Purpose of This PDQ Summary

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:

• Incidence and risk factors.
• Cellular and histopathologic classification.
• Stage information.
• Treatment options.

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.

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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.

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]

References:

1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.  

2. Pappo AS, Pratt CB: Soft tissue sarcomas in children. Cancer Treat Res 91: 205-22, 1997.  

3. Miser JS, Triche TJ, Kinsella TJ, et al.: Other soft tissue sarcomas of childhood. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia, Pa: Lippincott-Raven, 1997, pp 865-888.  

4. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, Mo: Mosby, 2001.  

5. Dillon P, Maurer H, Jenkins J, et al.: A prospective study of nonrhabdomyosarcoma soft tissue sarcomas in the pediatric age group. J Pediatr Surg 27 (2): 241-4; discussion 244-5, 1992.  

6. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec.  

7. Fletcher CD, Dal Cin P, de Wever I, et al.: Correlation between clinicopathological features and karyotype in spindle cell sarcomas. A report of 130 cases from the CHAMP study group. Am J Pathol 154 (6): 1841-7, 1999.  

8. Skytting BT, Bauer HC, Perfekt R, et al.: Clinical course in synovial sarcoma: a Scandinavian sarcoma group study of 104 patients. Acta Orthop Scand 70 (6): 536-42, 1999.  

9. Herzog CE: Overview of sarcomas in the adolescent and young adult population. J Pediatr Hematol Oncol 27 (4): 215-8, 2005.  

10. Dillon PW, Whalen TV, Azizkhan RG, et al.: Neonatal soft tissue sarcomas: the influence of pathology on treatment and survival. Children's Cancer Group Surgical Committee. J Pediatr Surg 30 (7): 1038-41, 1995.  

11. Neville H, Corpron C, Blakely ML, et al.: Pediatric neurofibrosarcoma. J Pediatr Surg 38 (3): 343-6; discussion 343-6, 2003.  

12. Zeytoonjian T, Mankin HJ, Gebhardt MC, et al.: Distal lower extremity sarcomas: frequency of occurrence and patient survival rate. Foot Ankle Int 25 (5): 325-30, 2004.  

13. Chang F, Syrjänen S, Syrjänen K: Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol 13 (4): 1009-22, 1995.  

14. deCou JM, Rao BN, Parham DM, et al.: Malignant peripheral nerve sheath tumors: the St. Jude Children's Research Hospital experience. Ann Surg Oncol 2 (6): 524-9, 1995.  

15. Stark AM, Buhl R, Hugo HH, et al.: Malignant peripheral nerve sheath tumours--report of 8 cases and review of the literature. Acta Neurochir (Wien) 143 (4): 357-63; discussion 363-4, 2001.  

16. McClain KL, Leach CT, Jenson HB, et al.: Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. N Engl J Med 332 (1): 12-8, 1995.  

17. Pappo AS, Fontanesi J, Luo X, et al.: Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience. J Clin Oncol 12 (11): 2360-6, 1994.  

18. Trassard M, Le Doussal V, Hacène K, et al.: Prognostic factors in localized primary synovial sarcoma: a multicenter study of 128 adult patients. J Clin Oncol 19 (2): 525-34, 2001.  

19. Guillou L, Benhattar J, Bonichon F, et al.: Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis. J Clin Oncol 22 (20): 4040-50, 2004.  

20. Ferrari A, Gronchi A, Casanova M, et al.: Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution. Cancer 101 (3): 627-34, 2004.  

21. Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997.  

22. Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999.  

23. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998.  

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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.

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 blood and lymph vessels

• Angiosarcoma.
• Lymphangiosarcoma.
• Hemangiopericytoma.
• Hemangioendothelioma.

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.[9][Level of evidence: 3iiA]

Tumors of more than one tissue type

• Malignant mesenchymoma.
• Malignant Triton tumor.[10]
• Malignant ectomesenchymoma.[11]

Tumors of unknown histogenesis

• Alveolar soft part sarcoma (ASPS).
• Epithelioid sarcoma.
• Clear cell sarcoma (malignant melanoma of soft parts [MMSP]).
• Synovial sarcoma.
• Desmoplastic small round cell tumor.[8]

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] 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]

Angiosarcoma

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 of soft parts

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

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

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

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

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]

Hemangioendothelioma

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

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.

Leiomyosarcoma

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]

Liposarcoma

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]

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.[48]

Malignant peripheral nerve sheath tumor

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

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

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]

Undifferentiated soft tissue sarcoma

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.

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. 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.

Soft Tissue Sarcoma Tumor 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.[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]

Grade 1 lesions

• Myxoid and well-differentiated liposarcoma.
• Deep-seated dermatofibrosarcoma protuberans.
• Well-differentiated or infantile (patient age 4 years or younger) fibrosarcoma.
• Well-differentiated or infantile (patient age 4 years or younger) hemangiopericytoma.
• Well-differentiated malignant peripheral nerve sheath tumor.
• Extraosseus myxoid chondrosarcoma.
• Angiomatoid malignant fibrous histiocytoma.

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

• Pleomorphic or round cell liposarcoma.
• Mesenchymal chondrosarcoma.
• Extraosseous osteosarcoma.
• Triton tumor (MPNST with rhabdomyosarcomatous elements).
• Alveolar soft part sarcoma.
• Synovial sarcoma.
• Epithelioid sarcoma.
• Clear cell sarcoma (MMSP).
• Mesenchymal chondrosarcoma.[9][Level of evidence: 3iiA]

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.

References:

1. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, Mo: Mosby, 2001.  

2. Recommendations for the reporting of soft tissue sarcomas. Association of Directors of Anatomic and Surgical Pathology. Mod Pathol 11 (12): 1257-61, 1998.  

3. Sandberg AA: Translocations in malignant tumors. Am J Pathol 159 (6): 1979-80, 2001.  

4. Slater O, Shipley J: Clinical relevance of molecular genetics to paediatric sarcomas. J Clin Pathol 60 (11): 1187-94, 2007.  

5. Ladanyi M, Lui MY, Antonescu CR, et al.: The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 20 (1): 48-57, 2001.  

6. Ladanyi M: The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol 4 (3): 162-73, 1995.  

7. Antonescu CR, Dal Cin P, Nafa K, et al.: EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer 46 (12): 1051-60, 2007.  

8. Barnoud R, Sabourin JC, Pasquier D, et al.: Immunohistochemical expression of WT1 by desmoplastic small round cell tumor: a comparative study with other small round cell tumors. Am J Surg Pathol 24 (6): 830-6, 2000.  

9. Dantonello TM, Int-Veen C, Leuschner I, et al.: Mesenchymal chondrosarcoma of soft tissues and bone in children, adolescents, and young adults: experiences of the CWS and COSS study groups. Cancer 112 (11): 2424-31, 2008.  

10. Rekhi B, Jambhekar NA, Puri A, et al.: Clinicomorphologic features of a series of 10 cases of malignant triton tumors diagnosed over 10 years at a tertiary cancer hospital in Mumbai, India. Ann Diagn Pathol 12 (2): 90-7, 2008.  

11. Oppenheimer O, Athanasian E, Meyers P, et al.: Malignant ectomesenchymoma in the wrist of a child: case report and review of the literature. Int J Surg Pathol 13 (1): 113-6, 2005.  

12. Reichardt P, Lindner T, Pink D, et al.: Chemotherapy in alveolar soft part sarcomas. What do we know? Eur J Cancer 39 (11): 1511-6, 2003.  

13. Kayton ML, Meyers P, Wexler LH, et al.: Clinical presentation, treatment, and outcome of alveolar soft part sarcoma in children, adolescents, and young adults. J Pediatr Surg 41 (1): 187-93, 2006.  

14. Fanburg-Smith JC, Miettinen M, Folpe AL, et al.: Lingual alveolar soft part sarcoma; 14 cases: novel clinical and morphological observations. Histopathology 45 (5): 526-37, 2004.  

15. Casanova M, Ferrari A, Bisogno G, et al.: Alveolar soft part sarcoma in children and adolescents: A report from the Soft-Tissue Sarcoma Italian Cooperative Group. Ann Oncol 11 (11): 1445-9, 2000.  

16. Argani P, Antonescu CR, Illei PB, et al.: Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 159 (1): 179-92, 2001.  

17. Roozendaal KJ, de Valk B, ten Velden JJ, et al.: Alveolar soft-part sarcoma responding to interferon alpha-2b. Br J Cancer 89 (2): 243-5, 2003.  

18. Azizi AA, Haberler C, Czech T, et al.: Vascular-endothelial-growth-factor (VEGF) expression and possible response to angiogenesis inhibitor bevacizumab in metastatic alveolar soft part sarcoma. Lancet Oncol 7 (6): 521-3, 2006.  

19. Stacchiotti S, Tamborini E, Marrari A, et al.: Response to sunitinib malate in advanced alveolar soft part sarcoma. Clin Cancer Res 15 (3): 1096-104, 2009.  

20. Ferrari A, Casanova M, Bisogno G, et al.: Malignant vascular tumors in children and adolescents: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Med Pediatr Oncol 39 (2): 109-14, 2002.  

21. Deyrup AT, Miettinen M, North PE, et al.: Angiosarcomas arising in the viscera and soft tissue of children and young adults: a clinicopathologic study of 15 cases. Am J Surg Pathol 33 (2): 264-9, 2009.  

22. Speleman F, Delattre O, Peter M, et al.: Malignant melanoma of the soft parts (clear-cell sarcoma): confirmation of EWS and ATF-1 gene fusion caused by a t(12;22) translocation. Mod Pathol 10 (5): 496-9, 1997.  

23. Coindre JM, Hostein I, Terrier P, et al.: Diagnosis of clear cell sarcoma by real-time reverse transcriptase-polymerase chain reaction analysis of paraffin embedded tissues: clinicopathologic and molecular analysis of 44 patients from the French sarcoma group. Cancer 107 (5): 1055-64, 2006.  

24. Buckley PG, Mantripragada KK, Benetkiewicz M, et al.: A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications. Hum Mol Genet 11 (25): 3221-9, 2002.  

25. Price VE, Fletcher JA, Zielenska M, et al.: Imatinib mesylate: an attractive alternative in young children with large, surgically challenging dermatofibrosarcoma protuberans. Pediatr Blood Cancer 44 (5): 511-5, 2005.  

26. Lewis JJ, Boland PJ, Leung DH, et al.: The enigma of desmoid tumors. Ann Surg 229 (6): 866-72; discussion 872-3, 1999.  

27. Lazar AJ, Tuvin D, Hajibashi S, et al.: Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol 173 (5): 1518-27, 2008.  

28. Faulkner LB, Hajdu SI, Kher U, et al.: Pediatric desmoid tumor: retrospective analysis of 63 cases. J Clin Oncol 13 (11): 2813-8, 1995.  

29. Leuschner I, Radig K, Harms D: Desmoplastic small round cell tumor. Semin Diagn Pathol 13 (3): 204-12, 1996.  

30. Kushner BH, LaQuaglia MP, Wollner N, et al.: Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J Clin Oncol 14 (5): 1526-31, 1996.  

31. Saab R, Khoury JD, Krasin M, et al.: Desmoplastic small round cell tumor in childhood: the St. Jude Children's Research Hospital experience. Pediatr Blood Cancer 49 (3): 274-9, 2007.  

32. Gerald WL, Ladanyi M, de Alava E, et al.: Clinical, pathologic, and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J Clin Oncol 16 (9): 3028-36, 1998.  

33. Chbani L, Guillou L, Terrier P, et al.: Epithelioid sarcoma: a clinicopathologic and immunohistochemical analysis of 106 cases from the French sarcoma group. Am J Clin Pathol 131 (2): 222-7, 2009.  

34. Hornick JL, Dal Cin P, Fletcher CD: Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol 33 (4): 542-50, 2009.  

35. Casanova M, Ferrari A, Collini P, et al.: Epithelioid sarcoma in children and adolescents: a report from the Italian Soft Tissue Sarcoma Committee. Cancer 106 (3): 708-17, 2006.  

36. Daller JA, Bueno J, Gutierrez J, et al.: Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 34 (1): 98-105; discussion 105-6, 1999.  

37. Lyons LL, North PE, Mac-Moune Lai F, et al.: Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol 28 (5): 559-68, 2004.  

38. Hu B, Lachman R, Phillips J, et al.: Kasabach-Merritt syndrome-associated kaposiform hemangioendothelioma successfully treated with cyclophosphamide, vincristine, and actinomycin D. J Pediatr Hematol Oncol 20 (6): 567-9, 1998 Nov-Dec.  

39. Deb G, Jenkner A, De Sio L, et al.: Spindle cell (Kaposiform) hemangioendothelioma with Kasabach-Merritt syndrome in an infant: successful treatment with alpha-2A interferon. Med Pediatr Oncol 28 (5): 358-61, 1997.  

40. Makhlouf HR, Ishak KG, Goodman ZD: Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 85 (3): 562-82, 1999.  

41. Pinet C, Magnan A, Garbe L, et al.: Aggressive form of pleural epithelioid haemangioendothelioma: complete response after chemotherapy. Eur Respir J 14 (1): 237-8, 1999.  

42. Kovach SJ, Fischer AC, Katzman PJ, et al.: Inflammatory myofibroblastic tumors. J Surg Oncol 94 (5): 385-91, 2006.  

43. Coffin CM, Hornick JL, Fletcher CD: Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol 31 (4): 509-20, 2007.  

44. Cecchetto G, Alaggio R, Dall'Igna P, et al.: Localized unresectable non-rhabdo soft tissue sarcomas of the extremities in pediatric age: results from the Italian studies. Cancer 104 (9): 2006-12, 2005.  

45. Spunt SL, Hill DA, Motosue AM, et al.: Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol 20 (15): 3225-35, 2002.  

46. Pollock BH, Jenson HB, Leach CT, et al.: Risk factors for pediatric human immunodeficiency virus-related malignancy. JAMA 289 (18): 2393-9, 2003.  

47. Lietman SA, Barsoum WK, Goldblum JR, et al.: A 20-year retrospective review of surgically treated liposarcoma at the Cleveland Clinic. Orthopedics 30 (3): 227-34, 2007.  

48. Randall RL, Albritton KH, Ferney BJ, et al.: Malignant fibrous histiocytoma of soft tissue: an abandoned diagnosis. Am J Orthop 33 (12): 602-8, 2004.  

49. Carli M, Ferrari A, Mattke A, et al.: Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. J Clin Oncol 23 (33): 8422-30, 2005.  

50. Hagel C, Zils U, Peiper M, et al.: Histopathology and clinical outcome of NF1-associated vs. sporadic malignant peripheral nerve sheath tumors. J Neurooncol 82 (2): 187-92, 2007.  

51. Okada K, Hasegawa T, Tajino T, et al.: Clinical relevance of pathological grades of malignant peripheral nerve sheath tumor: a multi-institution TMTS study of 56 cases in Northern Japan. Ann Surg Oncol 14 (2): 597-604, 2007.  

52. Dabska M, Huvos AG: Mesenchymal chondrosarcoma in the young. Virchows Arch A Pathol Anat Histopathol 399 (1): 89-104, 1983.  

53. Pappo AS, Devidas M, Jenkins J, et al.: Phase II trial of neoadjuvant vincristine, ifosfamide, and doxorubicin with granulocyte colony-stimulating factor support in children and adolescents with advanced-stage nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group Study. J Clin Oncol 23 (18): 4031-8, 2005.  

54. Okcu MF, Despa S, Choroszy M, et al.: Synovial sarcoma in children and adolescents: thirty three years of experience with multimodal therapy. Med Pediatr Oncol 37 (2): 90-6, 2001.  

55. Pappo AS, Rao BN, Jenkins JJ, et al.: Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: the St. Jude Children's Research Hospital experience. Med Pediatr Oncol 33 (2): 76-82, 1999.  

56. Brecht IB, Ferrari A, Int-Veen C, et al.: Grossly-resected synovial sarcoma treated by the German and Italian Pediatric Soft Tissue Sarcoma Cooperative Groups: discussion on the role of adjuvant therapies. Pediatr Blood Cancer 46 (1): 11-7, 2006.  

57. Raney RB: Synovial sarcoma in young people: background, prognostic factors, and therapeutic questions. J Pediatr Hematol Oncol 27 (4): 207-11, 2005.  

58. Okcu MF, Munsell M, Treuner J, et al.: Synovial sarcoma of childhood and adolescence: a multicenter, multivariate analysis of outcome. J Clin Oncol 21 (8): 1602-11, 2003.  

59. van de Rijn M, Barr FG, Collins MH, et al.: Absence of SYT-SSX fusion products in soft tissue tumors other than synovial sarcoma. Am J Clin Pathol 112 (1): 43-9, 1999.  

60. Krsková L, Sumerauer D, Stejskalová E, et al.: A novel variant of SYT-SSX1 fusion gene in a case of spindle cell synovial sarcoma. Diagn Mol Pathol 16 (3): 179-83, 2007.  

61. van de Rijn M, Barr FG, Xiong QB, et al.: Poorly differentiated synovial sarcoma: an analysis of clinical, pathologic, and molecular genetic features. Am J Surg Pathol 23 (1): 106-12, 1999.  

62. Parham DM, Webber BL, Jenkins JJ 3rd, et al.: Nonrhabdomyosarcomatous soft tissue sarcomas of childhood: formulation of a simplified system for grading. Mod Pathol 8 (7): 705-10, 1995.  

63. Skytting B, Meis-Kindblom JM, Larsson O, et al.: Synovial sarcoma--identification of favorable and unfavorable histologic types: a Scandinavian sarcoma group study of 104 cases. Acta Orthop Scand 70 (6): 543-54, 1999.  

64. Coindre JM, Terrier P, Guillou L, et al.: Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer 91 (10): 1914-26, 2001.  

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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 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]

Nonmetastatic Disease

• Group I: Tumor completely resected with histologically negative margins.
• Group II: Grossly resected tumor with microscopic residual tumor.
• 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 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]

References:

1. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, Mo: Mosby, 2001.  

2. Maurer HM, Beltangady M, Gehan EA, et al.: The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 61 (2): 209-20, 1988.  

3. Harmer MH, ed.: TNM Classification of Pediatric Tumors. Geneva: UICC, 1982.  

4. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec.  

5. Pisters PW, Leung DH, Woodruff J, et al.: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14 (5): 1679-89, 1996.  

6. Coindre JM, Terrier P, Bui NB, et al.: Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 14 (3): 869-77, 1996.  

7. Pappo AS, Fontanesi J, Luo X, et al.: Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience. J Clin Oncol 12 (11): 2360-6, 1994.  

8. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998.  

9. Brooks AD, Heslin MJ, Leung DH, et al.: Superficial extremity soft tissue sarcoma: an analysis of prognostic factors. Ann Surg Oncol 5 (1): 41-7, 1998 Jan-Feb.  

10. American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002.  

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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] 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

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]

Chemotherapy

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.

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.[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]

References:

1. Okcu MF, Despa S, Choroszy M, et al.: Synovial sarcoma in children and adolescents: thirty three years of experience with multimodal therapy. Med Pediatr Oncol 37 (2): 90-6, 2001.  

2. Sugiura H, Takahashi M, Katagiri H, et al.: Additional wide resection of malignant soft tissue tumors. Clin Orthop (394): 201-10, 2002.  

3. Cecchetto G, Guglielmi M, Inserra A, et al.: Primary re-excision: the Italian experience in patients with localized soft-tissue sarcomas. Pediatr Surg Int 17 (7): 532-4, 2001.  

4. Chui CH, Spunt SL, Liu T, et al.: Is reexcision in pediatric nonrhabdomyosarcoma soft tissue sarcoma necessary after an initial unplanned resection? J Pediatr Surg 37 (10): 1424-9, 2002.  

5. Paulino AC, Ritchie J, Wen BC: The value of postoperative radiotherapy in childhood nonrhabdomyosarcoma soft tissue sarcoma. Pediatr Blood Cancer 43 (5): 587-93, 2004.  

6. Kaste SC, Hill A, Conley L, et al.: Magnetic resonance imaging after incomplete resection of soft tissue sarcoma. Clin Orthop (397): 204-11, 2002.  

7. Chandrasekar CR, Wafa H, Grimer RJ, et al.: The effect of an unplanned excision of a soft-tissue sarcoma on prognosis. J Bone Joint Surg Br 90 (2): 203-8, 2008.  

8. Neville HL, Andrassy RJ, Lally KP, et al.: Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 35 (6): 961-4, 2000.  

9. Neville HL, Raney RB, Andrassy RJ, et al.: Multidisciplinary management of pediatric soft-tissue sarcoma. Oncology (Huntingt) 14 (10): 1471-81; discussion 1482-6, 1489-90, 2000.  

10. Kayton ML, Delgado R, Busam K, et al.: Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer 112 (9): 2052-9, 2008.  

11. Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997.  

12. Blakely ML, Spurbeck WW, Pappo AS, et al.: The impact of margin of resection on outcome in pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Pediatr Surg 34 (5): 672-5, 1999.  

13. Skytting B: Synovial sarcoma. A Scandinavian Sarcoma Group project. Acta Orthop Scand Suppl 291: 1-28, 2000.  

14. Hua C, Gray JM, Merchant TE, et al.: Treatment planning and delivery of external beam radiotherapy for pediatric sarcoma: the St. Jude Children's Research Hospital experience. Int J Radiat Oncol Biol Phys 70 (5): 1598-606, 2008.  

15. Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999.  

16. Merchant TE, Parsh N, del Valle PL, et al.: Brachytherapy for pediatric soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 46 (2): 427-32, 2000.  

17. Schomberg PJ, Gunderson LL, Moir CR, et al.: Intraoperative electron irradiation in the management of pediatric malignancies. Cancer 79 (11): 2251-6, 1997.  

18. Nag S, Shasha D, Janjan N, et al.: The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas. Int J Radiat Oncol Biol Phys 49 (4): 1033-43, 2001.  

19. Viani GA, Novaes PE, Jacinto AA, et al.: High-dose-rate brachytherapy for soft tissue sarcoma in children: a single institution experience. Radiat Oncol 3: 9, 2008.  

20. Sadoski C, Suit HD, Rosenberg A, et al.: Preoperative radiation, surgical margins, and local control of extremity sarcomas of soft tissues. J Surg Oncol 52 (4): 223-30, 1993.  

21. Virkus WW, Mollabashy A, Reith JD, et al.: Preoperative radiotherapy in the treatment of soft tissue sarcomas. Clin Orthop (397): 177-89, 2002.  

22. Zagars GK, Ballo MT, Pisters PW, et al.: Preoperative vs. postoperative radiation therapy for soft tissue sarcoma: a retrospective comparative evaluation of disease outcome. Int J Radiat Oncol Biol Phys 56 (2): 482-8, 2003.  

23. O'Sullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359 (9325): 2235-41, 2002.  

24. Spunt SL, Hill DA, Motosue AM, et al.: Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol 20 (15): 3225-35, 2002.  

25. Ferrari A: Role of chemotherapy in pediatric nonrhabdomyosarcoma soft-tissue sarcomas. Expert Rev Anticancer Ther 8 (6): 929-38, 2008.  

26. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 350 (9092): 1647-54, 1997.  

27. McGrory JE, Pritchard DJ, Arndt CA, et al.: Nonrhabdomyosarcoma soft tissue sarcomas in children. The Mayo Clinic experience. Clin Orthop (374): 247-58, 2000.  

28. Ferrari A, Gronchi A, Casanova M, et al.: Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution. Cancer 101 (3): 627-34, 2004.  

29. Van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al.: Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 17 (1): 150-7, 1999.  

30. Koscielniak E, Harms D, Henze G, et al.: Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J Clin Oncol 17 (12): 3706-19, 1999.  

31. Pappo AS, Devidas M, Jenkins J, et al.: Phase II trial of neoadjuvant vincristine, ifosfamide, and doxorubicin with granulocyte colony-stimulating factor support in children and adolescents with advanced-stage nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group Study. J Clin Oncol 23 (18): 4031-8, 2005.  

32. Ladenstein R, Treuner J, Koscielniak E, et al.: Synovial sarcoma of childhood and adolescence. Report of the German CWS-81 study. Cancer 71 (11): 3647-55, 1993.  

33. Okcu MF, Munsell M, Treuner J, et al.: Synovial sarcoma of childhood and adolescence: a multicenter, multivariate analysis of outcome. J Clin Oncol 21 (8): 1602-11, 2003.  

34. Suit H, Spiro I: Radiation as a therapeutic modality in sarcomas of the soft tissue. Hematol Oncol Clin North Am 9 (4): 733-46, 1995.  

35. Miser JS, Triche TJ, Kinsella TJ, et al.: Other soft tissue sarcomas of childhood. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia, Pa: Lippincott-Raven, 1997, pp 865-888.  

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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] These tumors include the following:

• Infantile fibrosarcoma.
• Hemangiopericytoma (in infants and young children).
• Desmoid tumors.
• Aggressive fibromatosis.
• Dermatofibrosarcoma.
• Angiomatoid malignant fibrous histiocytoma.

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.

Infantile fibrosarcoma and hemangiopericytoma (in infants and young children)

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

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.

Treatment of Childhood Soft Tissue Sarcoma with Adult-like Soft Tissue Sarcoma Biologic Characteristics

The pediatric neoplasms listed below exhibit similar biologic behavior that is similar to lesions in adults:

• Alveolar soft part sarcoma (ASPS).
• Clear cell sarcoma of soft parts.
• 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.
• Vascular tumors: angiosarcoma and hemangiosarcoma.

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.[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.

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.[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 options under clinical evaluation for alveolar soft part sarcoma

• COG-ARST0332 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 is ifosfamide and doxorubicin.[35]

Clear cell sarcoma of soft parts

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]

Desmoplastic small round cell tumor

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]

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.[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.)

Hemangioendothelioma

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]

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.[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

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: angiosarcoma and lymphangiosarcoma

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]

Current Clinical Trials

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.

References:

1. Miser JS, Pappo AS, Triche TJ: Other soft tissue sarcomas of childhood. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia, Pa: Lippincott, Williams and Wilkins, 2002, pp 1017-1050.  

2. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec.  

3. Dillon PW, Whalen TV, Azizkhan RG, et al.: Neonatal soft tissue sarcomas: the influence of pathology on treatment and survival. Children's Cancer Group Surgical Committee. J Pediatr Surg 30 (7): 1038-41, 1995.  

4. deCou JM, Rao BN, Parham DM, et al.: Malignant peripheral nerve sheath tumors: the St. Jude Children's Research Hospital experience. Ann Surg Oncol 2 (6): 524-9, 1995.  

5. Pappo AS, Fontanesi J, Luo X, et al.: Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience. J Clin Oncol 12 (11): 2360-6, 1994.  

6. Casanova M, Ferrari A, Bisogno G, et al.: Alveolar soft part sarcoma in children and adolescents: A report from the Soft-Tissue Sarcoma Italian Cooperative Group. Ann Oncol 11 (11): 1445-9, 2000.  

7. Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997.  

8. Merchant TE, Parsh N, del Valle PL, et al.: Brachytherapy for pediatric soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 46 (2): 427-32, 2000.  

9. Ferrari A, Casanova M, Bisogno G, et al.: Hemangiopericytoma in pediatric ages: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Cancer 92 (10): 2692-8, 2001.  

10. Cecchetto G, Carli M, Alaggio R, et al.: Fibrosarcoma in pediatric patients: results of the Italian Cooperative Group studies (1979-1995). J Surg Oncol 78 (4): 225-31, 2001.  

11. Buitendijk S, van de Ven CP, Dumans TG, et al.: Pediatric aggressive fibromatosis: a retrospective analysis of 13 patients and review of literature. Cancer 104 (5): 1090-9, 2005.  

12. Loh ML, Ahn P, Perez-Atayde AR, et al.: Treatment of infantile fibrosarcoma with chemotherapy and surgery: results from the Dana-Farber Cancer Institute and Children's Hospital, Boston. J Pediatr Hematol Oncol 24 (9): 722-6, 2002.  

13. Skapek SX, Ferguson WS, Granowetter L, et al.: Vinblastine and methotrexate for desmoid fibromatosis in children: results of a Pediatric Oncology Group Phase II Trial. J Clin Oncol 25 (5): 501-6, 2007.  

14. Gandhi MM, Nathan PC, Weitzman S, et al.: Successful treatment of life-threatening generalized infantile myofibromatosis using low-dose chemotherapy. J Pediatr Hematol Oncol 25 (9): 750-4, 2003.  

15. Merchant NB, Lewis JJ, Woodruff JM, et al.: Extremity and trunk desmoid tumors: a multifactorial analysis of outcome. Cancer 86 (10): 2045-52, 1999.  

16. Faulkner LB, Hajdu SI, Kher U, et al.: Pediatric desmoid tumor: retrospective analysis of 63 cases. J Clin Oncol 13 (11): 2813-8, 1995.  

17. Heinrich MC, McArthur GA, Demetri GD, et al.: Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). J Clin Oncol 24 (7): 1195-203, 2006.  

18. Gega M, Yanagi H, Yoshikawa R, et al.: Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis. J Clin Oncol 24 (1): 102-5, 2006.  

19. Merchant TE, Nguyen D, Walter AW, et al.: Long-term results with radiation therapy for pediatric desmoid tumors. Int J Radiat Oncol Biol Phys 47 (5): 1267-71, 2000.  

20. Zelefsky MJ, Harrison LB, Shiu MH, et al.: Combined surgical resection and iridium 192 implantation for locally advanced and recurrent desmoid tumors. Cancer 67 (2): 380-4, 1991.  

21. Weiss AJ, Lackman RD: Low-dose chemotherapy of desmoid tumors. Cancer 64 (6): 1192-4, 1989.  

22. Klein WA, Miller HH, Anderson M, et al.: The use of indomethacin, sulindac, and tamoxifen for the treatment of desmoid tumors associated with familial polyposis. Cancer 60 (12): 2863-8, 1987.  

23. Carli M, Ferrari A, Mattke A, et al.: Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. J Clin Oncol 23 (33): 8422-30, 2005.  

24. Okcu MF, Munsell M, Treuner J, et al.: Synovial sarcoma of childhood and adolescence: a multicenter, multivariate analysis of outcome. J Clin Oncol 21 (8): 1602-11, 2003.  

25. Suit H, Spiro I: Radiation as a therapeutic modality in sarcomas of the soft tissue. Hematol Oncol Clin North Am 9 (4): 733-46, 1995.  

26. Schomberg PJ, Gunderson LL, Moir CR, et al.: Intraoperative electron irradiation in the management of pediatric malignancies. Cancer 79 (11): 2251-6, 1997.  

27. Sadoski C, Suit HD, Rosenberg A, et al.: Preoperative radiation, surgical margins, and local control of extremity sarcomas of soft tissues. J Surg Oncol 52 (4): 223-30, 1993.  

28. Cannon CP, Ballo MT, Zagars GK, et al.: Complications of combined modality treatment of primary lower extremity soft-tissue sarcomas. Cancer 107 (10): 2455-61, 2006.  

29. Grobmyer SR, Maki RG, Demetri GD, et al.: Neo-adjuvant chemotherapy for primary high-grade extremity soft tissue sarcoma. Ann Oncol 15 (11): 1667-72, 2004.  

30. Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999.  

31. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998.  

32. Nathan PC, Tsokos M, Long L, et al.: Adjuvant chemotherapy for the treatment of advanced pediatric nonrhabdomyosarcoma soft tissue sarcoma: the National Cancer Institute experience. Pediatr Blood Cancer 44 (5): 449-54, 2005.  

33. Ogose A, Yazawa Y, Ueda T, et al.: Alveolar soft part sarcoma in Japan: multi-institutional study of 57 patients from the Japanese Musculoskeletal Oncology Group. Oncology 65 (1): 7-13, 2003.  

34. Lieberman PH, Brennan MF, Kimmel M, et al.: Alveolar soft-part sarcoma. A clinico-pathologic study of half a century. Cancer 63 (1): 1-13, 1989.  

35. Pappo AS, Devidas M, Jenkins J, et al.: Phase II trial of neoadjuvant vincristine, ifosfamide, and doxorubicin with granulocyte colony-stimulating factor support in children and adolescents with advanced-stage nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group Study. J Clin Oncol 23 (18): 4031-8, 2005.  

36. Ferrari A, Casanova M, Bisogno G, et al.: Clear cell sarcoma of tendons and aponeuroses in pediatric patients: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Cancer 94 (12): 3269-76, 2002.  

37. Leuschner I, Radig K, Harms D: Desmoplastic small round cell tumor. Semin Diagn Pathol 13 (3): 204-12, 1996.  

38. Kushner BH, LaQuaglia MP, Wollner N, et al.: Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J Clin Oncol 14 (5): 1526-31, 1996.  

39. Schwarz RE, Gerald WL, Kushner BH, et al.: Desmoplastic small round cell tumors: prognostic indicators and results of surgical management. Ann Surg Oncol 5 (5): 416-22, 1998 Jul-Aug.  

40. Goodman KA, Wolden SL, La Quaglia MP, et al.: Whole abdominopelvic radiotherapy for desmoplastic small round-cell tumor. Int J Radiat Oncol Biol Phys 54 (1): 170-6, 2002.  

41. Lal DR, Su WT, Wolden SL, et al.: Results of multimodal treatment for desmoplastic small round cell tumors. J Pediatr Surg 40 (1): 251-5, 2005.  

42. Wodowski K, Hill DA, Pappo AS, et al.: A chemosensitive pediatric extraosseous osteosarcoma: case report and review of the literature. J Pediatr Hematol Oncol 25 (1): 73-7, 2003.  

43. Goldstein-Jackson SY, Gosheger G, Delling G, et al.: Extraskeletal osteosarcoma has a favourable prognosis when treated like conventional osteosarcoma. J Cancer Res Clin Oncol 131 (8): 520-6, 2005.  

44. Daller JA, Bueno J, Gutierrez J, et al.: Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 34 (1): 98-105; discussion 105-6, 1999.  

45. Lyons LL, North PE, Mac-Moune Lai F, et al.: Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol 28 (5): 559-68, 2004.  

46. Hu B, Lachman R, Phillips J, et al.: Kasabach-Merritt syndrome-associated kaposiform hemangioendothelioma successfully treated with cyclophosphamide, vincristine, and actinomycin D. J Pediatr Hematol Oncol 20 (6): 567-9, 1998 Nov-Dec.  

47. Deb G, Jenkner A, De Sio L, et al.: Spindle cell (Kaposiform) hemangioendothelioma with Kasabach-Merritt syndrome in an infant: successful treatment with alpha-2A interferon. Med Pediatr Oncol 28 (5): 358-61, 1997.  

48. Makhlouf HR, Ishak KG, Goodman ZD: Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 85 (3): 562-82, 1999.  

49. Ferrari A, Bisogno G, Macaluso A, et al.: Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer 109 (7): 1406-12, 2007.  

50. Hagel C, Zils U, Peiper M, et al.: Histopathology and clinical outcome of NF1-associated vs. sporadic malignant peripheral nerve sheath tumors. J Neurooncol 82 (2): 187-92, 2007.  

51. McGrory JE, Pritchard DJ, Arndt CA, et al.: Nonrhabdomyosarcoma soft tissue sarcomas in children. The Mayo Clinic experience. Clin Orthop (374): 247-58, 2000.  

52. Ferrari A, Gronchi A, Casanova M, et al.: Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution. Cancer 101 (3): 627-34, 2004.  

53. Ladenstein R, Treuner J, Koscielniak E, et al.: Synovial sarcoma of childhood and adolescence. Report of the German CWS-81 study. Cancer 71 (11): 3647-55, 1993.  

54. Michal M, Fanburg-Smith JC, Lasota J, et al.: Minute synovial sarcomas of the hands and feet: a clinicopathologic study of 21 tumors less than 1 cm. Am J Surg Pathol 30 (6): 721-6, 2006.  

55. Brecht IB, Ferrari A, Int-Veen C, et al.: Grossly-resected synovial sarcoma treated by the German and Italian Pediatric Soft Tissue Sarcoma Cooperative Groups: discussion on the role of adjuvant therapies. Pediatr Blood Cancer 46 (1): 11-7, 2006.  

56. Coffin CM, Dehner LP: Vascular tumors in children and adolescents: a clinicopathologic study of 228 tumors in 222 patients. Pathol Annu 28 Pt 1: 97-120, 1993.  

57. Lezama-del Valle P, Gerald WL, Tsai J, et al.: Malignant vascular tumors in young patients. Cancer 83 (8): 1634-9, 1998.  

58. Fata F, O'Reilly E, Ilson D, et al.: Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 86 (10): 2034-7, 1999.  

59. Ferrari A, Casanova M, Bisogno G, et al.: Malignant vascular tumors in children and adolescents: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Med Pediatr Oncol 39 (2): 109-14, 2002.  

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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 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]

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.[10] Table 3 shows other promising agents currently being evaluated in clinical trials for specific histologic subtypes of nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS).

Current Clinical Trials

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.

References:

1. Demetri GD, Elias AD: Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematol Oncol Clin North Am 9 (4): 765-85, 1995.  

2. Elias A, Ryan L, Sulkes A, et al.: Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 7 (9): 1208-16, 1989.  

3. Edmonson JH, Ryan LM, Blum RH, et al.: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11 (7): 1269-75, 1993.  

4. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec.  

5. deCou JM, Rao BN, Parham DM, et al.: Malignant peripheral nerve sheath tumors: the St. Jude Children's Research Hospital experience. Ann Surg Oncol 2 (6): 524-9, 1995.  

6. Pappo AS, Rao BN, Jenkins JJ, et al.: Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: the St. Jude Children's Research Hospital experience. Med Pediatr Oncol 33 (2): 76-82, 1999.  

7. Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999.  

8. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998.  

9. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.  

10. Pappo AS, Devidas M, Jenkins J, et al.: Phase II trial of neoadjuvant vincristine, ifosfamide, and doxorubicin with granulocyte colony-stimulating factor support in children and adolescents with advanced-stage nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group Study. J Clin Oncol 23 (18): 4031-8, 2005.  

11. Stacchiotti S, Tamborini E, Marrari A, et al.: Response to sunitinib malate in advanced alveolar soft part sarcoma. Clin Cancer Res 15 (3): 1096-104, 2009.  

12. George S, Merriam P, Maki RG, et al.: Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol 27 (19): 3154-60, 2009.  

13. Maki RG, D'Adamo DR, Keohan ML, et al.: Phase II study of sorafenib in patients with metastatic or recurrent sarcomas. J Clin Oncol 27 (19): 3133-40, 2009.  

14. Sleijfer S, Ray-Coquard I, Papai Z, et al.: Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 27 (19): 3126-32, 2009.  

15. Davies DM, Johnson SR, Tattersfield AE, et al.: Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med 358 (2): 200-3, 2008.  

16. Johansson G, Mahller YY, Collins MH, et al.: Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. Mol Cancer Ther 7 (5): 1237-45, 2008.  

17. Grosso F, Jones RL, Demetri GD, et al.: Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol 8 (7): 595-602, 2007.  

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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 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.

References:

1. Belal A, Salah E, Hajjar W, et al.: Pulmonary metastatectomy for soft tissue sarcomas: is it valuable? J Cardiovasc Surg (Torino) 42 (6): 835-40, 2001.  

2. Zagars GK, Ballo MT, Pisters PW, et al.: Prognostic factors for disease-specific survival after first relapse of soft-tissue sarcoma: analysis of 402 patients with disease relapse after initial conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 57 (3): 739-47, 2003.  

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More Information

About PDQ  

• PDQ® - NCI's Comprehensive Cancer Database.
  • Full description of the NCI PDQ database.
   

Additional PDQ Summaries  

• PDQ® Cancer Information Summaries: Adult Treatment
  • Treatment options for adult cancers.
   
• PDQ® Cancer Information Summaries: Pediatric Treatment
  • Treatment options for childhood cancers.
   
• PDQ® Cancer Information Summaries: Supportive and Palliative Care
  • Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.
   
• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)
  • Tests or procedures that detect specific types of cancer.
   
• PDQ® Cancer Information Summaries: Prevention
  • Risk factors and methods to increase chances of preventing specific types of cancer.
   
• PDQ® Cancer Information Summaries: Genetics
  • Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.
   
• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine
  • Information about complementary and alternative forms of treatment for patients with cancer.
   

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).

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This information is provided by the National Cancer Institute.

This information was last updated on December 16, 2009.