Questions? Mail them to us!
We subscribe to the HONcode
principlesof the Health On the Net Foundation
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood soft tissue sarcoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Tretment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is also available in a patient version, which is written in less technical language, and in Spanish.
The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.
Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologist, pediatric hematologist/oncologist, rehabilitation specialist, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. [1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.
Pediatric soft tissue sarcomas are a group of malignant tumors that originate from primitive mesenchymal tissue and account for 7% of all childhood tumors. [2] Rhabdomyosarcomas, tumors of striated muscle, and undifferentiated sarcomas account for more than half of all cases of soft tissue sarcomas in children. (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.) The remaining nonrhabdomyosarcomatous soft tissue sarcomas (NRSTSs) account for approximately 3% of all childhood tumors. [3] This heterogeneous group of tumors includes neoplasms of smooth muscle (leiomyosarcomas), connective tissue (fibrous and adipose), vascular tissue (blood and lymphatic vessels), and the peripheral nervous system. [4] Synovial sarcomas, fibrosarcomas, and malignant peripheral nerve sheath tumors predominate in pediatric patients. [5] [6] [7] [8] [9]
NRSTSs are more common in adults [4] than in children; therefore, much of the information regarding the treatment and natural history of children with these lesions has been on the basis of findings from adult studies. Some pediatric NRSTSs are associated with a better outcome. This difference is most pronounced for infants and children younger than 4 years with fibrosarcoma, which is a locally aggressive but not metastatic tumor. These patients have an excellent prognosis given that the tumor is highly chemosensitive and surgery alone can cure a significant number of these patients. [3] [4] [10] [11] Soft tissue sarcomas in older children and adolescents often behave similarly to those in adult patients. [3] [4]
Although they can develop in any part of the body, NRSTSs arise most commonly in the trunk and extremities. [5] [6] [12] These neoplasms can present initially as an asymptomatic solid mass, or they may be symptomatic because of local invasion of adjacent anatomical structures. Systemic symptoms (e.g., fever, weight loss, and night sweats) are rare. Hypoglycemia and hypophosphatemic rickets have been reported in cases of hemangiopericytoma, whereas hyperglycemia has been noted in patients with fibrosarcoma of the lung. [4]
Some genetic and environmental factors have been associated with the development of NRSTS. Heritable cancer-associated changes of the p53 tumor suppressor gene can occur in families with Li-Fraumeni syndrome. [13] Members of these families have an increased risk of developing soft tissue tumors, bone sarcomas, breast cancer, brain tumors, and acute leukemia. [3] Approximately 4% of patients with neurofibromatosis type 1 develop malignant peripheral nerve sheath tumors, which usually develop after a long latency; some patients develop multiple lesions. [4] [14] [15] Some NRSTSs (particularly malignant fibrous histiocytoma) can develop within a previously irradiated site; others (e.g., leiomyosarcoma) have been linked to Epstein-Barr virus infection in patients with AIDS. [3] [4] [16]
Synovial sarcomas are the most common NRSTSs reported in children. The most common location is the lower extremity followed by upper extremity, trunk, abdomen, and head and neck. Approximately 30% of patients with synovial sarcoma are younger than 20 years. The most common site of metastasis is the lung. [17] Factors such as International Union Against Cancer/American Joint Committee on Cancer stage III/stage IVA, tumor necrosis, truncal locations, elevated mitotic rate, age, and histologic grade have been associated with a worse prognosis in adults. [18] [19] [20]
(Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information. Refer to the PDQ summary on Ewing Sarcoma Family of Tumors Treatment for more information on extraosseous Ewing, peripheral neuroepithelioma, and Askin tumors.)
The prognosis and biology of NRSTS tumors vary greatly depending on the age of the patient, the primary site, tumor size, tumor invasiveness, histologic grade, depth of invasion, and extent of disease at diagnosis. Because long-term related morbidity must be minimized while disease-free survival is maximized, the ideal therapy for each patient must be carefully and individually determined utilizing these prognostic factors before initiating therapy for these patients. [6] [10] [17] [21] [22] [23]
Nonrhabdomyosarcomatous soft tissue tumors are fairly readily distinguished from rhabdomyosarcoma or Ewing family of tumors; however, classification of childhood nonrhabdomyosarcomatous soft tissue sarcoma (NRSTS) type is often difficult. Obtaining adequate tumor tissue is crucial to allow for conventional histology, immunocytochemical analysis, and other studies such as light and electron microscopy, cytogenetics, fluorescence in situ hybridization, and molecular pathology. [1] [2] For this reason, open biopsy (or multiple core-needle biopsies) is strongly encouraged so that adequate tumor tissue can be obtained to allow for all of these crucial studies to be performed.
Many NRSTSs are characterized by chromosomal abnormalities. Some of these chromosomal translocations lead to a fusion of two disparate genes. The resulting fusion transcript can be readily detected by using polymerase chain reaction-based techniques, thus facilitating the diagnosis of those neoplasms that have translocations. Some of the most frequent aberrations seen in nonrhabdomyosarcomatous soft tissue tumors are listed in Table 1.
| Histology | Chromosomal Aberrations | Genes Involved |
|---|---|---|
| Alveolar soft part sarcoma | t(x;17)(p11.2;q25) | ASPL/TFE3 [4] [5] [6] |
| Angiomatoid fibrous histiocytoma | t(12;16)(q13;p11), t(2;22)(q33;q12) | FUS/ATF1, EWSR1/CREB1 [7] |
| Clear cell sarcoma (malignant melanoma of soft parts) | t(12;22)(q13;q12) | ATF1/EWS |
| Congenital (infantile) fibrosarcoma/mesoblastic nephroma | t(12;15)(p13,q25) [4] | ETV-NTRK3 [4] |
| Dermatofibrosarcoma | t(17;22)(q22;q13) | COL1A1/PDGFB |
| Desmoplastic small round cell tumors | t(11;22)(p13;q12) | WT1/EWS [8] |
| Extraskeletal myxoid chondrosarcoma | t(9;22)(q22;q12) | EWS-CHN |
| Hemangiopericytoma | t(12;19)(q13;q13.3) and t(13;22)(q22;q13.3) | |
| Leiomyosarcoma | t(12;14) | |
| Low-grade fibromyxoid sarcoma | t(7;16)(q33;p11) | FUS/BBF2H7 |
| Malignant fibrous histiocytoma | 19p+, ring chromosome | |
| Myxoid liposarcoma | t(12;16)(q13;p11) | FUS/CHOP |
| Neurofibrosarcoma | Deletion 17q11.2 | |
| Rhabdoid tumor | t(1;22)(p36:q11.2) [4] | SNFS/INI1 [4] |
| Synovial sarcoma | t(x;18)(p11.2;q11.2) | SYT/SSX |
| aAdapted from Sandberg [3] and Slater et al. [4] | ||
Pediatric soft tissue sarcomas are classified histologically according to the soft tissue cell they resemble and include the following: [1]
This is a tumor of uncertain histogenesis. A consistent chromosomal translocation t(X;17)(p11.2;q25) juxtaposes the ASPSCR1 gene with the TFE3 gene. [5] ASPS is considered a chemoresistant tumor. [12] In children, ASPS often presents with metastases, [13] and sometimes has a very indolent course. Pediatric ASPS seems to have a better outcome than its adult counterpart. [14] In a series of 19 treated patients, one group reported a 5-year overall survival (OS) rate of 80%, a 91% OS rate for patients with localized disease, a 100% OS rate for patients with tumors 5 cm or smaller, and a 31% OS rate for patients with tumors larger than 5 cm. [15] A subset of renal tumors found in young people was previously considered to be renal cell carcinoma, but the subset now appears to be genetically related to ASPS. [16] There are sporadic reports of objective responses to interferon-alpha, bevacizumab, and sunitinib. [17] [18] [19]
A review of 20 years of experience in the Italian and German Soft Tissue Sarcoma Cooperative Group identified 12 children with angiosarcoma. [20] Only one objective response to chemotherapy was observed, and the overall behavior of this tumor was identical to angiosarcoma in adults. Another review of 15 patients demonstrated a 33% survival rate. [21]
Clear cell sarcoma (malignant melanoma) of soft parts (also called clear cell sarcoma of tendons and aponeuroses) is somewhat similar to cutaneous malignant melanoma, but is cytogenetically distinct; most cases have a t(12;22)(q13;q12) translocation that has not been reported in melanoma. [22] Patients who have small, localized tumors with low mitotic rate, and intermediate histologic grade fare best. [23]
Dermatofibrosarcoma is a rare tumor, but many of the reported cases arise in children. [24] The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGF-beta gene. Most tumors are cured by surgical resection. When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective. [25]
Desmoid tumors are low-grade malignancies with very low potential to metastasize. The tumors are locally infiltrating, and surgical control can be difficult because of the need to preserve normal structures. These tumors also have a high potential for local recurrence. Desmoid tumors have a highly variable natural history, including well documented examples of spontaneous regression. [26] Mutations in exon 3 of the beta-catenin gene are seen in over 80% of desmoid tumors and the mutation 45F has been associated with an increased risk of disease recurrence. [27] Repeated surgical resection can sometimes bring recurrent lesions under control. [28]
Desmoplastic small round cell tumor is a primitive sarcoma that most frequently involves the abdomen, pelvis, or tissues around the testes. [29] [30] [31] The tumor occurs mainly in males and invades locally but may spread to the lungs and elsewhere. Cytogenetic studies of these tumors have demonstrated the recurrent translocation t(11;22)(p13;q12), which has been characterized as a fusion of the WT1 and EWS genes. [32]
Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis which displays multilineage differentiation. [33] It is characterized by inactivation of the SMARC/INI1 gene which is present in both conventional and proximal types of epithelioid sarcoma. [34] There are also alterations in rhabdoid tumors, but the mechanisms of inactivation seem to be distinctive. This tumor commonly presents as a slow growing firm nodule based in the deep soft tissue; the proximal type predominantly affects adults and involves the axial skeleton and proximal sites. The tumor is highly aggressive and has a propensity for lymph node metastases. The proximal type has a more aggressive clinical behavior. In a review of 30 pediatric patients with epithelioid sarcoma, the median age at presentation was 12 years, responses to chemotherapy were reported in 40% of patients using sarcoma-based regimens, and 60% of patients were alive at 5 years following initial diagnosis. [35]
Hemangioendotheliomas are tumors found in infants that arise within the liver or elsewhere and usually remain benign. [36] The tumors are sometimes associated with consumptive coagulopathy, also known as the Kasabach-Merritt syndrome (or phenomenon). [37] [38] [39] In older children and adults, hemangioendotheliomas may occur elsewhere in the body and can metastasize to lungs, lymph nodes, bones, and within the pleural or peritoneal cavities. The preferred pathologic designation for these lesions in older persons is epithelioid hemangioendothelioma, which connotes the possibility of distant spread. These latter lesions are considered of intermediate malignant potential, between benign hemangioma and angiosarcoma. [40] [41]
Inflammatory myofibroblastic tumor (IMT) is an incompletely characterized neoplasm of intermediate biologic potential. It recurs frequently but metastasizes rarely. [42] Roughly half of IMTs exhibit a clonal mutation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase gene at chromosome 2p23. [43] There are no well-documented responses to chemotherapy. There are case reports of response to either steroids or nonsteroidal anti-inflammatory drugs.
A 24-year retrospective analysis of the Italian cooperative group identified one child with leiomyosarcoma. [44] A retrospective analysis of the St. Jude Children’s Research Hospital experience from 1962 to 1996 identified 40 children with NRSTS; none had leiomyosarcoma. [45] Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma. [46]
A 24-year retrospective analysis of the Italian cooperative group identified two children with liposarcoma. [44] The tumors did not respond to chemotherapy. Outcomes were the same as those observed in adults with liposarcoma. [47]
At one time, MFH was the single most common histiotype among adults with soft tissue sarcomas. Since it was first recognized in the early 1960s, however, MFH has been plagued by controversy in terms of both its histogenesis and its validity as a clinicopathologic entity. The latest World Health Organization classification no longer includes MFH as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma. [48]
MPNST arises in children with type 1 neurofibromatosis (NF1), and it arises sporadically. [49] Features with favorable prognosis have been reported to include absence of NF1, less invasiveness, lower stage, and an extremity as the primary site. [49] [50] Chemotherapy has achieved objective responses in childhood MPNST. The role of adjuvant chemotherapy following resection of MPNST has not been prospectively evaluated. A retrospective survey of cancer centers in Japan identified 56 patients with MPNST, mostly adults, but including children and adolescents. [51] This survey identified large tumor size, metastasis at presentation, and high histologic grade as unfavorable prognostic features. In this report, documentation of NF1 did not confer an inferior prognosis.
Mesenchymal chondrosarcoma is a highly malignant tumor with a propensity to spread to the lungs. A recent review of 15 patients aged younger than 26 years from the German Cooperative Soft Tissue Sarcoma (11 with soft-tissue lesions) and German-Austrian-Swiss Cooperative Osteosarcoma Study Group (four with primary bone lesions) protocols suggests that complete surgical removal, or incomplete resection followed by radiation therapy, is necessary for local control. [9][Level of evidence: 3iiA] Multiagent chemotherapy may decrease the likelihood of lung metastases: OS at 10 years was 67%, compared with approximately 20% in an earlier series of young patients. [52]
Synovial sarcoma is considered to be more chemotherapy responsive than many other soft tissue sarcomas. There is ample documentation of objective response of synovial sarcoma to systemic chemotherapy. [44] [53] [54] [55] The value of adjuvant chemotherapy following resection of localized disease has not been conclusively supported in prospective trials, but most pediatric oncologists favor adjuvant chemotherapy for all but the smallest, completely resected tumors. [54] [56] [57] [58]
Diagnosis of synovial sarcoma is made by immunohistochemical analysis, ultrastructural findings, and demonstration of the specific chromosomal translocation t(x;18)(p11.2;q11.2). This abnormality is specific for synovial sarcoma and is found in all morphologic subtypes. Synovial sarcoma results in rearrangement of the SYT gene on chromosome 18 with one of the subtypes (1, 2, or 4) of the SSX gene on chromosome X. [59] [60] Synovial sarcoma can be subclassified as monophasic fibrous type, biphasic type with distinct epithelial and spindle cell components, or poorly differentiated. Poorly differentiated synovial sarcoma has features of monophasic or biphasic synovial sarcoma but also a variable proportion of poorly differentiated areas characterized by high cellularity, pleomorphism, and polygonal or small round-cell morphology, numerous mitoses, and often necrosis. [61]
Patients with undifferentiated sarcoma have been eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the Children’s Oncology Group (COG). The rationale for this inclusion was the observation that patients with undifferentiated sarcoma have similar sites of disease and outcome to those with alveolar rhabdomyosarcoma. In therapeutic trials for adults with soft tissue sarcoma, patients with undifferentiated sarcoma are included with all other histologies and treated in a similar manner. Contemporary treatment for adult soft tissue sarcoma utilizes ifosfamide and doxorubicin, sometimes with the addition of other chemotherapy agents, surgery, and radiation therapy. No data are available to compare these two approaches.
When a suspicious lesion is identified it is crucial that a complete workup followed by adequate biopsy be performed. Generally, it is better to image the lesion prior to any interventions. A core-needle biopsy or limited open biopsy that obtains an adequate amount of tissue for histopathology, immunohistochemistry, and molecular genetics is mandatory, given the diagnostic importance of translocations. Image-guided needle biopsy techniques must also obtain an adequate tissue sample and usually require obtaining multiple cores of tissue. Incisional biopsies are acceptable but should not compromise subsequent wide local excision. Transverse extremity incisions should be avoided to reduce skin loss, as should extensive surgical procedures prior to definitive diagnosis.
In most cases, accurate histopathologic classification of soft tissue sarcomas alone does not yield optimal information about their clinical behavior. Therefore, several histologic parameters, including degree of cellularity, cellular pleomorphism, mitotic activity, degree of necrosis, and invasive growth, are evaluated in the grading process. This process is used to improve the correlation between histologic findings and clinical outcome. [62] In children, grading of soft tissue sarcomas is compromised by the good prognosis of certain tumors such as infantile fibrosarcoma. In addition, testing of a grading system within the pediatric population is difficult because of the rarity of these neoplasms. In March 1986, the Pediatric Oncology Group conducted a prospective study on pediatric soft tissue sarcomas other than rhabdomyosarcoma and devised the grading system that is shown below. Analysis of outcome for patients with localized soft tissue sarcomas other than rhabdomyosarcoma demonstrated that patients with grade 3 tumors fared significantly worse than did those with grade 1 or grade 2 lesions. This finding suggests that this system can accurately predict the clinical behavior of nonrhabdomyosarcomatous soft tissue tumors in children. [2] [62] [63] The current COG protocol, (COG-ARST0332), is evaluating the grading systems developed by the COG (see below) and the French Federation of Cancer Centers Sarcoma Group. [64]
In grade 2 lesions, which are soft tissue sarcomas not included in grade 1 and grade 3 lesions, less than 15% of the surface area shows necrosis, and there are fewer than five mitotic figures per ten high-power fields (40X objective). As secondary criteria of grade 2 tumors, the incidence of nuclear atypia is not marked, and the tumor is not markedly cellular.
Any other sarcoma not included in grade 1 in which more than 15% of the surface area is necrotic or in which there are more than five mitotic figures per ten high-power fields (40X objective) is considered a grade 3 lesion. Marked atypia and cellularity are less predictive but may assist in placing tumors in this category.
Clinical staging has an important role in predicting the clinical outcome and determining the most effective therapy for pediatric soft tissue sarcomas. As yet, there is no well-accepted staging system that is applicable to all childhood sarcomas; the system from the American Joint Commission for Cancer (AJCC) that is used for adults has not been validated in pediatric studies, however, the current Children's Oncology Group (COG) trial is using the AJCC staging system (see Table 2 below) to facilitate comparison of results with other pediatric and adult soft tissue sarcoma trials. [1] Two systems are currently in use for staging pediatric nonrhabdomyosarcomatous soft tissue tumors. The surgicopathologic staging system used by the Intergroup Rhabdomyosarcoma Study (see below) is based on the amount of tumor that remains after initial surgery and whether the disease has metastasized. [2]
The other schema typically used to stage pediatric soft tissue tumors is the TNM system of the International Union Against Cancer. [3] In this staging system, T1 lesions are those that are confined to the organ of origin, and T2 lesions invade adjacent organs. These categories can be subclassified to reflect the maximum tumor diameter (a: ≤5 cm; b: >5 cm). Nodal involvement is indicated by N1 (N0: no nodal involvement), and the presence of distant metastases at the time of diagnosis is indicated by the M1 (vs. M0) designation. Several adult and pediatric series have shown that patients with large or invasive tumors have a significantly worse prognosis than do those with small, noninvasive tumors.
These two staging systems have proven to be of prognostic significance in pediatric and adult nonrhabdomyosarcomatous soft tissue sarcomas (NRSTSs). [4] [5] [6] [7] [8] In a review of a large adult series of nonrhabdomyosarcomas, superficial extremity sarcomas have a better prognosis than deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered. [9]
Although a standardized staging system for pediatric NRSTS does not exist, the current COG trial is using the sixth edition AJCC staging system for soft tissue sarcomas (with central pathology review) described in Table 2 below. [10]
| Primary Tumorb | Regional Lymph Nodes | Distant Metastasis | Histologic Gradec | |
|---|---|---|---|---|
| Stage I | Any tumor size, superfical or deep | N0 | M0 | G1 |
| G2 | ||||
| Stage II | T1a (tumor ≤5 cm in maximal diameter, superficial) | N0 | M0 | G3 |
| T1b (tumor ≤5 cm in maximal diameter, deep) | N0 | M0 | G3 | |
| T2a (tumor >5 cm in maximal diameter, superficial) | N0 | M0 | G3 | |
| Stage III | T2b (tumor >5 cm in maximal diameter, deep) | N0 | M0 | G3 |
| Stage IV | Any tumor size, superfical or deep | N1 | M0 or M1 | G1, G2, or G3 |
| Any tumor size, superfical or deep | N0 or N1 | M1 | G1, G2, or G3 | |
| G1 = well differentiated; G2 = moderately differentiated; G3 = poorly differentiated; M0 = no distant metastasis; M1 = distant metastasis; N0 = no regional lymph node metastasis; N1 = regional lymph node metastasis | ||||
| aAdapted from AJCC Cancer Staging Manual. [10] | ||||
| bSuperficial tumor is located above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia or superficial to the fascia with invasion of or through the fascia. All intraperitoneal visceral lesions, retroperitoneal, pelvic, and intrathoracic tumors, and the majority of head and neck tumors are classified as deep tumors. | ||||
| cThe histologic grade established by central pathology review is to be used for staging purposes. | ||||
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Because of the rarity of pediatric nonrhabdomyosarcomatous soft tissue sarcomas (NRSTSs), all children, adolescents, and young adults with these tumors should have their treatment coordinated by a multidisciplinary team comprised of pediatric oncologists, surgeons, and radiotherapists. To better define the tumors' natural history and response to therapy, children with rare neoplasms should be considered for entry into national or institutional treatment protocols.
Every attempt should be made to resect the primary tumor with negative margins before or after chemotherapy. Involvement of a surgeon with special expertise in the resection of soft tissue sarcomas in the decision is highly desirable. The timing of surgery depends on an assessment of the feasibility and morbidity of surgery. If the initial surgery fails to achieve pathologically negative tissue margins or if the initial surgery was done without the knowledge that cancer was present, a re-excision of the affected area should be performed to obtain clear, but not necessarily wide, margins. [1] [2] [3] [4] [5] This surgical tenet is true even if no mass was detected by magnetic resonance imaging after initial surgery. [6] [7][Level of evidence: 3iiA] Sentinel lymph node mapping is employed at some centers to identify the regional nodes that are the most likely to be involved, though its widespread contribution to the staging and management of these tumors has yet to be clearly defined. [8] [9] [10][Level of evidence: 3iiDii]
Radiation therapy is indicated for patients with inadequate surgical margins and for larger, high-grade tumors. [11] This is particularly important in high-grade tumors with tumor margins less than 1 cm. [12] [13] [14][Level of evidence: 3iiDiv] When using both surgery and radiation therapy, local control of the primary tumor can be achieved in more than 80% of patients. [15] [16] Brachytherapy and intraoperative radiation may be applicable in select situations. [16] [17] [18] [19][Level of evidence: 3iiiDii] Preoperative radiation therapy has been associated with excellent local control rates, [20] [21] [22] but has been associated with an increased rate of wound complications in adults. [23] Pediatric patients with unresected NRSTS have a poor outcome. Only about one-third of patients treated with multimodality therapy remain disease free. [23] [24]
The role of adjuvant (postoperative) chemotherapy remains controversial. [25] A meta-analysis of updated data from adult soft tissue sarcoma patients from all available randomized trials concluded that recurrence-free survival was better with adjuvant chemotherapy. [26] The largest prospective pediatric trial failed to demonstrate any benefit with adjuvant vincristine, dactinomycin, cyclophosphamide, and doxorubicin. [15] Synovial sarcoma appears to be more sensitive to chemotherapy than many other soft tissue sarcomas, and children with synovial sarcoma seem to have a better prognosis. [27] [28] [29] [30] [31] A German trial suggested a benefit for adjuvant chemotherapy in children with synovial sarcoma. [32] A meta-analysis also suggested that chemotherapy may provide benefit. [33] Many treatment centers advocate adjuvant chemotherapy following resection of synovial sarcoma in children and young adults; unequivocal proof of the value of this strategy from prospective, randomized clinical trials is lacking.
Therapeutic strategies for children and adolescents with soft tissue tumors are similar to those for adult patients, though there are important differences. For example, the biology of the neoplasm in pediatric patients may differ dramatically from that of the adult lesion. Additionally, limb-sparing procedures are more difficult to perform in pediatric patients. The morbidity associated with radiation therapy, particularly in infants and young children, may be much greater than that observed in adults. [34] Improved outcomes with multimodality therapy in adults and children with soft tissue sarcomas over the past 20 years has caused increasing concern about the potential long-term side effects of this therapy in children, especially when considering the expected longer life span of children versus adults. Therefore, to maximize tumor control and minimize long-term morbidity, treatment must be individualized for children and adolescents with NRST. These patients should be enrolled in prospective studies that accurately assess any potential complications. [35]
Standard treatment options for nonmetastatic pediatric nonrhabdomyosarcomatous soft tissue sarcomas (NRSTSs) include the following:
For nonmetastatic pediatric NRSTSs, treatment with surgery alone is often curative. [1] [2] [3] [4] [5] [6] If the initial surgery was performed without suspicion of malignancy, re-excision by a surgeon experienced in the treatment of soft tissue sarcoma is essential, even if imaging studies do not suggest the presence of residual tumor. Postoperatively, tumor-free margins must be confirmed through pathologic evaluation, and re-excision must be performed if the margins are positive. If further resection is not feasible, postoperative radiation therapy or, if possible, brachytherapy should be used. [7] [8]
The tumors discussed in this section are clinically less aggressive and rarely metastasize. [1] [9] [10] [11] These tumors include the following:
The standard treatment for these tumors is complete surgical excision followed by re-excision if tumor margins were positive or, radiation therapy or brachytherapy if re-excision is not possible. Several of these clinically less aggressive soft tissue sarcomas have been treated with other therapies and these tumors and treatments are discussed below.
In children with infantile fibrosarcoma, preoperative chemotherapy has made possible a more conservative surgical approach; agents active in this setting include vincristine, dactinomycin, cyclophosphamide, and ifosfamide. [1] [12] Responses to presurgical chemotherapy with similar agents have been reported in cases of infantile hemangiopericytoma. [1]
Desmoid tumors are well-differentiated fibrous lesions that rarely metastasize, but they have a significant potential for local invasiveness and recurrence. The treatment of choice is resection to achieve clear margins. If postoperative margins are positive, 70% of patients will have a recurrence of disease. When complete surgical excision is not feasible and the tumor poses significant potential for mortality or morbidity, preoperative strategies that include external-beam radiation therapy, postoperative interstitial iridium I 192, nonsteroidal anti-inflammatory agents, antiestrogens, vinblastine, and methotrexate should be considered. [13] [14] Evaluation of the benefit of chemotherapy for treatment of desmoid tumors has been extremely difficult because desmoid tumors have a highly variable natural history. Large adult series and a single pediatric series have reported long periods of disease stabilization and even regression without systemic therapy. [15] [16] A small series of mainly adult patients (n = 19) with desmoid tumors were treated with imatinib mesylate and showed infrequent objective responses. [17] A series of mainly adult familial adenomatous polyposis patients with unresectable desmoid tumors that were unresponsive to hormone therapy, showed that doxorubicin plus dacarbazine followed by meloxicam (a nonsteroidal anti-inflammatory agent) can be safely administered and can induce responses. [18] There are reports of objective responses to systemic chemotherapy in children with desmoid tumors. Combination chemotherapy using vinblastine and methotrexate has been used for the treatment of progressive desmoid tumor in children. [13] These should be interpreted cautiously in light of the variable natural history of the disease. Partially excised or recurrent lesions that do not pose a significant danger to vital organs may be monitored closely if other treatment alternatives are not available. [16] [19] [20] [21] [22] Whenever possible, however, the treatment of choice is complete resection.
The pediatric neoplasms listed below exhibit similar biologic behavior that is similar to lesions in adults:
Much of what is known about treating these tumors is derived from studies in adults. Standard treatment options for these tumors include the following:
Every attempt should be made to resect the primary tumor locally with negative margins. [23] [24] If the original operation failed to achieve pathologically negative tissue margins, a second surgery may be indicated. [2] Although combined surgery and radiation therapy have dramatically improved outcome in adults and children with soft tissue sarcomas over the past 20 years, [7] the morbidity of high-dose radiation therapy should be considered in infants and young children with these tumors. [25] The use of brachytherapy and intraoperative radiation therapy is under study. [8] [26] Preoperative radiation therapy has been associated with excellent local control rates in adults; [27] [28] this approach has not been used extensively in pediatric patients.
The role of adjuvant (postoperative) chemotherapy remains controversial. Virtually all trials of adjuvant chemotherapy in adults with soft tissue sarcoma report the results of treatment for all patients in aggregate. This may obscure important differences in chemosensitivity among histologic subtypes of soft tissue sarcoma. A retrospective analysis of neoadjuvant chemotherapy in adults with soft tissue sarcoma suggested a benefit for patients with larger tumors. [29] The largest prospective pediatric trial failed to document any benefit of adjuvant chemotherapy with vincristine, dactinomycin, cyclophosphamide, and doxorubicin in children with grossly resected tumors. [30] This trial also reported results in aggregate for a variety of soft tissue sarcomas. In patients with unresectable or metastatic disease treated with vincristine, dactinomycin, and cyclophosphamide, the overall survival (OS) and disease-free survival rates were 31% and 10%, respectively. [31] Achieving complete responses after aggressive chemotherapy, radiation therapy, and surgery is possible in most patients with more advanced NRSTS. [32]
Some of these tumors have been treated with other therapies and these selected tumors and treatments are discussed below.
The standard approach is complete resection of the primary lesion. [6] If complete excision is not feasible, radiation therapy should be administered. The value of adjuvant chemotherapy in completely resected ASPS remains unproven, particularly because patients with unresected or metastatic tumors failed to respond to chemotherapeutic agents frequently used to treat soft tissue sarcomas. [33] Patients with ASPS may relapse several years after a prolonged period of apparent remission. [34] The role of adjuvant chemotherapy in children with this malignancy has not been tested. Because these tumors are rare, all children with ASPS should be enrolled in prospective clinical trials.
Treatment for clear cell sarcoma of soft parts is primarily surgical with radiation therapy for uncertain or involved margins. Antisarcoma chemotherapy is rarely effective. [36]
Complete resection of this tumor is rarely possible, thus effective treatment must rely on chemotherapy and radiation therapy. Treatment for individuals with desmoplastic small round cell tumor following surgery requires aggressive chemotherapy with agents used for treatment of sarcoma combined with appropriate radiation treatment. Prognosis is dependent on the extent and aggressiveness of the tumor and its treatment. [37] [38] [39] Whole abdominopelvic radiation therapy is feasible but has not significantly improved the outcome for this diagnosis. [40] [41]
Chemotherapy for extraosseous osteosarcoma has not been well studied. Treatment has previously been recommended to follow soft tissue sarcoma guidelines rather than guidelines for osteosarcoma of bone. [42] Extraosseous osteosarcoma may be more chemosensitive in young patients than in adults. [42] A retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraskeletal osteosarcoma treated with surgery and conventional osteosarcoma chemotherapy. [43] (Refer to the PDQ summary on Osteosarcoma/Malignant Fibrous Histiocytoma of Bone for more information.)
Treatment of asymptomatic liver hemangioendothelioma in a child younger than 1 year may compromise close observation because some tumors will regress. Symptomatic lesions require urgent medical or surgical management, especially if coagulopathy is present. [44] [45] [46] [47] Epithelioid hemangioendothelioma of the liver should be managed surgically; some patients may need orthotopic liver transplantation because this disease does not respond to radiation therapy or chemotherapy. [48]
A large retrospective analysis of the German and Italian experience with MPNST identified incomplete resection, large tumor size, tumor invasiveness, nonextremity primary site, and clinical diagnosis of neurofibromatosis as unfavorable prognostic findings. [23] There was a trend toward improved outcome with adjuvant radiation therapy. While 65% of measurable tumors had objective responses to ifosfamide-containing chemotherapy regimens, the analysis did not conclusively demonstrate improved survival for chemotherapy. [23] A series of 37 young patients with MPNST and neurofibromatosis type 1 (NF1) showed that most patients had large invasive tumors that were poorly responsive to chemotherapy; progression-free survival was 19% and 5-year OS was 28%. [49] Another series of older patients with MPNST found that those with NF1 had a worse prognosis than those without NF1. [50]
Synovial sarcoma appears to be more sensitive to chemotherapy than many other NRSTSs. Children with synovial sarcoma have a higher probability for both event-free survival (EFS) and OS than children with other types of NRSTS. [51] [52] A German randomized trial suggested a benefit for adjuvant chemotherapy in children with synovial sarcoma. [53] A meta-analysis also suggested that chemotherapy may improve EFS but could not confirm improvement in OS. [24] Many treatment centers advocate adjuvant chemotherapy following resection of synovial sarcoma in children and young adults; unequivocal proof of the value of this strategy from prospective, randomized clinical trials is lacking. A study of 21 patients with small (<1 cm), localized synovial sarcomas showed an excellent survival rate with no metastatic events; only one patient received chemotherapy. [54] A retrospective analysis of synovial sarcoma in children treated in Germany and Italy identified tumor size (>5 cm or <5 cm in greatest dimension) as an important predictor of EFS. [55] In this analysis, local invasiveness conferred an inferior probability of EFS, but surgical margins did not predict outcome.
Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant. [56] Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients in response to local therapy. [57] [58] [59]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with nonmetastatic childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Standard treatment options for metastatic childhood soft tissue sarcoma include the following:
The prognosis for children with metastatic soft tissue sarcomas is poor, [1] [2] [3] [4] [5] [6] and these children should receive combined treatment with chemotherapy, radiation therapy, and surgical resection of pulmonary metastases. In a prospective randomized trial, chemotherapy with vincristine, dactinomycin, doxorubicin, and cyclophosphamide with or without dacarbazine led to tumor responses in one-third of patients with unresectable or metastatic disease. The estimated 4-year survival rate, however, was poor, with fewer than one-third of children surviving. [6] [7] [8] Children with isolated pulmonary metastases should undergo exploratory thoracotomy in an attempt to resect all gross disease. The estimated 5-year survival rate after thoracotomy for pulmonary metastasectomy has ranged from 10% to 58% in adult studies. Formal segmentectomy, lobectomy, and mediastinal lymph node dissection are unnecessary. [9]
Vincristine, doxorubicin, and ifosfamide with granulocyte colony-stimulating factor have been used in patients with unresected or metastatic tumors. The Pediatric Oncology Group evaluated the combination of doxorubicin and ifosfamide in children with unresected or metastatic soft tissue sarcomas because several adult trials have suggested that ifosfamide-based regimens may be superior to other chemotherapeutic regimens for soft tissue sarcomas. [10] Table 3 shows other promising agents currently being evaluated in clinical trials for specific histologic subtypes of nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS).
| Soft Tissue Sarcoma Histologic Subtype | Agent Under Study |
|---|---|
| Alveolar soft part sarcoma | Sunitinib [11] [12] |
| Angiosarcoma | Sorafenib [13] |
| Desmoplastic small round cell tumor | Sunitinib [11] [12] |
| Leiomyosarcoma | Pazopanib [14] |
| Malignant peripheral nerve sheath tumor | Mammalian target of rapamycin (mTOR)-inhibitors [15] [16] |
| Myxoid liposarcoma | Trabectedin [17] |
| Perivascular epithelioid cell tumor (PEcoma) | Mammalian target of rapamycin (mTOR)-inhibitors [15] [16] |
| Synovial sarcoma | Pazopanib [14] |
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with metastatic childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Decisions about treatment options for recurrent or progressive childhood soft tissue sarcoma are based on many factors, including the following:
Standard treatment options for recurrent or progressive disease include the following:
With the possible exception of infants with congenital fibrosarcoma, the prognosis for patients with recurrent or progressive disease is poor. Resection is the standard treatment for recurrent pediatric nonrhabdomyosarcomatous soft tissue sarcomas. If the patient has not yet received radiation therapy, adjuvant radiation should be considered after local excision of the recurrent tumor. Limb-sparing procedures with adjuvant brachytherapy have been evaluated in adults but have not been studied extensively in children. For some children with extremity sarcomas who have received previous radiation therapy, amputation may be the only therapeutic option. No prospective trial has been able to prove that enhanced local control of pediatric soft tissue sarcomas will ultimately improve survival. Therefore, treatment should be individualized for the site of recurrence and biologic characteristics (e.g., grade, invasiveness, and size) of the tumor. Pulmonary metastasectomy may achieve prolonged disease control for some patients. [1] A large, retrospective analysis of patients with recurrent soft tissue sarcoma showed that isolated local relapse had a better prognosis and that resection of pulmonary metastases improved the probability of survival. [2] All patients with recurrent tumors should be offered enrollment in current drug studies.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Call 1-800-4-CANCER
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. A trained Cancer Information Specialist is available to answer your questions.
Chat online
The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
Find Publications
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
About PDQ
Additional PDQ Summaries
Important:
This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
Date last modified: 2009-12-16Sponsors:
The following organisations have financed parts of our PhD research project on
improving the quality of online cancer information.
| Back to the Cancer.gov
contents overview Questions? Mail them to us! |
We subscribe to the HONcode
principles of the Health On the Net Foundation
|