General Information

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologist, pediatric hematologist/oncologist, rehabilitation specialist, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Incidence

Pediatric soft tissue sarcomas (STSs) are a heterogenous group of malignant tumors that originate from primitive mesenchymal tissue and account for 7% of all childhood tumors.[3] Rhabdomyosarcoma, a tumor of striated muscle, is the most common STS in children aged 0 to 14 years and accounts for 50% of tumors in this age group.[4] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.) The remaining STSs are commonly referred to as nonrhabdomyosarcomatous STSs and account for about 3% of all childhood tumors.[5] This heterogeneous group of tumors includes neoplasms of:[6]

• Connective tissue (fibrous and adipose).
• Peripheral nervous system.
• Smooth muscle (leiomyosarcomas).
• Vascular tissue (blood and lymphatic vessels).

In children, synovial sarcoma, fibrosarcoma, fibrohistiocytic tumors, and malignant peripheral nerve sheath tumors predominate.[7,8] The distribution of STSs by histology and age, based on the Surveillance Epidemiology and End Results (SEER) information from 1975 to 2008, is depicted in Table 1. The distribution of histologic types by age is shown in Figure 1.

Table 1. Frequency of Soft Tissue Sarcomas (STSs) in Children Aged 0 to 19 Years (SEER 1975–2008)

	Age <5 y	Age 5–9 y	Age 10–14 y	Age 15–19 y	Age <15 y	Age <20 y	% of the Total Number of STS Cases
pPNET = peripheral primitive neuroectodermal tumors; SEER = Surveillance Epidemiology and End Results.
Rhabdomyosarcomas	710	466	364	350	1,540	1,890	41
Fibrosarcomas, peripheral nerve, and other fibrous neoplasms	151	64	132	192	347	539	12
	Fibroblastic and myofibroblastic tumors	131	31	57	86	219	305
	Nerve sheath tumors	19	32	74	104	125	229
	Other fibromatous neoplasms	1	1	1	2	3	5
Kaposi sarcoma	1	2	0	12	3	15	0.3
Other specified soft tissue sarcomas	198	220	512	856	930	1,786	38
	Ewing tumor and Askin tumor of soft tissue	22	28	57	81	107	188
	pPNET of soft tissue	21	19	29	42	69	111
	Extrarenal rhabdoid tumor	37	3	8	3	48	51
	Liposarcomas	5	6	22	66	33	99
	Fibrohistiocytic tumors	53	69	171	293	293	586
	Leiomyosarcomas	13	19	22	57	54	111
	Synovial sarcomas	12	39	133	204	184	388
	Blood vessel tumors	15	7	11	33	33	66
	Osseous and chondromatous neoplasms of soft tissue	1	5	9	16	15	31
	Alveolar soft parts sarcoma	3	7	19	26	29	55
	Miscellaneous soft tissue sarcomas	16	18	31	35	65	100
Unspecified soft tissue sarcomas	70	58	136	163	264	427	9
All soft tissue and other extraosseous sarcomas	1,130	810	1,144	1,573	3,084	4,657	100

Figure 1. The distribution of nonrhabdomyosarcomatous soft tissue sarcomas in children aged 0 to 19 years, as reported by the Surveillance Epidemiology and End Results program from 1975 to 2008.

Nonrhabdomyosarcomatous STSs are more common in adolescents and adults,[6] and most of the information regarding treatment and natural history of the disease in younger patients has been based on adult studies.

Risk Factors

Some genetic and environmental factors have been associated with the development of nonrhabdomyosarcomatous STS:

• Genetic factors:
  • Li-Fraumeni syndrome: Patients with Li-Fraumeni syndrome (usually due to heritable cancer-associated changes of the p53 tumor suppressor gene) have an increased risk of developing soft tissue tumors (mostly nonrhabdomyosarcomatous STSs), bone sarcomas, breast cancer, brain tumors, and acute leukemia.[5,9]
  • Neurofibromatosis type 1: 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.[10,11,12]
  • Familial adenomatous polyposis: Patients with familial adenomatous polyposis are at increased risk of developing desmoid tumors.[13]
  • Werner syndrome: Werner syndrome is characterized by spontaneous chromosomal instability, resulting in increased susceptibility to cancer and premature aging. An excess of STSs has been reported in patients with Werner syndrome.[14]
  • Retinoblastoma gene: Germline mutations of the retinoblastoma gene have been associated with an increased risk of developing STSs, particularly leiomyosarcoma.[15]
• Environmental factors:
  • Radiation: Some nonrhabdomyosarcomatous STSs (particularly malignant fibrous histiocytoma) can develop within a previously irradiated site.[5,16]
  • Epstein-Barr virus infection in patients with AIDS: Some nonrhabdomyosarcomatous STSs (e.g., leiomyosarcoma) have been linked to Epstein-Barr virus infection in patients with AIDS.[5,17]

Clinical Presentation

Although nonrhabdomyosarcomatous STSs can develop in any part of the body, they arise most commonly in the trunk and extremities.[7,18,19] 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.[20]

Diagnosis

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.

Nonrhabdomyosarcomatous soft tissue tumors are fairly readily distinguished pathologically from rhabdomyosarcoma and Ewing sarcoma; however, classification of childhood nonrhabdomyosarcomatous STS type is often difficult. A core-needle biopsy or small incisional biopsy that obtains 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,[21,22] given the diagnostic importance of translocations. Needle biopsy techniques must obtain an adequate tissue sample and usually require obtaining multiple cores of tissue. Image guidance using ultrasound, computed tomography scan, or magnetic resonance imaging may be necessary to ensure a representative biopsy.[23] Incisional biopsies are acceptable but should not compromise subsequent wide local excision, and excisional biopsy of the lesion must be avoided. Transverse extremity incisions should be avoided to reduce skin loss, as should extensive surgical procedures prior to definitive diagnosis. For these reasons, open biopsy or multiple core-needle biopsies are strongly encouraged so that adequate tumor tissue can be obtained to allow for crucial studies to be performed and to avoid limiting future treatment options.

Many nonrhabdomyosarcomatous STSs 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 2.

Table 2. Frequent Chromosomal Aberrations Seen in Nonrhabdomyosarcomatous STS^a

Histology	Chromosomal Aberrations	Genes Involved
STS = soft tissue sarcoma.
a Adapted from Sandberg,[24]Slater et al.,[25]Mertens et al.,[26]and Romeo.[27]
Alveolar soft part sarcoma	t(x;17)(p11.2;q25)	ASPL/TFE3[28,29,30]
Angiomatoid fibrous histiocytoma	t(12;16)(q13;p11), t(2;22)(q33;q12), t(12;22)(q13;q12)	FUS/ATF1,EWSR1/CREB1,[31]EWS/ATF1
Clear cell sarcoma	t(12;22)(q13;q12), t(2;22)(q33;q12)	ATF1/EWS,EWSR1/CREB1
Congenital (infantile) fibrosarcoma/mesoblastic nephroma	t(12;15)(p13,q25)	ETV-NTRK3
Dermatofibrosarcoma protuberans	t(17;22)(q22;q13)	COL1A1/PDGFB
Desmoid fibromatosis	Trisomy 8 or 20, loss of 5q21	CTNNB1orAPCmutations
Desmoplastic small round cell tumors	t(11;22)(p13;q12)	EWS/WT1[32]
Epithelioid hemangioendothelioma	t(1;3)(p36;q25)[33]	WWTR1/CAMTA1
Epithelioid sarcoma	Inactivation INI1	INI1
Extraskeletal myxoid chondrosarcoma	t(9;22)(q22;q12), t(9:17)(q22;q11), t(9;15)(q22;q21), t(3;9)(q11;q22)	EWSR1/NR4A3,TAF2N/NR4A3,TCF12/NR4A3,TGF/NR4A3
Hemangiopericytoma	t(12;19)(q13;q13.3) and t(13;22)(q22;q13.3)
Inflammatory myofibroblastic tumor	t(1;2)(q23;q23), t(2;19)(q23;q13), t(2;17)(q23;q23), t(2;2)(p23;q13), t(2;11)(p23;p15)[34]	TPM3/ALK,TPM4/ALK,CLTC/ALK,RANBP2/ALK,CARS/ALK
Leiomyosarcoma	t(12;14)
Low-grade fibromyxoid sarcoma	t(7;16)(q33;p11), t(11;16)(p11;p11)	FUS/CREB3L2,FUS/CREB3L1
Malignant peripheral nerve sheath tumor	17q11.2, loss or rearrangement 10p, 11q, 17q, 22q	NF1
Myxoid/round cell liposarcoma	t(12;16)(q13;p11), t(12;22)(q13;q12)	FUS/DD1T3,EWSR/DD1T3
Rhabdoid tumor	Inactivation INI1	INI1
Synovial sarcoma	t(x;18)(p11.2;q11.2)	SYT/SSX
Tenosynovial giant cell tumor	t(1;2)(p13;q35)	CSF1

Prognosis

The prognosis of nonrhabdomyosarcomatous STS tumors varies greatly depending on the histologic grade, invasiveness, tumor size, resectability, use of radiation therapy, site of primary tumor, and presence of metastases.[35,36,37] Some pediatric nonrhabdomyosarcomatous STSs are associated with a better outcome. For instance, infantile fibrosarcoma, presenting in infants and children younger than 4 years, has an excellent prognosis given that the tumor is highly chemosensitive and surgery alone can cure a significant number of these patients.[5]

Soft tissue sarcomas in older children and adolescents often behave similarly to those in adult patients.[5,21]

Pediatric patients with unresected localized nonrhabdomyosarcomatous STSs have a poor outcome. Only about one-third of patients treated with multimodality therapy remain disease free.[35,38]; [39,40][Level of evidence: 3iiiA]

In a pooled analysis from U.S. and European pediatric centers, outcome was better for patients who received radiation therapy than for patients who did not, and outcome was better for patients whose tumor-removal procedure was deemed complete than for patients whose tumor removal was incomplete.[39][Level of evidence: 3iiiA]

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.[18,41,42,43,44,45]

Related Disease Summaries

Refer to the following PDQ summaries for information about other types of sarcoma:

• Childhood Rhabdomyosarcoma Treatment.
• Ewing Sarcoma Treatment (extraosseous Ewing, peripheral neuroepithelioma, and Askin tumors).
• Unusual Cancers of Childhood Treatment (gastrointestinal stromal tumors).
• Adult Soft Tissue Sarcoma Treatment.

References:

1.	Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2.	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.
3.	Pappo AS, Pratt CB: Soft tissue sarcomas in children. Cancer Treat Res 91: 205-22, 1997.
4.	Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed October 23, 2012.
5.	Okcu MF, Pappo AS, Hicks J, et al.: The nonrhabdomyosarcoma soft tissue sarcomas. In: Pizzo PA, Poplack DG: Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2010, pp 954-86.
6.	Weiss SW, Goldblum JR: General considerations. In: Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 5th ed. St. Louis, Mo: Mosby, 2008, pp 1-14.
7.	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.
8.	Herzog CE: Overview of sarcomas in the adolescent and young adult population. J Pediatr Hematol Oncol 27 (4): 215-8, 2005.
9.	Chang F, Syrjänen S, Syrjänen K: Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol 13 (4): 1009-22, 1995.
10.	Weiss SW, Goldblum JR: Benign tumors of peripheral nerves. In: Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 5th ed. St. Louis, Mo: Mosby, 2008, pp 825-901.
11.	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.
12.	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.
13.	Groen EJ, Roos A, Muntinghe FL, et al.: Extra-intestinal manifestations of familial adenomatous polyposis. Ann Surg Oncol 15 (9): 2439-50, 2008.
14.	Goto M, Miller RW, Ishikawa Y, et al.: Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev 5 (4): 239-46, 1996.
15.	Kleinerman RA, Tucker MA, Abramson DH, et al.: Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst 99 (1): 24-31, 2007.
16.	Weiss SW, Goldblum JR: Malignant fibrous histiocytoma (pleomorphic undifferentiated sarcoma). In: Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 5th ed. St. Louis, Mo: Mosby, 2008, pp 403-27.
17.	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.
18.	Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec.
19.	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.
20.	Weiss SW, Goldblum JR: Miscellaneous tumors of intermediate malignancy. In: Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 5th ed. St. Louis, Mo: Mosby, 2008, pp 1093-1160.
21.	Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, Mo: Mosby, 2001.
22.	Recommendations for the reporting of soft tissue sarcomas. Association of Directors of Anatomic and Surgical Pathology. Mod Pathol 11 (12): 1257-61, 1998.
23.	Chowdhury T, Barnacle A, Haque S, et al.: Ultrasound-guided core needle biopsy for the diagnosis of rhabdomyosarcoma in childhood. Pediatr Blood Cancer 53 (3): 356-60, 2009.
24.	Sandberg AA: Translocations in malignant tumors. Am J Pathol 159 (6): 1979-80, 2001.
25.	Slater O, Shipley J: Clinical relevance of molecular genetics to paediatric sarcomas. J Clin Pathol 60 (11): 1187-94, 2007.
26.	Mertens F, Antonescu CR, Hohenberger P, et al.: Translocation-related sarcomas. Semin Oncol 36 (4): 312-23, 2009.
27.	Romeo S, Dei Tos AP: Clinical application of molecular pathology in sarcomas. Curr Opin Oncol 23 (4): 379-84, 2011.
28.	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.
29.	Ladanyi M: The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol 4 (3): 162-73, 1995.
30.	Williams A, Bartle G, Sumathi VP, et al.: Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalin-fixed, paraffin-embedded tissue in a series of 18 cases of alveolar soft part sarcoma: useful diagnostic tools in cases with unusual histological features. Virchows Arch 458 (3): 291-300, 2011.
31.	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.
32.	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.
33.	Errani C, Zhang L, Sung YS, et al.: A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. Genes Chromosomes Cancer 50 (8): 644-53, 2011.
34.	Jain S, Xu R, Prieto VG, et al.: Molecular classification of soft tissue sarcomas and its clinical applications. Int J Clin Exp Pathol 3 (4): 416-28, 2010.
35.	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.
36.	Spunt SL, Poquette CA, Hurt YS, et al.: Prognostic factors for children and adolescents with surgically resected nonrhabdomyosarcoma soft tissue sarcoma: an analysis of 121 patients treated at St Jude Children's Research Hospital. J Clin Oncol 17 (12): 3697-705, 1999.
37.	Ferrari A, Casanova M, Collini P, et al.: Adult-type soft tissue sarcomas in pediatric-age patients: experience at the Istituto Nazionale Tumori in Milan. J Clin Oncol 23 (18): 4021-30, 2005.
38.	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.
39.	Ferrari A, Miceli R, Rey A, et al.: Non-metastatic unresected paediatric non-rhabdomyosarcoma soft tissue sarcomas: results of a pooled analysis from United States and European groups. Eur J Cancer 47 (5): 724-31, 2011.
40.	Smith KB, Indelicato DJ, Knapik JA, et al.: Definitive radiotherapy for unresectable pediatric and young adult nonrhabdomyosarcoma soft tissue sarcoma. Pediatr Blood Cancer 57 (2): 247-51, 2011.
41.	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.
42.	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.
43.	Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997.
44.	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.
45.	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.

Histopathological Classification

World Health Organization (WHO) Classification of Soft Tissue Sarcomas (STSs)

The WHO lists the following cell types in its classification of STSs:[1,2]

This summary focuses on high-grade sarcomas and low-grade tumors that present special problems in the pediatric and adolescent population, including desmoid tumor and infantile fibrosarcoma. For many low-grade STSs, surgical resection is curative and there is no need for additional therapy.

• Adipocytic tumors.
  • Liposarcoma—myxoid or well-differentiated.
• Chondro-osseous tumors.
  • Extraskeletal chondrosarcoma (mesenchymal and other variants).[3]
  • Extraskeletal osteosarcoma.
• Fibroblastic/myofibroblastic tumors.
  • Desmoid tumor (also called aggressive fibromatosis).^a
  • Fibrosarcoma.^b[4]
  • Inflammatory myofibroblastic tumor.^a
  • Low-grade fibromyxoid sarcoma.[5]
  • Myxofibrosarcoma, low grade.
  • Sclerosing epithelioid fibrosarcoma.
• Skeletal muscle tumors.
  • Rhabdomyosarcoma (embryonal, alveolar, and pleomorphic forms). (Refer to the Childhood Rhabdomyosarcoma Treatment summary for more information.)
• Smooth muscle tumors.
  • Leiomyosarcoma.
• So-called fibrohistiocytic tumors.
  • Plexiform fibrohistiocytic tumor.^a
  • Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (including pleomorphic, giant cell, myxoid/high-grade myxofibrosarcoma, and inflammatory forms).
• Tumors of peripheral nerves.
  • Malignant peripheral nerve sheath tumor.
• Tumors of uncertain differentiation.
  • Alveolar soft part sarcoma.
  • Clear cell sarcoma of soft tissue.
  • Desmoplastic small round cell tumor.[6]
  • Epithelioid sarcoma.
  • Extrarenal rhabdoid tumor.
  • Extraskeletal myxoid chondrosarcoma.
  • Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor.
  • Synovial sarcoma.
  • Undifferentiated sarcoma; sarcoma, not otherwise specified (NOS).[7]
• Vascular tumors.
  • Angiosarcoma, deep.^c
  • Epithelioid hemangioendothelioma.
  • Hemangiopericytoma (infantile).

^a Not a high-grade tumor; ^b The category of fibrosarcoma can be inclusive of fibrosarcomatous differentiation in dermatofibrosarcoma protuberans; ^c Cutaneous angiosarcoma may be difficult to stage using the American Joint Committee on Cancer system.

References:

1.	Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-6.
2.	Brodowicz T, Schwameis E, Widder J, et al.: Intensified Adjuvant IFADIC Chemotherapy for Adult Soft Tissue Sarcoma: A Prospective Randomized Feasibility Trial. Sarcoma 4 (4): 151-60, 2000.
3.	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.
4.	Steelman C, Katzenstein H, Parham D, et al.: Unusual presentation of congenital infantile fibrosarcoma in seven infants with molecular-genetic analysis. Fetal Pediatr Pathol 30 (5): 329-37, 2011.
5.	Evans HL: Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33 cases with long-term follow-up. Am J Surg Pathol 35 (10): 1450-62, 2011.
6.	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.
7.	Alaggio R, Collini P, Randall RL, et al.: Undifferentiated high-grade pleomorphic sarcomas in children: a clinicopathologic study of 10 cases and review of literature. Pediatr Dev Pathol 13 (3): 209-17, 2010 May-Jun.

Staging and Grading Systems for Childhood Soft Tissue Sarcoma

Clinical staging has an important role in predicting the clinical outcome and determining the most effective therapy for pediatric soft tissue sarcomas (STSs). As yet, there is no well-accepted staging system that is applicable to all childhood sarcomas. The system from the American Joint Committee on Cancer (AJCC) that is used for adults has not been validated in pediatric studies.

Although a standardized staging system for pediatric nonrhabdomyosarcomatous STS does not exist, the last Children's Oncology Group (COG) trial used the sixth edition AJCC cancer staging manual for STSs (with central pathology review) (see Tables 3–6 below).[1]

Two systems are currently in use for staging pediatric nonrhabdomyosarcomatous STS tumors.

• Surgico-pathologic staging system: The surgico-pathologic staging system used by the Intergroup Rhabdomyosarcoma Study (see below) is based on the amount, or extent, of tumor that remains after initial surgery and whether the disease has metastasized.[2]
• TNM staging system: The other system typically used to stage pediatric soft tissue tumors is the TNM system of the International Union Against Cancer. Staging is based on the extent of the tumor (T), the extent of spread to the lymph nodes (N), and the presence of metastasis (M).[3]

Intergroup Rhabdomyosarcoma Study Staging System

Nonmetastatic disease

• Group I: Localized tumor, completely resected with histologically negative margins.
• Group II: Grossly resected tumor with microscopic residual tumor at the margin(s) and/or extension into regional lymph nodes.
  • IIA: Localized, grossly resected tumor with microscopic residual disease.
  • IIB: Regional disease with involved nodes completely resected with no microscopic disease. The most proximal (to the patient, most distal to the tumor) regional lymph node must be negative.
  • IIC: Regional disease with involved nodes grossly resected but with evidence of residual microscopic disease at the primary site and/or histologic involvement of the most proximal regional lymph node in the dissection.
• Group III: Localized tumor, incompletely resected, or biopsy only, with gross residual tumor.

Metastatic disease

• Group IV: Any localized or regional tumor with distant metastases present at the time of diagnosis. This includes the presence of malignant cells in effusions (pleural, peritoneal) and/or cerebrospinal fluid (rare).

Recurrent/progressive disease

• Any STS that recurs after initial treatment or progresses after radiation therapy, chemotherapy, or initial surgery.

TNM Staging System

The AJCC has designated staging by the four criteria of tumor size, nodal status, histologic grade, and metastasis.[4]

Table 3. Primary Tumor (T)^a

a Reprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.
b Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia.
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
T1	Tumor ≤5 cm in greatest dimension.b
T1a	Superficial tumor.
T1b	Deep tumor.
T2	Tumor >5 cm in greatest dimension.b
T2a	Superficial tumor.
T2b	Deep tumor.

Table 4. Regional Lymph Nodes (N)^a

a Reprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.
b Presence of positive nodes (N1) in M0 tumors is considered Stage III.
NX	Regional lymph nodes cannot be assessed.
N0	No regional lymph node metastasis.
N1b	Regional lymph node metastasis.

Table 5. Distant Metastasis (M)^a

a Reprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.
M0	No distant metastasis.
M1	Distant metastasis.

Table 6. Anatomic Stage/Prognostic Groups^a

Stage	T	N	M	Grade
a Reprinted with permission from AJCC: Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-8.
IA	T1a	N0	M0	G1, GX
	T1b	N0	M0	G1, GX
IB	T2a	N0	M0	G1, GX
	T2b	N0	M0	G1, GX
IIA	T1a	N0	M0	G2, G3
	T1b	N0	M0	G2, G3
IIB	T2a	N0	M0	G2
	T2b	N0	M0	G2
III	T2a, T2b	N0	M0	G3
	Any T	N1	M0	Any G
IV	Any T	Any N	M1	Any G

Soft Tissue Sarcoma Tumor Pathological Grading System

In most cases, accurate histopathologic classification of STSs alone does not yield optimal information about their clinical behavior. Therefore, several histologic parameters, including degree of cellularity, cellular pleomorphism, mitotic activity, degree of necrosis, and invasive growth, are evaluated in the grading process. This process is used to improve the correlation between histologic findings and clinical outcome.[5] In children, grading of STSs is compromised by the good prognosis of certain tumors, such as infantile fibrosarcoma and hemangiopericytoma, which have a good prognosis in children younger than 4 years, and also angiomatoid fibrous histiocytoma and dermatosarcoma protuberans, which may recur locally if incompletely excised, but usually do not metastasize.

Testing a grading system within the pediatric population is difficult because of the rarity of these neoplasms. In March 1986, the Pediatric Oncology Group (POG) conducted a prospective study on pediatric STSs other than rhabdomyosarcoma and devised the grading system that is shown below. Analysis of outcome for patients with localized STSs other than rhabdomyosarcoma demonstrated that patients with grade 3 tumors fared significantly worse than those with grade 1 or grade 2 lesions. This finding suggests that this system can accurately predict the clinical behavior of nonrhabdomyosarcomatous STS.[5,6,7]

The grading systems developed by the POG and the French Federation of Comprehensive Cancer Centers (Fédération Nationale des Centres de Lutte Contre Le Cancer [FNCLCC]) Sarcoma Group are described below. These grading systems are being compared by the central review pathologists on the COG-ARST0332 study. The study has closed and results are pending.

POG grading system

The POG grading system is described below:[5]

Grade I

Grade I lesions are based on histologic type, well-differentiated cytohistologic features, and/or age of the patient.

• Liposarcoma–myxoid or well-differentiated.
• Well-differentiated or infantile (aged ≤4 years old) fibrosarcoma.
• Well-differentiated or infantile (aged ≤4 years old) hemangiopericytoma.
• Well-differentiated malignant peripheral nerve sheath tumor.
• Angiomatoid fibrous histiocytoma.
• Dermatofibrosarcoma protuberans.
• Myxoid chondrosarcoma.

Grade II

Grade II lesions are STSs not included in grade I or III by histologic diagnosis (with <5 mitoses/10 high-power fields or <15% necrosis):

• 15% or less of the surface area shows necrosis (primary criteria).
• The mitotic count is <5 mitotic figures per 10 high-power fields (40X objective) (primary criteria).
• Nuclear atypia is not marked (secondary criteria).
• The tumor is not markedly cellular (secondary criteria).

Grade III

Grade III lesions are similar to Grade II lesions and include certain tumors known to be clinically aggressive by virtue of histologic diagnosis and non-Grade I tumors (with >4 mitoses per 10 high-power fields or >15% necrosis):

• Pleomorphic or round-cell liposarcoma.
• Mesenchymal chondrosarcoma.
• Extraskeletal osteogenic sarcoma.
• Malignant triton tumor.
• Alveolar soft part sarcoma.
• Any other sarcoma not in grade I with >15% necrosis and/or ≤5 mitotic figures per 10 high-power fields (40X objective).

Any other sarcoma not included in grade I in which more than 15% of the surface area is necrotic or in which there are more than four mitotic figures per ten high-power fields (40X objective) is considered a grade III lesion. Marked atypia and cellularity are less predictive but may assist in placing tumors in this category.

FNCLCC grading system

The FNCLCC histologic grading system was developed for adults with STS. The purpose of the grading system is to predict which patients will develop metastasis and subsequently benefit from adjuvant chemotherapy.[8,9] The system is described in Tables 7 and 8.

Table 7. FNCLCC Histologic Grading System

FNCLCC = Fédération Nationale des Centres de Lutte Contre Le Cancer; HPF = high-power field.
Tumor Differentiation
Score 1	Sarcoma closely resembling normal adult mesenchymal tissue (e.g., well-differentiated liposarcoma)
Score 2	Sarcomas for which histologic typing is certain (e.g., myxoid liposarcoma)
Score 3	Embryonal and undifferentiated sarcomas, sarcomas of doubtful type, and synovial sarcomas
Mitotic Count
Score 1	0–9 mitoses per 10 HPF
Score 2	10–19 mitoses per 10 HPF
Score 3	≥20 mitoses per 10 HPF
Tumor Necrosis
Score 0	No necrosis
Score 1	<50% tumor necrosis
Score 2	≥50% tumor necrosis

Table 8. Histologic Grade Determined by Total Score

Total Score	Histologic Grade
2–3	Grade I
4–5	Grade II
6–8	Grade III

Prognostic Significance of Tumor Grading

The two grading systems described above have proven to be of prognostic value in pediatric and adult nonrhabdomyosarcomatous STSs.[10,11,12,13,14] In a study of 130 tumors from children and adolescents with nonrhabdomyosarcomatous STS enrolled in three prospective clinical trials, a correlation was found between the POG-assigned grade and the FNCLCC-assigned grade. However, grading did not correlate in all cases; 44 tumors received discrepant grades and their clinical outcome was intermediate between those who were assigned grades 1 and 2 or 3 in both systems. A mitotic index of 10 or greater emerged as an important prognostic factor.[15] The recently completed COG-ARST0332 trial will analyze data comparing the POG and FNCLCC pathologic grading systems to determine which system better correlates with clinical outcomes.

In a review of a large adult series of nonrhabdomyosarcomatous STSs, superficial extremity sarcomas had a better prognosis than deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.[16]

Several adult and pediatric series have shown that patients with large or invasive tumors have a significantly worse prognosis than do those with small, noninvasive tumors. A retrospective review of STSs in children and adolescents suggests that the 5 cm cutoff used for adults with STS may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and body surface area.[17] This relationship requires further study to determine the therapeutic implications of the observation.

References:

1.	American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002.
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.	Soft tissue sarcoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 291-6.
5.	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.
6.	Recommendations for the reporting of soft tissue sarcomas. Association of Directors of Anatomic and Surgical Pathology. Mod Pathol 11 (12): 1257-61, 1998.
7.	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.
8.	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.
9.	Guillou L, Coindre JM, Bonichon F, et al.: Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 15 (1): 350-62, 1997.
10.	Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec.
11.	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.
12.	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.
13.	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.
14.	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.
15.	Khoury JD, Coffin CM, Spunt SL, et al.: Grading of nonrhabdomyosarcoma soft tissue sarcoma in children and adolescents: a comparison of parameters used for the Fédération Nationale des Centers de Lutte Contre le Cancer and Pediatric Oncology Group Systems. Cancer 116 (9): 2266-74, 2010.
16.	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.
17.	Ferrari A, Miceli R, Meazza C, et al.: Soft tissue sarcomas of childhood and adolescence: the prognostic role of tumor size in relation to patient body size. J Clin Oncol 27 (3): 371-6, 2009.

Treatment Option Overview

Because of the rarity of pediatric nonrhabdomyosarcomatous soft tissue sarcomas (STSs), all children, adolescents, and young adults with these tumors should have their treatment coordinated by a multidisciplinary team comprising pediatric oncologists, pathologists, surgeons, and radiation oncologists. 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. Information about ongoing clinical trials is available from the NCI Web site.

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 STSs in the decision is highly desirable.

The timing of surgery depends on an assessment of the feasibility and morbidity of surgery. If the initial operation 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 is detected by magnetic resonance imaging after initial surgery.[6]; [7][Level of evidence: 3iiA]

Regional lymph node metastases at diagnosis are unusual and appear most likely with epithelioid and clear cell sarcomas.[8] Sentinel lymph node mapping is employed at some centers to identify the regional nodes that are the most likely to be involved, although its widespread contribution to the staging and management of these tumors has yet to be clearly defined.[9,10,11]

Radiation Therapy

Considerations for radiation therapy are based on the potential for surgery, with or without chemotherapy, to obtain local control without loss of critical organs, or significant functional, cosmetic or psychological impairment. This will vary according to patient variables, including age and gender, and tumor variables, including histopathology, site, size, and grade. Radiation therapy considerations include the same patient and tumor variables, surgical margin status, and expectations for radiation-induced morbidities such as impaired bone or muscle development, organ damage, or second malignancy. Radiation therapy can be given preoperatively or postoperatively, and the radiation field size and dose will again be based on patient and tumor variables and the operability of the tumor.

In general, radiation is indicated for patients with inadequate surgical margins and for larger, high-grade tumors.[12] This is particularly important in high-grade tumors with tumor margins smaller than 1 cm.[13,14]; [15][Level of evidence: 3iiDiv] With combined surgery and radiation therapy, local control of the primary tumor can be achieved in more than 80% of patients.[16,17] Preoperative radiation therapy has been associated with excellent local control rates.[18,19,20] This approach has the advantage of treating smaller tissue volumes because it does not necessitate treating a postsurgical bed; it also has the advantage of somewhat lower radiation doses because relative hypoxia from surgical disruption of vasculature and scarring is not present. Preoperative radiation therapy has been associated with an increased rate of wound complications in adults, primarily in lower extremity tumors, but the degree of this is questionable.[21] Conversely, preoperative radiation therapy may lead to less fibrosis than with postoperative approaches, perhaps due to the smaller treatment volume and dose.[22] Brachytherapy and intraoperative radiation may be applicable in select situations.[17,23,24]; [25][Level of evidence: 3iiiDii]

Retroperitoneal sarcomas are a special issue since radiosensitivity of the bowel to injury makes postoperative radiation therapy less desirable. Reasons for this include the postoperative adhesions and bowel immobility that increase the risk of damage from any given radiation dose. This is in contrast to the preoperative approach in which the tumor often displaces bowel outside of the radiation field, and any exposed bowel is more mobile, which decreases exposure to specific bowel segments.

Radiation volume and dose depend on all patient, tumor, and surgical variables as noted above. Considerations include patient age and growth potential, the ability to avoid critical organs, epiphyseal plates, and lymphatics (but not the neurovascular bundles that are relatively radiation tolerant), and the functional/cosmetic outcome. Radiation margins are typically 2 cm to 4 cm longitudinally, and encompassing fascial planes axially. Radiation doses are typically 45 Gy to 50 Gy preoperatively (with consideration for postoperative boost if resection margins are positive, or brachytherapy if the resection is predicted to be subtotal) or 55 Gy to 60 Gy postoperatively.

Chemotherapy

The role of adjuvant (postoperative) chemotherapy remains controversial.[26] A meta-analysis of updated data from adult STS patients from all available randomized trials concluded that recurrence-free survival was better with adjuvant chemotherapy for patients with high-grade tumors larger than 5cm.[27] The largest prospective pediatric trial failed to demonstrate any benefit with adjuvant vincristine, dactinomycin, cyclophosphamide, and doxorubicin.[16]

Special Treatment Considerations for Children With STS

Many therapeutic strategies for children and adolescents with soft tissue tumors are similar to those for adult patients, although 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.[28]

Improved outcomes with multimodality therapy in adults and children with STSs 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 nonrhabdomyosarcomatous STS. These patients should be enrolled in prospective studies that accurately assess any potential complications.[29]

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.	Daigeler A, Kuhnen C, Moritz R, et al.: Lymph node metastases in soft tissue sarcomas: a single center analysis of 1,597 patients. Langenbecks Arch Surg 394 (2): 321-9, 2009.
9.	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.
10.	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.
11.	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.
12.	Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997.
13.	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.
14.	Skytting B: Synovial sarcoma. A Scandinavian Sarcoma Group project. Acta Orthop Scand Suppl 291: 1-28, 2000.
15.	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.
16.	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.
17.	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.
18.	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.
19.	Virkus WW, Mollabashy A, Reith JD, et al.: Preoperative radiotherapy in the treatment of soft tissue sarcomas. Clin Orthop (397): 177-89, 2002.
20.	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.
21.	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.
22.	Davis AM, O'Sullivan B, Turcotte R, et al.: Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma. Radiother Oncol 75 (1): 48-53, 2005.
23.	Schomberg PJ, Gunderson LL, Moir CR, et al.: Intraoperative electron irradiation in the management of pediatric malignancies. Cancer 79 (11): 2251-6, 1997.
24.	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.
25.	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.
26.	Ferrari A: Role of chemotherapy in pediatric nonrhabdomyosarcoma soft-tissue sarcomas. Expert Rev Anticancer Ther 8 (6): 929-38, 2008.
27.	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.
28.	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.
29.	Okcu MF, Pappo AS, Hicks J, et al.: The nonrhabdomyosarcoma soft tissue sarcomas. In: Pizzo PA, Poplack DG: Principles and Practice of Pediatric Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2010, pp 954-86.

Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma

Adipocytic Tumors

Liposarcoma

Liposarcoma is rare in the pediatric population. In a review of 182 pediatric patients with adult-type sarcomas, only 14 had a diagnosis of liposarcoma.[1] One retrospective study identified 34 patients younger than 22 years from 1960 to 2011.[2] There were roughly equal numbers of male and female patients and the median age was 18 years. In an international clinicopathological review, the characteristics of 82 cases of pediatric liposarcoma were reported. The median age was 15.5 years and females were more commonly affected.[3] In both reports, the great majority of patients had myxoid liposarcoma.

Liposarcomas can be roughly divided into the following four large groups:

• Atypical lipomatous neoplasm/well-differentiated liposarcoma. These tumors do not metastasize unless they undergo dedifferentiation.
• Myxoid liposarcoma. Pure myxoid liposarcomas are characterized by a t(12;16)(q13;p11) translocation and can metastasize but usually have an excellent outcome in the absence of a round cell component.
• Dedifferentiated liposarcoma.
• Pleomorphic liposarcoma.

The great majority of liposarcomas in the pediatric and adolescent age range are low grade. Myxoid liposarcoma is typically low grade. Pleomorphic liposarcoma is typically high grade and much more likely to develop metastasis. Metastasis to lymph nodes is very uncommon, and the great majority of metastases are pulmonary. Tumors arising in the periphery are more likely to be low grade and myxoid. Tumors arising centrally are more likely to be high grade, pleomorphic, and present with metastasis or recur with metastasis.

Treatment

Surgery is the most important treatment for liposarcoma. After surgical resection of myxoid liposarcoma, event-free survival (EFS) and overall survival (OS) are roughly 90%. Local recurrences have been seen and are controlled with a second resection of the tumor. Higher grade or central tumors are associated with a significantly higher risk of death. In a retrospective review, 5-year survival for central tumors was 42%. In the international review, seven of ten patients with pleomorphic myxoid liposarcoma died because of their disease.[3] If initial surgery is incomplete, re-excision should be performed to achieve a wide margin of resection. There are reports of the use of chemotherapy to decrease the size of liposarcoma prior to surgery to facilitate complete resection, particularly in central tumors.[4,5] The role of adjuvant chemotherapy for liposarcoma is poorly defined. There does not appear to be a need for any adjuvant therapy for completely resected myxoid liposarcoma. Even with the use of adjuvant chemotherapy, the survival of pleomorphic liposarcoma remains poor.[6]

Chondro-osseous Tumors

Chondro-osseous tumors include the following tumor subtypes:

• Extraskeletal chondrosarcoma (mesenchymal and other variants).
• Extraskeletal osteosarcoma.

Extraskeletal chondrosarcoma (mesenchymal and other variants)

Mesenchymal chondrosarcoma is a highly malignant tumor with a propensity to spread to the lungs. A review of 15 patients younger than 26 years from the German Cooperative Soft Tissue Sarcoma Study Group (11 with soft-tissue lesions) and the 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.[7][Level of evidence: 3iiA]

Treatment

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.[8]

Extraskeletal osteosarcoma

Extraskeletal osteosarcoma is extremely rare in the pediatric and adolescent age range. A 2003 review identified only ten case reports in the medical literature.[9]

Extraskeletal osteosarcoma is associated with a high risk of local recurrence and pulmonary metastasis.[10]

Treatment

The primary therapy for extraskeletal osteosarcoma is surgical resection of the primary tumor. Chemotherapy for extraskeletal osteosarcoma has not been well studied. It has been recommended that the treatment for extraskeletal osteosarcoma abide by the soft tissue sarcoma (STS) guidelines, rather than the guidelines for osteosarcoma of bone.[9] A report of a series of adult patients with extraskeletal osteosarcoma suggested that adjuvant chemotherapy reduced the risk of recurrence.[10] Extraskeletal osteosarcoma may be more chemosensitive in young patients than in adults.[9] A retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraskeletal osteosarcoma treated with surgery and conventional osteosarcoma chemotherapy.[11] (Refer to the PDQ summary on Osteosarcoma/Malignant Fibrous Histiocytoma of Bone for more information.)

Fibroblastic/Myofibroblastic Tumors

Fibroblastic/myofibroblastic tumors include the following tumor subtypes:

• Desmoid tumor.^a
• Fibrosarcoma.
  • Infant fibrosarcoma.
  • Adult-type fibrosarcoma.
• Inflammatory myofibroblastic tumor.^a
• Low-grade fibromyxoid sarcoma.
• Sclerosing epithelioid fibrosarcoma.

^a Not a high-grade tumor.

Desmoid tumors

Desmoid tumors are also known as aggressive fibromatoses.

Desmoid tumors are low-grade malignancies with extremely 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.[12] 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.[13] Repeated surgical resection can sometimes bring recurrent lesions under control.[14]

Treatment

The treatment of choice is resection to achieve clear margins. If postoperative margins are positive, 70% of patients will have a recurrence of disease. Postoperative radiation therapy is a consideration when progression would entail additional surgery that might cause functional or cosmetic compromise and if radiation is considered acceptable in terms of morbidities. When the diagnosis is known and complete surgical excision is not feasible, and if the tumor poses significant potential for mortality or morbidity, preoperative strategies may include:[15,16]

• Chemotherapy.
• Antiestrogen therapy.
• Nonsteroidal anti-inflammatory agent therapy.
• Postoperative interstitial iridium-192.
• External-beam radiation therapy.

Evaluation of the benefit of interventions 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.[14,17] Combination chemotherapy using vinblastine and methotrexate produced objective responses in about one-third of patients with recurrent or unresectable desmoid tumors.[15] A small series of mainly adult patients (N = 19) with desmoid tumors were treated with imatinib mesylate and showed infrequent objective responses.[18] A series of mainly adult patients with familial adenomatous polyposis and 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.[19] Pegylated liposomal doxorubicin has also been used with some responses.[20]

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac have been used in single cases for desmoid tumors; the responses seen were usually disease stabilization. Similar results have been seen with antiestrogen treatment, usually tamoxifen. In some trials, these drugs were used in combination.[21]

Radiation has been used for unresectable desmoid tumors or adjuvantly for tumors with inadequate resections. The potential long-term complications of radiation therapy, especially subsequent neoplasms, makes use of this modality less appealing in a young population.[22]

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.[14,23,24,25,26] Whenever possible, however, the treatment of choice is complete resection.

Fibrosarcoma

There are two distinct types of fibrosarcoma in children and adolescents: infantile fibrosarcoma (also called congenital fibrosarcoma) and fibrosarcoma that is indistinguishable from fibrosarcoma seen in adults. These are two distinct pathologic diagnoses.

Infantile fibrosarcoma

Infantile fibrosarcoma usually occurs in children younger than 1 year. It occasionally occurs in children up to age 4 years. It usually presents with a rapidly growing mass, often noted at birth or even seen in prenatal ultrasound. The tumors are often quite large at the time of presentation. The tumor almost always has a characteristic cytogenetic translocation t(12;15)(ETV-NTRK3). Infantile fibrosarcoma shares this translocation and a virtually identical histologic appearance with mesoblastic nephroma. These tumors have a low incidence of metastases at diagnosis.

Treatment

Complete resection is curative in the majority of patients with infantile fibrosarcoma. However the large size of the lesion frequently makes resection without major functional consequences impossible (for instance, tumors of the extremities often require amputation for complete excision). Preoperative chemotherapy has made a more conservative surgical approach possible; agents active in this setting include vincristine, dactinomycin, cyclophosphamide, and ifosfamide.[27,28,29]; [30][Level of evidence: 3iiA]; [31][Level of evidence: 3iiB]

Adult-type fibrosarcoma

These tumors lack the translocation seen in infantile fibrosarcomas. They present like the great majority of nonrhabdomyosarcomas and the management approach is similar.

Dermatofibrosarcoma protuberans

Dermatofibrosarcoma is a rare tumor, but many of the reported cases arise in children.[32] The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGF-beta gene.

Treatment

Most dermatofibrosarcoma tumors can be cured by complete surgical resection. When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective.[33]

Inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumor is an incompletely characterized neoplasm of intermediate biologic potential. It recurs frequently but metastasizes rarely.[34,35] Roughly half of inflammatory myofibroblastic tumors exhibit a clonal mutation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase gene at chromosome 2p23.[36]

There are no well-documented responses to chemotherapy. A case report described a partial response in a patient with recurrent inflammatory myofibroblastic tumor who was treated with crizotinib, an ATP-competitive inhibitor of the ALK and MET tyrosine kinases.[37] There are case reports of response to either steroids or NSAIDs.[38,39]

Low-grade fibromyxoid sarcoma

Low-grade fibromyxoid sarcoma is somewhat misnamed, because its appearance is deceptively benign, but its behavior is malignant, although rather indolent.[40] In a review, 21 of 33 patients had local recurrences after intervals of up to 15 years (median, 3.5 years) and 15 had metastases, mostly in the lungs and pleura, after periods of up to 45 years (median, 5 years), indicating that follow-up must be lifelong.[40] Even after metastases occur, the course may be indolent.[41]

The limited treatment information for low-grade fibromyxoid sarcoma is summarized in the review above. This tumor is not very chemosensitive and there are little data regarding the use of chemotherapy and/or radiation therapy.

Myxofibrosarcoma, low grade

Myxofibrosarcoma, low grade, is a rare lesion, especially in childhood. It is typically treated with complete surgical resection.

Sclerosing epithelioid fibrosarcoma

Sclerosing epithelioid fibrosarcoma is another rare, usually low-grade, sarcoma. It is typically treated with complete surgical excision.

Skeletal Muscle Tumors

Rhabdomyosarcoma

There are three forms of rhabdomyosarcoma:

• Embryonal, plus subtypes of botryoid and spindle cells.
• Alveolar.
• Pleomorphic, also known as anaplastic sarcoma.

Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.

Smooth Muscle Tumors

Leiomyosarcoma

A 24-year retrospective analysis of the Italian cooperative group identified one child with leiomyosarcoma.[5] A retrospective analysis of the St. Jude Children's Research Hospital (SJCRH) experience from 1962 to 1996 identified 40 children with nonrhabdomyosarcomatous STS; none had leiomyosarcoma.[42] Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma.[43] Survivors of hereditary retinoblastoma have a statistically significant increased risk of developing leiomyosarcoma and 78% of these were diagnosed 30 or more years after the initial diagnosis of retinoblastoma.[44]

So-called Fibrohistiocytic Tumors

So-called fibrohistiocytic tumors include the following tumor subtypes:

• Plexiform fibrohistiocytic tumor.
• Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma.
  • Giant cell.
  • Inflammatory.
  • Myxoid/high-grade myxofibrosarcoma.
  • Pleomorphic.

Plexiform fibrohistiocytic tumor

Plexiform histiocytic tumor is a rare, low- to intermediate-grade tumor that most commonly affects children and young adults. Depending on the series, the median age at presentation ranges from 8 to 14.5 years; however, the tumor has been described in patients as young as 3 months.[45,46]

The tumor commonly arises as a painless mass in the skin or subcutaneous tissue and most often involves the upper extremities, including the fingers, hand, and wrist.[47,48,49] There are rare reports of spread to regional lymph nodes or the lungs.[45,49,50]

No consistent chromosomal anomalies have been detected but a t(4;15)(q21;q15) has been reported.[51]

Treatment

Surgery is the treatment of choice but local recurrence has been reported in 12% to 50% of cases.[52]

Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high-grade)

At one time, malignant fibrous histiocytoma was the single most common histiotype among adults with STSs. Since it was first recognized in the early 1960s, malignant fibrous histiocytoma 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 malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[53]

This entity accounts for 2% to 6% of all childhood STSs.[54] These tumors can arise in previously irradiated sites or as a second malignancy in patients with retinoblastoma.

These tumors occur mainly in the second decade of life. In a series of ten patients, the median age was 10 years and the tumor was most commonly located in the extremities. In this series, all tumors were localized and five of nine (for whom follow-up was available) were alive in first remission.[54] In another series of 17 pediatric patients with malignant fibrous histiocytoma, the median age at diagnosis was 5 years and the extremities were involved in eight cases.[55] All patients with metastatic disease died and two patients experienced a clinical response to a doxorubicin-based regimen.

Tumors of Peripheral Nerves

Malignant peripheral nerve sheath tumor (malignant schwannoma)

Malignant peripheral nerve sheath tumor arises in children with type 1 neurofibromatosis (NF1), and it arises sporadically.[56]

Features with favorable prognosis include the following:[56,56,57,58,59]

• Smaller tumor size—In a multivariate analysis, only tumor size and nuclear p53 expression were found to be independent predictors of disease-specific survival.[58]
• Localized disease; no metastasis at presentation—A retrospective review of 140 patients with malignant peripheral nerve sheath tumor from the MD Anderson Cancer Center included children and adolescents. The disease-specific survival at 10 years was 32%. In this series, presence of metastatic disease was associated with a much worse prognosis. For patients with localized disease, there was no significant difference in outcome between patients with and without NF1.[58]
• Lower stage.
• Lower histologic grade.
• Extremity as the primary site.

It is not clear whether the absence of NF1 is a favorable prognostic factor as it has been associated with both favorable [57] and unfavorable outcomes.[56,57,59]

Treatment

There is agreement that complete surgical removal of the tumor, whenever possible, is the mainstay of treatment. The role of radiation therapy is difficult to assess, but durable local control of known postsurgical microscopic residual tumor is not assured after radiation therapy. Chemotherapy has achieved objective responses in childhood malignant peripheral nerve sheath tumor. A large retrospective analysis of the German and Italian experience with malignant peripheral nerve sheath tumor reported that 65% of measurable tumors had objective responses to ifosfamide-containing chemotherapy regimens, but the analysis did not conclusively demonstrate improved survival for chemotherapy.[56] This retrospective analysis also noted a trend toward improved outcome with adjuvant radiation therapy.[56] A series of 37 young patients with malignant peripheral nerve sheath tumor and 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%.[60] The role of adjuvant chemotherapy following resection of malignant peripheral nerve sheath tumor has not been prospectively evaluated.

Tumors of Uncertain Differentiation

Tumors of uncertain differentiation include the following tumor subtypes:

• Alveolar soft part sarcoma.
• Clear cell sarcoma of soft tissue.
• Desmoplastic small round cell tumor.
• Epithelioid sarcoma.
• Extrarenal rhabdoid tumor.
• Extraskeletal myxoid chondrosarcoma.
• Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor.
• Synovial sarcoma.
• Undifferentiated sarcoma; sarcoma, not otherwise specified (NOS).

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.[61,62] In children, alveolar soft part sarcoma often presents with metastases [63] and sometimes has a very indolent course. 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 alveolar soft part sarcoma.[64]

Pediatric alveolar soft part sarcoma seems to have a better outcome than its adult counterpart.[65] In a series of 19 treated patients, one group reported a 5-year 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.[66] In another series of 33 patients, OS was 68% at 5 years from diagnosis and 53% at 10 years from diagnosis. Survival was better for smaller tumors (≤5 cm) and completely resected tumors.[67][Level of evidence: 3iiA]

Treatment

The standard approach is complete resection of the primary lesion.[66] If complete excision is not feasible, radiation therapy should be administered.

The value of adjuvant chemotherapy in completely resected alveolar soft part sarcoma remains unproven, particularly because patients with unresected or metastatic tumors failed to respond to chemotherapeutic agents frequently used to treat STSs.[68] Alveolar soft part sarcoma is considered a chemoresistant tumor.[69] There are sporadic reports of objective responses to interferon-alpha, bevacizumab, and sunitinib.[70,71,72,73]

Patients with alveolar soft part sarcoma may relapse several years after a prolonged period of apparent remission.[74] Because these tumors are rare, all children with alveolar soft part sarcoma should be considered for prospective clinical trials.

Treatment options under clinical evaluation for alveolar soft part sarcoma

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• NCT00942877 (Phase II Study of Cediranib in Patients With Alveolar Soft Part Sarcoma): This phase II study of cediranib in patients with alveolar soft part sarcoma is being conducted at the Clinical Center of the National Institutes of Health. Patients aged 18 years and older are eligible to participate.

Clear cell sarcoma of soft tissue

Clear cell sarcoma (formerly and inappropriately called 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.[75] In one series, clear cell sarcoma demonstrated a propensity to metastasize to regional lymph nodes (12%–43%).[76]

Patients who have small, localized tumors with low mitotic rate and intermediate histologic grade fare best.[77]

The primary treatment for clear cell sarcoma is complete surgical resection, with the addition of radiation therapy for uncertain or involved margins. Chemotherapy is rarely effective.[78]

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.[79,80,81] The tumor occurs more commonly 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.[82]

Treatment

There is no standard approach to the treatment of desmoplastic small round cell tumor. Complete surgical resections are rare, and the overall prognosis for desmoplastic small round cell tumor remains extremely poor, with reported rates of death at 90%. A small series of patients who were treated with hyperthermic intraperitoneal chemotherapy with acceptable toxicity has been reported.[83]

Greater than 90% tumor resection either at presentation or after neoadjuvant chemotherapy may be a favorable prognostic factor for overall survival.[84,85] Treatment may include chemotherapy, surgery, and radiation therapy. Multiagent chemotherapy analogous to that used for sarcomas has been used, as well as total abdominal radiation therapy.[79,80,84,86,87]

Epithelioid sarcoma

Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis which displays multilineage differentiation.[88] It is characterized by inactivation of the SMARC/INI1 gene, which is present in both conventional and proximal types of epithelioid sarcoma.[89]

Epithelioid sarcoma commonly presents as a slowly 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.

In a review of 30 pediatric patients with epithelioid sarcoma (median age at presentation, 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.[90]

Perivascular epitheloid cell tumors (PEComas)

PEComas (tumors showing perivascular epithelioid cell differentiation) include the following:

• Angiomyolipoma.
• Lymphangioleiomyomatosis.
• Clear cell "sugar" tumor.

Benign PEComas are common in tuberous sclerosis, an autosomal dominant syndrome that also predisposes to renal cell cancer and brain tumors. Tuberous sclerosis is caused by germline inactivation of either TSC1 (9q34) or TSC2 (16p13.3), and the same tumor suppressor genes are inactivated somatically in sporadic PEComas.[91] Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable PEComas with mTOR inhibitors.[92,93]

PEComas occur in various rare gastrointestinal, pulmonary, gynecologic, and genitourinary sites. Soft tissue, visceral, and gynecologic PEComas are more commonly seen in middle-aged female patients and are usually not associated with the tuberous sclerosis complex.[94] Most PEComas have a benign clinical course, but malignant behavior has been reported and can be predicted based on the size of the tumor, mitotic rate, and presence of necrosis.[95]

Extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma is relatively rare among STSs, representing only 2.3% of all STSs.[96] It has been reported in children and adolescents.[97]

Extraskeletal myxoid chondrosarcoma is a multinodular neoplasm. The rounded cells are arranged in cords and strands in a chondroitin sulfate myxoid background. Several cytogenetic abnormalities have been identified (see Table 2), with the most frequent being the translocation t(9;22)(q22;q12), involving the EWSR1/NR4A3 genes.[98] The tumor has traditionally been considered of low-grade malignant potential.[99] However, recent reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are followed for a long time.[100,101] Patients tend to have slow protracted courses. Nodal involvement has been well described. Local recurrence (57%) and metastatic spread to lungs (26%) have been reported.[101]

Treatment

The therapeutic benefit of chemotherapy has not been established. Aggressive local control and aggressive resection of metastases led to OS of 87% at 5 years and 63% at 10 years.[100] There may be potential genetic targets for small molecules, but these should be studied as part of a clinical trial.

Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor

(Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)

Synovial sarcoma

Synovial sarcoma is one of the most common nonrhabdomyosarcomatous STSs in children and adolescents. In a Surveillance Epidemiology and End Results review from 1973 to 2005, 1,268 patients with synovial sarcoma were identified. Approximately 17% of these patients were children and adolescents and the median age at diagnosis was 34 years.[102] The most common location is the extremities, followed by trunk and head and neck.[102] Patients younger than 10 years have more favorable outcomes and clinical features, including extremity primaries, smaller tumors, and localized disease, than do older patients.[102]

Synovial sarcoma can be subclassified as the following types:

• Monophasic fibrous type.
• Biphasic type with distinct epithelial and spindle cell components.
• Poorly differentiated. Poorly differentiated synovial sarcoma has features of monophasic or biphasic synovial sarcoma but also has a variable proportion of poorly differentiated areas characterized by high cellularity, pleomorphism, and polygonal or small round-cell morphology, numerous mitoses, and often necrosis.[103]

The 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.[104,105] It is thought that the SYT/SSX18 transcript promotes epigenetic silencing of key tumor suppressor genes.[106]

The most common site of metastasis is the lung.[107,108] The risk of metastases is highly influenced by tumor size; it is estimated that patients with tumors that measure greater than 5 cm have a 32-fold risk of developing metastases when compared with other patients.

In a retrospective analysis of synovial sarcoma in children and adolescents who were treated in Germany and Italy, tumor size (>5 cm or ≤5 cm in greatest dimension) was an important predictor of EFS.[109] In this analysis, local invasiveness conferred an inferior probability of EFS, but surgical margins were not associated with clinical outcome. A multicenter analysis of 219 children from various treating centers including Germany, SJCRH, Instituto Tumori, and MD Anderson Cancer Center reported an estimated 5-year OS of 80% and EFS rate of 72%. In this analysis, an interaction between tumor size and invasiveness was observed; in multivariate analysis, patients with large or invasive tumors or with Intergroup Rhabdomyosarcoma Study (IRS) Clinical Group III and IV disease had decreased OS. Treatment with radiation therapy was related to improved OS (hazard ratio, 0.4; 95% confidence interval, 0.2–0.7). In IRS Group III patients, objective response to chemotherapy (18 of 30 [60%]) correlated with improved survival. In adults, factors such as International Union Against Cancer/American Joint Committee on Cancer stage III and stage IVA, tumor necrosis, truncal location, elevated mitotic rate, age, and histologic grade have been associated with a worse prognosis.[110,111,112]

Treatment

Synovial sarcoma appears to be more sensitive to chemotherapy than many other STSs, and children with synovial sarcoma seem to have a better prognosis when compared with adults.[5,108,112,113,114,115,116,117,118] The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[116,119,120] Response rates to the ifosfamide and doxorubicin regimen are higher than in other nonrhabdomyosarcomatous STSs.[121] A meta-analysis also suggested that response to chemotherapy was correlated with improved survival.[120]

Several treatment centers advocate adjuvant chemotherapy following resection and radiation therapy of synovial sarcoma in children and young adults.[109,117,120,122,123,124] The International Society of Pediatric Oncology-Malignant Mesenchymal Tumors studies showed that patients with nonmetastatic synovial sarcoma can have excellent outcome in the absence of radiation, but it is still unclear whether or not that obviates an advantage of radiation for local or regional control.[123] A German trial suggested a benefit for adjuvant chemotherapy in children with synovial sarcoma.[124] A meta-analysis also suggested that chemotherapy may provide benefit.[120] However, unequivocal proof of the value of adjuvant chemotherapy from prospective, randomized clinical trials is lacking and the results of COG-ARST0332 are pending. Survival following relapse is poor (30% at 5 years). Factors associated with outcome after relapse include duration of first remission (> or ≤ 18 months) and lack of a second remission.[125]

Undifferentiated sarcoma; sarcoma, NOS

Patients with undifferentiated STS had been eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group (COG) from 1972 to 2006. The rationale was the observation that patients with undifferentiated STS had similar sites of disease and outcome as those with alveolar rhabdomyosarcoma. Therapeutic trials for adults with STS include patients with undifferentiated STS and other histologies, which are treated similarly, using ifosfamide and doxorubicin, and sometimes with other chemotherapy agents, surgery, and radiation therapy. Currently in the COG, they are treated on clinical trials for patients with nonrhabdomyosarcomatous STSs.

Vascular Tumors

Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant.[126] Vascular tumors include the following tumor subtypes:

• Angiosarcoma (deep).
• Epithelioid hemangioendothelioma.
• Hemangiopericytoma (infantile).

Angiosarcoma (deep)

Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients in response to local or systemic therapy.[127,128,129,130] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.[130]

A review of 20 years of experience in the Italian and German Soft Tissue Sarcoma Cooperative Group identified 12 children with angiosarcoma.[129] One objective response to chemotherapy was observed, and the overall behavior of this tumor was identical to angiosarcoma in adults. A subsequent retrospective study of 14 children with angiosarcoma performed by the Polish and German Cooperative Paediatric Soft Tissue Sarcoma Study Groups identified four chemotherapy responses in ten children.[131] Another review of 15 patients demonstrated a 33% survival rate.[132]

Anti-angiogenesis therapy may prove useful in the treatment of this group of neoplasms.[133]

Epithelioid hemangioendothelioma

Hemangioendotheliomas are tumors found in infants that arise within the liver or elsewhere and usually remain benign.[134,135] The tumors are sometimes associated with consumptive coagulopathy, also known as the Kasabach-Merritt syndrome (or phenomenon).[136,137,138]; [139][Level of evidence: 3iiiDiv] Chemotherapy and interferon have had some benefit in isolated cases.[137,138] 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 to be of intermediate malignant potential, between benign hemangioma and angiosarcoma.[140,141] In more extensive hemangioendothelioma, inhibition of mTOR pathway may be helpful.[142] However, this should be investigated as part of a clinical trial before use in the clinical setting.

Treatment of asymptomatic liver hemangioendothelioma in a child younger than 1 year may include close observation, because some tumors will regress. Symptomatic lesions require urgent medical or surgical management, especially if coagulopathy is present.[134,136,137,138] 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.[140]

Hemangiopericytoma (infantile)

Hemangiopericytoma is a highly vascularized tumor of uncertain origin. Hemangiopericytoma in children younger than 1 year seems to have a better prognosis than in children older than 1 year.[143,144,145] Histologically, hemangiopericytomas are composed of packed round or fusiform cells that are arranged around a complex vasculature, forming many branch-like structures. Hyalinization is often present. Infantile hemangiopericytomas have similar histology but many are multilobular with vasculature outside the tumor mass.[146]

In a series of 17 children, the differences in metastatic potential and response to treatment were clearly demonstrated for adult and infantile hemangiopericytomas.[29] Eleven children were older than 1 year. Several of these patients had disease in the lymph nodes or lungs. Six patients with stage II and III disease progressed and died. Three patients with stage I disease survived, although one had recurrence in the lungs. Six patients had infantile hemangiopericytoma, most were greater than stage I (5 of 6). All six survived and three had good responses to vincristine, actinomycin, and cyclophosphamide.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with nonmetastatic childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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Treatment of Metastatic Childhood Soft Tissue Sarcoma

Standard treatment options for metastatic childhood soft tissue sarcoma (STS) include the following:

• Combination therapy using chemotherapy, radiation therapy, and surgical resection of pulmonary metastases.

The prognosis for children with metastatic STSs 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]

Pulmonary Metastases

Children with isolated pulmonary metastases should undergo a surgical procedure in an attempt to resect all gross disease. For patients with multiple or recurrent pulmonary metastases, additional surgical procedures can be performed if the morbidity is deemed acceptable. An alternative approach is focused radiation therapy (fractionated stereotactic radiation therapy), which has been successfully used in adults to sterilize lesions. The estimated 5-year survival rate after thoracotomy for pulmonary metastasectomy has ranged from 10% to 58% in adult studies. Emerging data suggest a similar outcome following the use of focused radiation therapy in adults.[9] Formal segmentectomy, lobectomy, and mediastinal lymph node dissection are unnecessary.[10]

Treatment Options Under Clinical Evaluation

The following agents are being studied for the treatment of certain metastatic STSs:

Table 9. Agents With Selective Activity Against Subtypes of Soft Tissue Tumors

Agent	Soft Tissue Sarcoma Subtype
Sunitinib[11,12]	Alveolar soft part sarcoma
Sunitinib[13]	Solitary fibrous tumor
Sirolimus[14]	Perivascular epitheloid cell tumor (PEComa)
Crizotinib[15]	Inflammatory myofibroblastic tumor
Imatinib	Tenosynovial giant cell tumor
Imatinib[16]	Chordoma

The Children's Oncology Group COG-ARST0332 trial entered 552 eligible patients younger than 30 years with localized and metastatic nonrhabdomyosarcoma STSs from 2007 until 2012. The study is now closed and awaits analysis as the first risk-based treatment program for nonrhabdomyosarcoma STS in this age group.

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• NCT00942877 (Phase II Study of Cediranib [AZD2171] in Patients With Alveolar Soft Part Sarcoma): This study is designed for individuals aged 18 years and older who have been diagnosed with alveolar soft part sarcoma. AZD2171 blocks the creation of new blood vessels. Patients will take AZD2171 orally once a day, every day, for the duration of the study. The treatment will be given in 28-day cycles.
• COG-ADVL0921 (MLN8237 in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia): This phase II study is evaluating the side effects and efficacy of MN8237, an aurora A kinase inhibitor. Patients receive oral MN8237 once daily on days 1 to 7. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
• COG-ADVL1221 (Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma): This phase II study is investigating the efficacy and toxicity of cixutumumab and temsirolimus given in combination. Patients receive cixutumumab intravenously over 1 hour and temsirolimus intravenously over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with metastatic childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

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10.	Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995.
11.	Stacchiotti S, Negri T, Zaffaroni N, et al.: Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. Ann Oncol 22 (7): 1682-90, 2011.
12.	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.
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14.	Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al.: Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol 28 (5): 835-40, 2010.
15.	Butrynski JE, D'Adamo DR, Hornick JL, et al.: Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 363 (18): 1727-33, 2010.
16.	Stacchiotti S, Longhi A, Ferraresi V, et al.: Phase II study of imatinib in advanced chordoma. J Clin Oncol 30 (9): 914-20, 2012.

Treatment of Progressive / Recurrent Childhood Soft Tissue Sarcoma

With the possible exception of infants with infantile fibrosarcoma, the prognosis for patients with recurrent or progressive disease is poor. No prospective trial has been able to prove that enhanced local control of pediatric soft tissue sarcomas (STSs) 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.

Decisions about treatment options for progressive or recurrent childhood STS 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).
• Gemcitabine and docetaxel.[1]
• Trabectedin.[2,3,4]
• A clinical trial of new chemotherapeutic regimens.

Resection is the standard treatment for recurrent pediatric nonrhabdomyosarcomatous STSs. 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.

Pulmonary metastasectomy may achieve prolonged disease control for some patients.[5] A large, retrospective analysis of patients with recurrent STS showed that isolated local relapse had a better prognosis and that resection of pulmonary metastases improved the probability of survival.[6] All patients with recurrent tumors should be considered for current clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Maki RG, Wathen JK, Patel SR, et al.: Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 25 (19): 2755-63, 2007.
2.	Cesne AL, Cresta S, Maki RG, et al.: A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas. Eur J Cancer 48 (16): 3036-44, 2012.
3.	Garcia-Carbonero R, Supko JG, Maki RG, et al.: Ecteinascidin-743 (ET-743) for chemotherapy-naive patients with advanced soft tissue sarcomas: multicenter phase II and pharmacokinetic study. J Clin Oncol 23 (24): 5484-92, 2005.
4.	Garcia-Carbonero R, Supko JG, Manola J, et al.: Phase II and pharmacokinetic study of ecteinascidin 743 in patients with progressive sarcomas of soft tissues refractory to chemotherapy. J Clin Oncol 22 (8): 1480-90, 2004.
5.	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.
6.	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.

Changes to This Summary (10 / 23 / 2012)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood soft tissue sarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Soft Tissue Sarcoma Treatment are:

• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Holcombe Edwin Grier, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Michael P. LaQuaglia, MD (Memorial Sloan-Kettering Cancer Center)
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• R. Beverly Raney, MD (Consultant)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Soft Tissue Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/child-soft-tissue-sarcoma/HealthProfessional. Accessed <MM/DD/YYYY>.

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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.

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Last Revised: 2012-10-23