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CA Cancer J Clin 2004; 54:94
doi: 10.3322/canjclin.54.2.94
© 2004 American Cancer Society
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Soft Tissue Sarcomas

Janice N. Cormier, MD, MPH and Raphael E. Pollock, MD, PhD


Dr. Cormier is Assistant Professor, Department of Surgical Oncology and Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX.
Dr. Pollock is Head, Division of Surgery, University of Texas MD Anderson Cancer Center, Hous-ton, TX.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 INITIAL ASSESSMENT
 TREATMENT
 SPECIAL SITUATIONS
 CONCLUSIONS
 REFERENCES
 
Sarcomas are a heterogeneous group of rare tumors that arise predominantly from the embryonic mesoderm. They present most commonly as an asymptomatic mass originating in an extremity but can occur anywhere in the body, particularly the trunk, retroperitoneum, or the head and neck. Pretreatment radiologic imaging is critical for defining the local extent of a tumor, staging the disease, guiding biopsies, and aiding in diagnosis. Core-needle biopsy is the preferred biopsy technique for diagnosing soft tissue sarcomas. The American Joint Committee on Cancer (AJCC) staging system for soft tissue sarcomas is based on histologic grade, the tumor size and depth, and the presence of distant or nodal metastases. Despite improvements in local control rates with wide local resections and radiation therapy, metastasis and death remain a significant problem in 50% of patients who present with high-risk soft tissue sarcomas. The most common site of metastasis is the lungs, and metastasis generally occurs within two to three years after the completion of therapy. Progress in the molecular characteristics of these tumors should in the near future translate into molecularly based therapies that can be incorporated into standard treatment strategies.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
INITIAL ASSESSMENT
 TREATMENT
 SPECIAL SITUATIONS
 CONCLUSIONS
 REFERENCES
 
    Incidence
Sarcomas are a heterogeneous group of rare tumors that arise predominantly from the embryonic mesoderm. The various sarcomas include bone sarcomas (osteosarcomas and chondrosarcomas), Ewing’s sarcomas, peripheral primitive neuroectodermal tumors, and soft tissue sarcomas, which are the most frequent. We will focus on soft tissue sarcomas in this review. In 2004, approximately 8,680 new cases are expected to be diagnosed in the United States, and 3,660 deaths from soft tissue sarcomas are predicted, accounting for 0.63% of all cases and 1.15% of deaths from cancer.1

Soft tissue sarcomas can occur anywhere in the body, but most originate in an extremity (59%), the trunk (19%), the retroperitoneum (15%), or the head and neck (9%).2 Currently, more than 50 histologic types of soft tissue sarcoma have been identified (Table 1), but the most common are malignant fibrous histiocytoma (28%), leiomyosarcoma (12%), liposarcoma (15%), synovial sarcoma (10%), and malignant peripheral nerve sheath tumors (6%).3 Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood.


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  		TABLE 1 Histologic Subtypes of Soft Tissue Sarcoma

 

    Epidemiology
In general, soft tissue sarcomas do not seem to result from malignant changes or the dedifferentiation of benign soft tissue tumors, and despite the variety of histologic subtypes, soft tissue sarcomas have many clinical and pathologic features in common. For example, the clinical behavior of most soft tissue sarcomas is similar and, as defined by the staging system, is determined by the anatomic location (depth), grade, and size of the tumor. The dominant pattern of metastasis is hematogenous. Lymph node metastasis is rare (less than 5%), except for a few histologic subtypes such as epithelioid sarcoma, synovial sarcoma, rhabdomyosarcoma, clear-cell sarcoma, and angiosarcoma.4

External radiation therapy is a well-established risk factor for soft tissue sarcoma, as shown by the fact that the incidence of sarcomas is increased eightfold to 50-fold in patients treated with radiation therapy for cancer of the breast, cervix, ovary, testes, or lymphatic system.5,6 However, the risk of sarcoma appears to be commensurate with the dose of radiation. Regardless, the median latency period is approximately 10 years. Other risk factors include occupational exposure to certain chemicals, including herbicides such as phenoxyacetic acids and wood preservatives containing chlorophenols.7,8 Chronic lymphedema following axillary dissection is another risk factor; the subsequent lymphangiosarcoma is known as Stewart-Treves syndrome. Lymphangiosarcoma has also been seen after filarial infections and in the setting of congenital or heritable lymphedema, in which case the lower extremities are usually the site of the tumor.9

    Genetics
Specific inherited genetic alterations are associated with an increased risk of both bone and soft tissue sarcomas. The oncogenes (ie, genes that can induce malignant transformation and tend to drive cells toward proliferation) that have been implicated in the development of soft tissue sarcomas include MDM2, N-myc, c-erbB2, and members of the ras family. Amplification of these genes in several subtypes of soft tissue sarcomas has been shown to correlate with an adverse outcome.10 Cytogenetic analysis of soft tissue tumors has also identified distinct chromosomal translocations that code for oncoproteins associated with certain histologic subtypes. The best characterized gene rearrangements have been found in Ewing’s sarcoma (EWS–FLI-1 fusion), clear-cell sarcoma (EWS–ATF1 fusion), myxoid liposarcoma (TLS–CHOP fusion), alveolar rhabdomyosarcoma (PAX3–FHKR fusion), desmoplastic small round-cell tumor (EWS–WT1 fusion), and synovial sarcoma (SSX–SYT fusion).11

Tumor suppressor genes play a critical role in cell growth inhibition and can suppress the growth of cancer cells. However, these genes can be inactivated by hereditary or sporadic mechanisms. Two such genes that are particularly relevant to soft tissue tumors are the retinoblastoma (Rb) gene and the p53 tumor suppressor gene. Mutations or deletions in the Rb gene can lead to the development of retinoblastomas and sarcomas of the soft tissue and bone. In addition, although mutations in the p53 tumor suppressor gene are the most common mutations in human solid tumors, they have also been observed in 30% to 60% of soft tissue sarcomas.12,13 There is also a high incidence of soft tissue sarcomas in patients with germline mutations in the tumor suppressor gene p53 (ie, the Li-Fraumeni syndrome).


   INITIAL ASSESSMENT
TOP
 ABSTRACT
 INTRODUCTION
 INITIAL ASSESSMENT
TREATMENT
 SPECIAL SITUATIONS
 CONCLUSIONS
 REFERENCES
 
    Clinical Presentation
Soft tissue sarcomas most commonly present as an asymptomatic mass. The size at presentation usually depends on the location of the tumor. Tumors in the distal extremities are often small when discovered, whereas tumors in the proximal extremities and retroperitoneum can become quite large before they are apparent. Soft tissue sarcomas grow in a centrifugal fashion and compress surrounding normal structures, but rarely does impingement on bone or neurovascular bundles produce pain, edema, and swelling. Similarly, retroperitoneal soft tissue sarcomas are almost always observed as a large asymptomatic mass. Infrequently, patients may initially exhibit obstructive gastrointestinal symptoms or neurologic symptoms related to compression of the lumbar or pelvic nerves.

The differential diagnosis of a soft tissue mass includes benign lesions, including lipomas, lymphangiomas, leiomyomas, and neuromas. Besides sarcomas, other malignant lesions, such as primary or metastatic carcinoma, melanoma, or lymphoma, must also be considered. Small lesions that have not changed for several years may just be closely observed. However, biopsy should be considered in patients with all other types of tumors to establish a definitive diagnosis.

    Diagnostic Imaging
Pretreatment radiologic imaging is critical for defining the local extent of a tumor, staging the disease, guiding biopsies, and aiding in diagnosis. Imaging studies are also crucial in monitoring tumor changes after treatment, especially after preoperative chemotherapy or radiation therapy, and in detecting recurrences after surgical resection. Each imaging modality, however, has a particular place in patients with soft tissue sarcomas.

Although radiography is useful for providing information on primary bone tumors, it is not useful for evaluating soft tissue tumors of the extremities. Nonetheless, chest radiography should be performed in patients with primary sarcoma to look for lung metastases. Computed tomography (CT) of the chest should be considered for patients with high-grade lesions or tumors larger than 5 cm (T2). Contrast-enhanced CT can assess the extent of the soft tissue tumor burden and the proximity of the tumor to vital structures. CT is also the preferred imaging technique for evaluating retroperitoneal sarcomas.14 Current techniques can provide detailed information on the abdomen and pelvis and delineate adjacent organs and vascular structures. CT of the abdomen and pelvis should also be done when a myxoid liposarcoma is identified in an extremity, because this subtype of soft tissue sarcoma often metastasizes to the abdomen.15

Magnetic resonance imaging (MRI) is the preferred imaging modality for extremity sar-comas.16,17 It can accurately delineate muscle groups and distinguish among bone, vascular structures, and tumor. Sagittal and coronal views can show the anatomic compartments in three dimensions. Special techniques, including magnetic resonance angiography, can be performed if adjacent vascular structures must also be delineated. Additionally, MRI may help distinguish benign lesions such as lipomas, hemangiomas, schwannomas, neurofibromas, and intramuscular myxomas from their malignant counterparts. Before the start of chemotherapy, contrast-enhanced T1-weighted MRI can be used to determine the existence and extent of intratumoral necrosis. MRI is also valuable for identifying tumor recurrence after surgery; a baseline image is usually obtained three months after surgery.

    Biopsy Techniques
    Fine-needle Aspiration Biopsy
Fine-needle aspiration biopsy is an acceptable method for the diagnosis of most soft tissue sarcomas, particularly when it is performed in conjunction with clinical and imaging studies. However, fine-needle aspiration biopsy should be used for the primary diagnosis of soft tissue tumors only at centers where cytopathologists have experience with both the technique of the fine-needle biopsy of soft tissue tumors and the interpretation of the results. Fine-needle aspiration biopsy is the procedure of choice to confirm or rule out a metastatic focus or local recurrence. If tumor grading is essential for treatment planning, fine-needle aspiration biopsy has limitations. Fine-needle aspiration biopsy of superficial lesions is often done in the clinic. However, an interventional radiologist may need to perform the biopsy of deeper tumors under sonographic or CT guidance. The diagnostic accuracy of fine-needle aspiration biopsy-based findings in patients with primary tumors ranges from 60% to 96%.18 In general, the amount of material obtained by fine-needle aspiration biopsy is small, and the diagnostic accuracy clearly depends on the experience and skill of the cytopathologist.

    Core-needle Biopsy
Core-needle biopsy is a safe, accurate, and economical procedure for diagnosing soft tissue sarcomas. In addition, enough tissue is usually obtained for use in several diagnostic tests, such as electron microscopy, cytogenetic analysis, and flow cytometry. Complications occur in less than 1% of patients who undergo core needle biopsy.19 The use of CT or sonography to guide a core-needle biopsy can increase the yield of tumor tissue by more accurately pinpointing the location of the tumor. Obviously, it is particularly important to precisely locate the needle in the tumor mass to avoid sampling necrotic or cystic areas of the tumor that are of no diagnostic value. The diagnostic accuracy of core-needle biopsy-based findings is reported to be 93%.19

    Incisional Biopsy
Open biopsy is a reliable diagnostic method that obtains adequate tissue. However, incisional biopsies are usually performed only when fine-needle aspiration biopsy or core-needle biopsy specimens yield nondiagnostic findings. An open biopsy ideally should be performed in a designated treatment center by the same surgeon who will perform the definitive surgery. The biopsy incision should be oriented longitudinally along the extremity to allow a subsequent wide local excision that encompasses the biopsy site, scar, and tumor en bloc. A poorly oriented biopsy incision can result in an excessively large surgical defect from a wide local excision, which in turn necessitates a larger postoperative radiation therapy field to encompass all tissue at risk. Adequate hemostasis must also be achieved at the time of biopsy to prevent the dissemination of tumor cells resulting from the formation of hematomas in adjacent tissue planes.

    Excisional Biopsy
An excisional biopsy of easily accessible (superficial) extremity or truncal lesions smaller than 3 cm can often be performed. However, the benefits of excisional biopsies rarely exceed those of other biopsy techniques, and these procedures may also cause postoperative complications that could ultimately delay definitive therapy.

    Staging and Prognostic Factors
The current American Joint Committee on Cancer (AJCC) staging criteria for soft tissue sarcomas rely on the histologic grade, the tumor size and depth, and the presence of distant or nodal metastases (Table 2). 20 These criteria do not apply to visceral sarcomas, Kaposi sarcoma, dermatofibrosarcoma, or desmoid tumors.


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  		TABLE 2 Staging System for Soft Tissue Sarcoma

 

    Histologic Grade
The histologic grade of a soft tissue sarcoma remains the most important prognostic factor. To accurately determine the tumor grade, however, an adequate tissue sample must be appropriately fixed, stained, and examined by an experienced sarcoma pathologist. The features that define the grade are the degree of cellularity, differentiation, pleomorphism, and necrosis as well as the number of mitoses. Certain tumors have an assigned grade based on the histologic diagnosis (eg, Grade 1 for well-differentiated liposarcomas; Grade 3 for rhabdomyosarcoma). Sarcomas may be misdiagnosed or misclassified by the general pathologist in up to 25% to 40% of cases;21–24 therefore, it is strongly recommended that cases be reviewed before therapy by experts in sarcoma pathology. This high rate of discordance illustrates the need for more objective molecular and biochemical markers to improve the accuracy of conventional histologic assessments.

The metastatic potentials for soft tissue sarcomas by grade are as follows: 5% to 10% for low-grade lesions, 25% to 30% for intermediate-grade lesions, and 50% to 60% for high-grade tumors.25 In the 2002 AJCC staging system, four tumor grades are designated: well differentiated (G1), moderately differentiated (G2), poorly differentiated (G3), and undifferentiated (G4). In this four-tiered system, Grades 1 and 2 are considered low grade and Grades 3 and 4 are considered high grade.20 Some recommend using other grading systems based on necrosis26 or mitoses and necrosis.27

    Tumor Size
The size of a soft tissue sarcoma is an important prognostic variable. Sarcomas have classically been stratified into two groups on the basis of size; T1 lesions are 5 cm or smaller, and T2 lesions are larger than 5 cm. Some authors have suggested that the further stratification of tumors larger than 5 cm would provide more accurate prognostic information. For example, when 316 patients with soft tissue sarcomas were grouped into four subgroups on the basis of tumor size (less than 5 cm, 5 to less than 10 cm, 10 to 15 cm, and greater than 15 cm), each subgroup was found to have a different prognosis, as shown by respective five-year survival rates of 84%, 70%, 50%, and 33%.28

The prognostic significance of the anatomic tumor location with respect to its relationship to the investing fascia of the extremity or trunk was incorporated into the AJCC staging system in 1998.29 Soft tissue tumors above the superficial investing fascia of the extremity or trunk are designated by the addition of an "a" in the T score, whereas tumors invading or deep to the fascia as well as all retroperitoneal, mediastinal, and visceral lesions tumors are designated by a "b" in the T score.

    Nodal Metastasis
Lymph node metastasis of soft tissue sarcomas is rare; less than 5% show nodal spread. A few histologic subtypes, including rhabdomyosarcoma, epithelioid sarcoma, synovial sarcoma, angiosarcoma, clear cell sarcoma, and malignant fibrous histiocytoma, show a higher incidence of nodal involvement (10% to 20%). Nodal disease is designated Stage IV disease.

    Distant Metastasis
Distant metastases occur most often to the lung. Selected patients with pulmonary metastases may survive for long periods after surgical resection.30 Other potential sites of metastasis include bone, the brain, and the liver. Visceral and retroperitoneal sarcomas show a propensity to metastasize to the liver and peritoneum.2


   TREATMENT
TOP
 ABSTRACT
 INTRODUCTION
 INITIAL ASSESSMENT
 TREATMENT
SPECIAL SITUATIONS
 CONCLUSIONS
 REFERENCES
 
Accurate preoperative histologic diagnosis is of critical importance in choosing the appropriate primary treatment strategy for patients with soft tissue sarcomas. An intact primary tumor following biopsy affords the best opportunity for the treatment planning team to evaluate the tumor’s proximity to vital structures and for the surgeon to achieve a surgical resection with negative histologic margins. In addition, the tumor can serve as a biologic marker of response in patients who are to be enrolled in preoperative treatment protocols.

The overall five-year survival rate in patients with soft tissue sarcomas of all stages remains only 50% to 60%.31 Most patients die of metastatic disease, which becomes evident within two to three years of the initial diagnosis in 80% of cases. However, several subsets of patients have benefited from multimodality treatment approaches. For example, a multidisciplinary approach is taken in patients with soft tissue sarcomas of the extremities; it includes a margin-negative resection plus radiation therapy to the tumor bed and has resulted in local control rates up to and exceeding 90%. Nonetheless, despite improvements in local control rates, metastasis and death remain significant problems in patients with high-risk soft tissue sarcomas. Patients considered at high risk of recurrence and death include those presenting with metastatic disease, localized sarcomas at sites other than the extremities, or sarcomas larger than 5 cm of an intermediate or high histologic grade (T2).25,32 Patients with abdominal sarcomas continue to show particularly high rates of recurrence and poor overall survival.33–35

    Surgery
The type of surgical resection is determined by several factors, including tumor location, tumor size, the depth of invasion, the involvement of nearby structures, the need for skin grafting or autogenous tissue reconstruction, and the patient’s performance status. Local therapy consisting of surgery, either alone or in combination with radiation therapy when wide pathologic margins are limited by anatomic constraints, is the approach taken in patients with small (less than 5 cm) primary tumors with no evidence of distant metastatic disease.

In 1985, the National Institutes of Health formulated a consensus statement recommending limb-sparing surgery for most patients with high-grade extremity sarcomas.36 However, amputation remains the treatment of choice for the estimated 5% of patients whose tumor cannot be grossly resected with a limb-sparing procedure that preserves function.37 Wide local excision is the primary treatment strategy for extremity sarcomas, with the goal to resect the tumor with a 2-cm margin of surrounding normal soft tissue. The biopsy site or tract (if applicable) should also be included en bloc with the resected specimen.

Soft tissue sarcomas are generally surrounded by a zone of compressed reactive tissue that forms a pseudocapsule, which may mistakenly be used by inexperienced surgeons to guide resection (enucleation). Microscopic extensions of tumor beyond the pseudocapsule must always be considered when planning surgery and radiation therapy. Patients with microscopically positive surgical margins are at increased risk of local recurrence. Indeed, margin status after surgical resection is an independent prognostic factor for local recurrence.32,38 However, negative margins cannot be attained in some anatomic areas because of the tumor’s proximity to vital structures. In addition, because neither a positive surgical margin nor local recurrence has been shown to clearly adversely affect overall survival,39 this should be taken into consideration if achieving clear surgical margins would require amputation or substantial functional compromise of an extremity.

    Radiation Therapy
In the 1970s, 50% of patients with extremity sarcomas underwent amputation for local control of their tumors. However, large numbers of patients died of metastatic disease despite a local recurrence rate of less than 10% after radical surgery. This realization prompted the development of local therapy involving conservative surgical excision in combination with postoperative radiation therapy, which yielded improved local control rates of 78% to 91%.40,41

The evidence for using adjunctive radiation therapy in patients eligible for a conservative surgical resection came from two randomized trials42,43 and three large single-institution studies.44–46 In a randomized trial from the National Cancer Institute, 91 patients with high-grade extremity tumors were treated with limb-sparing surgery followed by chemotherapy alone or radiation therapy plus adjuvant chemotherapy. A second group of 50 patients with low-grade tumors were treated with resection alone or resection with radiation therapy. The 10-year local control rate for all patients receiving radiation therapy was 98%, compared with 70% for those not receiving radiation therapy (P = 0.0001).42 Similarly, in a randomized trial conducted at Memorial Sloan-Kettering Cancer Center, 164 patients were either just observed or underwent brachytherapy after conservative surgery. The five-year local control rate for patients with high-grade tumors was 66% in the observation group and 89% in the brachytherapy group (P = 0.003).43 No significant difference was observed between the treatment groups consisting of patients with low-grade tumors.

Until recently, the standard treatment was to administer radiation therapy as an adjunct to surgery in all patients with intermediate- or high-grade tumors of any size. However, small tumors (less than or equal to 5 cm) are less frequently associated with local recurrence, indicating that radiation therapy may not be necessary in these patients.25,28,32,47,48 The finding in at least two contemporary series that postoperative radiation therapy did not improve the five-year local recurrence or survival rates in patients with small soft tissue sarcomas further raised a question about the value of radiation therapy in patients with small tumors.49,50 These investigators attributed the previously reported higher recurrence rates after less radical surgery in patients with small tumors to the fact that the findings were made in the era before the use of preoperative MRI and the advent of improved surgical and pathologic techniques.

The optimal mode (external beam or brachytherapy) and timing (preoperative, intraoperative, or postoperative) of radiation therapy have yet to be defined. The optimal margin is also not well defined; although a radiation margin of 5 to 7 cm is standard, some centers advocate wider margins for tumors larger than 15 cm. At most institutions, the typical preoperative dose is 50 Gy, given in 25 fractions. Postoperative radiation therapy planning is based on the tumor grade, the status of the surgical margins, and institutional preferences. Regardless, the entire surgical scar and drain sites should be included in the field so that a near-full dose is given to the superficial skin. Metallic clips placed in the tumor bed during surgery can help define the limits of the resection and aid in radiation therapy planning. Doses of 60 to 70 Gy are usually necessary for postoperative treatment.

There are also those who believe that the radiation therapy should be administered preoperatively. Proponents cite several advantages to this approach. First, they contend that multidisciplinary planning with radiation oncologists, medical oncologists, and surgeons is facilitated when it is done early in the course of therapy while the tumor is in place and ensures that treatment is not delayed or omitted because of postoperative wound complications. Second, they maintain that lower doses of radiation can more easily be delivered preoperatively to an undisturbed tumor bed, which may also have improved tissue oxygenation.46,51,52 Third, the preoperative radiation fields can be smaller and the number of joints included in those fields fewer than those in postoperative radiation fields, which may result in an improved functional outcome.53 And finally, advocates of preoperative radiation therapy contend that by shrinking the tumor, radiation therapy can facilitate surgical resection. 52 Critics of preoperative radiation therapy cite the difficulty of pathologically assessing surgical margins in irradiated specimens and the increased rate of wound complications (Table 3). 54–58


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  		TABLE 3 Postoperative Complications Following Preoperative Radiation Therapy for Extremity Soft Tissue Sarcoma

 

The only randomized comparison of preoperative and postoperative radiation therapy for soft tissue sarcoma conducted to date was performed by the National Cancer Institute of Canada Clinical Trials Group.58 This trial was designed to compare the complications and functional outcomes of sarcoma patients treated with preoperative or postoperative external-beam radiation therapy. From October 1994 to December 1997, 190 patients were randomized to receive preoperative radiation therapy (50 Gy) or postoperative radiation therapy (66 Gy). At a median follow-up of 3.3 years, wound complications had occurred in 35% of patients given preoperative radiation therapy but only 17% of patients given postoperative radiation therapy (P = 0.01). Most of the wound complications occurred in patients with lower extremity sarcomas. Both groups achieved similarly high rates of local control and progression-free survival at three years.58 These findings suggest that preoperative external-beam radiation therapy is effective but that patients should be informed of the increased risk for major wound complications—particularly those with soft tissue sarcoma in a lower extremity.

Brachytherapy is another approach to radiation therapy in patients with soft tissue sarcomas. The primary benefit of brachytherapy, which involves the placement of multiple catheters in the tumor resection bed to administer iridium192, is the shorter overall treatment time of four to six days, compared with the four to six weeks generally consumed by preoperative or postoperative radiation therapy regimens. Brachytherapy also produces less radiation scatter in critical anatomic regions (eg, gonads or joints), and this can potentially lead to improved function. A cost-analysis comparison of brachytherapy and external beam irradiation further showed that adjuvant irradiation with brachytherapy was less expensive than external beam therapy in the treatment of soft tissue sarcoma.59 Brachytherapy can also be used for recurrent disease previously treated with external-beam radiation. The primary disadvantage of brachytherapy is that it requires an extended inpatient hospital stay and bed rest.

The long-term effects of radiation therapy (those occurring more than one year after the completion of therapy) are generally related to fibrosis, necrosis, edema, fractures, and contractures, all of which can substantially impair function. Variables associated with poor long-term functional outcome after radiation therapy include large tumors, high doses of radiation (greater than 63 Gy), long radiation fields (greater than 35 cm), poor radiation technique, neural sacrifice, postoperative fractures, and wound complications.60,61 The risks of edema and fracture are also greater in patients with tumors in the lower as opposed to upper extremities, and these potential complications should be discussed in detail with patients before treatment.

    Systemic Therapy
From the standpoint of response to chemotherapy, sarcomas range from histologic subtypes that are very responsive to cytotoxic chemotherapy to subtypes that are universally resistant to current agents. Only three drugs–doxorubicin, dacarbazine, and ifosfamide–are consistently associated with response rates of 20% or more in patients with advanced soft tissue sarcomas. Response rates to ifosfamide, however, have been observed to range from 20% to 60% in single-institution series in which higher-dose regimens or combination treatment with doxorubicin has been used.62–66

A major deterrent to the use of adjuvant chemotherapy has been the risk of its causing adverse toxic effects in patients who do not otherwise respond to therapy. With the advent of growth factors such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, the morbidity related to neutropenia has been minimized; however, dose-limiting thrombocytopenia continues to pose a challenge in the treatment of patients with chemotherapy. The use of high-dose doxorubicin has also been limited by myelotoxicity, epithelial toxicity, painful hand/foot syndrome, and potentially severe cardiac toxicity.67

    Integrating Multimodality Therapy
The primary objective of multimodality treatment is cure; when this goal is not possible, the goal is palliation of symptoms. Whenever possible, patients with a deep soft tissue mass should be referred, even before biopsy is performed, to a tertiary treatment center that offers care overseen by a team of specialists. Such multidisciplinary teams typically include oncologists from several disciplines (medicine, surgery, and radiation therapy), as well as a pathologist, radiologist, and ancillary staff.

    Postoperative Chemotherapy
The use of chemotherapy in patients with resectable soft tissue sarcomas remains controversial. A major deterrent to the use of postoperative chemotherapy in such patients has been the risk of adverse toxic effects in the absence of a response to therapy. Further discouraging its use has been the finding in more than a dozen individual randomized trials of postoperative chemotherapy that the therapy does not improve disease-free and overall survival in patients with soft tissue sarcomas. For example, the Sarcoma Meta-analysis Collaboration evaluated the effect of adjuvant chemotherapy on localized, resectable soft tissue sarcomas in 1,568 patients from 14 trials of doxorubicin-based adjuvant chemotherapy.68 At a median follow-up time of 9.4 years, the time to local and distant recurrence and recurrence-free survival rates was significantly better in the patients who received the doxorubicin-based chemotherapy than in the control group. However, the difference in the overall survival rate in the treatment group was only 4%, which was not significant (P = 0.12). In a subset analysis, patients with extremity tumors showed a 7% benefit in survival (P = 0.029).68 Subsequent randomized controlled trials of more modern (drugs, dose, and schedule) anthracycline/ifosfamide combinations in relatively small numbers of patients have yielded conflicting results.69–71 Because interpretation of this literature is complex72 and the evidence pertaining to the treatment of Stage III disease is inconclusive, considerable variation still exists in treatment standards.

    Preoperative Chemotherapy
There are several theoretical benefits to early systemic treatment. In addition to the early treatment of micrometastatic disease, preoperative systemic chemotherapy may shrink the primary tumor, resulting in improved chances of limb salvage. The ability to assess the tumor response in situ using radiologic imaging as well as pathologically after surgical resection is another advantage. Such an approach also spares patients who do not respond to therapy preoperatively the prolonged toxicities of an ineffective treatment postoperatively. On the other hand, patients who respond to preoperative chemotherapy can then also be treated with it postoperatively with the hope of improving their outcome.

As with postoperative chemotherapy, there is little survival data to support the use of preoperative chemotherapy. For example, the treatment-induced pathologic responses that have been seen after induction chemotherapy range from no response to a complete response with no residual viable cancer cells. The incidence of treatment-induced pathologic necrosis and its correlation with clinical outcomes are also not well defined in patients with soft tissue sarcomas.73 Small studies have shown complete pathologic tumor necrosis occurring in only 5% to 9% of the patients receiving doxorubicin-based induction chemotherapy.74–76 In addition, in a retrospective analysis of 496 patients with intermediate- and high-grade extremity soft tissue sarcomas who were treated with preoperative therapy (consisting primarily of doxorubicin-based chemotherapy and radiation therapy), complete pathologic responses (greater than or equal to 95% necrosis) were noted in only 69 patients (14%). Furthermore, with a mean follow-up of 10 years, the 10-year local recurrence rate in these patients with complete pathologic necrosis was only 11%, compared with 23% in patients with less than 95% pathologic necrosis. However, the 10-year survival rate for patients with complete pathologic responses was 71%, compared with 55% in the other patients (P = 0.001).69 On the basis of these results, the authors concluded that the extent of pathologic necrosis may be considered a surrogate endpoint for survival outcomes in patients with soft tissue sarcomas.73

The ways in which a response to induction therapy (eg, radiation therapy or chemotherapy) translates into other clinically meaningful outcomes (eg, reduction in the scope of surgical resection) are also not well defined. A recent retrospective analysis did examine the impact of preoperative chemotherapy on the scope of surgery. The study included a blinded assessment of imaging studies obtained before and after induction chemotherapy in 65 patients with Stage II or III soft tissue sarcomas.77 The radiographically documented responses to preoperative chemotherapy included partial responses in 34%, minimal responses in 9%, stable disease in 31%, and progressive disease in 26%. Only eight patients (12%) were believed to show a response sufficient enough to allow the scope of their operation to be reduced, and the disease progressed enough in six patients (9%) to require an increase in the scope of their operation.77 Of interest, limb salvage could not be done after chemotherapy in any of the nine patients who were determined to require amputation before chemotherapy. Thus, there is no definitive evidence to support the perception that locally advanced soft tissue sarcoma in an extremity can be downstaged enough by induction chemotherapy to permit function-preserving, limb-sparing surgery.

    Concurrent Treatment Approaches
Treatments that combine systemic chemotherapy with radiosensitizers and concurrent external-beam radiation may theoretically improve disease-free survival by treating microscopic disease while enhancing the treatment of macroscopic disease. One concurrent approach that reportedly produces favorable local control rates in patients with soft tissue sarcoma is concurrent chemoradiation therapy with doxorubicin-based regimens.78,79 The initial approach consisted of intraarterial doxorubicin and high-dose-per-fraction radiation therapy and was used in patients with extremity soft tissue sarcomas. Since these findings have been published, several groups have attempted to evaluate the optimal route of administration,78,80–83 alternative chemotherapeutic agents,84–86 and the toxicity of combined therapies.87

It is difficult to compare the relative merits of the various chemotherapeutic agents and treatment regimens because of the diversity of the patient populations, but in general, preoperative intravenous chemotherapy administered with concurrent radiation therapy is feasible, has an acceptable toxicity, and results in favorable local control rates in patients with either localized or locally advanced soft tissue sarcomas. Besides the theoretical therapeutic advantages of concurrent treatment, in a practical sense, the concurrent use of local and systemic therapies also decreases the total treatment time for patients with high-risk sarcoma. In contrast to the six to nine months frequently consumed by current sequential multimodality treatment approaches that include radiation therapy, chemotherapy, surgery, and rehabilitation, concurrent treatment may take only two to three months.

    Surveillance Strategies
Most soft tissue sarcomas that recur do so in the first two years after the completion of therapy. History and physical examination are the most useful components of follow-up for identifying possible local recurrence after definitive treatment. These should be performed every three months and chest radiography should be done every six months during the two to three years when patients are at the highest risk of recurrence. CT and MRI are useful for evaluating less accessible regions, such as the retroperitoneum, and for assessing equivocal changes found during physical examination. Most experts also recommend that the tumor site should be evaluated every six months by sonography or MRI in patients with extremity tumors or by CT in patients with intraabdominal or retroperitoneal tumors. Guidelines have been established for using MRI to distinguish recurrences from typical postoperative changes. A discrete nodule with a low signal intensity on T1-weighted images and a higher signal intensity on T2-weighted images that enhances after the administration of intravenous contrast agent strongly suggests a recurrence, and a biopsy should be performed.88 Follow-up intervals can be lengthened to every six months, with imaging done annually, during years two through five after the completion of therapy. After five years, patients should be evaluated and undergo chest radiography annually.

It is common for abdominal soft tissue sarcomas to recur after surgery. CT is useful for detecting recurrences at primary and distant anatomic sites in the abdomen and pelvis. It has been recommended that cross-sectional imaging be done every three to six months during the first two years after surgery and every six months for three years thereafter. However, many experienced surgeons now advocate less aggressive imaging for asymptomatic patients, particularly after a second recurrence of retroperitoneal sarcoma. They argue that this is because there is no evidence that earlier detection improves survival.89


   SPECIAL SITUATIONS
TOP
 ABSTRACT
 INTRODUCTION
 INITIAL ASSESSMENT
 TREATMENT
 SPECIAL SITUATIONS
CONCLUSIONS
 REFERENCES
 
    Retroperitoneal Sarcomas
Fifteen percent of adult soft tissue sarcomas occur in the retroperitoneum. The most common histologic types occurring at this site are liposarcomas, malignant fibrous histiocytomas, and leiomyosarcomas.90 Retroperitoneal sarcomas are generally large at presentation; indeed, nearly 50% are larger than 20 cm at the time of diagnosis. They typically do not produce symptoms until they grow large enough to compress or invade contiguous structures. The differential diagnosis of a retroperitoneal tumor includes lymphoma, germ-cell tumors, and undifferentiated carcinomas. The workup for patients with a retroperitoneal mass begins with an accurate history that should exclude the signs and symptoms of lymphoma (eg, fever and night sweats). Complete physical examination, with particular attention to all nodal basins and testicular examination in men, is critically important. Laboratory assessment can be helpful; an elevated lactate dehydrogenase level suggests lymphoma, and elevated beta-human chorionic gonadotropin or alpha-fetoprotein levels suggest a germ-cell tumor.

The overall prognosis for patients with retroperitoneal tumors is worse than that for patients with extremity sarcomas. Survival rates at five years range from 40% to 50%. The best chance for long-term survival for patients with retroperitoneal sarcoma is achieved with a margin-negative resection. In one series, the five-year disease-free survival rate was 50% for patients who had margin-negative resection, as compared with 28% for patients who had undergone incomplete resection.90 About 75% of patients with retroperitoneal sarcomas ultimately die of locally recurrent disease without distant metastasis.85 Large tumors at presentation as well as tumors of high histologic grade, unresectability, and grossly positive resection margins are strongly associated with high mortality in patients with retroperitoneal sarcoma.89

Radiologic assessment at presentation should include CT of the abdomen and pelvis to define the extent of the tumor and its relationship to surrounding structures, particularly vascular structures. Imaging should also encompass the liver to look for metastases, the abdomen to look for discontiguous disease, and the kidneys bilaterally to ascertain function. Thoracic CT is indicated to detect lung metastases. CT-guided core-needle or laparoscopic biopsy is appropriate for patients with an unusual-appearing mass, an unresectable tumor, or distant metastasis to obtain a sample for histologic evaluation.

Complete surgical resection is the most effective treatment for primary or recurrent retroperitoneal sarcomas. This was clearly illustrated by an analysis of 500 patients with retroperitoneal soft tissue sarcomas treated at Memorial Sloan-Kettering Cancer Center; the median survival time was 103 months in those who underwent complete resection and only 18 months in those who underwent either incomplete resection or observation without resection.89 However, because these tumors often involve vital structures, surgical resection is not possible, and even if surgical resection can be performed, the margins are often compromised because of anatomic constraints. For these reasons, in several retrospective assessments, complete surgical excision was achieved in only 40% to 60% of patients with retroperitoneal sarcoma of patients.90,91

Protocols are ongoing at several centers to determine whether preoperative chemotherapy and radiation therapy are effective in retroperitoneal sarcomas. A drawback to this strategy is that administering preoperative radiation therapy to retroperitoneal soft tissue sarcomas is complex because of the proximity of these tumors to vital radiosensitive anatomic structures. There are, however, several advantages to this strategy in these patients: (1) the gross tumor volume can be defined, allowing accurate treatment planning; (2) tumors often displace radiosensitive viscera outside of the radiation field; and (3) lower radiation doses may be biologically effective preoperatively.92 Several groups have prospectively examined the effects of preoperative and intraoperative radiation therapy in patients with retroperitoneal sarcomas and have found that reasonable doses of radiation can be delivered to the retroperitoneum with acceptable treatment-related toxicity.93–95

    Gastrointestinal Sarcomas
Gastrointestinal sarcomas have posed a diagnostic and therapeutic dilemma for decades. As is true for sarcomas at other sites, high histologic grade and large tumor size (greater than 5 cm) adversely affect prognosis. Regional recurrence in the peritoneum (sarcomatosis) is common after surgical resection in patients with this sarcoma. Patients with gastrointestinal sarcomas most often present with nonspecific gastrointestinal symptoms that are determined by the site of the primary tumor. Establishing the diagnosis of a gastrointestinal sarcoma preoperatively is often difficult. Radiologic assessment, including CT of the abdomen or pelvis, is sometimes useful to determine the anatomic location, size, and extent of disease.

Endoscopy (esophagoduodenoscopy or colonoscopy) is the established method for evaluating the gastrointestinal tract. For tumors involving the stomach, upper endoscopy with endoscopic ultrasonography and biopsy are important diagnostic tests to distinguish adenocarcinoma from gastrointestinal stromal tumors. This distinction is clinically significant because the extent of resection (local excision versus gastrectomy) and the role of regional lymph node dissection differ depending on the tumor. The general recommendation is to perform a margin-negative resection with a 2- to 4-cm margin of normal tissue in patients with gastrointestinal sarcomas. Lymphatic spread is not the primary route of metastasis for gastrointestinal sarcomas; lymph node metastasis occurs in only 0% to 16% of cases.96–100 Consequently, lymphadenectomy is not routinely performed as part of resection.

Gastrointestinal stromal tumors (GISTs), which constitute the majority of gastrointestinal sarcomas, have distinctive immunohistochemical and genetic features. They are thought to arise from a pacemaker cell within the gastrointestinal tract known as the interstitial cell of Cajal,101,102 because both the interstitial cells of Cajal and GIST cells express the hematopoietic progenitor cell marker CD34 and the growth factor receptor c-Kit (CD117).101,103–106 c-Kit is a transmembrane glycoprotein receptor with an internal tyrosine kinase component that, when activated, triggers a cascade of intracellular signals regulating cell growth and survival.107–110

Surgery remains the primary treatment for both localized and locally advanced GISTs. Complete resection with negative margins, even in patients with locally advanced tumors, is associated with improved survival.33 The five-year survival rate ranges from 20% to 44% for all patients with GISTs and up to 75% for patients with early-stage tumors that have been completely excised.33,111

c-Kit expression has emerged as an important defining feature of GISTs, the pathogenesis of which may be related to c-Kit mutations, which are common in GISTs. Most of the mutations result from in-frame deletions or point mutations that lead to ligand-independent activation of the tyrosine kinase of c-Kit.103,105,112 The resulting constitutive c-Kit tyrosine kinase activity has been shown to promote tumor growth in vitro, and thus, it may be the key event in the pathogenesis of GISTs.103,112 Such information has served as the basis for the development of imatinib (Gleevec, ST1,571), a selective c-Kit inhibitor. Imatinib has now been found to produce impressive clinical responses in a large percentage of patients with advanced GISTs, as will be discussed below.

In February 2002, the US Food and Drug Administration approved imatinib for the treatment of GISTs. Imatinib is the first effective systemic therapy for patients with metastatic or locally advanced GISTs. Initial results from clinical trials showed that 54% of patients with GISTs responded to imatinib therapy, with only 10% to 15% experiencing progressive disease.113,114 However, little is known about the optimal length of treatment, the duration of benefit, or the long-term toxicity. Less than 4% of patients with GISTs receiving imatinib have experienced serious adverse events. Mild gastrointestinal toxicity is the most frequently reported adverse event, but gastrointestinal tract hemorrhage, presumably resulting from rapid tumor necrosis, has also been reported. Thus, all patients with GISTs treated on clinical protocols should be closely monitored by a team of medical professionals that includes a surgeon.

    Recurrent Sarcomas
As noted earlier, most soft tissue sarcomas that recur do so within two to three years of the completion of treatment. The pattern of recurrence is related to the anatomic site of the primary tumor. Distant pulmonary metastases are the typical pattern in patients with extremity sarcomas, with disease recurring in up to 20% of these patients. Patients with retroperitoneal or intraabdominal sarcomas tend to have local recurrences.115 Other less common sites of metastasis in patients with soft tissue sarcomas include bone (7%), the liver (4%),116 and lymph nodes (less than 4%).4 Myxoid liposarcoma of the extremity tends to metastasize to the abdomen and pelvis, and staging CT of these regions must be done before definitive local therapy can be instituted.15

It is important to bear in mind that the early recognition and treatment of recurrent, local, or distant disease can prolong survival. An isolated local recurrence should be treated aggressively with margin-negative resection. This frequently requires amputation in patients with extremity sarcomas. However, at times, acceptable rates of local control can be achieved in these patients with function-preserving resection combined with additional radiation therapy, with or without chemotherapy.117–119 A few studies involving small numbers of patients have shown that salvage treatment consisting of radical reexcision with or without radiation therapy can effectively eradicate recurrent local disease.120 The preferred treatment for locally recurrent retroperitoneal tumors is also surgical resection, if possible. In the largest series of patients with retroperitoneal sarcoma, investigators were able to adequately resect recurrent tumors in 57% of the patients. However, adequate resection was possible in only 20% after a second recurrence and in 10% after a third.89

Complete pulmonary resection can achieve long-term survival in 15% to 40% of patients with lung metastases who have a limited number of pulmonary nodules (fewer than four), long disease-free intervals, and no endobronchial invasion.115 Similarly, the five-year overall survival rate after the resection of metastatic disease was 38% in 255 patients with pulmonary metastases in a retrospective multiinstitutional study.121 Favorable prognostic factors in that study included margins that are microscopically disease-free, patients who are younger than 40 years of age, and tumor grades I or II.121 These limited data form the basis for the use of aggressive surveillance in all patients with soft tissue sarcoma.

Currently, however, the only available treatment for most patients with metastatic disease is chemotherapy. Unfortunately, historically, the response rates to chemotherapy in patients with Stage IV soft tissue sarcoma have been low. Several prognostic factors have been identified that can predict the response to chemotherapy; these include the performance status, previous response to chemotherapy, age, presence or absence of hepatic metastases, tumor grade, and duration of the disease-free interval.122


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 INITIAL ASSESSMENT
 TREATMENT
 SPECIAL SITUATIONS
 CONCLUSIONS
REFERENCES
 
Soft tissue sarcomas are a heterogeneous group of rare tumors. The vast majority of the tumors are sporadic. The management of such diverse tumors is complex and depends on the stage, site, and histologic characteristics of the tumor. The most common site of metastasis is the lungs, and metastasis generally occurs within two to three years after the completion of therapy. Progress is, however, being made in our understanding of the molecular characteristics of these tumors. This information should in the near future translate into molecularly based therapies that can be incorporated into standard treatment strategies that together will be of increasing benefit to all patients with soft tissue sarcomas.


   Footnotes
 
This article is available online at: http://CAonline.AmCancerSoc.org


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 INITIAL ASSESSMENT
 TREATMENT
 SPECIAL SITUATIONS
 CONCLUSIONS
 REFERENCES
 

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