Anatomy

Macroscopically, parts of the genitourinary tract, gastrointestinal (GI) tract, aorta and its branches, inferior vena cava and its tributaries, and lymphatic and nervous systems form important components of the retroperitoneum (Figure 23-1). The pancreas, ascending colon, descending colon, and duodenum are located anteriorly within the anterior pararenal space (APS), and the aorta, inferior vena cava, and lymph nodes are in the midline. Laterally, the kidneys and adrenals are surrounded by renal fascia within the perirenal space (PS). The psoas, quadratus lumborum, paraverterbral muscles, and bony skeleton form the posterior boundary of the retroperitoneum. Retroperitoneal fat, vessels, lymphatics, and nerves continue from the retroperitoneum into the small bowel mesentery, providing anatomic continuity between these compartments (Figure 23-2). The displacement or contiguous involvement of these major organs, and in particular of the major vascular branches, is of critical importance when planning surgical resection.

Figure 23-1 The major organs in the retroperitoneum are shown without the gastrointestinal tract. The aorta, inferior vena cava, renal vessels, and lymphatics lie close to the midline, and the kidneys and ureters are located more laterally. The psoas and quadratus lumborum muscles are visible posteriorly.

Figure 23-2 The position of all components of retroperitoneum are well depicted in the cross-sectional format. The duodenum lies closer to the midline, and the ascending and descending colon are located laterally.

Pathology

Microscopically, primary sarcomas can arise from fat, smooth or skeletal muscle, fibrous connective tissue, peripheral nerve cells, vascular tissue, or other mesenchymal cells (Table 23-1). STSs are classified according to the adult cell type that the tumor cells most closely resemble. However, this does not mean that the tumor arose from that cell type. The use of immune markers provides important additional information in the classification of STS. Liposarcomas are the most common type of tumor in adults, followed by leiomyosarcoma.⁷ In the older reports, the category of “malignant fibrous histiocytoma (MFH)” was common, whereas in current series, it is distinctly uncommon and classified instead as “undifferentiated pleomorphic sarcoma.”⁸ Ten percent to 15% of all sarcomas occur in children. In reviews from single institutions, the most common retroperitoneal sarcoma in the pediatric age is rhabdomyosarcoma, followed by fibrosarcoma and liposarcoma.^9,10

Table 23-1 World Health Organization Classification of Soft Tissue Sarcomas

MFH, malignant fibrous histiocytoma; PNET, primitive neuroectodermal tumor.

From Fletcher C, Unni KK, Mertens F. Pathology and Genetics of Soft Tissue and Bone: World Health Organization Classification of Tumors. Lyon, France: IARC Press; 2002.

Liposarcomas are tumors composed of fat cells. The most common form that arises in the retroperitoneum is well-differentiated liposarcoma (WDLPS). Morphologically, it is similar to a typical lipoma; histologically, the presence of lipoblasts allows its recognition. WDLPSs show slow but progressive growth over many years without development of any metastasis. In approximately 25% of the cases, there is transformation into a higher grade of tumor. When dedifferentiation occurs, there is loss of mature fat, and the tumor grows faster and has the capacity to metastasize. These areas of dedifferentiated liposarcomas (DDLPSs) always occur in preexisting WDLPS and show an abrupt transition to a nonfat component. Sometimes, these areas that show dedifferentiation may display features of leiomyosaroma or other sarcoma on histology and by immune markers. Dedifferentiation is characterized by more aggressive local growth, a greater risk of recurrence after resection, and development of distant metastases in 15% to 30%. The myxoid/round cell and pleomorphic subtypes of liposarcomas are uncommon in the retroperitoneum.¹¹

The common STSs in children are age-dependent. Up to age 14, rhabdomyosarcoma is the most common tumor type, whereas nonrhabdomyosarcomas are common in adolescents and young adults.^10,12 In a single institutional report covering 30 years that specifically looked at retroperitoneal site of tumor origin, rhabdomyosarcoma, followed by fibrosarcoma, were reported as common types of RPSs in the pediatric age group.⁹ This pattern is distinctly different from common tumor histology in adults. The common subtype of rhabdomyosarcoma is embryonal arising in the genitourinary system. These tumors are large, infiltrative, and liable to involve adjacent organs at the time of initial presentation. Thus, positive margins may be present after gross resection of tumor. Microscopically, these tumor cells do not arise from skeletal myoblasts but rather resemble them.¹¹

T Definition: Tumor Size

T Definition: Tumor Depth

Because the investing fascia of muscle is used as the division between superficial and deep, all retroperitoneal tumors are regarded as deep lesions with the suffix b.

N Definition

Clinical, imaging, or pathologic criteria are accepted for N designation. Note that involvement of nodes is uncommon in all STSs.

M Definition

Pathologic Criteria: Grading

A three-point grade from G1 to G3 using the French system (FNCLCC, the French Federation of Cancer Centers Sarcoma Group) is utilized. It is based on scores obtained from

This combination of T, N, M, and G for AJCC staging is depicted in Figure 23-3.

Figure 23-3 This diagram shows the important components of the current AJCC staging system (GTNM) with the histological grade or tumor type (inset, G), spread by lymphatics to nodes (N) (arrows) and hematogenous spread to liver and lungs (M) (arrows).

The survival graph shows better survival at lower stages (Figure 23-4). However, the absence of a major difference in survival between stage II (N0 disease) and stage III (N1 disease) points to a limitation in the current AJCC staging for RPSs (Figure 23-5).

Figure 23-4 Pooled data from Surveillance, Epidemiology, and End Results (SEERS) study show better survival at lower stages.

Redrawn from Nathan H, Raut CP, Thornton K, et al. Predictors of survival after resection of retroperitoneal sarcoma: a population-based analysis and critical appraisal of the AJCC staging system. Ann Surg. 2009;250:970-976.

Figure 23-5 M. D. Anderson Cancer Center data confirm better survival for stage I disease; however, there is not much difference between stage II (N0) and stage III (N1).

Redrawn from Anaya DA, Lahat G, Liu J, et al. Multifocality in retroperitoneal sarcoma: a prognostic factor critical to surgical decision-making. Ann Surg. 2009;249:137-142.

Limitations of American Joint Committee on Cancer Classification

Margin Status of Resected Tumor

R definition

R0 = Resection with negative microscopic margin

R1 = Resection with positive microscopic margin

R2 = Macroscopic disease remaining after surgery.

The status of resected margin after surgery is an important prognostic factor but not a part of the AJCC staging^20–22 (Figure 23-6).

Figure 23-6 Resection with residual disease, particularly R2, carries a poorer prognosis.

Redrawn from 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;26:1577-1581.

Other Staging Systems

The most important common variables in the AJCC system for RPSs are the presence of distant metastasis M1 and the tumor grade G1-3. Therefore, alternate staging systems based only on tumor grade or with additional criteria of multifocality and the degree of residual tumor left after surgery (R0, R1, or R2) have been proposed and are as good as or even better than AJCC.^17,18

Today, we are poised at the brink of important change with the availability of high-throughput technology of genomic, proteomic, and tissue microarray analysis in sarcoma. As the data about relevant genes and molecular markers are integrated with disease progression, tumor response, and survival, future modifications can be made to AJCC staging.

Local Spread

Local involvement of an adjacent organ is common because these tumors present at an advanced stage. This will manifest as displacement or invasion, particularly with high-grade tumors. When tumors arise from the upper retroperitoneum, displacement of liver, spleen, kidney, aorta, inferior vena cava, small bowel, or colon is commonly seen. Bladder displacement occurs when the tumor involves the pelvis. When the tumor invades an adjacent organ such as the ureters, bladder, or GI tract, urinary or bowel obstruction can occur. Bone involvement of lumbar spine, sacrum, or pelvis can occur through contiguous spread. Malignant peripheral nerve sheath tumor, in particular, exhibits spread along the nerve sheath. This is an important consideration when surgical excision is undertaken. A negative frozen section is used to determine the extent of surgery.

Hematogenous, Lymphatic, and Peritoneal Spread

RPSs primarily spread to the liver via the hematogenous route. Such a pattern is seen in 44% of patients.¹⁴ Liver metastases, particularly from leiomyosarcoma and angiosarcoma, can have marked enhancement; hence, both pre- and postintravenous contrast CT of the liver should be performed as a routine in these patients. As the disease spreads further through the bloodstream, metastases can involve lungs in 38%, with additional sites of involvement of adrenals, muscles, subcutaneous tissue, bones, and brain.

Lymph node metastases are distinctly uncommon, occurring in only 3.5% of patients with STS.²³ Lymph node involvement is more likely in patients with rhabdomyosarcoma, synovial, vascular, and epithelioid sarcoma.

Peritoneal spread can occur in the abdomen with seeding to produce disseminated implants in omentum, mesentery, and peritoneum.

All possible sites for tumor spread must be evaluated thoroughly on CT of chest, abdomen, pelvis, and other appropriate imaging modalities before any therapeutic decisions can be made.

Primary Tumor Detection and Characterization

The initial imaging workup of a patient with suspected RPS consists of a CT scan of the abdomen and pelvis. It should be performed with GI contrast and before as well as after the administration of intravenous contrast. CT permits the determination of size and location of primary tumor and its relationship to adjacent organs. Re-formatted images in coronal and sagittal planes are especially useful in demonstrating proximity to or invasion of small bowel, colon, kidneys, ureters, and the major vasculature. When there is a question of major arterial or venous involvement, a dedicated CT arteriogram or venogram can be very helpful in further assessment. Magnetic resonance imaging (MRI) of the abdomen and pelvis can serve as an alternate when the patient is unable to receive intravenous contrast for CT related to either renal dysfunction or a past history of severe reaction to intravenous contrast. Although an ultrasound can detect the larger RPSs, its shortcomings are in the characterization of fat and calcification from bowel and delineation of the relationship of the tumor with adjacent organs. If an ultrasound examination is initially obtained in a patient in whom RPS is being considered, a CT scan should be performed for the detailed information it provides.

Radiologic considerations are critical in the successful management of RPS. The important imaging features to report are size, internal attenuation characteristics (fat, soft tissue, or calcification), enhancement or necrosis, relationship to adjacent organs (displacement or invasion), the spread of disease to distant organs, and the response to treatment when follow-up CT is performed. These are important considerations for the surgeon, who is concerned about anatomic constraints to complete resection. The key imaging characteristics of the common RPS are presented next.

Liposarcoma

Liposarcoma is the most common RPS. Its typical appearance on CT is a bulky tumor with fat attenuation. It is recognized from generalized excess fat deposition seen with obesity by the mass effect that results in displacement of bowel loops or adjacent solid viscera. They may contain a few septations (Figure 23-7). These tumors are regarded as atypical lipomatous tumor (ALT) or WDLPS. When the attenuation of any area of tumor is greater than that of normal fat, has the attenuation of soft tissue density, or if contrast enhancement is seen, it must be reported as an area consistent with dedifferentiation (Figures 23-8 and 23-9). Such areas must be targeted for subsequent biopsy or surgery because DDLPS can be seen in as many as 15% of ALT/WDLSs.¹⁸ Whereas ALT/WDLPSs lack metastatic capacity, the DDLPS do disseminate and, consequently, have a particularly ominous prognosis.²⁴

Figure 23-7 A and B, An atypical lipomatous tumor/well-differentiated liposarcoma demonstrates fat density with a few septations (arrows)extending from the left midabdomen into the upper pelvis. The craniocaudal extent is easier to appreciate on the reformatted coronal (C and D) and sagittal (E and F) images.

Figure 23-8 Coronal (A) and midline sagittal (B and C) reformatted computed tomography (CT) scans show two tumors: one in the left retroperitoneum and the second one in the pelvis (arrows) representing multifocal liposarcoma.

Figure 23-9 A-D, A dedifferentiated liposarcoma shows areas of calcification and soft tissue density without any recognizable fat. It is in close contact with the left kidney, ureter, psoas muscle, jejunum, and decending colon. E, After receiving chemotherapy, a follow-up CT scan shows response with reduction in tumor size. At surgery, it was resected with R0 (microscopic negative) margin and preservation of the left kidney.

Leiomyosarcoma

A leiomyosarcoma is the second most common histologic type of RPS. It has a typical CT appearance as a large mass with a central necrotic core. This is due to the rapidity with which it can proliferate and outgrow its blood supply. A subset of leiomyosarcoma arises from the inferior vena cava and commonly produces venous occlusion (Figures 23-10 and 23-11). Leiomyosarcoma, high-grade pleomorphic sarcoma (formerly called “malignant fibrous histiocytoma [MFH]”), and synovial sarcoma are infiltrative tumors (Figure 23-12). Thus, invasion of adjacent organs and the development of distant metastases are seen much more frequently with these tumors than with liposarcomas (Figures 23-13 and 23-14).

Figure 23-10 A-C, A leiomyosarcoma arises from the inferior vena cava and produces right hydronephrosis. Its intra- and extraluminal extent is depicted on arterial, venous, and delayed phases of CT (arrows)D, On the fused positron-emission tomography (PET)/CT scan, the tumor (arrow) is fluoro-2-deoxy-D-glucose (FDG)-avid.

Figure 23-11 A-D, This enhancing tumor (arrows) in the left retroperitoneum is in close contact with the left renal vein and left ureter. It was removed at surgery with preservation of the left kidney and resection with reanastomosis of the left ureter. At pathology, it was a leiomyosarcoma with R1 margin.

Figure 23-12 This tumor involves right renal hilum and renal pelvis. It was resected with the right kidney and, at pathology, was found to be a well-capsulated epithelioid leiomyosarcoma.

Figure 23-13 High-grade pleomorphic sarcoma of the retroperitoneum shows local invasion of the psoas and left paraspinal muscles.

Figure 23-14 High-grade sarcoma arising in the pelvis shows direct invasion of the bladder on CT (A and B) and pelvic ultrasound (C). Note the vascularity of the tumor component in the bladder with color Doppler (arrow)D, A CT scan of the chest reveals one of multiple lung metastases (arrow)E, After receiving systemic chemotherapy and radiation therapy to the pelvis, there is a decrease in tumor size (arrow) and relief of urinary symptoms from bladder involvement.

Sarcomas Related to Genetic Syndromes

The manifestations of underlying genetic syndrome can be a tip off for related sarcomas. Desmoid tumors, typically in the root of the mesentery, can be multiple and are seen as a component of Gardner’s syndrome. In a patient with neurofibromatosis-1, any tumor associated with pain or enlargement of a plexiform neurofibroma must be assumed to represent malignant transformation and confirmed with a biopsy (Figures 23-15 and 23-16).

Figure 23-15 A-E, In this patient with neurofibromatosis-1, numerous plexiform neurofibromas (arrows) are seen on T1- and T2-weighted magnetic resonance imaging (MRI) studies. There is transformation into a malignant peripheral nerve sheath tumor in the left retroperitoneum (arrow inE).

Figure 23-16 A-D, A malignant nerve sheath tumor arises in the left retroperitoneum laterally. Its overall extent and relationship to small bowel and descending colon are well seen on the coronal and sagittal reformatted CT scans.

Pediatric Sarcomas

The most common RPS in children is rhabdomyosarcoma.⁹ It frequently arises from the genitourinary tract. These tumors are large, infiltrative, and liable to involve adjacent organs at the time of initial presentation (Figure 23-17). Nonrhabdomyosarcomas in pediatric age patients can be desmoplastic small round cell tumors (Figures 23-18 and 23-19), Ewing’s sarcomas (Figure 23-20), fibrosarcomas, and liposarcomas among others.

Figure 23-17 A 3-year-old presented with an inability to bear weight on the right side. A-C, Axial and coronal CT scans reveal a retroperitoneal tumor with right hydronephrosis. Note local invasion of the psoas muscle and low-attenuation center, representing necrosis (arrow in C). A biopsy revealed this to be an embryonal rhabdomyosarcoma. D, FDG fusion PET/CT reveals metabolic activity at the periphery with diminished activity in the center in areas of necrosis (arrow). E, After 8 weeks of chemotherapy, a follow-up FDG-PET/CT shows no change in size but a decrease in FDG uptake by the tumor (arrow), providing an early indication of response to chemotherapy.

Figure 23-18 A 19-year-old presented with tumors (arrows) in the right lower quadrant and pelvis that, at pathology, were multifocal desmoplastic small round cell tumors.

Figure 23-19 A and B, This desmoplastic small round cell tumor involves the retroperitoneum and contiguous mesentery. The third portion of duodenum had to be resected en bloc with the tumor at surgery.

Figure 23-20 A-D, Retroperitoneal and gluteal disease is seen in multicompartment involvement by Ewing’s sarcoma. There is permeative metastatic involvement of the left iliac wing appreciated on the bone windows.

Lymph Node Metastases (N)

Although metastatic involvement of lymph nodes is defined as stage III disease in the most recent edition of the AJCC scheme, it is distinctly an uncommon occurrence.¹⁶ It is estimated to occur in 3.5% of all STSs in adults and slightly more commonly in children. When CT detects and characterizes RPS, attention should be directed to the regional lymph node drainage. The enlargement or any abnormal enhancement pattern must be included in the imaging findings. MRI can detect adenopathy using size, abnormal signal characteristics, and enhancement with gadolinium contrast as criteria for involvement. Metastatic adenopathy is characterized on positron-emission tomography (PET)/CT studies as fluoro-2-deoxy-D-glucose (FDG)-avid areas that correspond to lymph nodes anatomically.

Distant Metastases (M)

When CT is initially employed for the detection and characterization of RPSs, simultaneously an evaluation is made of the liver, which is a common site for hematogenous metastases (Figure 23-21). Other sites of metastases (i.e., adrenals, peritoneum, bones, and intramuscular or subcutaneous sites) are also assessed at the same time (Figures 23-22 and 23-23). This is especially important when CT demonstrates tumors other than ALT/WDLPS. A CT of the chest is very helpful for the detection of any metastasis to the lungs. MRI is necessary in the assessment of the brain and spine, especially when the patient has neurologic symptoms or impending cord compression (Figure 23-24). FDG-PET/CT will accumulate in distant sites of high-grade tumors, but these should be differentiated from areas of physiologic uptake or sites of infection. A nuclear medicine bone scan is useful in detection of bony metastases.

Figure 23-21 A and B, Metastatic sarcoma has spread to the liver and lungs (M1) by the hematogenous route, making this stage IV disease.

Figure 23-22 A-D, CT scans reveal leiomyosarcoma (arrows) spread by the hematogenous route to involve the liver, tail of pancreas, abdominal wall, right quadratus lumborum muscle, and spinous process of the L2 vertebra.

Figure 23-23 A and B, Enhancing sarcoma metastases (arrows) involve the liver and right psoas muscle.

Figure 23-24 A and B, The extent of vertebral involvement is well depicted on MRI of the thoracic and lumbar spine (arrows). There is no cord compression in this patient.

After the initial CT, it is possible to provide a clinical (TNM) stage of disease. Then, for the pathologic aspects to complete staging, tissue diagnosis is necessary. If the tumor characteristics (small size or well-defined margins that displace adjacent structures) favor total surgical extirpation, surgery will serve as an excisional biopsy. When adjuvant therapy is a consideration (as in pediatric sarcomas), an imaging-guided biopsy is performed next. CT can guide the targeting of solid, non-necrotic portions of the tumor for biopsy. Although fine-needle biopsy can yield material for the diagnosis of malignancy, a core biopsy is preferred for the greater amount of tissue it provides. This allows determination of tumor grade based on the criteria of cellular differentiation and necrosis to be made for a comprehensive AJCC staging. In the event of a negative biopsy, an open biopsy should be pursued.²⁵ With the imaging detection of metastases, a core biopsy can be obtained from either the primary tumor or the metastatic site as appropriate.

Surgical Therapy

From the surgeon’s perspective, the radiologist can help in patient management by providing initial insight into possible histologic subtype, confirmation of the diagnosis by image-directed biopsy necessary for access to neoadjuvant treatment protocols, and also helping the surgeon reach decisions regarding resectability. Prior to surgical intervention, it is important to be aware of the involvement of stomach, small intestine, colon, rectum, pancreas, liver, spleen, kidney, ureter, bladder, vertebral bodies (including possible intramedullary extension of tumor), aorta, vena cava, celiac axis vasculature, and superior mesenteric artery and vein. Tumor involvement with many, if not most, of these anatomic structures can be successfully managed intraoperatively but is greatly aided by advanced presurgical planning. Hence, the role of diagnostic imaging is central in the formulation of specific surgical strategies.

Complete resection is much more difficult to achieve in infiltrating lesions versus the more indolent pushing type of sarcoma, which usually abut but do not invade critical structures that are in immediate proximity to the tumor. Major arterial and venous reconstruction can be undertaken with the simultaneous resection of GI tract and multiple organs during en bloc surgery for RPSs^26,27 (Figure 23-25). When comparing the current practice of aggressive surgery with the higher incidence of multiple organ resection with the earlier surgical experience, a study found improvement in the rate of complete resection (78% vs. 49%) and overall survival (58% vs. 39%). However, local recurrence continues to be a significant problem.²⁸ Because new surgical options are limited, this calls for adjuvant therapy for further improvement in outcome.

Figure 23-25 A and B, MRI obtained after gadolinium contrast reveals a high-grade pleomorphic sarcoma (formerly regarded as malignant fibrous histiocytoma [MFH]) (arrows). Radical surgical excision of tumor with adjacent inferior vena cava required a venous graft. C and D, Follow-up CT scans 20 months later show a patent venous graft. There is tumor recurrence (arrows) adjacent to the right psoas muscle.

Contraindications to resection must be individualized; however, long segment superior mesenteric vein encasement is particularly worrisome because of the high likelihood of venous compromise after resection. Although R0 resection is the goal, it may not be possible owing to tumor size or its location. R1 resection, for primary and recurrent lesions, particularly in well-differentiated, low-grade liposarcomas, may create a meaningful span of freedom from disease. It may, therefore, be quite favorable for the individual patient.^29,30 Unfortunately, recurrence occurs eventually in the vast majority (Figure 23-26).

Figure 23-26 A and B, There is tumor recurrence of a high-grade sarcoma (arrow) 18 months after a baseline postoperative study. C and D, Fusion images from FDG-PET/CT in the axial and coronal planes show that the tumor is metabolically active (arrows)E and F, Three months later, there is interval enlargement of the tumor with areas of enhancement and necrosis (arrows). There is now obstruction of a solitary right kidney and invasion of a loop of ileum in the lower right quadrant (arrow in F), presenting clinically with bowel obstruction.

Radiation Therapy

Whereas surgical resection is the mainstay of management for RPSs, radiation therapy is sometimes employed for primary local management in an effort to improve local control of these tumors.³¹ The decision to use radiation therapy as an adjuvant to surgical management can hinge on many factors, and it should be undertaken in a multidisciplinary team setting. The diagnostic imaging and its interpretation are critical to the decision-making process and in planning delivery of radiation treatment. Current practice patterns have evolved such that, in the preoperative setting, a lower total dose is preferred over radiation therapy administered postoperatively.⁷ Even so, the recommended total dose of 45 to 50.4 Gy given preoperatively exceeds the normal tissue tolerance for many of the critical structures that are often in proximity to these tumors. CT is the preferred imaging modality for radiotherapy management decisions as well as treatment planning.

An appreciation on imaging studies of the size and extent of RPS is important to decide the feasibility and technique for radiation therapy. Also, it is important to assess multifocality of tumor deposits because such patients may not be suitable candidates to receive radiation therapy. The amount of small bowel approximating the tumor is critical because a proposed therapy field that would include a large volume of small bowel will be a contraindication to the use of radiation therapy. For right-sided retroperitoneal tumors, the proximity to liver is of importance because significant volumes (>30%) of the liver tissue cannot be irradiated to the prescribed dose without risk of unacceptable toxicity.³² If a large volume of liver must be irradiated to cover the area at risk, radiotherapy may not be advisable in such cases. The proximity of the kidneys is important to assess whether radiation therapy is feasible. If one kidney may be rendered nonfunctional by radiation therapy, a renal scan is advisable to ascertain the function of the contralateral kidney to ensure that adequate renal function will remain after radiation therapy. In children, consideration should be given to the proximity to any growth plates that could result in subsequent bone deformity.

The premature closure of a prospective trial to evaluate surgery alone versus preoperative radiotherapy and surgery for lack of accrual is symptomatic of the inherent problems in the study of RPS: low incidence of disease and negative perception about randomization to adjuvant therapy.³³ Intraoperative radiotherapy, intensity-modulated radiation therapy (IMRT), and proton therapy hold promise and deserve to be evaluated on a rigorous basis in the future with the goal of maximum benefit and minimum toxicity customized to the individual patient.

Chemotherapy

It is imperative that a multidisciplinary review of the clinical information at a specialized center precede implementation of chemotherapy. Tumors that are small or low grade are unlikely to metastasize and are, therefore, well managed with surgery with or without radiation therapy. Large or high-grade tumors have a greater propensity for metastases and need to be discussed in a multidisciplinary conference to determine the appropriateness of systemic therapy and the most beneficial sequence (preoperative vs. postoperative), acknowledging that the standard of care is complete surgical resection.³⁴ Systemic therapy remains the palliative standard of care for patients who have metastatic disease. Surgical consolidation may be appropriate for a select minority of these patients who can be resected completely and rendered free of all gross disease.

Conventional chemotherapy remains the standard of care for the majority of patients with RPSs. RPSs that are chemosensitive include synovial sarcoma and primitive neuroectodermal tumors; however, these are uncommon. Low-grade liposarcoma and leiomyosarcoma occur more frequently but tend to be chemoresistant. Commonly used drugs with known activity include doxorubicin, ifosfamide, dacarbazine, gemcitabine, and docetaxel. Our usual front-line regimen includes the combination of doxorubicin and ifosfamide. Special caution needs to be exercised with the use of ifosfamide in patients older than 65 years and those who have had a nephrectomy. Gemcitabine with or without docetaxel is generally used as a second-line regimen, although it may be used up front in patients with leiomyosarcomas, especially of gynecologic origin. Trabectedin, an investigational drug in the United States, but approved by the European Medicines Agency (EMA), has shown activity in liposarcomas and leiomyosarcomas. Other alternatives may include any available phase 1 or 2 clinical trials of new agents in an investigational setting.

Monitoring Tumor Response

Radiation or chemotherapy may be directed at preoperative tumor reduction so that subsequent surgery will provide tumor-free (R0) resection margins. Alternatively, such therapy may be given after surgery when there is microscopic (R1) or gross residual disease (R2) for local control. In addition, conventional chemotherapy is used for palliation in the patient with distant metastatic disease (M1). It is important to be able to evaluate tumor response in all these settings. Reduction in the size of tumor and target lesions using Response Evaluation Criteria In Solid Tumors (RECIST) has been used as a sign of response historically. However, such response does not necessarily lead to increased survival. Recent experience in the treatment of GISTs has shown the utility of tumor metabolism as an indicator of tumor response when evaluated with PET. A change in tumor attenuation but not tumor size by CT is a consequence of such targeted therapy.³⁵ PET is valuable in assessment of early tumor response in high-grade RPSs.³⁶ Whereas different parameters of glucose kinetics have been suggested, the standard uptake value (SUV) is utilized most commonly in everyday practice.³⁷ FDG-PET may also prove very useful when novel targeted therapy is being investigated because reduction in SUV can provide an early separation of responders from nonresponders. Newer radiotracers such as thymidine analogue 3’-deoxy-3’ ¹⁸F fluorothymidine appear promising for even better means of evaluating tumor metabolism.³⁸ Tumor volume reduction and tumor necrosis as indicators of tumor response may be evaluated with MRI and deserve to be evaluated rigorously.

Detection of Recurrence

The risk of local recurrence is the highest early after surgery, with two thirds occurring within 2 years.⁶ The overall local recurrence rate in RPS ranges from 40% to 90%. Recurrence in the abdomen is common, with metastases to liver being frequent, followed by lung metastases. It is, therefore, recommended that, in patients with high-grade tumors, CT of the chest, abdomen, and pelvis be performed at 3- to 4-month intervals for 3 years, subsequently at 6-month intervals for 2 years, and then annually. For low-grade tumors, the recommendation is to undergo CT of the chest, abdomen, and pelvis at 3- to 6-month intervals for 2 to 3 years and then annually. Such surveillance frequency is widely used in clinical practice, but its benefit has not been proved in a prospective trial.²⁵ The 5-year survival rate in RPS is from 40% to 52%, and it drops to 28% if there is local recurrence.^39,40 The duration of surveillance should continue beyond the conventional timeframe because recurrence and metastases in RPS do occur beyond 5 years.

While local recurrence occurs 40% to 90% in RPS, the recurrence rate in extremity sarcoma is only about 10%. The resection of recurrent tumor in the retroperitoneum has been shown to provide prolonged local control, and it can be undertaken multiple times, especially in patients with low-grade well-differentiated liposarcoma, However, whereas primary resection results in complete resection in 80% of patients, with recurrence, complete resection is achieved in 57%, and it gets less with subsequent recurrence.^14,15

There remain many unanswered questions in the management of the patient with metastatic sarcoma. What is the place of metastatectomy of liver or lung lesions? What is the optimal combination and sequence for chemotherapy, radiation therapy, and surgery? Such topics can best be addressed definitively in large, multiple-institution clinical trials. Until then, multi-institutional cooperative groups can work to provide the best possible data for the care of the patient with RPS to improve quality of life and prolong survival.

Surgical Therapy

The overall complication rate is 5% to 10%.⁴¹ Complications are usually in the early postoperative period and, when severe, can include bleeding, myocardial infarction, or sepsis. Wound dehiscence, abscess, anastomotic leak, or bowel obstruction may also occur.⁴²

Radiation Therapy

Acute GI toxicity may occur when small bowel loops are in the irradiated field. In severe cases, dehydration may necessitate treatment with intravenous fluids. With brachytherapy, duodenitis, stricture formation, and perforation, especially if nasojejunal intubation is performed, may occur. If preoperative radiotherapy is given, delayed wound healing may be seen. Any portion of the kidney in the radiation field will lose function, so adequate reserve of renal function should be ensured before radiation therapy. Stricture and bowel obstruction can be seen as late complications.^42,43 In a child, if any growth plate is included in the radiation portal, impaired growth and bony deformity may occur later. A slightly higher risk of radiation-induced second tumor is possible. However, the benefit of radiation therapy far outweighs this relatively small risk and it must not be withheld when indicated.

Chemotherapy

Nausea and vomiting can be seen frequently and will respond to antiemetic therapy. Neutropenia, anemia, and thrombocytopenia may be seen from myelosuppression. These may manifest by neutropenic fever, infection, fatigue, or a tendency to bleed. Mucositis is usually of short duration. Cardiac toxicity can occur with doxorubicin. Ifosfamide may lead to impaired renal function or neurotoxicity.