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Topic Contents
- General Information
- Cellular and Histopathologic Classification
- Stage Information
- Treatment Option Overview
- Treatment of Nonmetastatic Childhood Soft Tissue Sarcoma
- Treatment of Metastatic Childhood Soft Tissue Sarcoma
- Recurrent / Progressive Childhood Soft Tissue Sarcoma
- Changes to This Summary (03 / 23 / 2012)
- About This PDQ Summary
- Get More Information From NCI
Childhood Soft Tissue Sarcoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Childhood Soft Tissue Sarcoma Treatment
General Information
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.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] 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.[2] 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.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%.[1] 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.[3] 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.[4] 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.[5] Synovial sarcomas, fibrosarcomas, and malignant peripheral nerve sheath tumors predominate in pediatric patients.[6,7,8,9,10]
NRSTSs are more common in adults [5] 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.[4,11,12,13] Soft tissue sarcomas in older children and adolescents often behave similarly to those in adult patients.[4,14]
Although they can develop in any part of the body, NRSTSs arise most commonly in the trunk and extremities.[6,7,15] 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.[16]
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.[17] Members of these families have an increased risk of developing soft tissue tumors, bone sarcomas, breast cancer, brain tumors, and acute leukemia.[4] 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.[18,19,20] Patients with familial adenomatous polyposis are at increased risk for developing desmoid tumors.[21] 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.[4,22,23]
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.[24] 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.[25,26,27]
(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.[7,12,24,28,29,30]
References:
Cellular and Histopathologic Classification
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.
Chromosomal Abnormalities
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.
Table 1. Frequent Aberrations Seen In NRSTSa
| Histology | Chromosomal Aberrations | Genes Involved |
| NRSTS = nonrhabdomyosarcomatous soft tissue sarcoma. | ||
| a Adapted from Sandberg[3]and Slater et al.[4] | ||
| 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 | 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) | |
| Inflammatory myofibroblastic tumor | t(1;2)(q23;q23), t(2;19)(q23;q13), t(2;17)(q23;q23), t(2;2)(p23;q13)[9] | TPM3/ALK,TPM4/ALK,CLTC/ALK,RANBP2/ALK |
| 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 |
Histologic Classification
Pediatric soft tissue sarcomas are classified histologically according to the soft tissue cell they resemble and include the following:[1]
Tumors of fibrous tissue
- Fibromatoses (desmoid tumors).
- Adult and infantile fibrosarcoma.
- Dermatofibrosarcoma.
Fibrohistiocytic tumors
- Malignant fibrous histiocytoma (MFH) (also called undifferentiated pleomorphic sarcoma, or spindle cell sarcoma).
Tumors of adipose tissue
- Liposarcoma.
Tumors of smooth muscle
- Leiomyosarcoma.
Tumors of peripheral nervous system
- Malignant schwannoma (malignant peripheral nerve sheath tumor [MPNST]).
Tumors of bone and cartilage
- Extraosseous osteosarcoma.
- Extraosseous myxoid chondrosarcoma.
- Mesenchymal chondrosarcoma.[10]
Tumors of more than one tissue type
Tumors of unknown histogenesis
- Alveolar soft part sarcoma (ASPS).
- Clear cell sarcoma(malignant melanoma of soft parts [MMSP]).
- Desmoplastic small round cell tumor.[8]
- Epithelioid sarcoma.
- Synovial sarcoma.
- Undifferentiated soft tissue sarcoma.[13]
Tumors of vascular structures
- Angiosarcoma.
- Hemangioendothelioma.
- Hemangiopericytoma.
- Lymphangiosarcoma.
Selected Soft Tissue Sarcomas in Children
Alveolar soft part sarcoma
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.[5,14] ASPS is considered a chemoresistant tumor.[15] In children, ASPS often presents with metastases,[16] and sometimes has a very indolent course. Pediatric ASPS seems to have a better outcome than its adult counterpart.[17] 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.[18] In another series of 33 patients, OS was 68% at 5 years and 53% at 10 years from diagnosis. Survival was better for smaller tumors (≤5 cm) and completely resected tumors.[19][Level of evidence: 3iiA] 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.[20] There are sporadic reports of objective responses to interferon-alpha, bevacizumab, and sunitinib.[21,22,23]
Clear cell sarcoma
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.[24] Patients who have small, localized tumors with low mitotic rate, and intermediate histologic grade fare best.[25]
Dermatofibrosarcoma
Dermatofibrosarcoma is a rare tumor, but many of the reported cases arise in children.[26] 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.[27]
Desmoid tumors
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.[28] 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.[29] Repeated surgical resection can sometimes bring recurrent lesions under control.[30]
Desmoplastic small round cell tumor
Desmoplastic small round cell tumor is a primitive sarcoma that most frequently involves the abdomen, pelvis, or tissues around the testes.[31,32,33] 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.[34]
Epithelioid sarcoma
Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis which displays multilineage differentiation.[35] It is characterized by inactivation of the SMARC/INI1 gene which is present in both conventional and proximal types of epithelioid sarcoma.[36] 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.[37]
Inflammatory myofibroblastic tumor
Inflammatory myofibroblastic tumor (IMT) is an incompletely characterized neoplasm of intermediate biologic potential. It recurs frequently but metastasizes rarely.[38] Roughly half of IMTs exhibit a clonal mutation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase gene at chromosome 2p23.[39] There are no well-documented responses to chemotherapy. A case report described a partial response in a patient with recurrent IMT who was treated with crizotinib, an ATP-competitive inhibitor of the ALK and MET tyrosine kinases.[40] There are case reports of response to either steroids or nonsteroidal anti-inflammatory drugs.
Leiomyosarcoma
A 24-year retrospective analysis of the Italian cooperative group identified one child with leiomyosarcoma.[41] A retrospective analysis of the St. Jude Children's Research Hospital experience from 1962 to 1996 identified 40 children with NRSTS; none had leiomyosarcoma.[42] Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma.[43] Survivors of hereditary retinoblastoma have a statistically significant increased risk of developing leiomyosarcoma and 78% of these were diagnosed 30 years and older after the initial diagnosis of retinoblastoma.[44]
Liposarcoma
Liposarcoma is rare in the pediatric population. Liposarcomas can be roughly divided into the following four large groups:
- Atypical lipomatous neoplasm/well-differentiated liposarcoma. These tumors do not metastasize unless they undergo dedifferentiation.
- Myxoid liposarcoma. Pure myxoid liposarcomas are characterized by a t(12;16)(q13;p11) translocation and can metastasize but usually have an excellent outcome in the absence of a round cell component.
- Dedifferentiated liposarcoma.
- Pleomorphic liposarcoma.
In a review of 182 pediatric patients with adult-type sarcomas, only 14 had a diagnosis of liposarcoma.[45] In another review, the characteristics of 82 cases of pediatric liposarcoma were reported. The median age was 15.5 years and females were more commonly affected. Myxoid liposarcoma was the predominant histologic subtype, and 94% of these patients were alive following surgical resection. In contrast, seven of ten patients with pleomorphic myxoid liposarcoma in this series died of their disease.[46]
Malignant fibrous histiocytoma
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.[47] (Refer to the Osteosarcoma and Malignant Fibrous Histiocytoma of Bone summary for information on MFH of bone.)
Malignant peripheral nerve sheath tumor
MPNST arises in children with type 1 neurofibromatosis (NF1), and it arises sporadically.[48] Features with favorable prognosis have been reported to include localized disease, absence of NF1, smaller tumor size, lower stage, and an extremity as the primary site.[48,49,50] 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. A retrospective review of 140 patients with MPNST from the MD Anderson Cancer Center included children and adolescents. The disease-specific survival at 10 years was 32%. In this series, presence of metastatic disease was associated with a much worse prognosis. For patients with localized disease, there was no significant difference in outcome between patients with and without NF1. In a multivariate analysis, only tumor size and nuclear p53 expression were found to be independent predictors of disease-specific survival.[50]
Mesenchymal chondrosarcoma
Mesenchymal chondrosarcoma is a highly malignant tumor with a propensity to spread to the lungs. A 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.[10][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]
Perivascular epithelioid cell neoplasms (PEComas)
PEComas include angiomyolipoma, lymphangioleiomyomatosis, and clear cell "sugar" tumor. Benign PEComas are common in tuberous sclerosis, an autosomal dominant syndrome that also predisposes to renal cell cancer and brain tumors. Tuberous sclerosis is caused by germline inactivation of either TSC1 (9q34) or TSC2 (16p13.3), and the same tumor suppressor genes are inactivated somatically in sporadic PEComas.[53] Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of non-surgically curable PEComas with mTOR inhibitors.[54,55]
PEComas occur in various rare gastrointestinal, pulmonary, gynecologic, and genitourinary sites. Soft tissue, visceral, and gynecologic PEComas are more commonly seen in middle-aged female patients and are usually not associated with the tuberous sclerosis complex.[56] Most PEComas have a benign clinical course, but malignant behavior has been reported and can be predicted based on the size of the tumor, mitotic rate, and presence of necrosis.[57]
Plexiform histiocytic tumor
Plexiform histiocytic tumor is a low to intermediate grade tumor. It most commonly arises in the skin or subcutaneous tissue of children and young adults.[58,59,60] Treatment is limited to surgical resection. There are rare reports of spread to regional lymph nodes or the lung. The majority of patients are cured by surgery, but local recurrence has been reported in 10% to 40% of cases.
Synovial sarcoma
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.[41,61,62,63] 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.[62,64,65,66]
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.[67,68] 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.[69]
Undifferentiated soft tissue sarcoma
Patients with undifferentiated sarcoma were eligible for participation in rhabdomyosarcoma (RMS) trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group (COG) from 1972 to 2006. The rationale was the observation that patients with undifferentiated sarcoma had similar sites of disease and outcome compared with those with alveolar RMS. Therapeutic trials for adults with soft tissue sarcoma include patients with undifferentiated sarcoma and other histologies, which are treated similarly, utilizing ifosfamide and doxorubicin, sometimes with other chemotherapy agents, surgery, and radiation therapy. The COG is studying the use of a combination of surgery and/or radiation therapy, with or without ifosfamide and doxorubicin, for patients with undifferentiated sarcoma of soft tissue in its open protocol COG-ARST0332 for patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).
Vascular tumors
Angiosarcoma: A review of 20 years of experience in the Italian and German Soft Tissue Sarcoma Cooperative Group identified 12 children with angiosarcoma.[70] Only one objective response to chemotherapy was observed, and the overall behavior of this tumor was identical to angiosarcoma in adults. A subsequent retrospective study performed by the Polish and German Cooperative Paediatric Soft Tissue Sarcoma Study Groups identified four chemotherapy responses in ten children treated (total 14 children with angiosarcoma).[71] Another review of 15 patients demonstrated a 33% survival rate.[72] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.[73] Anti-angiogenesis therapy may prove useful in the treatment of this group of neoplasms.[74]
Hemangioendothelioma: Hemangioendotheliomas are tumors found in infants that arise within the liver or elsewhere and usually remain benign.[75] The tumors are sometimes associated with consumptive coagulopathy, also known as the Kasabach-Merritt syndrome (or phenomenon).[76,77,78] 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.[79,80]
Biopsy Technique for Soft Tissue Sarcoma
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. Needle biopsy techniques must obtain an adequate tissue sample and usually require obtaining multiple cores of tissue. Image guidance using ultrasound, computed tomography scan, or magnetic resonance imaging may be necessary to ensure a representative biopsy.[81] Incisional biopsies are acceptable but should not compromise subsequent wide local excision, and extensive dissection around the lesion must be avoided. Transverse extremity incisions should be avoided to reduce skin loss, as should extensive surgical procedures prior to definitive diagnosis.
References:
Stage Information
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 Tables 2–5 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 sarcoma (NRSTS) 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]
Nonmetastatic Disease
- Group I: Tumor completely resected with histologically negative margins.
- Group II: Grossly resected tumor with microscopic residual tumor.
- IIA: Grossly resected tumor with microscopic residual disease.
- IIB: Regional disease with involved nodes completely resected with no microscopic disease.
- IIC: Regional disease with involved nodes grossly resected but with evidence of residual microscopic disease and/or histologic involvement of the most distal regional lymph node in the dissection.
- Group III: Incomplete resection or biopsy with gross residual tumor.
Metastatic Disease
- Group IV: Any localized or regional tumor with distant metastases present at the time of diagnosis.
Recurrent/Progressive Disease
- Any soft tissue sarcoma that recurs after initial treatment or progresses after radiation therapy, chemotherapy, or initial surgery.
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 5 cm or less in greatest dimension, and T2 lesions are more than 5 cm in greatest dimension. These categories can be subclassified to reflect the maximum tumor depth (a: superficial tumor; b: deep tumor). Regional nodal involvement is indicated by the N1 (N0: no regional nodal involvement) designation and the presence of distant metastases at the time of diagnosis is indicated by the M1 (M0: no metastatic involvement) designation.
TNM Stage Information
The American Joint Committee on Cancer (AJCC) has designated staging by the four criteria of tumor size, nodal status, grade, and metastasis (TNGM).[4]
Table 2. Primary Tumor (T)a
| a Reprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8. | |
| b Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia. | |
| TX | Primary tumor cannot be assessed. |
| T0 | No evidence of primary tumor. |
| T1 | Tumor ≤5 cm in greatest dimension.b |
| T1a | Superficial tumor. |
| T1b | Deep tumor. |
| T2 | Tumor >5 cm in greatest dimension.b |
| T2a | Superficial tumor. |
| T2b | Deep tumor. |
Table 3. Regional Lymph Nodes (N)a
| a Reprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8. | |
| b Presence of positive nodes (N1) in M0 tumors is considered Stage III. | |
| NX | Regional lymph nodes cannot be assessed. |
| N0 | No regional lymph node metastasis. |
| N1b | Regional lymph node metastasis. |
Table 4. Distant Metastasis (M)a
| a Reprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8. | |
| M0 | No distant metastasis. |
| M1 | Distant metastasis. |
Table 5. Anatomic Stage/Prognostic Groupsa
| Stage | T | N | M | Grade |
| a Reprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8. | ||||
| IA | T1a | N0 | M0 | G1, GX |
| T1b | N0 | M0 | G1, GX | |
| IB | T2a | N0 | M0 | G1, GX |
| T2b | N0 | M0 | G1, GX | |
| IIA | T1a | N0 | M0 | G2, G3 |
| T1b | N0 | M0 | G2, G3 | |
| IIB | T2a | N0 | M0 | G2 |
| T2b | N0 | M0 | G2 | |
| III | T2a, T2b | N0 | M0 | G3 |
| Any T | N1 | M0 | Any G | |
| IV | Any T | Any N | M1 | Any G |
Soft Tissue Sarcoma Tumor Pathological Grading System
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.[5] 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.[5,6,7] 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.[8]
Grade 1 lesions
- Angiomatoid malignant fibrous histiocytoma.
- Deep-seated dermatofibrosarcoma protuberans.
- Extraosseous myxoid chondrosarcoma.
- Myxoid and well-differentiated liposarcoma.
- Well-differentiated malignant peripheral nerve sheath tumor.
- Well-differentiated or infantile (patient age 4 years or younger) fibrosarcoma.
- Well-differentiated or infantile (patient age 4 years or younger) hemangiopericytoma.
Grade 2 lesions
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.
Grade 3 lesions
- Alveolar soft part sarcoma.
- Clear cell sarcoma (MMSP).
- Desmoplastic small round cell tumor.
- Epithelioid sarcoma.
- Extraosseous osteosarcoma.
- Mesenchymal chondrosarcoma.[9]
- Pleomorphic or round cell liposarcoma.
- Synovial sarcoma.
- Triton tumor (MPNST with rhabdomyosarcomatous elements).
- Undifferentiated soft tissue sarcoma.
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.
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).[10]
Prognostic Significance of Tumor Staging
These two staging systems have proven to be of prognostic significance in pediatric and adult NRSTSs.[11,12,13,14,15] In a review of a large adult series of NRSTSs, 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.[16]
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. A retrospective review of soft tissue sarcomas in children and adolescents suggests that the 5 cm cutoff used for adults with soft tissue sarcoma may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and body surface area.[17] This relationship requires further study to determine the therapeutic implications of the observation.
References:
Treatment Option Overview
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.
Surgery
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] Regional lymph node metastases at diagnosis are unusual and appear most likely with epithelioid and clear cell sarcomas.[8] 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.[9,10,11]
Radiation Therapy
Radiation therapy is indicated for patients with inadequate surgical margins and for larger, high-grade tumors.[12] This is particularly important in high-grade tumors with tumor margins less than 1 cm.[13,14]; [15][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.[16,17] Brachytherapy and intraoperative radiation may be applicable in select situations.[17,18,19]; [20][Level of evidence: 3iiiDii] Preoperative radiation therapy has been associated with excellent local control rates,[21,22,23] but has been associated with an increased rate of wound complications in adults.[24] Pediatric patients with unresected NRSTS have a poor outcome. Only about one-third of patients treated with multimodality therapy remain disease free.[24,25]
Chemotherapy
The role of adjuvant (postoperative) chemotherapy remains controversial.[26] 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.[27] The largest prospective pediatric trial failed to demonstrate any benefit with adjuvant vincristine, dactinomycin, cyclophosphamide, and doxorubicin.[16] 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.[28,29,30,31,32] A German trial suggested a benefit for adjuvant chemotherapy in children with synovial sarcoma.[33] A meta-analysis also suggested that chemotherapy may provide benefit.[34] 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.
Special Treatment Considerations for Children with Soft Tissue Sarcoma
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.[35] 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.[36]
References:
Treatment of Nonmetastatic Childhood Soft Tissue Sarcoma
Standard treatment options for nonmetastatic pediatric nonrhabdomyosarcomatous soft tissue sarcomas (NRSTSs) include the following:
- Complete surgical resection alone (if margins were tumor-free) or followed by re-excision if margins were positive.
- Surgical excision followed by postoperative radiation therapy or brachytherapy (if tumor margins were positive and further resection is not possible).
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]
Treatment of Childhood Soft Tissue Sarcoma with Low Potential for Metastasis
The tumors discussed in this section are clinically less aggressive and rarely metastasize.[1,9,10,11,12] These tumors include the following:
- Angiomatoid malignant fibrous histiocytoma.
- Dermatofibrosarcoma.
- Desmoid tumors, also known as aggressive fibromatosis.
- Hemangiopericytoma (in infants and young children).
- Infantile fibrosarcoma.
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.
Desmoid tumors
Desmoid tumors (aggressive fibromatoses) 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 produced objective responses in about one-third of patients with recurrent or unresectable desmoids.[13]
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.
Hemangiopericytoma (in infants and young children) and infantile fibrosarcoma
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.[1,23] Responses to presurgical chemotherapy with similar agents have been reported in cases of infantile hemangiopericytoma.[1]
Treatment of Childhood Soft Tissue Sarcoma with Adult-like Soft Tissue Sarcoma Biologic Characteristics
The pediatric neoplasms listed below exhibit biologic behavior that is similar to lesions in adults:
- Alveolar soft part sarcoma (ASPS).
- Clear cell sarcoma.
- Desmoplastic small round cell tumor.
- Epithelioid sarcoma.
- Extraosseous osteosarcoma.
- Fibrosarcoma in older children and adolescents.
- Hemangioendothelioma.
- Hemangiopericytoma in older children and young adults.
- Leiomyosarcoma.
- Liposarcoma.
- Malignant fibrous histiocytoma.
- Malignant peripheral nerve sheath tumor (MPNST).
- Mesenchymal chondrosarcoma.
- Synovial sarcoma.
- Undifferentiated soft tissue sarcoma.
- Vascular tumors: angiosarcoma, hemangioendothelioma, hemangiopericytoma in older children and young adults (aged >4 years), and lymphangiosarcoma.
Much of what is known about treating these tumors is derived from studies in adults. Standard treatment options for these tumors include the following:
- Complete surgical resection alone (if margins were tumor-free) or followed by re-excision if margins were positive.
- Surgical excision followed by postoperative radiation therapy or brachytherapy if tumor margins were positive and further resection is not possible.
Every attempt should be made to resect the primary tumor locally with negative margins.[24,25] 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.[26] The use of brachytherapy and intraoperative radiation therapy is under study.[8,27] Preoperative radiation therapy has been associated with excellent local control rates in adults;[28,29] 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.[30] 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.[31] 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.[32] Achieving complete responses after aggressive chemotherapy, radiation therapy, and surgery is possible in most patients with more advanced NRSTS.[33]
Some of these tumors have been treated with other therapies and these selected tumors and treatments are discussed below.
Alveolar soft part sarcoma
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.[34] Patients with ASPS may relapse several years after a prolonged period of apparent remission.[35] 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 options under clinical evaluation for alveolar soft part sarcoma
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-ARST0332(Observation, Radiation Therapy, Combination Chemotherapy, and/or Surgery in Treating Young Patients With Soft Tissue Sarcoma): This is a prospective study for children and young adults with soft tissue sarcomas other than rhabdomyosarcoma. Patients are stratified by tumor grade and extent. Patients with lower-grade tumors and patients with small, completely resected high-grade tumors are observed after surgical resection alone. Patients with positive microscopic margins receive adjuvant radiation. Patients with high-grade tumors larger than 5 cm undergo resection and receive adjuvant chemotherapy and radiation. Patients with unresectable or metastatic disease receive neoadjuvant chemotherapy. Chemotherapy for all eligible patients consists of ifosfamide and doxorubicin. Patients eligible for this trial will have one of the following histologies:[36]
- ASPS.
- Angiosarcoma.
- Clear cell sarcoma.
- Epithelioid sarcoma.
- Extraosseous osteosarcoma.
- Fibrosarcoma in older children and adolescents.
- Hemangioendothelioma.
- Hemangiopericytoma in older children and young adults.
- Leiomyosarcoma.
- Liposarcoma.
- Malignant peripheral nerve sheath tumor.
- Mesenchymal chondrosarcoma.
- Synovial sarcoma.
- Undifferentiated soft tissue sarcoma.
This study uses the 6th edition of the AJCC Staging Manual to stage the child's disease. Refer to the protocol for further information about staging on COG-ARST0332.
- NCT00942877(Phase II Study of Cediranib in Patients With ASPS): This phase II study of cediranib in patients with ASPS is being conducted at the Clinical Center of the National Institutes of Health. Patients aged 18 years and older are eligible to participate.
Clear cell sarcoma
Treatment for clear cell sarcoma is primarily surgical with radiation therapy for uncertain or involved margins. Antisarcoma chemotherapy is rarely effective.[37] In one series, clear cell sarcoma demonstrated a propensity to metastasize to regional lymph nodes (12%–43%).[38]
Desmoplastic small round cell tumor
Complete resection of this tumor is rarely possible at diagnosis, but greater than 90% tumor resection after neoadjuvant chemotherapy has been shown to be a prognostic factor for overall survival. Therefore, treatment may include chemotherapy, surgery, and radiation therapy. Multiagent chemotherapy analogous to that used for sarcomas has been used, as well as total abdominal radiotherapy.[39,40,41,42,43]
Extraosseous osteosarcoma
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.[44] Extraosseous osteosarcoma may be more chemosensitive in young patients than in adults.[44] A retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraskeletal osteosarcoma treated with surgery and conventional osteosarcoma chemotherapy.[45] (Refer to the PDQ summary on Osteosarcoma/Malignant Fibrous Histiocytoma of Bone for more information.)
Malignant peripheral nerve sheath tumor
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.[24] 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.[24] 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%.[46] Another series of older patients with MPNST found that those with NF1 had a worse prognosis than those without NF1.[47]
Synovial sarcoma
Synovial sarcoma appears to be more sensitive to chemotherapy than many other NRSTSs. The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[25,36,48] Children with synovial sarcoma have a higher probability for both event-free survival (EFS) and OS than children with other types of NRSTS.[49,50] A German randomized trial suggested a benefit for adjuvant chemotherapy in children with synovial sarcoma.[51] A meta-analysis also suggested that chemotherapy may improve EFS but could not confirm improvement in OS.[25] 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.[52] 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.[53] In this analysis, local invasiveness conferred an inferior probability of EFS, but surgical margins did not predict outcome.
Undifferentiated soft tissue sarcoma
Patients with undifferentiated soft tissue sarcoma were eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group (COG) from 1972 to 2006. The rationale was the observation that patients with undifferentiated soft tissue sarcoma had similar sites of disease and outcome compared with those with alveolar rhabdomyosarcoma. Therapeutic trials for adults with soft tissue sarcoma include patients with undifferentiated soft tissue sarcoma and other histologies, which are treated similarly, using ifosfamide and doxorubicin, and sometimes with other chemotherapy agents, surgery, and radiation therapy. The COG is studying the use of a combination of surgery and/or radiation therapy, with or without ifosfamide and doxorubicin, for patients with undifferentiated soft tissue sarcoma in its open protocol COG-ARST0332, which is for patients with NRSTS.
Vascular tumors: angiosarcoma and lymphangiosarcoma
Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant.[54] Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients in response to local therapy.[55,56,57,58]
Treatment of asymptomatic liver hemangioendothelioma in a child younger than 1 year may include close observation because some tumors will regress. Symptomatic lesions require urgent medical or surgical management, especially if coagulopathy is present.[59,60,61,62] 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.[63]
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
COG-ARST0332 (Observation, Radiation Therapy, Combination Chemotherapy, and/or Surgery in Treating Young Patients With Soft Tissue Sarcoma): This prospective study is for children and young adults with soft tissue sarcomas other than rhabdomyosarcoma. Patients are stratified by tumor grade and extent. Patients with lower-grade tumors and patients with small, completely resected high-grade tumors are observed after surgical resection alone. Patients with positive microscopic margins receive adjuvant radiation therapy. Patients with high-grade tumors larger than 5 cm undergo resection and receive adjuvant chemotherapy and radiation therapy. Patients with unresectable or metastatic disease receive neoadjuvant chemotherapy. Chemotherapy for all eligible patients consists of ifosfamide and doxorubicin. Patients eligible for this trial will have one of the following histologies:[36]
- ASPS.
- Angiosarcoma.
- Clear cell sarcoma.
- Epithelioid sarcoma.
- Extraosseous osteosarcoma.
- Fibrosarcoma in older children and adolescents.
- Hemangioendothelioma.
- Hemangiopericytoma in older children and young adults.
- Leiomyosarcoma.
- Liposarcoma.
- Malignant peripheral nerve sheath tumor.
- Mesenchymal chondrosarcoma.
- Synovial sarcoma.
- Undifferentiated soft tissue sarcoma.
This study uses the 6th edition of the AJCC Staging Manual to stage the child's disease. Refer to the protocol for further information about staging on COG-ARST0332.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
References:
Treatment of Metastatic Childhood Soft Tissue Sarcoma
Standard treatment options for metastatic childhood soft tissue sarcoma include the following:
- Combination therapy using chemotherapy, radiation therapy, and surgical resection of pulmonary metastases.
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 a surgical procedure in an attempt to resect all gross disease. For patients with multiple or recurrent pulmonary metastases, additional surgical procedures can be performed if the morbidity is expected to be acceptable. An alternative approach is focused radiation therapy (fractionated stereotactic radiation therapy) that has been successfully used in adults to sterilize lesions. The estimated 5-year survival rate after thoracotomy for pulmonary metastasectomy has ranged from 10% to 58% in adult studies. Emerging data suggest a similar outcome following the use of focused radiation therapy in adults.[9] Formal segmentectomy, lobectomy, and mediastinal lymph node dissection are unnecessary.[10]
Treatment Options Under Clinical Evaluation
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.[11] Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
References:
Recurrent / Progressive Childhood Soft Tissue Sarcoma
Decisions about treatment options for recurrent or progressive childhood soft tissue sarcoma are based on many factors, including the following:
- Site of recurrence.
- Tumor biologic characteristics.
- Prior therapies.
- Individual patient considerations.
Standard treatment options for recurrent or progressive disease include the following:
- Surgical excision of local recurrence or isolated pulmonary recurrence.
- Surgical excision of local recurrence followed by radiation therapy or brachytherapy (if no prior radiation therapy was given).
- Limb amputation (only for some children with extremity sarcomas that have already received radiation therapy).
- A clinical trial of new chemotherapeutic regimens.
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.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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.
References:
Changes to This Summary (03 / 23 / 2012)
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.
Cellular and Histopathologic Classification
Revised Table 1 to include chromosomal aberrations and genes involved with the inflammatory myofibroblastic tumor (IMT) histology (cited Jain et al. as reference 9).
Added Alaggio et al. as reference 13 and Williams et al. as reference 14.
Added text to state that in another series of 33 patients, overall survival was 68% at 5 years and 53% at 10 years from diagnosis; survival was better for smaller tumors and completely resected tumors (cited Pennacchioli et al. as reference 19 and level of evidence 3iiA).
Added text to state that a case report described a partial response in a patient with recurrent inflammatory myofibroblastic tumor who was treated with crizotinib, an ATP-competitive inhibitor of the ALK and MET tyrosine kinases (cited Butrynski et al. as reference 40).
Revised text to state that inactivation of either TSC1 (9q34) or TSC2 (16p13.3) results in stimulation of the mTOR pathway, providing the basis for the treatment of non-surgically curable PEComas with mTOR inhibitors.
Added text to state that a subsequent retrospective study performed by the Polish and German Cooperative Paediatric Soft Tissue Sarcoma Study Groups identified four chemotherapy responses in ten children treated; anti-angiogenesis therapy may prove useful in the treatment of this group of neoplasms (cited Bien et al. and Park et al. as references 71 and 74, respectively).
Stage Information
Expanded text on Group II nonmetastatic disease to include subgroups IIA, IIB, and IIC.
Treatment of Nonmetastatic Childhood Soft Tissue Sarcoma
Added text to state that in one series, clear cell sarcoma demonstrated a propensity to metastasize to regional lymph nodes (cited Blazer et al. as reference 38).
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood soft tissue sarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Soft Tissue Sarcoma Treatment are:
- Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
- Holcombe Edwin Grier, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Michael P. LaQuaglia, MD (Memorial Sloan-Kettering Cancer Center)
- Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
- Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
- Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
- R. Beverly Raney, MD (Consultant)
- Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
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 Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Childhood Soft Tissue Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/child-soft-tissue-sarcoma/HealthProfessional. Accessed <MM/DD/YYYY>.
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- 800-437-4010
- Sioux Falls, SD
- 605-333-1000
Nurse by Phone
- My Sanford Nurse
North Dakota, NW Minnesota - 800-821-5167
- 701-234-5000
- My Sanford Nurse
South Dakota, SW Minnesota, NW Iowa - 800-445-5788
- 605-333-4444
Physician Finder
- Fargo, ND
- 877-234-4240
- 701-234-5570
- Sioux Falls, SD
- 877-945-5678
Latest Sanford Health News
- Sanford Research Announces PROMISE Scholars, Fellows
- Sanford Health Receives American Heart Association’s Mission: Lifeline Quality Achievement Awards for Heart Attack Care
- Sanford receives supply chain management award
- Wisconsin, St. John’s University and Timberwolves to visit Sanford Pentagon this fall
- Sanford Stroke Team Recognized for Stroke Care
Resources
Now there is an app for that - Valley News Live - KVLY/KXJB - Fargo/Grand Forks http://t.co/qge3WkEEQk