function of each kidney. Contraindications to primary resection are believed to be bilateral renal involvement; encasement of the superior mesenteric artery, celiac axis, and porta hepatis; and spinal cord involvement.[13,17]
When planning for surgery, it is paramount to take into consideration the histology of the RPS as well as its predicted behavior pattern, as these differ widely. Indeed, the largest transatlantic multi-institutional series identified histologic subtype as a predictor of patterns of local and distant recurrence.[18] Moreover, analysis of a large, single-institution database demonstrated that histologic subtype is the strongest predictor of disease-specific death and affects both local and distant recurrence.[12] Of greater interest, the patterns of contiguous organ involvement are also heavily dependent on histologic subtype.[19] A recently published single-institution analysis of 302 patients reported that evidence of histopathologic organ involvement is a significant predictor of overall survival.[20]
In light of these data, clinicians should decide the extent of surgical resection in a multidisciplinary setting at a specialized center after review of imaging and pathology, given that the pattern of growth and prognostic risks vary broadly among the different histologic subtypes.[14,21,22] For example, liposarcoma is the histologic subtype with the highest recurrence rate. In addition, it is the one with the least clear separation from normal retroperitoneal fat, given that the well-differentiated component of liposarcoma is virtually undistinguishable from normal fat. As a consequence, the extent of surgery should be aimed at removing all ipsilateral retroperitoneal fat en bloc with the mass at the price of sacrificing at least the ipsilateral kidney and colon and part of or the entire psoas muscle.
A staged approach can be followed in virtually all cases (Figure 1). The stages include:
A. Generous laparotomy, exploration, and retraction.
B. Division of the gastrocolic ligament, division of the transverse colon (plus distal ileum if on the right side), and assessment of the duodenum/head of the pancreas if on the right side, or body/tail of the pancreas and spleen if on the left side.
C. Liberation of duodenum/head of the pancreas if on the right side or body/tail of the pancreas and spleen and duodenojejunal junction if on the left side (when possible) and partial duodenal resection or pancreaticoduodenectomy (< 5% of right-sided retroperitoneal sarcomas) if on the right side or distal pancreatectomy and splenectomy if on the left (40%–50% of left-sided retroperitoneal sarcomas), when too adherent/invaded by the tumor.
D. Dissection of the inferior vena cava (IVC) if on the right side or aorta if on the left side, ligating ipsilateral renal vessels and other collaterals and dissection of the iliac vessels.
E. Peritonectomy, resection of the psoas muscle in the pelvis (plus rectal resection if on the left side) after identification and liberation of the femoral nerve (unless directly invaded) and possibly of the femoral cutaneous branch, while the genitofemoralis and ilioinguinal nerves are usually resected, as these lie between the tumor and the psoas fascia.
F. Section of the origin of the psoas major from the spine, sparing the roots of the femoral nerve and possibly the iliohypogastric nerve, liberation/resection of the costodiaphragmatic fold, and removal of the specimen.
Subcapsular liver dissection or partial hepatectomy are rarely needed for tumors located on the right side, whereas a complete liberation of the right liver lobe is usually of help. Similarly, sleeve gastrectomy or proximal gastrectomy is rarely required for tumors located on the left side. Finally, vascular resections (predominantly iliac vessels on either side and IVC on the right side) are required in 4% of cases.
Leiomyosarcoma and other rarer histologic subtypes such as solitary fibrous tumor are much more well-defined tumors. Their border can be clearly separated from retroperitoneal fat/structures. A wide resection is still required but not necessarily involving the adjacent organs if these are not clearly invaded (Figure 2).
Extended surgery may raise concern for added morbidity. A recent multi-institutional collaboration, however, found that a radical resection is safe and is associated with low 30-day mortality (1.8%). Severe complications were associated with increased age, transfusion requirements, and organ resection score, with a more pronounced risk in patients undergoing splenectomy and pancreatectomy and Whipple procedure.[23]
Although major vascular resection (MVR) is associated with higher morbidity, vascular involvement does not preclude resection because it can be safely performed in specialized centers. MVR may be necessary either due to the origin of the RPS, as is the case for leiomyosarcoma of the IVC, or due to local invasion and involvement.[24] Whereas multiple strategies for approaching MVR can be used, a good understanding of the vasculature and collaterals is critical prior to attempting resection and reconstruction, given that IVC resections are well tolerated if a good network of collaterals is present.[25]
In essence, resection of RPS requires technical expertise in multiple sites throughout the abdominal and pelvic cavity, including the handling of large vessels. Single organ/site expertise is not sufficient. The ability to orchestrate a team of complementary surgical experts is critical to successful management of RPS patients. To minimize the risk of intraoperative and perioperative morbidity, RPS resection should be undertaken by surgical teams with expertise in specific aspects of the anatomy of the retroperitoneal space-for example, expertise in retroperitoneal autonomic and somatic nerves, the lymphatic system, paravertebral vessels, and organs of the gastrointestinal tract. Required expertise also includes experience with additional procedures, such as full-thickness thoracoabdominal wall resection and reconstruction, diaphragmatic resection and reconstruction, major vascular resection and reconstruction, and bone resection. Surgical teams with these abilities, which may accrue from prior participation in multidisciplinary surgical teams, can achieve macroscopically complete tumor resection in the majority of patients.
Radiation Therapy
Given the importance of local control in a majority of RPS subtypes, radiation therapy (RT) has long been an important tool in the multimodal treatment of this disease. There has been great debate, however, over the use of RT in either the adjuvant setting or the neoadjuvant setting, based on lessons learned from extremity sarcomas. Analysis of retrospective series has shown mixed results.[26] The first randomized, controlled trial comparing neoadjuvant RT with surgery (ACOSOG Z9031) closed prematurely in 2004 due to low accrual rates because of concerns over treatment toxicity and delays in surgery. However, the STRASS trial (NCT01344018), an international randomized, controlled trial assessing oncologic outcomes in patients undergoing neoadjuvant RT and surgery compared with patients undergoing upfront surgery, has completed accrual and final results are expected to be released at the 2019 American Society of Clinical Oncology Annual Meeting. An interim safety analysis presented at the Connective Tissue Oncology Society meeting in 2016 did not identify an increased risk of perioperative events in the neoadjuvant radiation group.
KEY POINTS
- The best chance of resection with curative intent is at the time of primary presentation. Gross complete resection is the cornerstone of management. Surgery should aim to achieve macroscopically complete resection, with a single specimen encompassing the tumor and involved contiguous organs, and with microscopically positive margins minimized. This is best achieved by resecting the tumor en bloc with adherent structures, even if not overtly infiltrated.
- The extent of surgical resection depends on histologic subtype. A systematic resection of the ipsilateral kidney, colon, and psoas muscle is often required in liposarcoma, whereas a more limited resection, albeit without giving up the attempt at minimizing marginality, is required in leiomyosarcoma and other rare subtypes such as solitary fibrous tumor.
- Neoadjuvant therapies (chemotherapy, external beam radiation, or combination radiation and chemotherapy) are safe in well-selected patients and may be considered after careful review by a multidisciplinary sarcoma tumor board when the recurrence risk is high. The preferred modality is chosen based on the pattern of recurrence, chemotherapy being employed in histologies with the highest systemic risk (eg, leiomyosarcoma and high-grade dedifferentiated liposarcoma), and radiotherapy in those with the highest locoregional risk (eg, well-differentiated liposarcoma and low/intermediate dedifferentiated liposarcoma). None of the neoadjuvant/adjuvant modalities, however, has proven its value in terms of improved survival rates.
While awaiting these results, an analysis of the prospectively collected National Cancer Database looked at the impact of radiation on overall survival. This propensity-matched cohort analysis identified improved survival in both patients receiving neoadjuvant RT as well as those receiving adjuvant RT.[27] Although this study has many limitations, including the lack of granularity of the data, it does provide a glimpse into the potential impact of RT in the largest series of RPS patients to date. Nevertheless, it should be emphasized that postoperative/adjuvant external beam RT following complete gross resection is of no study-proven value and is associated with significant short- and long-term toxicities. A therapeutic RT dose can be achieved in a minority of patients following resection. The quality of microscopic surgical margins should not be factored into the decision (in R1 patients with positive margins), not only because adjuvant RT holds little value, but because higher doses of RT in the case of R1 resection are not even possible in the postoperative setting. If considered, RT should be given in the preoperative setting.
Although the use of preoperative RT in inoperable/borderline resectable patients is a well-accepted strategy, the STRASS study will soon provide randomized data about the prognostic impact of this approach in patients who are candidates for macroscopic complete resection. Intraoperative radiation therapy has been utilized with mixed results, but it has not been associated with an improvement in survival. Moreover, the increased toxicity associated with this modality limits its use to experienced centers and in the context of clinical trials.
Systemic Treatment
Because of the many different subtypes of RPS, no clinical trials have assessed the use of adjuvant chemotherapy. Sarcoma patients receiving adjuvant chemotherapy are often in clinical trials mainly recruiting patients with extremity sarcomas for whom primarily anthracycline-based regimens have demonstrated a small but statistically significant survival advantage. The RPS subtypes that might benefit the most from chemotherapy are high-grade (G3 according to the Fédération Nationale des Centres de Lutte Contre Le Cancer grading system), dedifferentiated liposarcoma, leiomyosarcoma, and undifferentiated pleomorphic sarcoma, which tend to be chemosensitive.[28] Following the success of recruitment to STRASS, a second randomized study addressing the role of neoadjuvant chemotherapy in RPS is in preparation. So far, however, systemic chemotherapy has a limited role in the treatment of RPS.
Another treatment modality that is gaining traction is neoadjuvant chemotherapy as a radiosensitizer in conjunction with radiation therapy. A recently published phase I/II study assessed the long-term outcomes of 83 RPS patients treated with three cycles of high-dose, long-infusion ifosfamide in conjunction with RT prior to surgery.[29] This trial demonstrated the feasibility and tolerability of such a regimen, even though prognosis remained poor.[30] The combination of radiotherapy with other compounds, such as trabectedin or molecular target agents, is under investigation.
Recurrent Retroperitoneal Sarcoma
Unfortunately, local recurrence is still possible in RPS despite optimal surgical excision at primary presentation and multimodal therapy. The TARPSWG has published consensus guidelines to guide decision making in these often complex surgical cases.[31] A careful review of the preoperative imaging, operative report, and pathology, as well as current findings in a multidisciplinary setting, are essential. It is important to realize that the oncologic outcome deteriorates with each surgical resection while the risks and major associated morbidities increase.[32] Thus, the risk and benefits need to be judiciously weighed when planning and timing treatment for recurrence.
An analysis of the TARPSWG collaborative multi-institutional series has attempted to identify the strongest predictors of survival after treatment for local recurrence. Time from initial surgery to time of recurrence was the strongest predictor of survival. Patients who successfully underwent resection of their recurrence also had a aurvival advantage.[33] Multifocal disease carries in itself a poorer prognosis, with a very high rate of re-recurrence.[34] Although multifocal tumors are difficult to distinguish from peritoneal sarcomatosis, an analysis of a large, single-institution cohort identified the cutoff between them at seven lesions, and it seems that prognosis is significantly affected by this cutoff. As expected, incomplete debulking was not associated with improved survival, highlighting the importance of patient selection when resecting recurrent disease.[35] Complete debulking and heated intraperitoneal chemotherapy has not proven effective in sarcoma, but it can be considered on a case-by-case basis; the decision heavily relies on histologic subtype.[36]
Metastatic Retroperitoneal Sarcoma
Patient evaluation for metastatic RPS should aim to give the patient access to clinical trials and comprehensive multidisciplinary care. A tailored treatment plan should be designed, taking into consideration histopathology, previous therapy, disease-free interval, symptomatology, comorbidities, and functional status.[37] Metachronal hepatic or pulmonary metastasectomy should be considered following principles well established for other malignancies, as well as for extremity sarcomas. Selected patients should have undergone complete resection of the primary, and have a low, well-localized burden of disease that is easily accessible and amenable to complete resection. Moreover, a disease-free interval of more than 12 months would be ideal, as is response to systemic treatment or stable disease. There is no established role for resection of metastatic RPS, nor is there one for palliative surgery except in select cases.[38]
Conclusion
RPS comprises a multitude of histologic subtypes with specific prognoses. Complete surgical excision is the only chance at a cure and should be performed at specialized centers by an experienced team. Recurrent and metastatic disease should be addressed on a case-by-case basis by a multidisciplinary team and possibly in prospective studies.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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