Childhood Soft Tissue Sarcoma Treatment (PDQ®)–Health Professional Version

General Information About Childhood Soft Tissue Sarcoma

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1] Childhood and adolescent cancer survivors require close monitoring 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.)

Rhabdomyosarcoma, a tumor of striated muscle, is the most common soft tissue sarcoma in children aged 0 to 14 years and accounts for 50% of tumors in this age group.[2] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.) In pediatrics, the remaining soft tissue sarcomas are commonly referred to as nonrhabdomyosarcomatous soft tissue sarcomas and account for approximately 3% of all childhood tumors.[3] This heterogeneous group of tumors includes the following neoplasms:[4]

  • Connective tissue (e.g., desmoid-type fibromatosis).
  • Peripheral nervous system (e.g., malignant peripheral nerve sheath tumor).
  • Smooth muscle (e.g., leiomyosarcoma).
  • Vascular tissue (blood and lymphatic vessels, e.g., angiosarcoma). (Refer to the PDQ summary on Childhood Vascular Tumors Treatment for more information about childhood vascular tumors.)

Distribution of Soft Tissue Sarcoma by Age and Histology

Pediatric soft tissue sarcomas are a heterogenous group of malignant tumors that originate from primitive mesenchymal tissue and account for 7% of all childhood tumors (rhabdomyosarcomas, 4%; other soft tissue sarcomas, 3%).[5]

The distribution of soft tissue sarcomas by histology and age, on the basis of the Surveillance, Epidemiology, and End Results (SEER) information from 2000 to 2015, is depicted in Table 1. The distribution of histologic subtypes by age is also shown in Figure 2.

Table 1. Age Distribution of Soft Tissue Sarcomas in Children Aged 0 to 19 Years (SEER 2000–2015)a
  Age <5 y Age 5–9 y Age 10–14 y Age 15–19 y Age <20 y All Ages (Including Adults)
pPNET = peripheral primitive neuroectodermal tumors; SEER = Surveillance, Epidemiology, and End Results.
aSource: SEER database.[6]
All soft tissue and other extraosseous sarcomas 1,124 773 1,201 1,558 4,656 80,269
 
Rhabdomyosarcomas 668 417 382 327 1,794 3,284
Fibrosarcomas, peripheral nerve, and other fibrous neoplasms 137 64 112 181 494 6,645
  Fibroblastic and myofibroblastic tumors 114 33 41 77 265   4,228
  Nerve sheath tumors 23 31 70 102 226   2,303
  Other fibromatous neoplasms 0 0 1 2 3   114
Kaposi sarcoma 2 1 2 10 15 7,722
Other specified soft tissue sarcomas 237 238 559 865 1,899 49,004
  Ewing tumor and Askin tumor of soft tissue 37 36 72 113 258   596
  pPNET of soft tissue 24 23 42 56 145   402
  Extrarenal rhabdoid tumor 75 8 9 4 96   205
  Liposarcomas 4 6 37 79 126   10,749
  Fibrohistiocytic tumors 43 73 142 223 481   13,531
  Leiomyosarcomas 11 14 19 41 85   14,107
  Synovial sarcomas 12 39 141 210 402   2,608
  Blood vessel tumors 12 9 11 32 64   4,238
  Osseous and chondromatous neoplasms of soft tissue 1 6 16 14 37   1,018
  Alveolar soft parts sarcoma 4 5 22 33 64   211
  Miscellaneous soft tissue sarcomas 14 19 48 60 141   1,339
Unspecified soft tissue sarcomas 80 53 146 175 454 13,614

Nonrhabdomyosarcomatous soft tissue sarcomas are more common in adolescents and adults,[4] and most of the information regarding treatment and natural history of the disease in younger patients has been based on adult studies. The distributions of these tumors by age according to stage, histologic subtype, and tumor site are shown in Figures 1, 2, and 3, respectively.[7]

EnlargeChart showing the distribution of nonrhabdomyosarcomatous soft tissue sarcomas by age according to stage.
Figure 1. The distribution of nonrhabdomyosarcomatous soft tissue sarcomas by age according to stage.
EnlargeChart showing the distribution of nonrhabdomyosarcomatous soft tissue sarcomas by age according to histologic subtype.
Figure 2. The distribution of nonrhabdomyosarcomatous soft tissue sarcomas by age according to histologic subtype.
EnlargeChart showing the distribution of nonrhabdomyosarcomatous soft tissue sarcomas by age according to tumor site.
Figure 3. The distribution of nonrhabdomyosarcomatous soft tissue sarcomas by age according to tumor site.

Risk Factors

Some genetic factors and external exposures have been associated with the development of nonrhabdomyosarcomatous soft tissue sarcoma, including the following:

  • Genetic factors:
    • Li-Fraumeni syndrome: Patients with Li-Fraumeni syndrome (usually due to heritable cancer-associated changes of the TP53 tumor suppressor gene) have an increased risk of developing soft tissue tumors (mostly nonrhabdomyosarcomatous soft tissue sarcomas), bone sarcomas, breast cancer, brain tumors, and acute leukemia.[8,9]
    • Familial adenomatous polyposis: Patients with familial adenomatous polyposis are at increased risk of developing desmoid-type fibromatosis.[10]
    • Retinoblastoma (RB1) gene: Germline mutations of the retinoblastoma gene have been associated with an increased risk of developing soft tissue sarcomas, particularly leiomyosarcoma, and the risk appears higher among those younger than 1 year who were treated with alkylating agents.[11,12]
    • SMARCB1 gene: Germline mutations or deletions of the SMARCB1 (INI1) gene are associated with an increased risk of developing extrarenal rhabdoid tumors.[13]
    • 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.[14-16]
    • Werner syndrome: Werner syndrome is characterized by spontaneous chromosomal instability, resulting in increased susceptibility to cancer and premature aging. An excess of soft tissue sarcomas has been reported in patients with Werner syndrome.[17]
    • Tuberous sclerosis complex: Tuberous sclerosis complex is associated with the development of various tumors showing perivascular epithelioid cell differentiation (PEComas), including lymphangioleiomyomatosis and hepatic and renal angiomyolipomas.[18-20]
    • Adenosine deaminase-deficient severe combined immunodeficiency: Patients with adenosine deaminase-deficient severe combined immunodeficiency have been reported to be at increased risk of developing multicentric dermatofibrosarcoma protuberans, which usually presents at an average age of 8.9 years.[21]
  • External exposures:
    • Radiation: Some nonrhabdomyosarcomatous soft tissue sarcomas (particularly malignant fibrous histiocytoma) can develop within a previously irradiated site.[3,22-25]
    • Epstein-Barr virus infection in patients with AIDS: Some nonrhabdomyosarcomatous soft tissue sarcomas (e.g., leiomyosarcoma) have been linked to Epstein-Barr virus infection in patients with AIDS.[3,26]

Clinical Presentation

Although nonrhabdomyosarcomatous soft tissue sarcomas can develop in any part of the body, they arise most commonly in the trunk and extremities.[27-29] These neoplasms can present initially as an asymptomatic solid mass, or they may be symptomatic because of local invasion of adjacent anatomical structures. Although rare, these tumors can arise primarily in brain tissue and are treated according to the histotype.[30]

Systemic symptoms (e.g., fever, weight loss, and night sweats) are rare. Hypoglycemia and hypophosphatemic rickets have been reported in cases of hemangiopericytoma (now identified as a solitary fibrous tumor in the revised World Health Organization classification system), whereas hyperglycemia has been noted in patients with fibrosarcoma of the lung.[31]

Diagnostic and Staging Evaluation

When a suspicious lesion is identified, it is crucial that a complete workup, followed by adequate biopsy be performed. It is best to image the lesion using the following procedures before initiating any intervention:

  • Plain films. Plain films can be used to rule out bone involvement and detect calcifications that may be seen in soft tissue tumors such as extraskeletal osteosarcoma or synovial sarcoma.
  • Chest computed tomography (CT). Chest CT is essential to assess the presence of metastases.
  • Abdominal CT or magnetic resonance imaging (MRI). Abdominal CT or MRI can be used to image intra-abdominal tumors, such as liposarcoma.
  • Extremity MRI. MRI is essential for extremity lesions.
  • Positron emission tomography (PET) scan and bone scan. In children with rhabdomyosarcoma, PET-CT performed better than conventional imaging in identifying nodal, bone, bone marrow, and soft tissue disease. The authors of an imaging comparison study suggested that bone scans with technetium Tc 99m might be eliminated as a staging procedure.[32] In a retrospective study, 46 PET scans were completed in 25 pediatric patients with soft tissue sarcoma.[33] The positive predictive value of finding metastatic disease was 89%, and the negative predictive value was 67%. The use of this modality in pediatric nonrhabdomyosarcomatous soft tissue sarcoma has not been studied prospectively. A small study of nine patients with nonrhabdomyosarcomatous soft tissue sarcoma suggested that PET-CT was more accurate and cost-effective than either modality alone in identifying distant metastatic disease.[34]

The imaging characteristics of some tumors can be highly suggestive of this diagnosis. For example, the imaging characteristics of pediatric low-grade fibromyxoid sarcoma and alveolar soft part sarcoma have been described and can aid in the diagnosis of these rare neoplasms.[35]

Biopsy strategies

Although nonrhabdomyosarcomatous soft tissue tumors are fairly readily distinguished pathologically from rhabdomyosarcoma and Ewing sarcoma, the classification of childhood nonrhabdomyosarcomatous soft tissue sarcoma type is often difficult. Core-needle biopsy, incisional biopsy, or excisional biopsy can be used to diagnose a nonrhabdomyosarcomatous soft tissue sarcoma. If possible, the surgeon who will perform the definitive resection needs to be involved in the biopsy decision. Poorly placed incisional or needle biopsies may adversely affect the ability to achieve negative margins.

Considerations related to the selection of a biopsy procedure are as follows:

  • Given the diagnostic importance of translocations and other molecular changes, 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.[36,37] Core-needle biopsy for a deep-seated tumor can lead to formation of a hematoma, which affects subsequent resection and/or radiation. Of 530 suspected soft tissue masses (largely in adult patients) that underwent core-needle biopsies, one biopsy set was adequate for diagnosis in 93% of patients; the complication rate was only 0.4%.[38]
  • Fine-needle biopsy is usually not recommended because it is difficult to determine the accurate histologic diagnosis and grade of the tumor in this heterogeneous group of tumors.
  • Image guidance using ultrasound, CT scan, or MRI may be necessary to ensure a representative biopsy.[39] Image guidance is particularly helpful in deep lesions and to avoid cystic changes or necrotic tumors.[40]
  • Needle biopsy techniques must ensure adequate tissue sampling. The acquisition of multiple cores of tissue may be required.
  • Incisional biopsies must not compromise subsequent wide local excision.
  • Excisional biopsy of the lesion is only appropriate for small superficial lesions (<3 cm in size) and are discouraged.[41,42] If an excisional biopsy is contemplated, then MRI of the area is recommended to define the area of involvement as subsequent surgery or radiation therapy is likely.
  • Various institutional series have demonstrated the feasibility and effectiveness of sentinel node biopsy as a staging procedure in pediatric patients with soft tissue sarcomas.[43-48]
  • Transverse extremity incisions are avoided to reduce skin loss at re-excision and because they require a greater cross-sectional volume of tissue to be covered in the radiation field. Other extensive surgical procedures are also avoided before 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 crucial studies to be performed and to avoid limiting future treatment options.

Unplanned resection

In children with unplanned resection of nonrhabdomyosarcomatous soft tissue sarcomas, primary re-excision is frequently recommended because many patients will have tumor present in the re-excision specimen.[49,50] A single-institution analysis of adolescents and adults compared patients with unplanned excision of soft tissue sarcoma to stage-matched controls. In this retrospective analysis, unplanned initial excision of soft tissue sarcoma resulted in increased risk of local recurrence, metastasis, and death; this increase was greatest for high-grade tumors.[51][Level of evidence: 3iiA] In this case, a second resection is expected.

Chromosomal abnormalities

Many nonrhabdomyosarcomatous soft tissue sarcomas 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 Soft Tissue Sarcomaa
Histology Chromosomal Aberrations Genes Involved
aAdapted from Sandberg,[52] Slater et al.,[53] Mertens et al.,[54] and Romeo.[55]
Alveolar soft part sarcoma t(x;17)(p11.2;q25) ASPL/TFE3 [56-58]
Angiomatoid fibrous histiocytoma t(12;16)(q13;p11), t(2;22)(q33;q12), t(12;22)(q13;q12) FUS/ATF1, EWSR1/CREB1,[59] EWSR1/ATF1
BCOR-rearranged sarcomas inv (X)(p11.4;p11.2) BCOR/CCNB3
CIC-rearranged sarcomas t(4;19)(q35;q13), t(10;19)(q26;q13) CIC-DUX4
Clear cell sarcoma t(12;22)(q13;q12), t(2;22)(q33;q12) ATF1/EWSR1, EWSR1/CREB1 [60]
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 CTNNB1 or APC mutations
Desmoplastic small round cell tumors t(11;22)(p13;q12) EWSR1/WT1 [61,62]
Epithelioid hemangioendothelioma t(1;3)(p36;q25) [63] WWTR1/CAMTA1
Epithelioid sarcoma Inactivation SMARCB1 SMARCB1
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) LMNA-NTRK1 [64]
Infantile fibrosarcoma t(12;15)(p13;q25) ETV6/NTRK3
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) [65] TPM3/ALK, TPM4/ALK, CLTC/ALK, RANBP2/ALK, CARS/ALK, RAS
Infantile myofibromatosis   PDGFRB [66]
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
Mesenchymal chondrosarcoma Del(8)(q13.3q21.1) HEY1/NCOA2
Myoepithelioma t(19;22)(q13;q12), t(1;22)(q23;q12), t(6;22)(p21;q12) EWSR1/ZNF44, EWSR1/PBX1, EWSR1/POU5F1
Myxoid/round cell liposarcoma t(12;16)(q13;p11), t(12;22)(q13;q12) FUS/DD1T3, EWSR1/DD1T3
Primitive myxoid mesenchymal tumor of infancy   BCOR internal tandem duplications
Rhabdoid tumor Inactivation SMARCB1 SMARCB1
Sclerosing epithelioid fibrosarcoma   EWSR1/CREB3L2
Solitary fibrous tumor Inv(12)(q13q13) NAB2/STAT6
Synovial sarcoma t(x;18)(p11.2;q11.2) SYT/SSX
Tenosynovial giant cell tumor t(1;2)(p13;q35) COL6A3/CSF1

Prognosis

The prognosis of nonrhabdomyosarcomatous soft tissue sarcoma varies greatly depending on the following factors:[67-69]

  • Site of the primary tumor.
  • Tumor size.
  • Tumor grade. (Refer to the Prognostic Significance of Tumor Grading section of this summary for more information.)
  • Tumor histology.
  • Depth of tumor invasion.
  • Presence of metastases.
  • Resectability of the tumor.
  • Use of radiation therapy.

Several adult and pediatric series have shown that patients with large or invasive tumors have a significantly worse prognosis than do those with small, noninvasive tumors. A retrospective review of soft tissue sarcomas in children and adolescents suggests that the 5 cm cutoff used for adults with soft tissue sarcoma may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and body surface area.[70] This relationship requires further study to determine the therapeutic implications of the observation.

In a review of a large adult series of nonrhabdomyosarcomatous soft tissue sarcomas, superficial extremity sarcomas had a better prognosis than did deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.[71]

Some pediatric nonrhabdomyosarcomatous soft tissue sarcomas are associated with a better outcome. For instance, infantile fibrosarcoma, presenting in infants and children younger than 5 years, has an excellent prognosis given that surgery alone can cure a significant number of these patients and the tumor is highly chemosensitive.[3]

Soft tissue sarcomas in older children and adolescents often behave similarly to those in adult patients.[3,72] A large, prospective, multinational Children's Oncology Group study (ARST0332 [NCT00346164]) enrolled newly diagnosed patients younger than 30 years. Patients were assigned to treatment on the basis of their risk group (refer to Figure 4).[73][Level of evidence: 2A]

Enlarge Chart showing risk stratification and treatment assignment for the Children's Oncology Group ARST0332 trial.
Figure 4. Risk stratification and treatment assignment for the Children's Oncology Group ARST0332 trial. Credit: Sheri L. Spunt, M.D., M.B.A.

  1. Arm A (grossly excised low-grade tumor and ≤5 cm widely excised high-grade tumor): Surgery only.
  2. Arm B (≤5 cm marginally resected high-grade tumor): 55.8 Gy of radiation therapy.
  3. Arm C (>5 cm grossly resected tumor ± metastases): Ifosfamide/doxorubicin chemotherapy and 55.8 Gy of radiation therapy.
  4. Arm D (>5 cm unresected tumor ± metastases): Preoperative ifosfamide/doxorubicin chemotherapy and 45 Gy of radiation therapy, and then surgery and a radiation boost that was based on margins.

Of 551 patients enrolled, at a median follow-up of 2.6 years, the preliminary analysis estimated the following 3-year survival rates:[73]

  • Arm A: 91% event-free survival (EFS); 99% overall survival (OS).
  • Arm B: 79% EFS; 100% OS.
  • Arm C: 68% EFS; 81% OS.
  • Arm D: 52% EFS; 66% OS.

Pediatric patients with unresected localized nonrhabdomyosarcomatous soft tissue sarcomas have a poor outcome. Only about one-third of patients treated with multimodality therapy remain disease free.[67,74]; [75,76][Level of evidence: 3iiiA] In a review of 30 Italian patients with nonrhabdomyosarcomatous soft tissue sarcoma at visceral sites, only ten patients survived at 5 years. Unfavorable prognostic factors included inability to achieve complete resection, large tumor size, tumor invasion, histologic subtype, and lung-pleura sites.[77][Level of evidence: 3iiB]

In a pooled analysis from U.S. and European pediatric centers, outcome was better for patients whose tumor removal procedure was deemed complete than for patients whose tumor removal was incomplete. Outcome was better for patients who received radiation therapy than for patients who did not.[75][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.[28,78-82]

Related Summaries

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

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  45. 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. [PUBMED Abstract]
  46. Dall'Igna P, De Corti F, Alaggio R, et al.: Sentinel node biopsy in pediatric patients: the experience in a single institution. Eur J Pediatr Surg 24 (6): 482-7, 2014. [PUBMED Abstract]
  47. Parida L, Morrisson GT, Shammas A, et al.: Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int 28 (6): 571-8, 2012. [PUBMED Abstract]
  48. Alcorn KM, Deans KJ, Congeni A, et al.: Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging. J Pediatr Surg 48 (9): 1903-6, 2013. [PUBMED Abstract]
  49. 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. [PUBMED Abstract]
  50. 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. [PUBMED Abstract]
  51. Qureshi YA, Huddy JR, Miller JD, et al.: Unplanned excision of soft tissue sarcoma results in increased rates of local recurrence despite full further oncological treatment. Ann Surg Oncol 19 (3): 871-7, 2012. [PUBMED Abstract]
  52. Sandberg AA: Translocations in malignant tumors. Am J Pathol 159 (6): 1979-80, 2001. [PUBMED Abstract]
  53. Slater O, Shipley J: Clinical relevance of molecular genetics to paediatric sarcomas. J Clin Pathol 60 (11): 1187-94, 2007. [PUBMED Abstract]
  54. Mertens F, Antonescu CR, Hohenberger P, et al.: Translocation-related sarcomas. Semin Oncol 36 (4): 312-23, 2009. [PUBMED Abstract]
  55. Romeo S, Dei Tos AP: Clinical application of molecular pathology in sarcomas. Curr Opin Oncol 23 (4): 379-84, 2011. [PUBMED Abstract]
  56. 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. [PUBMED Abstract]
  57. Ladanyi M: The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol 4 (3): 162-73, 1995. [PUBMED Abstract]
  58. 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. [PUBMED Abstract]
  59. 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. [PUBMED Abstract]
  60. Hisaoka M, Ishida T, Kuo TT, et al.: Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol 32 (3): 452-60, 2008. [PUBMED Abstract]
  61. 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. [PUBMED Abstract]
  62. Wang LL, Perlman EJ, Vujanic GM, et al.: Desmoplastic small round cell tumor of the kidney in childhood. Am J Surg Pathol 31 (4): 576-84, 2007. [PUBMED Abstract]
  63. 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. [PUBMED Abstract]
  64. Haller F, Knopf J, Ackermann A, et al.: Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern. J Pathol 238 (5): 700-10, 2016. [PUBMED Abstract]
  65. 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. [PUBMED Abstract]
  66. Agaimy A, Bieg M, Michal M, et al.: Recurrent Somatic PDGFRB Mutations in Sporadic Infantile/Solitary Adult Myofibromas But Not in Angioleiomyomas and Myopericytomas. Am J Surg Pathol 41 (2): 195-203, 2017. [PUBMED Abstract]
  67. 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. [PUBMED Abstract]
  68. 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. [PUBMED Abstract]
  69. 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. [PUBMED Abstract]
  70. 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. [PUBMED Abstract]
  71. 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. [PUBMED Abstract]
  72. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, Mo: Mosby, 2001.
  73. Spunt SL, Million L, Anderson JR, et al.: Risk-based treatment for nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) in patients under 30 years of age: Children’s Oncology Group study ARST0332. [Abstract] J Clin Oncol 32 (Suppl 15): A-10008, 2014. Also available online. Last accessed November 20, 2018.
  74. 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. [PUBMED Abstract]
  75. 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. [PUBMED Abstract]
  76. 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. [PUBMED Abstract]
  77. Ferrari A, Magni C, Bergamaschi L, et al.: Pediatric nonrhabdomyosarcoma soft tissue sarcomas arising at visceral sites. Pediatr Blood Cancer 64 (9): , 2017. [PUBMED Abstract]
  78. 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. [PUBMED Abstract]
  79. 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. [PUBMED Abstract]
  80. Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997. [PUBMED Abstract]
  81. 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. [PUBMED Abstract]
  82. 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. [PUBMED Abstract]

Histopathological Classification of Childhood Soft Tissue Sarcoma

World Health Organization (WHO) Classification of Soft Tissue Sarcomas

The WHO classification system for cancer represents the common nomenclature for cancer worldwide. In the United States, it has been adopted by the American Joint Committee on Cancer (AJCC) for sarcoma staging and the College of American Pathologists (CAP) cancer protocols for bone and soft tissue sarcomas. The fourth edition of the WHO Classification of Tumors of Soft Tissue and Bone was published in February 2013.[1]

The grading of soft tissue tumors has always been a controversial issue. While the WHO does not strictly state a preference in grading systems, one of the major modifications made to the WHO classification was the designation of two distinct types of intermediate malignancy in terms of biological potential—locally aggressive and rarely metastasizing.[1]

The WHO acknowledged the poorly defined nature of malignant fibrous histiocytoma (also known as undifferentiated pleomorphic sarcoma) and hemangiopericytoma (now considered within the spectrum of solitary fibrous tumors).[1]

With the current advances in molecular and genetic studies, a subset of tumors has been moved into new sections, including angiomatoid malignant fibrous histiocytoma and extraskeletal myxoid chondrosarcoma, which were previously classified as tumors of uncertain differentiation. Multiple entities were newly recognized, and a few entities belonging to tumors of skin were also added to this book. A few entities that were found to most likely represent morphologic variants of other tumors were deleted from the current classification and subsumed into other sections.[1]

  1. Adipocytic tumors.
    1. Benign.
      • Lipoma.
      • Lipomatosis.
      • Lipomatosis of nerve.
      • Lipoblastoma/lipoblastomatosis.
      • Angiolipoma.
      • Myolipoma.
      • Chondroid lipoma.
      • Extra-renal angiomyolipoma.
      • Extra-adrenal myelolipoma.
      • Spindle cell/pleomorphic lipoma.
      • Hibernoma.
    2. Intermediate (locally aggressive).
    3. Malignant.
  2. Chondro-osseous tumors.
  3. Fibroblastic/myofibroblastic tumors.
    1. Benign.
      • Nodular fasciitis.
      • Proliferative fasciitis.
      • Proliferative myositis.
      • Myositis ossifficans.
      • Fibro-osseous pseudotumor of digits.
      • Ischemic fasciitis.
      • Elastofibroma.
      • Fibrous hamartoma of infancy.
      • Fibromatosis colli.
      • Juvenile hyaline fibromatosis.
      • Inclusion body fibromatosis.
      • Fibroma of tendon sheath.
      • Desmoplastic fibroblastoma.
      • Mammary-type myofibroblastoma.
      • Calcifying aponeurotic fibroma.
      • Angiomyofibroblastoma.
      • Cellular angiofibroma.
      • Nuchal-type fibroma.
      • Gardner fibroma.
      • Calcifying fibrous tumor.
    2. Intermediate (locally aggressive).
      • Palmar/plantar fibromatosis.
      • Desmoid-type fibromatosis (previously called desmoid tumor or aggressive fibromatoses).
      • Lipofibromatosis.
      • Giant cell fibroblastoma.
    3. Intermediate (rarely metastasizing).
    4. Malignant.
  4. Skeletal muscle tumors.
  5. Smooth muscle tumors.
    1. Benign.
      • Deep leiomyoma.
    2. Malignant.

      Angioleiomyoma was reclassified under perivascular tumors.

  6. So-called fibrohistiocytic tumors.
    1. Benign.
      • Tenosynovial giant cell tumor.
        • Localized type.
        • Diffuse type.
        • Malignant.
      • Deep benign fibrous histiocytoma.
    2. Intermediate (rarely metastasizing).

      The malignant counterpart of so-called fibrohistiocytic tumors, formerly known as malignant fibrous histiocytoma and its subtypes was renamed undifferentiated sarcoma and previously classified under the undifferentiated/unclassified sarcomas section.

  7. Nerve sheath tumors.
    1. Benign.
      • Schwannoma (including variants).
      • Melanotic schwannoma.
      • Neurofibroma (including variants).
        • Plexiform neurofibroma.
      • Perineurioma.
        • Malignant perineurioma.
      • Granular cell tumor.
      • Dermal nerve sheath myxoma.
      • Solitary circumscribed neuroma.
      • Ectopic meningioma.
      • Nasal glial heterotopia.
      • Benign Triton tumor.
      • Hybrid nerve sheath tumors.
    2. Malignant.
  8. Pericytic (perivascular) tumors.
    • Glomus tumor (and variants).
      • Glomangiomatosis.
      • Malignant glomus tumor.
    • Myopericytoma.
    • Angioleiomyoma.
  9. Tumors of uncertain differentiation.
    1. Benign.
      • Acral fibromyxoma.
      • Intramuscular myxoma (including cellular variant).
      • Juxta-articular myxoma.
      • Deep (aggressive) angiomyxoma.
      • Pleomorphic hyalinizing angiectatic tumor.
      • Ectopic hamartomatous thymoma.
    2. Intermediate (locally aggressive).
      • Hemosiderotic fibrolipomatous tumor.
    3. Intermediate (rarely metastasizing).
      • Atypical fibroxanthoma.
      • Angiomatoid fibrous histiocytoma.
      • Ossifying fibromyxoid tumor.
        • Ossifying fibromyxoid tumor, malignant.
      • Mixed tumor NOS.
      • Mixed tumor NOS, malignant.
      • Myoepithelioma.
      • Myoepithelial carcinoma.
      • Phosphaturic mesenchymal tumor, benign.
      • Phosphaturic mesenchymal tumor, malignant.
    4. Malignant.
  10. Undifferentiated/unclassified sarcomas.

    Genetic subgroups are emerging within this family and this work is ongoing:

    • Undifferentiated round cell and spindle cell sarcoma.

      In this group, EWSR1 is involved in non-ETS fusions with genes such as PATZ1, POU5F1, SMARCA5, NFATC2, or SP3. Another recurrent rearrangement involves the CIC-DUX4 fusion gene resulting in the chimeric CIC-DUX4 protein, which upregulates genes of the PEA3 subclass of ETS family. (Refer to the Genomics of Ewing Sarcoma section of the PDQ summary on Ewing Sarcoma Treatment for more information.)

      It is unclear whether these cases represent one or more separate entities, or whether they are better classified as variants of Ewing sarcoma.

    • Undifferentiated pleomorphic sarcoma.

      Undifferentiated pleomorphic sarcoma was most often called malignant fibrous histiocytoma in the past. Historically, this entity has been difficult to evaluate because of the shifting diagnostic criteria. Analysis of 70 cases diagnosed as malignant fibrous histiocytosis of no specific type, storiform or pleomorphic malignant fibrous histiocytoma, pleomorphic sarcoma or undifferentiated pleomorphic sarcoma showed highly complex karyotype with no specific recurrent aberrations. Undifferentiated sarcomas with 12q13–15 amplification, including MDM2 and CDK4, are best classified as dedifferentiated liposarcomas. The relationship between this tumor and the family of undifferentiated/unclassified tumors with spindle cell morphology remains relatively undefined and is somewhat problematic in application at a practical level.

  11. Vascular tumors.
    1. Benign.
      • Hemangioma. (Refer to the PDQ summary on Childhood Vascular Tumors Treatment for more information.)
        • Synovial.
        • Venous.
        • Arteriovenous haemangioma/malformation.
        • Intramuscular.
      • Epithelioid hemangioma.
      • Angiomatosis.
      • Lymphangioma.
    2. Intermediate (locally aggressive).
    3. Intermediate (rarely metastasizing).
    4. Malignant.
References
  1. Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013.
  2. 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. [PUBMED Abstract]
  3. 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. [PUBMED Abstract]
  4. 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. [PUBMED Abstract]
  5. 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. [PUBMED Abstract]

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. 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 soft tissue sarcoma does not exist, two systems are currently in use for staging pediatric nonrhabdomyosarcomatous soft tissue sarcoma.[1]

  • Surgico-pathologic staging system: The surgico-pathologic staging system used by the Intergroup Rhabdomyosarcoma Study is based on the amount, or extent, of tumor that remains after initial surgery and whether the disease has metastasized (refer to the Intergroup Rhabdomyosarcoma Study Staging System section of this summary for more information). This staging system was used in early pediatric trials.[2]
  • TNM staging system: The TNM staging system is a collaborative effort between the AJCC (United States) and the International Union Against Cancer (worldwide). 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). Refer to Tables 3, 4, 5, and 6 for the staging of soft tissue sarcoma from the eighth edition of the AJCC Cancer Staging Manual.[3-7] The last Children's Oncology Group (COG) trial used the sixth edition AJCC Cancer Staging Manual for soft tissue sarcoma (with central pathology review).[1] A review of children with non-rhabdomyosarcoma soft tissue sarcomas was performed with data from the Surveillance, Epidemiology, and End Results (SEER) program and identified 941 patients between 1988 and 2007.[8] The COG risk stratification was validated in this cohort.

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 soft tissue sarcoma that recurs after initial treatment or progresses after radiation therapy, chemotherapy, or initial surgery.

TNM Staging System

The eighth edition of the AJCC Cancer Staging Manual has designated staging by the four criteria of tumor size, nodal status, histologic grade, and metastasis and by anatomic primary tumor site (head and neck; trunk and extremities; abdomen and thoracic visceral organs; retroperitoneum; and unusual histologies and sites) (refer to Tables 3, 4, 5, and 6).[3-7] For information on unusual histologies and sites, refer to the AJCC Cancer Staging Manual.[7]

Table 3. Definition of Primary Tumor (T) for Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneum; Head and Neck; and Abdomen and Thoracic Visceral Organsa
T Category Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneum Soft Tissue Sarcoma of the Head and Neck Soft Tissue Sarcoma of the Abdomen and Thoracic Visceral Organs
aAdapted from O'Sullivan et al.,[3] Yoon et al.,[4] Raut et al.,[5] and Pollock et al.[6]
TX Primary tumor cannot be assessed. Primary tumor cannot be assessed. Primary tumor cannot be assessed.
T0 No evidence of primary tumor.    
T1 Tumor ≤5 cm in greatest dimension. Tumor ≤2 cm. Organ confined.
T2 Tumor >5 cm and ≤10 cm in greatest dimension. Tumor >2 to ≤4 cm. Tumor extension into tissue beyond organ.
T2a     Invades serosa or visceral peritoneum.
T2b     Extension beyond serosa (mesentery).
T3 Tumor >10 cm and ≤15 cm in greatest dimension. Tumor >4 cm. Invades another organ.
T4 Tumor >15 cm in greatest dimension. Tumor with invasion of adjoining structures. Multifocal involvement.
T4a   Tumor with orbital invasion, skull base/dural invasion, invasion of central compartment viscera, involvement of facial skeleton, or invasion of pterygoid muscles. Multifocal (2 sites).
T4b   Tumor with brain parenchymal invasion, carotid artery encasement, prevertebral muscle invasion, or central nervous system involvement via perineural spread. Multifocal (3–5 sites).
T4c     Multifocal (>5 sites).
Table 4. Definition of Regional Lymph Node (N) for Soft Tissue Sarcoma of the Head and Neck; Trunk and Extremities; Abdomen and Thoracic Visceral Organs; and Retroperitoneuma
aAdapted from O'Sullivan et al.,[3] Yoon et al.,[4] Raut et al.,[5] and Pollock et al.[6]
bFor soft tissue sarcoma of the abdomen and thoracic visceral organs, N0 = no lymph node involvement or unknown lymph node status and N1 = lymph node involvement present.
N0 No regional lymph node metastasis or unknown lymph node status.b
N1 Regional lymph node metastasis.b
Table 5. Definition of Distant Metastasis (M) for Soft Tissue Sarcoma of the Head and Neck; Trunk and Extremities; Abdomen and Thoracic Visceral Organs; and Retroperitoneuma
aAdapted from O'Sullivan et al.,[3] Yoon et al.,[4] Raut et al.,[5] and Pollock et al.[6]
bFor soft tissue sarcoma of the abdomen and thoracic visceral organs, M0 = no metastases and M1 = metastases present.
M0 No distant metastasis.b
M1 Distant metastasis.b
Table 6. AJCC Prognostic Stage Groups for Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneuma
Stage T N M Grade
T = primary tumor; N = regional lymph node; M = distant metastasis.
aAdapted from Yoon et al. [4] and Pollock et al.[6]
bStage IIIB for soft tissue sarcoma of the retroperitoneum; stage IV for soft tissue sarcoma of the trunk and extremities.
IA T1 N0 M0 G1, GX
IB T2, T3, T4 N0 M0 G1, GX
II T1 N0 M0 G2, G3
IIIA T2 N0 M0 G2, G3
IIIB T3, T4 N0 M0 G2, G3
IIIB/IVb 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 alone of soft tissue sarcomas does not yield optimal information about their clinical behavior. Therefore, several histologic parameters are evaluated in the grading process, including the following:

  • Degree of cellularity.
  • Cellular pleomorphism.
  • Mitotic activity.
  • Degree of necrosis.
  • Invasive growth.

This process is used to improve the correlation between histologic findings and clinical outcome.[9] In children, grading of soft tissue sarcoma 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 dermatofibrosarcoma protuberans, which may recur locally if incompletely excised, but usually do not metastasize.

Testing the validity of 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 soft tissue sarcomas other than rhabdomyosarcoma and devised the POG grading system. Analysis of outcome for patients with localized soft tissue sarcomas 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 soft tissue sarcoma.[9-11]

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.[9] It is an older grading system of historical value that is no longer being used for treatment.

Grade I

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

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

Grade II lesions are soft tissue sarcomas 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):

  • Alveolar soft part sarcoma.
  • Extraskeletal osteogenic sarcoma.
  • Malignant Triton tumor.
  • Mesenchymal chondrosarcoma.
  • Pleomorphic or round-cell liposarcoma.
  • Any other sarcoma not in grade I with >15% necrosis and/or ≥5 mitotic figures per 10 high-power fields (40X objective). 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 soft tissue sarcoma. The purpose of the grading system is to predict which patients will develop metastasis and subsequently benefit from postoperative chemotherapy.[12,13] The system is described in Table 7 and Table 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 POG and FNCLCC grading systems have proven to be of prognostic value in pediatric and adult nonrhabdomyosarcomatous soft tissue sarcomas.[14-18] In a study of 130 tumors from children and adolescents with nonrhabdomyosarcomatous soft tissue sarcoma 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 patients whose tumors received discrepant grades (POG grade 3, FNCLCC grade 1 or 2) had outcomes between concurrent grade 3 and grades 1 and 2. A mitotic index of 10 or greater emerged as an important prognostic factor.[19] The completed COG-ARST0332 trial will analyze data comparing the POG and FNCLCC pathologic grading systems to determine which system better correlates with clinical outcomes. The closed COG trial (ARST1321 [NCT02180867]) used the FNCLCC system to assign histological grade.

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. [PUBMED Abstract]
  3. O'Sullivan B, Maki RG, Agulnik M, et al.: Soft tissue sarcoma of the head and neck. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 499-505.
  4. Yoon SS, Maki RG, Asare EA, et al.: Soft tissue sarcoma of the trunk and extremities. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 507-15.
  5. Raut CP, Maki RG, Baldini EH, et al.: Soft tissue sarcoma of the abdomen and thoracic visceral organs. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 517-21.
  6. Pollock RE, Maki RG, Baldini EH, et al.: Soft tissue sarcoma of the retroperitoneum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 531-7.
  7. Maki RG, Folpe AL, Guadagnolo BA, et al.: Soft tissue sarcoma - unusual histologies and sites. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 539-45.
  8. Waxweiler TV, Rusthoven CG, Proper MS, et al.: Non-Rhabdomyosarcoma Soft Tissue Sarcomas in Children: A Surveillance, Epidemiology, and End Results Analysis Validating COG Risk Stratifications. Int J Radiat Oncol Biol Phys 92 (2): 339-48, 2015. [PUBMED Abstract]
  9. 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. [PUBMED Abstract]
  10. Recommendations for the reporting of soft tissue sarcomas. Association of Directors of Anatomic and Surgical Pathology. Mod Pathol 11 (12): 1257-61, 1998. [PUBMED Abstract]
  11. 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. [PUBMED Abstract]
  12. 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. [PUBMED Abstract]
  13. 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. [PUBMED Abstract]
  14. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec. [PUBMED Abstract]
  15. 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. [PUBMED Abstract]
  16. 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. [PUBMED Abstract]
  17. Pappo AS, Fontanesi J, Luo X, et al.: Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience. J Clin Oncol 12 (11): 2360-6, 1994. [PUBMED Abstract]
  18. 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. [PUBMED Abstract]
  19. 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. [PUBMED Abstract]

Treatment Option Overview for Childhood Soft Tissue Sarcoma

Because of the rarity of pediatric nonrhabdomyosarcomatous soft tissue sarcomas, coordination of treatment by a multidisciplinary team comprising oncologists (pediatric or medical), pathologists, surgeons, and radiation oncologists should be considered for all children, adolescents, and young adults with these tumors. In addition, to better define the tumors' natural history and response to therapy, entry into national or institutional treatment protocols should be considered for children with rare neoplasms. Information about ongoing clinical trials is available from the NCI website.

Surgery

After an appropriate biopsy and pathologic diagnosis, every attempt is made to resect the primary tumor with negative margins before or after chemotherapy and/or radiation therapy. Involvement of a surgeon with special expertise in the resection of soft tissue sarcomas in the decision is highly desirable.

The timing of surgery depends on an assessment of the feasibility and morbidity of surgery. If the initial 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 is performed to obtain clear, but not necessarily wide, margins.[1-4] This surgical tenet is true even if no mass is detected by magnetic resonance imaging after initial surgery.[5]; [6][Level of evidence: 3iiA]

Regional lymph node metastases at diagnosis are unusual and are most often seen in patients with epithelioid and clear cell sarcomas.[7,8] Various institutional series have demonstrated the feasibility and effectiveness of sentinel node biopsy as a staging procedure in pediatric patients with soft tissue sarcomas.[9-14]

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 the following:

  • Patient variables (e.g., age and sex).
  • Tumor variables (e.g., histopathology, site, size, and grade).
  • Use of surgery and margin status.
  • Expectations for radiation-induced morbidities (e.g., impaired bone or muscle development, organ damage, or second malignancy).

Radiation therapy can be given preoperatively, postoperatively, or as definitive therapy in rare situations in which surgical resection is not performed.[15] Radiation field size and dose will be based on patient and tumor variables and the surgical procedure.[16]

Preoperative radiation therapy has been associated with excellent local control rates.[17-19] The advantages of this approach include treating smaller tissue volumes without the need to treat a postsurgical bed and 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; however, the degree of these complications is questionable.[20] Conversely, preoperative radiation therapy may lead to less fibrosis than with postoperative approaches, perhaps because of the smaller treatment volume and dose.[21] Radiation therapy was associated with improved overall survival (OS) compared with surgery alone when delivered preoperatively or postoperatively.[22]

Retroperitoneal sarcomas are unique in that radiosensitivity of the bowel to injury makes postoperative radiation therapy less desirable.[23,24] Postoperative adhesions and bowel immobility can increase the risk of damage from any given radiation dose. This contrasts with 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 therapy can also be given postoperatively. In general, radiation is indicated for patients with inadequate surgical margins and for larger, high-grade tumors.[25,26] This is particularly important in high-grade tumors with tumor margins smaller than 1 cm.[27,28]; [29][Level of evidence: 3iiDiv] With combined R0 (negative margin) surgery and radiation therapy, local control of the primary tumor can be achieved in about 90% of patients with extremity sarcomas, 70% to 75% of patients with retroperitoneal sarcomas, and 80% of patients overall.[30-34]

Brachytherapy and intraoperative radiation may be applicable in select situations.[31,35,36]; [37][Level of evidence: 3iiiDii]

Radiation volume and dose depend on the patient, tumor, and surgical variables noted above, as well as the following:

  • Patient age and growth potential.
  • Ability to avoid critical organs, epiphyseal plates, and lymphatics (but not the neurovascular bundles that are relatively radiation tolerant).
  • Functional/cosmetic outcome.

Radiation doses are typically 45 Gy to 50 Gy preoperatively, with consideration for postoperative boost of 10 Gy to 20 Gy if resection margins are microscopically or grossly positive, or planned brachytherapy if the resection is predicted to be subtotal. However, data documenting the efficacy of a postoperative boost are lacking.[38] The postoperative radiation dose is 55 Gy to 60 Gy for R0 resections, up to 65 Gy for R1 resections (microscopic positive margins), and higher when unresectable gross residual disease exists depending on overall treatment goals (e.g., definitive local control vs. palliation).

Radiation margins are typically 2 cm to 4 cm longitudinally and encompass fascial planes axially.[39,40]

Chemotherapy

The role of postoperative chemotherapy remains unclear.[41]

Evidence (lack of clarity regarding postoperative chemotherapy):

  1. A meta-analysis of data from all randomized trials of adults with soft tissue sarcoma concluded that recurrence-free survival was better with postoperative chemotherapy for patients with high-grade tumors larger than 5 cm.[42]
  2. In a European trial, adults with completely resected soft tissue sarcoma were randomly assigned to observation or postoperative chemotherapy with ifosfamide and doxorubicin.[43][Level of evidence: 1iiA]
    • Postoperative chemotherapy was not associated with improved event-free survival (EFS) or OS.
    • It is difficult to extrapolate this trial to pediatric patients because the trial included: 1) a wide variety of histologies; 2) a relatively low dose of ifosfamide; 3) patients assigned to chemotherapy had definitive radiation delayed until completion of chemotherapy; and 4) almost one-half of the patients in the trial had intermediate-grade tumors.
    • In the discussion section, the authors merged their patients with previously published series, including those from the European meta-analysis, and concluded that the results suggested a benefit for postoperative chemotherapy.
  3. The largest prospective pediatric trial failed to demonstrate any benefit with postoperative vincristine, dactinomycin, cyclophosphamide, and doxorubicin.[30]
  4. Doxorubicin and ifosfamide were used in the risk-based COG ARST0332 (NCT00346164) trial.[44][Level of evidence: 3iiiA]
    • Although this was not a randomized study, results at 2.6 years showed that patients with high-risk (>5 cm and high grade), grossly resected, nonmetastatic tumors who were treated with radiation therapy and postoperative doxorubicin and ifosfamide had a 3-year EFS of 68% and OS of 81%.
    • In patients with metastatic disease treated with preoperative chemotherapy and radiation therapy, the estimated 3-year failure-free survival was 52% and OS was 66%.

Targeted Therapy

The use of angiogenesis and mammalian target of rapamycin (mTOR) inhibitors has been explored in the treatment of adult soft tissue sarcomas but not in pediatrics.

Evidence (targeted therapy in adults with soft tissue sarcoma):

  1. In a trial of 711 randomly assigned adult patients who achieved a response or stable disease after chemotherapy, the administration of ridaforolimus was associated with a 3-week improvement in progression-free survival (PFS) when compared with placebo.[45]
  2. In another trial of 371 randomly assigned adult patients with metastatic soft tissue sarcoma that progressed after chemotherapy, pazopanib was compared with placebo.[46]
    • The median PFS for the pazopanib arm was 4.6 months compared with 1.6 months for the placebo arm. OS was not different between the two arms.
  3. In a randomized study of 182 previously treated adult patients with recurrent liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas, patients with nonadipocytic tumors who were treated with regorafenib had significant improvements in PFS when compared with patients who were treated with placebo.[47]

Special Considerations for the Treatment of Children With Soft Tissue Sarcoma

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[48] 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 following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgical specialists.
  • Pediatric radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.

(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.[49] 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. Multidisciplinary evaluation in pediatric cancer centers that have surgical and radiotherapeutic expertise is of critical importance to ensure the best clinical outcome for these patients. Although surgery with or without radiation therapy can be curative for a significant proportion of patients, the addition of chemotherapy might benefit subsets of children with the disease; therefore, enrollment into clinical trials is encouraged. 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 website.

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.[50]

Improved outcomes with multimodality therapy in adults and children with soft tissue sarcomas over the past 20 years has caused increasing concern about the potential long-term side effects of this therapy in children, especially when considering the expected longer life span of children versus adults. Therefore, to maximize tumor control and minimize long-term morbidity, treatment must be individualized for children and adolescents with nonrhabdomyosarcomatous soft tissue sarcoma. These patients should be enrolled in prospective studies that accurately assess any potential complications.[51]

References
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  2. 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. [PUBMED Abstract]
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  4. 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. [PUBMED Abstract]
  5. Kaste SC, Hill A, Conley L, et al.: Magnetic resonance imaging after incomplete resection of soft tissue sarcoma. Clin Orthop (397): 204-11, 2002. [PUBMED Abstract]
  6. 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. [PUBMED Abstract]
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  8. Mazeron JJ, Suit HD: Lymph nodes as sites of metastases from sarcomas of soft tissue. Cancer 60 (8): 1800-8, 1987. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  12. Dall'Igna P, De Corti F, Alaggio R, et al.: Sentinel node biopsy in pediatric patients: the experience in a single institution. Eur J Pediatr Surg 24 (6): 482-7, 2014. [PUBMED Abstract]
  13. Parida L, Morrisson GT, Shammas A, et al.: Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int 28 (6): 571-8, 2012. [PUBMED Abstract]
  14. Alcorn KM, Deans KJ, Congeni A, et al.: Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging. J Pediatr Surg 48 (9): 1903-6, 2013. [PUBMED Abstract]
  15. Haas RL, Gronchi A, van de Sande MAJ, et al.: Perioperative Management of Extremity Soft Tissue Sarcomas. J Clin Oncol 36 (2): 118-124, 2018. [PUBMED Abstract]
  16. Crompton JG, Ogura K, Bernthal NM, et al.: Local Control of Soft Tissue and Bone Sarcomas. J Clin Oncol 36 (2): 111-117, 2018. [PUBMED Abstract]
  17. Virkus WW, Mollabashy A, Reith JD, et al.: Preoperative radiotherapy in the treatment of soft tissue sarcomas. Clin Orthop (397): 177-89, 2002. [PUBMED Abstract]
  18. 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. [PUBMED Abstract]
  19. Dickie C, Parent A, Griffin AM, et al.: The value of adaptive preoperative radiotherapy in management of soft tissue sarcoma. Radiother Oncol 122 (3): 458-463, 2017. [PUBMED Abstract]
  20. 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. [PUBMED Abstract]
  21. 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. [PUBMED Abstract]
  22. Nussbaum DP, Rushing CN, Lane WO, et al.: Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score-matched analysis of a nationwide clinical oncology database. Lancet Oncol 17 (7): 966-975, 2016. [PUBMED Abstract]
  23. Baldini EH, Wang D, Haas RL, et al.: Treatment Guidelines for Preoperative Radiation Therapy for Retroperitoneal Sarcoma: Preliminary Consensus of an International Expert Panel. Int J Radiat Oncol Biol Phys 92 (3): 602-12, 2015. [PUBMED Abstract]
  24. Bishop AJ, Zagars GK, Torres KE, et al.: Combined Modality Management of Retroperitoneal Sarcomas: A Single-Institution Series of 121 Patients. Int J Radiat Oncol Biol Phys 93 (1): 158-65, 2015. [PUBMED Abstract]
  25. Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997. [PUBMED Abstract]
  26. Delaney TF, Kepka L, Goldberg SI, et al.: Radiation therapy for control of soft-tissue sarcomas resected with positive margins. Int J Radiat Oncol Biol Phys 67 (5): 1460-9, 2007. [PUBMED Abstract]
  27. 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. [PUBMED Abstract]
  28. Skytting B: Synovial sarcoma. A Scandinavian Sarcoma Group project. Acta Orthop Scand Suppl 291: 1-28, 2000. [PUBMED Abstract]
  29. 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. [PUBMED Abstract]
  30. Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999. [PUBMED Abstract]
  31. 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. [PUBMED Abstract]
  32. Karakousis CP, Driscoll DL: Treatment and local control of primary extremity soft tissue sarcomas. J Surg Oncol 71 (3): 155-61, 1999. [PUBMED Abstract]
  33. 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. [PUBMED Abstract]
  34. Raut CP, Miceli R, Strauss DC, et al.: External validation of a multi-institutional retroperitoneal sarcoma nomogram. Cancer 122 (9): 1417-24, 2016. [PUBMED Abstract]
  35. Schomberg PJ, Gunderson LL, Moir CR, et al.: Intraoperative electron irradiation in the management of pediatric malignancies. Cancer 79 (11): 2251-6, 1997. [PUBMED Abstract]
  36. 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. [PUBMED Abstract]
  37. 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. [PUBMED Abstract]
  38. Al Yami A, Griffin AM, Ferguson PC, et al.: Positive surgical margins in soft tissue sarcoma treated with preoperative radiation: is a postoperative boost necessary? Int J Radiat Oncol Biol Phys 77 (4): 1191-7, 2010. [PUBMED Abstract]
  39. Wang D, Bosch W, Kirsch DG, et al.: Variation in the gross tumor volume and clinical target volume for preoperative radiotherapy of primary large high-grade soft tissue sarcoma of the extremity among RTOG sarcoma radiation oncologists. Int J Radiat Oncol Biol Phys 81 (5): e775-80, 2011. [PUBMED Abstract]
  40. Bahig H, Roberge D, Bosch W, et al.: Agreement among RTOG sarcoma radiation oncologists in contouring suspicious peritumoral edema for preoperative radiation therapy of soft tissue sarcoma of the extremity. Int J Radiat Oncol Biol Phys 86 (2): 298-303, 2013. [PUBMED Abstract]
  41. Ferrari A: Role of chemotherapy in pediatric nonrhabdomyosarcoma soft-tissue sarcomas. Expert Rev Anticancer Ther 8 (6): 929-38, 2008. [PUBMED Abstract]
  42. 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. [PUBMED Abstract]
  43. Woll PJ, Reichardt P, Le Cesne A, et al.: Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Lancet Oncol 13 (10): 1045-54, 2012. [PUBMED Abstract]
  44. Spunt SL, Million L, Anderson JR, et al.: Risk-based treatment for nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) in patients under 30 years of age: Children’s Oncology Group study ARST0332. [Abstract] J Clin Oncol 32 (Suppl 15): A-10008, 2014. Also available online. Last accessed November 20, 2018.
  45. Demetri GD, Chawla SP, Ray-Coquard I, et al.: Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol 31 (19): 2485-92, 2013. [PUBMED Abstract]
  46. van der Graaf WT, Blay JY, Chawla SP, et al.: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379 (9829): 1879-86, 2012. [PUBMED Abstract]
  47. Mir O, Brodowicz T, Italiano A, et al.: Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 17 (12): 1732-1742, 2016. [PUBMED Abstract]
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  51. Spunt SL, Million L, Coffin C: The nonrhabdomyosarcoma soft tissue sarcoma. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2015, pp 827-54.

Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma

Adipocytic Tumors

Liposarcoma

Liposarcoma accounts for 3% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).

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.

Histopathologic classification

The World Health Organization (WHO) classification for liposarcoma is as follows:[4]

  1. Intermediate (locally aggressive).
    • Atypical lipomatous neoplasm/well-differentiated liposarcoma. These tumors do not metastasize unless they undergo dedifferentiation.
  2. Malignant.
    • Dedifferentiated liposarcoma.
    • 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.[5]
    • Pleomorphic liposarcoma.
    • Liposarcoma, not otherwise specified (NOS).
Clinical presentation

Most liposarcomas in the pediatric and adolescent age range are low grade and located subcutaneously. 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.

Prognosis

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 of their disease.[3] In a retrospective study of 14 patients, 5-year survival was 78% and tumor grade, histologic subtype, and primary location correlated with survival.[2]

Treatment

Treatment options for liposarcoma include the following:

  1. Surgery. If the tumor is not completely removed or locally recurs, a second surgery may be performed.[6-8]
  2. Chemotherapy followed by surgery.
  3. Surgery preceded or followed by radiation therapy (evidence based on adult studies).[9,10]

Surgery is the most important treatment for liposarcoma. After surgical resection of well-differentiated or myxoid liposarcoma, event-free survival (EFS) and overall survival (OS) are roughly 90%. If initial surgery is incomplete, re-excision should be performed to achieve a wide margin of resection. Local recurrences have been seen and are controlled with a second resection of the tumor, particularly for low-grade liposarcomas. Adjuvant radiation therapy is also considered either preoperatively or postoperatively depending on the cosmetic/functional consequences of additional surgery and radiation therapy.

There are reports of the use of chemotherapy to decrease the size of liposarcoma before surgery to facilitate complete resection, particularly in central tumors.[11,12] The role of postoperative chemotherapy for liposarcoma is poorly defined. There does not appear to be a need for any postoperative therapy for completely resected myxoid liposarcoma. Even with the use of postoperative chemotherapy, the survival of pleomorphic liposarcoma remains poor.[13]

Trabectedin has produced encouraging responses in adults with advanced myxoid liposarcoma.[14] In one study, adult patients with recurrent liposarcoma and leiomyosarcoma were randomly assigned to treatment with either trabectedin or dacarbazine. Patients treated with trabectedin had a 45% reduction in disease progression.[15][Level of evidence: 1iiDiii] There are very limited data to support the use of trabectedin in pediatric patients.[16]

Treatment with eribulin, a nontaxane microtubule dynamics inhibitor, significantly improved survival in adult patients with recurrent liposarcoma compared with dacarbazine, with a median OS of 15.6 months versus 8.4 months, respectively. Survival differences were more pronounced in patients with dedifferentiated and pleomorphic liposarcoma. Eribulin was effective in prolonging survival of patients with either high-grade or intermediate-grade tumors.[17][Level of evidence: 1iiA] A pediatric phase I trial of eribulin did not accrue any patients with liposarcoma.[18]

Chondro-osseous Tumors

Chondro-osseous tumors include the following subtypes:

Extraskeletal mesenchymal chondrosarcoma

Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).

Histopathology and molecular features

Mesenchymal chondrosarcoma is a rare tumor characterized by small round cells and hyaline cartilage that more commonly affects young adults and has a predilection for involving the head and neck region.

Mesenchymal chondrosarcoma has been associated with consistent chromosomal rearrangement. A retrospective analysis of cases of mesenchymal chondrosarcoma identified a HEY1-NCOA2 fusion in 10 of 15 tested specimens.[19] This gene fusion was not associated with chromosomal changes that could be detected by karyotyping. In one instance, translocation t(1;5)(q42;q32) was identified in a case of mesenchymal chondrosarcoma and shown to be associated with a novel IRF2BP-CDX1 fusion gene.[20]

Prognosis

A retrospective survey of European institutions identified 113 children and adults with mesenchymal chondrosarcoma. Factors associated with better outcome included the following:[21][Level of evidence: 3iiiA]

  • Lack of metastatic disease at initial presentation.
  • Clear resection margins.
  • Administration of postoperative chemotherapy after resection for patients with initially localized disease.

A retrospective analysis of Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 2011 identified 205 patients with mesenchymal chondrosarcoma; 82 patients had skeletal primary tumors, and 123 patients had extraskeletal tumors.[22] The outcomes of skeletal and extraskeletal primary tumors were the same. Factors associated with outcome included the following:

  • Primary site: 5-year OS was 50% for appendicular tumors, 37% for axial tumors, and 74% for cranial tumors.
  • Metastases and tumor size: Presence of metastatic disease and larger tumor size were independently associated with an increased risk of death.
Treatment

Treatment options for extraskeletal mesenchymal chondrosarcoma include the following:

  1. Surgery. If the tumor is not completely removed, radiation therapy may also be given.
  2. Surgery preceded or followed by radiation therapy.[9,10]
  3. Chemotherapy followed by surgery and additional chemotherapy. Radiation therapy may also be given.

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

A single-institution, retrospective review identified 12 pediatric patients with mesenchymal chondrosarcoma.[24] The presence of the NCOA2 rearrangement in tumors was documented in these patients. It was also confirmed that surgical resection is necessary for cure. Eleven patients presented with localized disease and one presented with pulmonary nodules. All patients received chemotherapy—six patients before and after surgical resection and six patients only after resection. All patients received postoperative chemotherapy (most commonly ifosfamide/doxorubicin) with or without radiation therapy (median dose, 59.4 Gy). At a median follow-up of 4.8 years, 5-year disease-free survival (DFS) was 68.2% (95% confidence interval [CI], 39.8%–96.6%), and OS was 88.9% (95% CI, 66.9%–100%).

A single-institution retrospective review identified 43 cases of mesenchymal chondrosarcoma from 1979 to 2010.[25] Thirty patients with localized disease were evaluated. Five-year OS was 51%, and 10-year OS was 37%. Younger age (<30 years) and male sex were associated with poorer OS and DFS. Patients who did not receive adjuvant radiation therapy were more likely to have a local recurrence.

A Japanese study of patients with extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma randomly assigned patients to treatment with either trabectedin or best supportive care.[26] OS of the patients assigned to receive trabectedin was superior to that of patients assigned to receive best supportive care.

Extraskeletal osteosarcoma

Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).

Extraskeletal osteosarcoma is extremely rare in the pediatric and adolescent age range. An analysis of SEER data identified 256 patients (6%) with extraskeletal osteosarcoma among 4,173 patients with high-grade osteosarcoma from 1973 to 2009. Compared with skeletal osteosarcoma, patients with extraskeletal osteosarcoma were more likely to be older, female, have an axial primary tumor, and have regional lymph node involvement. Adverse prognostic features included presence of metastatic disease, larger tumor size, older age, and axial primary tumor site.[27]

In a review of 274 patients with a median age of 57 years at diagnosis (range, 12–91 years), 5-year DFS and OS rates were significantly better for those who received chemotherapy, and the use of an osteosarcoma-type regimen was associated with improved response rates.[28][Level of evidence: 3iiiA]

Molecular features

A review of 32 adult patients with extraskeletal osteosarcomas consistently revealed several alterations.[29] Frequent genomic alterations included copy number losses in CDKN2A (70%), TP53 (56%), and RB1 (49%). Mutations were identified that affected methylation/demethylation (40%), chromatin remodeling (27%), and the WNT/SHH pathways (27%). Cases with simultaneous TP53 and RB1 biallelic copy number losses were associated with worse DFS and OS.

Prognosis

Extraskeletal osteosarcoma is associated with a high risk of local recurrence and pulmonary metastasis.[30] A single-institution retrospective review identified 43 patients with extraskeletal osteosarcoma; 37 patients had localized disease, and 6 patients presented with metastatic disease.[31] Median age was 55 years (range, 7–81 years). Median progression-free survival was 21 months; median OS was 50 months. Seventy-five percent of patients received chemotherapy. There was a trend toward better survival for patients who received chemotherapy, and a statistically significant improvement in survival for patients who received chemotherapy that included cisplatin.

The European Musculoskeletal Oncology Society performed a retrospective analysis of 266 eligible patients with extraskeletal osteosarcoma treated between 1981 and 2014.[28] Fifty patients (19%) presented with metastatic disease. An analysis of the 211 patients who achieved complete remission after surgical resection of the primary tumor showed a 5-year OS of 51% and a 5-year DFS of 43%. There was a favorable trend for survival among patients who were treated with chemotherapy that is usually employed for patients with osseous osteosarcoma. In a multivariable analysis, factors associated with better prognosis included younger age (<40 years), smaller tumors, and use of chemotherapy.

Treatment

Treatment options for extraskeletal osteosarcoma include the following:

  1. Surgery followed by chemotherapy.[28,30,31]

Typical chemotherapy regimens used for osteosarcoma includes some combination of cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide.[28,30,31]

(Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment for more information about treatment, including chemotherapy options, of extraosseous osteosarcoma.)

Fibroblastic/Myofibroblastic Tumors

Fibroblastic/myofibroblastic tumors include the following subtypes:

  1. Fibroblastic/myofibroblastic tumors.
    1. Intermediate (locally aggressive).
      • Palmar/plantar fibromatosis.
      • Desmoid-type fibromatosis (previously called desmoid tumor or aggressive fibromatoses).
      • Lipofibromatosis.
      • Giant cell fibroblastoma.
    2. Intermediate (rarely metastasizing).
    3. Malignant.

Desmoid-type fibromatosis

Desmoid-type fibromatosis has previously been called desmoid tumors or aggressive fibromatoses.

Risk factors

A small number of desmoid-type fibromatosis tumors may occur in association with a mutation in the adenomatous polyposis coli (APC) gene (associated with intestinal polyps and a high incidence of colon cancer). In a study of 519 patients older than 10 years with a diagnosis of desmoid-type fibromatosis, 39 patients (7.5%, a possible underestimation) were found to have familial adenomatous polyposis (FAP).[32] The patients with FAP and desmoid-type fibromatosis were younger, more often male, and had more abdominal wall or mesenteric tumors than did patients with desmoid-type fibromatosis without FAP.

A family history of colon cancer, the presence of congenital hyperplasia of the retinal pigment epithelium,[33,34] or location of the desmoid-type fibromatosis in the abdomen or abdominal wall [32] should prompt referral to a genetic counselor. Currently, there are no general recommendations for genetic testing in children with desmoid-type fibromatosis. Pathology and molecular characteristics of the tumor only provide guidance for screening. If the tumor has a somatic CTNNB1 mutation, screening is not necessary, because the APC gene mutation has not been described in this setting. If a CTNNB1 mutation is not identified, screening for the APC mutation may be warranted.[35,36] (Refer to the Familial Adenomatous Polyposis (FAP) section of the PDQ summary on Genetics of Colorectal Cancer for more information.)

Prognosis

Desmoid-type fibromatosis has an extremely low potential to metastasize. The tumors are locally infiltrating, and surgical control can be difficult because of the need to preserve normal structures.

Desmoid-type fibromatosis has a high potential for local recurrence. These tumors have a highly variable natural history, including well documented examples of spontaneous regression.[37] Mutations in exon 3 of the beta-catenin (CTNNB1) gene are seen in over 80% of desmoid-type fibromatosis and the mutation 45F has been associated with an increased risk of disease recurrence.[38] Repeated surgical resection can sometimes bring recurrent lesions under control.[39]

Treatment

Evaluation of the benefit of interventions for treatment of desmoid-type fibromatosis has been extremely difficult, because desmoid-type fibromatosis has a highly variable natural history. Large adult series and smaller pediatric series have reported long periods of disease stabilization and even regression without systemic therapy.[39,40]; [41][Level of evidence: 3iiiDi]

Treatment options for desmoid-type fibromatosis include the following:

  1. Surgery.
  2. Observation, for tumors that are incompletely resected or recurrent that do not pose a danger to vital organs, if other treatment options are not available.[39,42-48] Whenever possible, however, the treatment of choice is complete resection.
  3. Chemotherapy, for unresectable or recurrent tumors.
  4. Targeted therapy with sorafenib, for unresectable or recurrent tumors.[49]
  5. Other drug therapy, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or antiestrogen therapy.
  6. Surgery preceded or followed by radiation therapy, for incompletely resected tumors or to avoid recurrence and subsequent surgery that may result in functional or cosmetic compromise.[50]
  7. Radiation therapy alone, for unresectable tumors.

The treatment of choice is resection to achieve clear margins. However, a retrospective review of children who underwent surgery for desmoid-type fibromatosis at the St. Jude Children’s Research Hospital (SJCRH) reported no correlation between surgical margins and risk of recurrence.[48]

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 the following:[51,52]

  • Observation.
  • Chemotherapy.
  • Antiestrogen therapy.
  • NSAID therapy.
  • External-beam radiation therapy.

Desmoid-type fibromatosis often behaves in a nonaggressive manner. In a study that included mostly adults with extra-abdominal primary fibromatosis, nonsurgical approaches (medical and observation) had similar 3-year EFS compared with surgery.[43] In a subsequent study of adolescents and adults with abdominal wall aggressive fibromatosis, 102 patients were treated with a watch and wait approach, of which 65 patients required no further treatment at 3 years. Approximately one-third of patients had regression of the tumor.[42]

Treatment regimens may include the following:

  • Tyrosine kinase inhibitors.
    • Sorafenib: An international prospective phase III double-blind study was conducted through the National Clinical Trials Network (NCTN) to evaluate the efficacy of sorafenib in unresectable progressive or symptomatic desmoid tumors. Patients were randomly assigned in a 2:1 fashion (sorafenib: placebo); crossover to sorafenib was permitted after disease progression. Eighty-seven patients were enrolled (aged 18–72 years). The 1-year PFS was 43% for patients receiving the placebo versus 87% for patients treated with sorafenib, with a median PFS of 9.4 months for patients receiving placebo, and the median PFS for patients receiving sorafenib has not been reached (HR, 0.14; 95% CI, 0.06–0.33; P < .0001).[49][Level of evidence: 1iDiii]
    • Pazopanib: A small series reported symptomatic improvement and stable disease in seven patients with desmoid-type fibromatosis who were treated with pazopanib.[53]
  • Chemotherapy.
    • Combination chemotherapy using vinblastine and methotrexate produced objective responses in about one-third of patients with unresectable or recurrent desmoid-type fibromatosis.[51]
    • A series of mainly adult patients with FAP and unresectable desmoid-type fibromatosis that were unresponsive to hormone therapy showed that doxorubicin plus dacarbazine followed by meloxicam (an NSAID) can be safely administered and can induce responses.[54]
    • Pegylated liposomal doxorubicin has been used with some responses.[55] In a series of five patients, a median progression-free interval of 29 months was reported.[56]
    • Hydroxyurea has been used successfully to treat a few patients after other treatments, but more data are needed.[57-59]
  • NOTCH pathway inhibitor.
    • The NOTCH pathway has been implicated in the development of desmoid tumors.[60] Partial responses to the gamma secretase inhibitor PF-03084014 have been noted in adults with desmoid-type fibromatosis.[61][Level of evidence: 3iiiDiv]

Other drug therapy may include the following:

  • NSAIDs such as sulindac have been used in single cases for desmoid-type fibromatosis; the responses seen were usually disease stabilization.[62]
  • Antiestrogen treatment, usually tamoxifen, plus sulindac has also resulted in disease stabilization.[63] A prospective trial of the combination of tamoxifen and sulindac reported few side effects, although asymptomatic ovarian cysts were common in girls. This combination showed relatively little activity, as measured by rates of response and PFS.[64][Level of evidence: 2Diii]

Postoperative radiation therapy can be considered when progression would entail additional surgery that might cause functional or cosmetic compromise and if radiation is considered acceptable in terms of morbidities.

Radiation has been used for unresectable desmoid-type fibromatosis or postoperatively for tumors with inadequate resections. The potential long-term complications of radiation therapy, especially subsequent neoplasms, make using this modality less appealing in a young population.[65]

Dermatofibrosarcoma protuberans

Dermatofibrosarcoma is a rare tumor that can be present in all age groups, but many of the reported cases arise in children.[66-68] A review of 451 cases in children younger than 20 years in the SEER database found that the incidence was 1 case per 1 million, highest among black patients aged 15 to 19 years. The most common sites were trunk and extremities, which is similar to what is found in adults. Ninety-five percent of patients underwent surgery. OS was 100% at 5 years, 98% at 15 years, and 97% at 30 years. Males had decreased survival compared with females (P < .05).[69][Level of evidence: 3iA]

Molecular features

The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGFRB gene.

Treatment

Treatment of dermatofibrosarcoma protuberans includes the following:

  1. Surgery.
  2. Surgery preceded or followed by radiation therapy.
  3. Radiation therapy and imatinib therapy, for unresectable or recurrent tumors.

Most dermatofibrosarcoma tumors can be cured by complete surgical resection. Wide excision with negative margins or Mohs/modified-Mohs surgery will prevent most tumors from recurring.[70] Despite the locally aggressive behavior of the tumor, lymph node or visceral metastasis rarely occurs.

In retrospective reviews, postoperative radiation therapy after incomplete excision may have decreased the likelihood of recurrence.[71,72]

When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective.[73-75] Because metastatic disease is more likely after multiple recurrences, radiation or other adjuvant therapy should be considered in patients with recurrence that cannot be managed surgically.[67,69]

Guidelines for workup and management of dermatofibrosarcoma protuberans have been published.[76]

Inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumor is a rare mesenchymal tumor that has a predilection for children and adolescents.[77-79]

Clinical presentation

Inflammatory myofibroblastic tumors are rare tumors that affect soft tissues and visceral organs of children and young adults.[80] They rarely metastasize but tend to be locally invasive. Usual anatomical sites of disease include soft tissue, lungs, spleen, colon, and breast.[77] A review of 42 cases of pediatric inflammatory myofibroblastic tumor of the bladder was published in 2015.[81]

Molecular features

Roughly one-half of inflammatory myofibroblastic tumors exhibit a clonal mutation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase gene at chromosome 2p23.[82] ROS1 and PDGFRB kinase fusions have been identified in 8 of 11 cases (73%) who are negative for ALK by immunohistochemistry.[83][Level of evidence: 3iiiDiv]

Prognosis

Inflammatory myofibroblastic tumor recurs frequently but is rarely metastatic.[77-79]

Treatment

Treatment options for inflammatory myofibroblastic tumor include the following:

  1. Surgery.
  2. Chemotherapy.
  3. Steroid therapy.
  4. NSAID therapy.
  5. Targeted therapy (ALK inhibitors).

Complete surgical removal, when feasible, is the mainstay of therapy.[84] In a series of nine patients, four patients achieved continuous remission after complete resection, three patients with residual disease recurred but later achieved continuous remission, and one patient with metastatic disease responded to multiagent chemotherapy.[85][Level of evidence: 3iiA] The benefit of chemotherapy has been noted in case reports.[86]

There are case reports of response to either steroids or NSAIDs.[87,88] A series of 32 patients aged 18 years and younger found that complete excision was the mainstay of therapy, although some patients were treated with steroids or cytotoxic chemotherapy. OS was 94%; three patients relapsed, and two of them died of the disease. When complete excision was performed, with or without other treatments such as steroids, there was a high survival rate for patients with this disease.[89][Level of evidence: 3iiA]

Inflammatory myofibroblastic tumors respond to crizotinib. Two adults with ALK-rearranged inflammatory myofibroblastic tumor achieved partial response with crizotinib.[90][Level of evidence: 3iiiDiv] For pediatric patients with measurable disease, the use of crizotinib achieved partial tumor responses in three of six patients with ALK-translocated inflammatory myofibroblastic tumors.[91] A case report of a patient aged 16 years with metastatic/multifocal ALK-positive inflammatory myofibroblastic tumor demonstrated a complete response and a 3-year disease-free interval with crizotinib therapy.[92] In a phase I trial of ceritinib for adult patients previously treated with ALK inhibitors, one patient with inflammatory myofibroblastic tumor had a partial response.[93] Finally, one study included 14 patients with inflammatory myofibroblastic tumors who were treated with crizotinib. With crizotinib therapy, five patients had a complete response, seven had a partial response, and the remaining two had stable disease; no patient had relapsed at the time the article was published.[94][Level of evidence: 3iiDiv]

Infantile 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 and require different treatments. Adult fibrosarcoma is addressed below.

Clinical presentation

Infantile fibrosarcoma 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.[95]

Molecular features

The tumor usually has a characteristic cytogenetic translocation t(12;15)(ETV-NTRK3). Infantile fibrosarcoma shares this translocation and a virtually identical histologic appearance with mesoblastic nephroma.

Infantile fibrosarcoma usually occurs in children younger than 1 year. It occasionally occurs in children up to age 4 years. A tumor with similar morphology has been identified in older children; in these older children, the tumors do not have the t(12;15)(ETV-NTRK3) translocation that is characteristic of the younger patients.[96] BRAF intragenic deletions have been described in cases of infantile fibrosarcoma and co-occur with NTRK3 fusions.[97]

Prognosis

These tumors have a low incidence of metastases at diagnosis.

Treatment

Treatment options for infantile fibrosarcoma include the following:

  1. Surgery followed by observation.
  2. Surgery followed by chemotherapy.
  3. Chemotherapy followed by surgery.

Complete resection is curative in most 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). The European pediatric group has reported that observation may also be an option in patients with group II disease after surgery.[98] Twelve patients with group II disease received no further therapy and two patients relapsed. One patient obtained a complete remission after chemotherapy. Postoperative chemotherapy was administered to patients with higher group disease and those who progressed. In a subsequent study, only one of seven patients with group II disease progressed during observation; that patient achieved complete remission with chemotherapy.[99][Level of evidence: 3iiA]

Preoperative chemotherapy has made a more conservative surgical approach possible; agents active in this setting include vincristine, dactinomycin, cyclophosphamide, and ifosfamide.[100,101]; [99,102][Level of evidence: 3iiA]; [103][Level of evidence: 3iiB]

Three studies of patients with infantile fibrosarcoma suggest that an alkylator-free regimen is effective and should be used as the first treatment choice in patients with macroscopic disease.[98,99,104] Two cases with variant LMNA-NTRK1 fusions responded to crizotinib.[105,106]

In a phase I/II trial of larotrectinib—an oral ATP-competitive inhibitor of TRK A, B, and C—durable objective responses were seen in all eight patients with recurrent infantile fibrosarcoma who harbored an NTRK fusion. Three of five patients who achieved a partial response after neoadjuvant larotrectinib underwent a complete surgical resection with negative margins and achieved an excellent pathologic response (>98% treatment effect) and remained disease free 7 to 15 months after surgery.[107] One of eight patients in this trial with an ETV6-NTRK3–rearranged infantile fibrosarcoma developed progressive disease after 8 months of larotrectinib therapy and was found to have a G623R acquired resistance mutation. The patient was treated with LOXO195, a selective TRK inhibitor designed to overcome acquired resistance mediated by recurrent kinase domain mutations, and experienced a transient partial response.[108]

A patient aged 2 months with infantile fibrosarcoma was initially treated with chemotherapy. At disease progression, a response was seen with pazopanib.[109]

A rare case of spontaneous regression without treatment has been reported.[110][Level of evidence: 3iiiDiv]

Treatment options under clinical evaluation

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

  • LOXO-TRK-15003 (NCT02637687) (Oral TRK Inhibitor LOXO-101 for Treatment of Advanced Pediatric Solid or Primary Central Nervous System [CNS] Tumors): A phase I trial of the pan-TRK inhibitor LOXO-101 is being conducted for children with solid tumors or brain tumors whose disease has progressed or was nonresponsive to available therapies, and for which no standard or available curative therapy exists. LOXO-101 is a highly selective inhibitor of all three TRK family kinases.
  • RXDX-101-03 (NCT02650401) (Study of RXDX-101 in Children With Recurrent or Refractory Solid Tumors and Primary CNS Tumors): This is a four-part, open-label, phase I/Ib, dose-escalation study in pediatric patients with: 1) relapsed or refractory solid tumors; 2) primary CNS tumors; 3) neuroblastoma; and 4) non-neuroblastoma, extracranial solid tumors with NTRK1/2/3, ROS1 or ALK gene rearrangements. The study is designed to explore the safety, maximum tolerated dose or recommended phase II dose, pharmacokinetics, and antitumor activity of entrectinib (RXDX-101).
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

    The phase II subprotocol is evaluating LOXO-101 (larotrectinib) in patients with tumors harboring actionable NTRK fusions.

  • NCT03215511 (Phase I/II Study of LOXO-195 in Patients With Previously Treated NTRK Fusion Cancers): This is a phase I/II, multicenter, open-label study designed to evaluate the safety and efficacy of LOXO-195 when administered orally to patients aged 1 month and older with NTRK fusion cancers treated with a prior TRK inhibitor.
  • NCT02568267 (Basket Study of Entrectinib [RXDX-101] for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements [Fusions] [STARTRK-2]): This is an open-label, multicenter, global phase II basket study of entrectinib (RXDX-101) for the treatment of patients 18 years and older with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene fusion. Patients will be assigned to different baskets according to type of tumor and gene fusion.

Adult fibrosarcoma

These tumors lack the translocation seen in infantile fibrosarcomas. They present like most nonrhabdomyosarcomas, and the management approach is similar.

Myxofibrosarcoma

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

Low-grade fibromyxoid sarcoma

Low-grade fibromyxoid sarcoma is a histologically deceptive soft tissue neoplasm that most commonly affects young and middle-aged adults, is commonly located deep within the extremities, and is characterized by a FUS-CREB3L3 translocation.[111,112]

Prognosis

In a review of 33 patients (three were younger than 18 years) with low grade fibromyxoid sarcoma, 21 of 33 patients developed a local recurrence after intervals of up to 15 years (median, 3.5 years); 15 patients developed metastases up to 45 years (median, 5 years) from diagnosis, most commonly to the lungs and pleura, emphasizing the need for continued follow-up of these patients.[111] Even after metastases occur, the course may be indolent.[113]

In another report, 14 of 73 patients were younger than 18 years. In this series with a relatively short follow up (median of 24 months), only 8 of 54 patients with adequate follow-up developed local (9%) or distant (6%) recurrence. This report suggests that the behavior of this tumor might be significantly better than previously reported.[114] However, because of the occurrence of late metastases, careful monitoring of these patients is warranted.

The most recent Children's Oncology Group (COG) trial (ARST0332 [NCT00346164]) enrolled 11 patients with this tumor entity. The median age at diagnosis was 13 years and males were more commonly affected. The most common sites were the lower and upper extremity (n = 9) and none of the patients had developed local or distant disease recurrence at a median follow up of 2.7 years.[115]

Treatment

Treatment options for low-grade fibromyxoid sarcoma include the following:

  1. Surgery.

The limited treatment information for low-grade fibromyxoid sarcoma suggests that surgery is the treatment of choice because the tumor is not very chemosensitive.[113] There are little data regarding the use of chemotherapy and/or radiation therapy in this disease. One report suggests that trabectedin may be effective in the treatment of low-grade fibromyxoid sarcoma.[116]

Sclerosing epithelioid fibrosarcoma

Sclerosing epithelioid fibrosarcoma is a rare malignant sarcoma that commonly harbors EWSR1 gene fusions, has an aggressive clinical course, and is poorly responsive to chemotherapy;[117-119] therefore, it is typically treated with complete surgical excision. Long-term follow-up is recommended because late local recurrence and metastases can occur.

Skeletal Muscle Tumors

Rhabdomyosarcoma

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

Smooth Muscle Tumors

Leiomyosarcoma

Leiomyosarcoma accounts for 2% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).

Risk factors

Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma.[120] Survivors of hereditary retinoblastoma have a statistically significant increased risk of developing leiomyosarcoma, and 78% of these patients were diagnosed 30 or more years after the initial diagnosis of retinoblastoma.[121]

Treatment

Treatment options for leiomyosarcoma include the following:

  1. Chemotherapy (trabectedin).

In an open-label study of trabectedin in adult patients with recurrent sarcomas, the best overall response rate (complete remission and partial remission) was seen in patients with leiomyosarcoma (7.5%).[122] The clinical benefit rate (includes stable disease) for leiomyosarcoma was 54%. In another adult study, patients with recurrent liposarcoma and leiomyosarcoma were randomly assigned to receive treatment with either trabectedin or dacarbazine. Patients treated with trabectedin had a 45% reduction in disease progression.[15] There are no data to support the use of trabectedin in pediatric patients.

So-called Fibrohistiocytic Tumors

So-called fibrohistiocytic tumors include the following subtypes:

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.[123,124]

Clinical presentation

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.[125-127] There are rare reports of the tumor spreading to regional lymph nodes or the lungs.[123,127,128]

Molecular features

No consistent chromosomal anomalies have been detected but a t(4;15)(q21;q15) translocation has been reported.[129]

Prognosis

Plexiform fibrohistiocytic tumor is an intermediate-grade tumor that rarely metastasizes.

Treatment

Surgery is the treatment of choice but local recurrence has been reported in 12% to 50% of cases.[130]

Nerve Sheath Tumors

Malignant peripheral nerve sheath tumor

Malignant peripheral nerve sheath tumors account for 5% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).

Risk factors

Malignant peripheral nerve sheath tumor can arise sporadically and in children with neurofibromatosis type 1 (NF1).[131] Among patients with NF1, a family history of malignant peripheral nerve sheath tumor is associated with an increased risk of developing early-onset malignant peripheral nerve sheath tumor.[132]

Molecular features

Molecular features of malignant peripheral nerve sheath tumor include the following:

  • Inactivating mutations of SUZ12 have been described in these tumors and are absent in neurofibromas.[133]
  • A DNA methylation array for methylome-based and profile-based chromosomal characterization was performed on 171 peripheral nerve sheath tumors.[134] Atypical neurofibromas and low-grade malignant peripheral nerve sheath tumors were indistinguishable, with a common methylation profile and loss of CDKN2A. Epigenomic analysis identified two groups of conventional high-grade malignant peripheral nerve sheath tumor sharing a frequent loss of neurofibromin. The larger group showed an additional loss of trimethylation of H3K27me3. The smaller group of patients with predominantly spinal primary sites showed retention of H3K27me3.
  • Genomic profiling was performed on 201 malignant peripheral nerve sheath tumors.[135] Thirteen of 201 tumors demonstrated BRAF alterations.
Prognosis

Features associated with a favorable prognosis include the following:[131,136-138]

  • Smaller tumor size. In a multivariate analysis, only tumor size and nuclear p53 expression were found to be independent predictors of disease-specific survival.[137]
  • Male sex and non-Hispanic white race.[139]
  • 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.[137]
  • Lower stage.
  • Lower histologic grade.
  • Extremity as the primary site.

Features associated with an unfavorable prognosis include the following:[140]

  • High grade.
  • Deep tumor location.
  • Locally advanced stage at diagnosis.
  • Macroscopically incomplete resection (R2).
  • Inactivation of p53, either by mutation or amplification of MDM2.[141]

For patients with localized disease in the MD Anderson Cancer Center study, there was no significant difference in outcome between patients with and without NF1.[137] In other studies, it was not clear whether the absence of NF1 is a favorable prognostic factor as it has been associated with both favorable [136] and unfavorable outcomes.[131,136,138] In the French Sarcoma Group study, NF1 was associated with other adverse prognostic features, but was not an independent predictor of poor outcome.[140] The Italian Sarcoma Group reported on outcomes after recurrence in 73 children and adolescents with malignant peripheral nerve sheath tumor.[142][Level of evidence: 3iiiA] The median OS after first relapse was 11 months, and the survival rates were 39.2% at 1 year and 15.8% at 5 years. The factors associated with a better prognosis for these patients who relapsed were less initial tumor invasiveness, longer time to relapse, and the achievement of a secondary complete remission (which was related to the feasibility of radical surgery).

Treatment

Treatment options for malignant peripheral nerve sheath tumor include the following:

  1. Surgery.
  2. Surgery preceded or followed by radiation therapy.[9,10]
  3. Chemotherapy, for unresectable tumors.

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 postoperative 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 with chemotherapy.[131] This retrospective analysis also noted a trend toward improved outcome with postoperative radiation therapy.[131] 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; PFS was 19%, and 5-year OS was 28%.[143]

Recurrent malignant peripheral nerve sheath tumor

Of 120 patients enrolled in Italian pediatric protocols from 1979 to 2004, an analysis identified 73 patients younger than 21 years with relapsed malignant peripheral nerve sheath tumor. The time to relapse from initial diagnosis ranged from 1 month to 204 months, with a median time to relapse of 7 months. Median OS from first relapse was 11 months, with an OS rate of 39% at 1 year and 16% at 5 years. The factors associated with a higher probability of survival after relapse were lower tumor invasiveness at initial presentation, longer time to relapse, and complete surgical resection of the tumor at relapse.[142]

Treatment options under clinical evaluation

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

  • SARC023 (NCT02008877) (Ganetespib and Sirolimus in Patients With Malignant Peripheral Nerve Sheath Tumors): This trial is testing the combination of ganetespib, the heat shock protein inhibitor, and sirolimus, the mammalian target of rapamycin (mTOR) inhibitor, for the treatment of patients with unresectable or metastatic malignant peripheral nerve sheath tumors. Patients with unresectable soft tissue or bone sarcomas are eligible for phase I of the trial. Patients with unresectable malignant peripheral nerve sheath tumors are eligible for phase II of the trial. Eligibility is restricted to patients aged 18 years and older.
  • NCT02601937 (A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.

Malignant Triton tumor

Malignant Triton tumors are a variant of malignant peripheral nerve sheath tumors. They occur most often in patients with NF1 and consist of neurogenic and rhabdomyoblastic components. Malignant Triton tumors are high-grade malignancies. They usually occur before age 35 years and are very rare in children (case reports only).[144]

Malignant Triton tumors are not usually responsive to chemotherapy and radiation therapy but have been treated with rhabdomyosarcoma therapy.[144][Level of evidence: 3iiiA] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)

Ectomesenchymoma

Ectomesenchymoma is a rare nerve sheath tumor that mainly occurs in children. It is a biphenotypic soft tissue sarcoma with both mesenchymal and ectodermal components. A retrospective review of six patients with malignant ectomesenchymoma from a single institution identified rhabdomyosarcoma as the mesenchymal element in five of six tumors.[145] Tumors with an alveolar rhabdomyosarcoma morphology exhibited the characteristic translocation. No unifying molecular aberrations were identified. A single-institution retrospective review identified seven cases of malignant ectomesenchymoma.[146] All seven patients were male, with a mean age of 7.5 months (range, 0.6–17 months). Most patients showed elements of embryonal rhabdomyosarcoma. The mixed neuroectodermal elements were scattered ganglion cells, ganglioneuroma, or ganglioneuroblastoma. Six of seven cases had HRAS mutations. The trimethylation at lysine 27 of histone H3 (H3K27me3), typically lost in malignant peripheral nerve sheath tumor, was retained in all cases.

The German Soft Tissue Sarcoma Group (Cooperative Weichteilsarkom Studiengruppe [CWS]) reported on six patients (ages 0.2–13.5 years) registered over 14 years.[147][Level of evidence: 3iiA] The tumors were located in various sites including the extremities, abdomen, and orbit. All six patients were treated with surgery and chemotherapy directed at rhabdomyosarcoma. Two patients received radiation therapy. Three patients recurred with rhabdomyosarcoma features. Although data are scant, it appears that the tumor may respond to chemotherapy.[147]

Pericytic (Perivascular) Tumors

Myopericytoma

Infantile hemangiopericytoma is a subtype of myopericytoma.

Hemangiopericytoma is a highly vascularized tumor of uncertain origin.

Histology

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.[148]

Treatment and outcome

Treatment of infantile hemangiopericytomas includes the following:

  1. Chemotherapy.

In a series of 17 children, the differences in metastatic potential and response to treatment were clearly demonstrated for adult and infantile hemangiopericytomas.[149] Eleven children were older than 1 year. Several of these patients had disease in the lymph nodes or lungs. Six patients with stage II or stage III disease progressed and died. Three patients with stage I disease survived, although one patient had recurrence in the lungs. Six patients had infantile hemangiopericytoma, most were greater than stage I (5 of 6). All six patients survived, and three patients had good responses to vincristine, actinomycin, and cyclophosphamide. Children younger than 1 year with hemangiopericytoma seem to have a better prognosis than do children older than 1 year with hemangiopericytoma.[150-152]

Several studies have reported on tumors in children that were more akin to infantile myofibromatosis (refer to the Infantile myofibromatosis section of this summary) or hemangiopericytoma.[106,153] Rather than the ETV6-NTRK3 fusion protein seen in congenital infantile fibrosarcoma, a LMNA-NTRK1 fusion protein was identified.[154] One patient carrying this fusion responded to crizotinib.

Infantile myofibromatosis

This entity is a fibrous tumor of infancy and childhood that most commonly presents in the first 2 years of life.[155] The lesion can present as a single subcutaneous nodule (myofibroma) most commonly involving the head and neck region, or lesions can affect multiple skin areas, muscle, and bone (myofibromatosis).[156-159]

An autosomal dominant form of the disease has been described and it is associated with germline mutations of the PDGFRB gene.[160] Somatic PDGFRB mutations have also been identified without germline mutations.[161]

Treatment and outcome

These lesions have an excellent prognosis and can regress spontaneously.

About one-third of cases with multicentric involvement will also have visceral involvement, and the prognosis for these patients is poor.[158,159,162] The use of combination therapy with vincristine/dactinomycin and vinblastine/methotrexate have proven effective in cases of multicentric disease with visceral involvement and in cases in which the disease has progressed and has threatened the life of the patient (e.g., upper airway obstruction).[158,159,163]

Tumors of Uncertain Differentiation

Tumors of uncertain differentiation include the following subtypes:

Synovial sarcoma NOS

Synovial sarcoma accounts for 9% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).

Synovial sarcoma is one of the most common nonrhabdomyosarcomatous soft tissue sarcomas in children and adolescents. In a 1973 to 2005 SEER review, 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.[164]

Histologic classification

Synovial sarcoma can be subclassified as the following types:

  • Synovial sarcoma NOS.
  • Synovial sarcoma, spindle cell.
  • Synovial sarcoma, biphasic.
Clinical presentation

The most common tumor location is the extremities, followed by trunk and head and neck.[164] Rarely, a synovial sarcoma may arise in the heart or pericardium.[165]

The most common site of metastasis is the lung.[166,167] The risk of metastases is highly influenced by tumor size; it is estimated that patients with tumors that are larger than 5 cm have a 32-fold risk of developing metastases when compared with other patients.

Diagnostic evaluation

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.[168,169] It is thought that the SYT/SSX18 transcript promotes epigenetic silencing of key tumor suppressor genes.[170]

In one report, reduced INI1 nuclear reactivity on immunohistochemical staining was seen in 49 cases of synovial sarcoma, suggesting that this pattern may help distinguish synovial sarcoma from other histologies.[171]

Prognosis

Patients younger than 10 years have more favorable outcomes and clinical features—including extremity primaries, smaller tumors, and localized disease—than do older patients.[164,172] A meta-analysis also suggested that response to chemotherapy was correlated with improved survival.[173]

The following studies have reported multiple factors associated with unfavorable outcomes:

  • 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.[174] In this analysis, local invasiveness conferred an inferior probability of EFS, but surgical margins were not associated with clinical outcome.
  • In a single-institution retrospective analysis of 111 patients with synovial sarcoma who were younger than 22 years at diagnosis, larger tumor size, greater depth in tissue, greater local invasiveness, and more proximal tumor location were associated with poorer OS.[175][Level of evidence: 3iiA]
  • 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%.[173] 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) group III disease (localized, incompletely resected or with biopsy only) and group IV disease (metastases at diagnosis) had decreased OS. Treatment with radiation therapy was related to improved OS (hazard ratio, 0.4; 95% CI, 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.[176-178]
  • Expression and genomic index prognostic signatures have been studied in synovial sarcoma. Complex genomic profiles, with greater rearrangement of the genome, are more common in adults than in younger patients with synovial sarcoma and are associated with a higher risk of metastasis.[179]
  • A review of 84 patients with localized synovial sarcoma who had information on fusion status (SYT-SSX) and histologic grading found no difference in OS according to these criteria. However, for tumor size at diagnosis, the study showed that patients with tumors between 5 cm and 10 cm had a worse prognosis than those with smaller tumors (P = .02), and patients with tumors larger than 10 cm had even worse OS (P = .0003).[180][Level of evidence: 3iiiA]
  • The German CWS group reviewed 27 evaluable patients younger than 21 years with pulmonary metastases among 296 patients with synovial sarcoma. Metastases involved the lungs in all patients. The 5-year EFS rate was 26%, and the OS rate was 30%. The most important prognostic factor at presentation was that the metastases were limited to one lesion in one lung or one lesion in both lungs (a group they termed oligometastatic). Treatment elements associated with superior survival were adequate local therapy of the primary tumor and, if feasible, for the metastases. The use of whole-lung irradiation did not correlate with better outcomes.[181][Level of evidence: 3iiA]

Survival after relapse is poor (30%–40% at 5 years). Factors associated with outcome after relapse include duration of first remission (> or ≤ 18 months) and lack of a second remission.[182,183]

Treatment

Treatment options for synovial sarcoma include the following:

  1. Surgery. Radiation therapy and/or chemotherapy may be given before or after surgery.[9,10]
  2. Chemotherapy.

The COG and the European Pediatric Soft Tissue Sarcoma Study Group reported a combined analysis of 60 patients younger than 21 years with localized synovial sarcoma prospectively assigned to surgery without adjuvant radiation therapy or chemotherapy.[184] Enrollment was limited to patients with initial complete resection with histologically free margins, with a grade 2 tumor of any size or a grade 3 tumor 5 cm or smaller. The 3-year EFS was 90% (median follow-up, 5.2 years; range, 1.9–9.1). All eight events were local tumor recurrence; no metastatic recurrences were seen. All patients with recurrent disease were effectively treated with salvage therapy, resulting in 100% OS.

Synovial sarcoma appears to be more sensitive to chemotherapy than many other soft tissue sarcomas, and children with synovial sarcoma seem to have a better prognosis than do adults with synovial sarcoma.[12,167,178,185-189] The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[173,188,190] Response rates to the ifosfamide and doxorubicin regimen are higher than in other nonrhabdomyosarcomatous soft tissue sarcomas.[191]

Several studies have reported the following chemotherapy-associated treatment findings:

  • Several treatment centers advocate postoperative chemotherapy after resection and radiation therapy of synovial sarcoma in children and young adults.[173,174,192-194]
  • The International Society of Pediatric Oncology-Malignant Mesenchymal Tumors studies showed that select patients (young age, <5 cm resected tumors) with nonmetastatic synovial sarcoma can have excellent outcomes in the absence of radiation, but it is still unclear whether that approach obviates an advantage of radiation for local or regional control.[193]
  • A German trial suggested a benefit for postoperative chemotherapy in children with synovial sarcoma.[194]
  • A meta-analysis also suggested that chemotherapy may provide benefit.[173]
  • In the COG ARST0332 (NCT00346164) study, 129 patients with synovial sarcoma were prospectively treated using a risk-based therapy program (as detailed in the prognosis section), of which 43 were categorized as low risk, 66 as intermediate risk, and 20 as high risk. At a median follow-up of 2.6 years, 3-year EFS for low-, intermediate-, and high-risk groups were 83%, 79%, and 16%, respectively. The use of risk factor–directed therapy accurately predicted outcomes.[195]
  • The European Pediatric Soft Tissue Sarcoma Study Group performed a prospective study of patients younger than 21 years with synovial sarcoma (CCLG-EPSSG-NRSTS-2005 [NCT00334854]).[196][Level of evidence: 3iiA] Patients were stratified into the following three risks groups and nonrandomly assigned to treatment by risk group:
    • Low-risk patients had IRS group I tumors less than 5 cm in size and nonaxial primary tumors.
    • Intermediate-risk patients had no axial primary tumors and IRS group I tumors greater than 5 cm or IRS group II tumors.
    • High-risk patients included all patients with axial primary sites (head and neck, lung and pleura, trunk, retroperitoneal), IRS group III tumors, or N1 tumors.

    Outcomes for patients treated on the CCLG-EPSSG-NRSTS-2005 trial are described in Table 9.

    Table 9. Event-Free Survival (EFS) and Overall Survival (OS) in Patients With Low-, Intermediate-, and High-Risk Synovial Sarcoma Treated on the CCLG-EPSSG-NRSTS-2005 Trial
    Risk GroupTreatment3-Year EFS (%)3-Year OS (%)
    IRS = Intergroup Rhabdomyosarcoma Study; RT = radiation therapy.
    aChemotherapy was ifosfamide/doxorubicin, with doxorubicin omitted during radiation therapy.
    b59.4 Gy in cases without the option of secondary resection; 50.4 Gy as preoperative radiation therapy; 50.4, 54, and 59.4 Gy as postoperative radiation therapy, in the case of R0, R1, and R2 resections, respectively (no additional radiation therapy in the case of secondary complete resections with free margins, in children younger than 6 years).
    LowSurgery alone92100
    IntermediateSurgery, 3–6 cycles chemotherapya ± RTb91100
    High (IRS group III)3 cycles of chemotherapya surgery, 3 additional cycles of chemotherapy, ± RTb7794
    High (axial primary sites)Surgery, 6 cycles of chemotherapya, RTb78100
Treatment options under clinical evaluation

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • ADP 04511 (NCT01343043) (A Pilot Study of Genetically Engineered NY-ESO-1 Specific [c259] T Cells in HLA-A2+ Patients With Synovial Sarcoma): Patients with unresectable, metastatic, or recurrent synovial sarcoma undergo apheresis. Cells are shipped to a central laboratory where they undergo NY-ESO-1 transduction, expansion, and cryopreservation. Patients undergo lymphodepletion with fludarabine and cyclophosphamide, followed by an infusion of autologous transfected cells. Eligibility is restricted to patients with HLA type A2+, age older than 4 years, and weight greater than 18 kg.

Epithelioid sarcoma

Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis that displays multilineage differentiation.[197]

Clinical presentation

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.

Molecular features

Epithelioid sarcoma is characterized by inactivation of the SMARCB1 gene, which is present in both conventional and proximal types of epithelioid sarcoma.[198] This abnormality leads to increased dependence on EZH2 and tumor formation.[199]

Treatment

Treatment options for epithelioid sarcoma include the following:

  1. Chemotherapy.
  2. Surgery.
  3. Surgery preceded or followed by radiation therapy.

Patients should be carefully evaluated for the presence of involved lymph nodes; suspicious lymph nodes are biopsied. Surgical removal of primary and recurrent tumor(s) is the most effective treatment.[200][Level of evidence: 3iiiA] Because of the propensity of this disease to have occult metastasis to the lymph nodes, sentinel lymph node biopsy is recommended for epithelioid sarcoma of the extremities or buttocks in the absence of clinically (by imaging or physical examination) enlarged lymph nodes.[201]

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 after initial diagnosis.[202] A single-institution retrospective review of 20 patients, which included children and adults (median age, 27.3 years), found no difference in the probability of recurrence between patients who received chemotherapy and those who did not receive chemotherapy and suggested that radiation therapy may be useful.[200]

Treatment options under clinical evaluation

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • NCT02601937 (A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.

Alveolar soft part sarcoma

Alveolar soft part sarcomas account for 1.4% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).

Clinical presentation

The median age at presentation is 25 years, and alveolar soft part sarcoma most commonly arises in the extremities but can occur in the oral and maxillofacial region.[203-205] Alveolar soft part sarcoma in children can present with evidence of metastatic disease.[206]

In a series of 61 patients with alveolar soft part sarcoma who were treated in four consecutive CWS trials and the SoTiSaR registry, 46 patients presented with localized disease and 15 patients had evidence of metastasis at diagnosis.[207] Of the nine children with alveolar soft part sarcoma younger than 30 years who were treated between 1980 and 2014 at four major institutions, the median age at diagnosis was 17 years, and 64% of patients were female. The most common site of disease was the lower extremity, and 26 patients had an ASSPL-TFE3 translocation. The distribution by Intergroup Rhabdomyosarcoma Study (IRS) group was as follows: 19 patients with IRS I disease, 7 patients with IRS II disease, 5 patients with IRS III disease, and 38 patients with IRS IV disease.[208]

Molecular features

This tumor of uncertain histogenesis is characterized by a consistent chromosomal translocation t(X;17)(p11.2;q25) that fuses the ASPSCR1 gene with the TFE3 gene.[209,210]

Prognosis

Alveolar soft part sarcoma in children may have an indolent course.[206] Patients with alveolar soft part sarcoma may relapse several years after a prolonged period of apparent remission.[207,211] Because these tumors are rare, all children with alveolar soft part sarcoma should be considered for enrollment in prospective clinical trials.

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.[212] 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.[213][Level of evidence: 3iiA] Delayed metastases to the brain and lung are uncommon.[203] A retrospective review of children and young adults younger than 30 years (median age, 17 years; range, 1.5–30 years) from four institutions identified 69 patients treated primarily with surgery between 1980 and 2014.[208][Level of evidence: 3iiA] The ASPL-TFE3 translocation was present in all 26 patients tested. There were 19 patients with IRS postsurgical staging group I tumors (28%), 7 patients with IRS group II tumors (10%), 5 patients with IRS group III tumors (7%), and 38 patients with IRS group IV tumors (55%). The 5-year EFS was 80% and the OS was 87% for the 31 patients with localized tumors (IRS postsurgical groups I, II, and III). The 5-year EFS was 7% and the OS was 61% for the 38 patients with metastatic tumors (IRS postsurgical group IV).

Treatment

Treatment options for alveolar soft part sarcoma include the following:

  1. Surgery.
  2. Surgery preceded or followed by radiation therapy.[9,10]
  3. Targeted therapy (tyrosine kinase inhibitor).

The standard approach is complete resection of the primary lesion.[212] If complete excision is not feasible, radiation therapy is administered. A study from China reported on 18 patients with alveolar soft part sarcoma of the oral and maxillofacial region; 15 patients were younger than 30 years.[205][Level of evidence: 3iiDii] Surgical removal with negative margins was the primary treatment. All patients survived, and only one patient had metastatic disease recurrence.

A series of 51 pediatric patients aged 0 to 21 years with alveolar soft part sarcoma found an OS rate at 10 years of 78% and an EFS rate of about 63%. Patients with localized disease (n = 37) had a 10-year OS of 87%, and the 14 patients with metastases at diagnosis had a 10-year OS of 44%, partly resulting from surgical removal of primary tumor and lung metastases in some patients. Only 3 of 18 patients (17%) with measurable disease had a response to conventional antisarcoma chemotherapy, but two of four patients treated with sunitinib had a partial response.[203][Level of evidence: 3iiiA] There have been sporadic reports of objective responses to interferon-alpha and bevacizumab.[203,214,215]

Studies of tyrosine kinase inhibitors have observed the following:

  • A small retrospective study of nine adult patients with metastatic alveolar soft part sarcoma treated with sunitinib reported partial responses in five patients and stable disease in two patients.[216][Level of evidence: 3iiiDiv]
  • In another study, 15 patients with alveolar soft part sarcoma were treated with sunitinib, and six patients experienced partial responses. The median PFS was 19 months, and the median OS was 56 months. The 5-year OS rate was 49%.[217][Level of evidence: 3iiA] Five patients were treated with sunitinib for longer than 2 years.
  • In a phase II trial of cediranib, an inhibitor of all three known vascular epidermal growth factor receptors, 15 of 43 adult patients (35%) with metastatic alveolar soft part sarcoma had partial responses.[218][Level of evidence: 3iiDiv]
  • In an open-label trial that evaluated the efficacy of pazopanib in six adult patients, one patient achieved a partial response and five patients had stable disease.[219] In another trial of 30 adult patients treated with pazopanib, one patient experienced a complete response, seven patients experienced partial responses, and 17 patients had stable disease. The median PFS was 13.6 months.[220]

There have been no open trials for patients with metastatic alveolar soft part sarcoma.

Treatment options under clinical evaluation for alveolar soft part sarcoma

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • NCT01391962 (Sunitinib or Cediranib for Alveolar Soft Part Sarcoma): A phase II trial in which patients with metastatic alveolar soft part sarcoma are randomly assigned to either sunitinib or cediranib monotherapy, with crossover at disease progression. Patients aged 16 years and older are eligible. This study is being conducted at the Clinical Center of the National Institutes of Health.

Clear cell sarcoma of soft tissue

Clear cell sarcoma (formerly and inappropriately called malignant melanoma of soft parts) is a rare soft tissue sarcoma that typically involves the deep soft tissues of the extremities. It is also called clear cell sarcoma of tendons and aponeuroses. The tumor often affects adolescents and young adults.

Patients who have small, localized tumors with low mitotic rate and intermediate histologic grade fare best.[221]

Clinical presentation

The tumor most commonly affects the lower extremity, particularly the foot, heel, and ankle.[222,223] It has a high propensity for nodal dissemination, especially metastases to regional lymph nodes (12%–43%).[223,224] The tumor typically has an indolent clinical course.

Molecular features

Clear cell sarcoma of soft tissue is characterized by an EWSR1-ATF1 or EWSR1-CREB1 fusion.[225,226]

Treatment

Treatment options for clear cell sarcoma of soft tissue include the following:

  1. Surgery.
  2. Surgery preceded or followed by radiation therapy.[9,10]

In a series of 28 pediatric patients reported by the Italian and German Soft Tissue Cooperative Studies, the median age at diagnosis was 14 years and the lower extremity was the most common primary site (50%). Surgery with or without radiation therapy is the treatment of choice and offers the best chance for cure. In this series, 12 of 13 patients with completely resected tumors were cured. For patients with more advanced disease, the outcome is poor and chemotherapy is rarely effective.[227]; [228][Level of evidence: 3iiDii]

Extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma is relatively rare among soft tissue sarcomas, representing only 2.3% of all soft tissue sarcoma.[229] It has been reported in children and adolescents.[230]

Molecular features

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 (refer to Table 2), with the most frequent being the translocation t(9;22)(q22;q12), involving the EWSR1-NR4A3 genes.[231]

Prognosis

The tumor has traditionally been considered of low-grade malignant potential.[232] However, recent reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are monitored for a long time.[233,234] 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.[234]

Treatment

Treatment options for extraskeletal myxoid chondrosarcoma include the following:

  1. Surgery.
  2. Radiation therapy.

The therapeutic benefit of chemotherapy has not been established. Aggressive local control and resection of metastases led to OS rates of 87% at 5 years and 63% at 10 years. Tumors were relatively resistant to radiation therapy.[233]

There may be potential genetic targets for small molecules, but these should be studied as part of a clinical trial. In an adult study, six of ten patients who received sunitinib achieved partial responses.[235]

Treatment options under clinical evaluation

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • NCT02601937 (A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.

Extraskeletal Ewing sarcoma

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

Desmoplastic small round cell tumor

Desmoplastic small round cell tumor is a rare primitive sarcoma.

Clinical presentation

Desmoplastic small round cell tumor most frequently involves the peritoneum in the abdomen, pelvis, and/or peritoneum into the scrotal sac, but it may occur in the kidney or other solid organs.[236-240] The tumor occurs in males (85%) and may spread to the lungs and elsewhere. Dozens to hundreds of intraperitoneal implants are often found.[240,241]

In a large, single-institution series of 65 patients, a correlation was made between computed tomography (CT) scans in most patients and positron emission tomography (PET)-CT scans in 11 patients. PET-CT scans had very few false-negative results and detected metastatic sites missed on conventional CT scans.[241]

Molecular features

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 EWSR1 genes.[239,242] The WT1-EWSR1 fusion confirms the diagnosis of desmoplastic small round cell tumor.

Prognosis

The overall prognosis for desmoplastic small round cell tumor remains extremely poor, with reported rates of death at 90%. Greater than 90% tumor resection either at presentation or after preoperative chemotherapy may be a favorable prognostic factor for OS.[243,244]; [245][Level of evidence: 3iiiA] Response to neoadjuvant chemotherapy and complete resection (near 100%) is associated with improved outcome.[240]

Treatment

There is no standard approach to the treatment of desmoplastic small round cell tumor.

Treatment options for desmoplastic small round cell tumor include the following:

  1. Surgery.
  2. Chemotherapy followed by surgery.
  3. Radiation therapy.

Complete surgical resections are rare, but critical for any improved survival. 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.[236,237,243,246-249]

A single-institution study reported that five of five patients with recurrent desmoplastic small round cell tumor had partial responses to treatment with the combination of vinorelbine, cyclophosphamide, and temsirolimus.[250]

The Center for International Blood and Marrow Transplant Research analyzed patients with desmoplastic small round cell tumor in their registry who received consolidation with high-dose chemotherapy and autologous stem cell reconstitution.[251] While this retrospective registry analysis suggested some benefit to this approach, other investigators have abandoned the approach because of excessive toxicity and lack of efficacy.[243]

Extra-renal (extracranial) rhabdoid tumor

Malignant rhabdoid tumors were first described in children with renal tumors in 1981 (refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information) and were later found in a variety of extra-renal sites. These tumors are uncommon and highly malignant, especially in children younger than 2 years.

Extra-renal (extracranial) rhabdoid tumors account for 2% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).

Molecular features

The first sizeable series of 26 children with extra-renal extracranial malignant rhabdoid tumor of soft tissues came from patients enrolled on the Intergroup Rhabdomyosarcoma Studies I through III during a review of pathology material. Only five patients (19%) were alive without disease.[252] Later, investigation of children with atypical teratoid/rhabdoid tumors of the brain, as well as those with renal and extra-renal malignant rhabdoid tumors, found germline and acquired mutations of the SMARCB1 gene in all 29 tumors tested.[253] Rhabdoid tumors may be associated with germline mutations of the SMARCB1 gene and may be inherited from an apparently unaffected parent.[254] This observation was extended to 32 malignant rhabdoid tumors at all sites in patients whose mean age at diagnosis was 12 months.[255]

Prognosis

In a SEER study of 229 patients with renal, central nervous system (CNS), and extra-renal malignant rhabdoid tumor, patients aged 2 to 18 years, limited extent of tumor, and delivery of radiation therapy were shown to affect the outcome favorably compared with other patients (P < .002 for each comparison). Site of the primary tumor was not prognostically significant. OS at 5 years was 33%.[256]

Treatment

Treatment options for extra-renal (extracranial) rhabdoid tumor include the following:[257][Level of evidence: 3iA]; [258,259][Level of evidence: 3iiiB]

  1. Surgical removal when possible.
  2. Chemotherapy as used for soft tissue sarcomas (but no single regimen is currently accepted as best).
  3. Radiation therapy.

Responses to alisertib have been documented in four patients with CNS atypical teratoid/rhabdoid tumors.[260] (Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment summary for more information about CNS atypical teratoid/rhabdoid tumors.)

Treatment options under clinical evaluation

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

  • NCT02601937 (A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

Neoplasms with perivascular epithelioid cell differentiation (PEComas)

Risk factors and molecular features

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.[261] Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable PEComas with mTOR inhibitors.[262,263] A small proportion of PEComas have TFE3 rearrangements with fusions involving various genes, including SFPQ/PSF and RAD51B.[264]

Clinical presentation

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.[265] The disease course may be indolent.

Prognosis

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.[266]

Treatment

Treatment options have not been defined. Treatment may include surgery or observation followed by surgery when the tumor is large.[267]

Clinical activity with mTOR inhibitors, such as sirolimus, in tumors with evidence of mTORC1 activation and TSC loss has been well documented.[268]

Undifferentiated/Unclassified Sarcoma

Patients with undifferentiated soft tissue sarcoma had been eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the COG from 1972 to 2006. The rationale was the observation that patients with undifferentiated soft tissue sarcoma had sites of disease and outcomes that were similar to those in patients with alveolar rhabdomyosarcoma. Therapeutic trials for adults with soft tissue sarcoma include patients with undifferentiated soft tissue sarcoma and other histologies, which are treated similarly, using ifosfamide and doxorubicin, and sometimes with other chemotherapy agents, surgery, and radiation therapy.

In the COG ARST0332 (NCT00346164) trial, patients with high-grade undifferentiated sarcoma were treated with an ifosfamide and doxorubicin-based regimen and were treated with rhabdomyosarcoma-directed therapies in previous Intergroup Rhabdomyosarcoma Study Group studies, with a 5-year survival estimate for nonmetastatic patients of 72%.[269][Level of evidence: 3iiA]

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

At one time, malignant fibrous histiocytoma was the single most common histotype among adults with soft tissue sarcomas. 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 WHO classification no longer includes malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[4,270]

This entity accounts for 2% to 6% of all childhood soft tissue sarcomas.[271] 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 and in first remission.[271] 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.[272] All patients with metastatic disease died and two patients experienced a clinical response to a doxorubicin-based regimen.

(Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment for more information about the treatment of malignant fibrous histiocytoma of bone.)

Undifferentiated round cell sarcomas with BCOR-CCNB3 rearrangements

Molecular features

Undifferentiated round cell sarcomas are characterized by paracentric inversion of chromosome X and a BCOR-CCNB3 rearrangement; alternative BCOR partners, including MAML3 and ZC3H7B, have also been reported.[273] Despite clinical pathologic similarities to Ewing sarcoma, these tumors are biologically different by expression profiling and single-nucleotide polymorphism array analysis.

Clinical presentation

Undifferentiated round cell sarcoma accounts for about 5% of all EWSR1-negative rearranged sarcomas and more commonly affects males. Over 70% of cases occur in patients younger than 18 years (median age at diagnosis, 13–15 years).[274,275][Level of evidence: 3iiA] These tumors more commonly arise in the bones of the pelvis and extremities, and metastases are present in about 30% of cases.

Treatment

When treated with Ewing sarcoma–like therapies, 75% of patients show significant treatment-associated pathologic responses. In one series of 36 cases, the 3-year and 5-year survival rates were 93% and 72%, respectively.[274][Level of evidence: 3iiA] In another series of 26 patients, the 5-year OS was 76.5%, and survival was better for patients who received induction therapy using a Ewing sarcoma–type regimen.[276][Level of evidence: 3iiA]

Undifferentiated round cell sarcomas with CIC-DUX rearrangements

Molecular features

These tumors are characterized by a CIC-DUX fusion resulting from a recurrent t(4;19) or t(10;19) and are the most common EWSR1-FUS fusion–negative undifferentiated round cell sarcomas.[277]

Clinical presentation

These tumors most commonly affect young adults, with 50% of cases being between the ages of 21 and 40 years. In a series of 115 cases, the median age at diagnosis was 32 years, and 22% of cases occurred in patients younger than 18 years.[275,277] This entity more commonly affects males and usually originates from the soft tissues of the trunk and extremities.

Treatment

In a series of 115 cases of CIC-rearranged round cell sarcomas, 57 patients had adequate follow-up information.[277] Nine patients presented with metastases, and 53% of patients with localized disease experienced a recurrence commonly involving the lung. Patients treated with neoadjuvant chemotherapy had an inferior survival compared with patients who were treated with up-front surgical resection; however, this difference might have been related to a larger tumor size at presentation in the former group. The 2-year and 5-year survival rates were 53% and 43%, respectively. These survival rates are significantly shorter than the survival rates observed in patients with Ewing sarcoma. Further study is required to identify optimal treatments for this disease.

Vascular Tumors

Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant.[278] Malignant vascular tumors include the following subtypes:

Epithelioid hemangioendothelioma

Incidence and outcome

This tumor was first described in soft tissue by Weiss and Enzinger in 1982. Epithelioid hemangioendotheliomas can occur at younger ages, but the peak incidence is in the fourth and fifth decades of life. The tumors can have an indolent or very aggressive course, with overall survival of 73% at 5 years. There are case reports of patients with untreated multiple lesions who have a very benign course compared with other patients who have a very aggressive course. Some pathologists have tried to stratify patients to evaluate risks and adjust treatment, but more research is needed.[279-285]

The presence of effusions, tumor size larger than 3 cm, and a high mitotic index (>3 mitoses/50 high-power fields) have been associated with unfavorable outcomes.[281]

Pathology and biology

A WWTR1-CAMTA1 gene fusion has been found in a large percentage of patients; less commonly, a YAP1-TFE3 gene fusion has been reported.[279] These fusions are not directly targetable with current medicines. Monoclonality has been described in multiple liver lesions, suggesting a metastatic process.

Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns, with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, one or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.[281]

The number of pediatric patients reported in the literature is limited.

Clinical presentation and diagnostic evaluation

Common sites of involvement are liver alone (21%), liver plus lung (18%), lung alone (12%), and bone alone (14%).[281,286,287] Clinical presentation depends on site of involvement, as follows:

  • Liver: Hepatic nodules have central vascularity on ultrasound, contrast-enhancing lesions by computed tomography, and low T1 signal and moderate T2 signal on magnetic resonance imaging.
  • Lung: Pulmonary epithelioid hemangioendothelioma may be an asymptomatic finding on chest x-ray or be associated with pleuritic pain, hemoptysis, anemia, and fibrosis.
  • Bone: Bone metastasis may be associated with pathologic fracture. On x-rays, they are well-defined osteolytic lesions and can be multiple or solitary.
  • Soft tissue: Thirty percent of soft tissue cases are associated with metastases, and when present, can have a very aggressive course, with limited response to chemotherapy.
  • Skin: Cutaneous lesions can be raised and nodular or can be warm red-brown plaques.
Treatment of epithelioid hemangioendothelioma

Treatment options for epithelioid hemangioendothelioma include the following:

  1. Observation.
  2. Surgery.
  3. Immunotherapy.
  4. Targeted therapy.
  5. Chemotherapy.

For indolent cases, observation is warranted. For more aggressive cases, multiple medications have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus.[288] The most aggressive cases are treated with angiosarcoma-type chemotherapy. Surgery is used when possible. Liver transplantation has been used with aggressive liver lesions, both with and without metastases.[281,289-292]

Treatment options under clinical evaluation for epithelioid hemangioendothelioma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

  1. NCT03148275 (Trametinib in Treating Patients with Epithelioid Hemangioendothelioma That Is Metastatic, Locally Advanced, or Cannot Be Removed by Surgery): This is a phase II trial assessing the efficacy of trametinib, with patient-reported outcomes as secondary aims.
  2. NCT01532687 (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma): This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.
Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Angiosarcoma of the soft tissue

Incidence

Angiosarcoma is a rare (accounting for 2% of sarcomas), aggressive, vascular tumor that can arise in any part of the body, but is more common in the soft tissue. Angiosarcoma has an estimated incidence of 2 cases per 1 million people; in the United States, it annually affects approximately 600 people who are typically aged 60 to 70 years.[293]

Angiosarcomas are extremely rare in children and it is unclear if the pathophysiology of this tumor is different in the pediatric population. Cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive.[294-297] Most angiosarcomas involve the skin and superficial soft tissue, although the liver, spleen, and lung can be affected; bone is rarely affected.

Risk factors

Established risk factors include vinyl chloride exposure, radiation exposure, and chronic lymphedema from any cause, including Stewart-Treves syndrome.[298]

Pathology and biology

Angiosarcomas are largely aneuploid tumors. The rare cases of angiosarcoma that arise from benign lesions such as hemangiomas have a distinct pathway that needs to be investigated. MYC amplification is seen in radiation-induced angiosarcoma. KDR-VEGFR2 mutations and FLT4-VEGFR3 amplifications have been seen with a frequency of less than 50%.[298]

Histopathologic diagnosis can be very difficult because there can be areas of varied atypia. The common feature is an irregular network of channels in a dissective pattern along dermal collagen bundles. There is varied cellular shape, size, mitosis, endothelial multilayering, and papillary formation. Epithelioid cells can also be present. Necrosis and hemorrhage are common. Tumors stain for factor VIII, CD31, and CD34. Some liver lesions can mimic infantile hemangiomas and have focal GLUT1 positivity. Nomenclature of these liver lesions has been difficult and confusing with use of terminology from 1971 (e.g., type I hemangioendothelioma: infantile hemangioma; type II hemangioendothelioma: low-grade angiosarcoma; type III hemangioendothelioma: high-grade angiosarcoma).[295]

Treatment of angiosarcoma of the soft tissue

Treatment options for angiosarcoma of the soft tissue include the following:

  1. Surgery (localized disease).
  2. Radiation therapy (localized cutaneous disease in adults).
  3. Surgery, chemotherapy, and radiation therapy (metastatic disease).

Localized disease is cured by aggressive surgery. Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients who were treated with local or systemic therapy.[296,299-301] 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.[301] Data on liver transplantation for localized angiosarcoma are limited.[302][Level of evidence: 3iiA]

Localized disease, especially cutaneous angiosarcoma, can be treated with radiation therapy. Most of these reported cases are in adults.[303]

Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative.[304] Disease control is the objective in metastatic angiosarcoma, with published progression-free survival rates between 3 months and 7 months [305] and a median overall survival (OS) rate of 14 months to 18 months.[306] In both adults and children, 5-year OS rates between 20% and 35% are reported.[296,297,307]

In a child diagnosed with angiosarcoma secondary to malignant transformation from infantile hemangioma, response to treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, combined with systemic chemotherapy, has been reported.[294,304] A report of eight cases of liver angiosarcoma in children highlighted the misuse of the term hemangioendothelioma and the importance of early diagnosis and treatment of these tumors.[308]

Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcoma.[295,307]

Treatment options under clinical evaluation for angiosarcoma of the soft tissue

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  1. NCT01532687 (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma): This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.
Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  295. Dehner LP, Ishak KG: Vascular tumors of the liver in infants and children. A study of 30 cases and review of the literature. Arch Pathol 92 (2): 101-11, 1971. [PUBMED Abstract]
  296. Ferrari A, Casanova M, Bisogno G, et al.: Malignant vascular tumors in children and adolescents: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Med Pediatr Oncol 39 (2): 109-14, 2002. [PUBMED Abstract]
  297. Deyrup AT, Miettinen M, North PE, et al.: Pediatric cutaneous angiosarcomas: a clinicopathologic study of 10 cases. Am J Surg Pathol 35 (1): 70-5, 2011. [PUBMED Abstract]
  298. Elliott P, Kleinschmidt I: Angiosarcoma of the liver in Great Britain in proximity to vinyl chloride sites. Occup Environ Med 54 (1): 14-8, 1997. [PUBMED Abstract]
  299. Lezama-del Valle P, Gerald WL, Tsai J, et al.: Malignant vascular tumors in young patients. Cancer 83 (8): 1634-9, 1998. [PUBMED Abstract]
  300. Fata F, O'Reilly E, Ilson D, et al.: Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 86 (10): 2034-7, 1999. [PUBMED Abstract]
  301. Lahat G, Dhuka AR, Hallevi H, et al.: Angiosarcoma: clinical and molecular insights. Ann Surg 251 (6): 1098-106, 2010. [PUBMED Abstract]
  302. Orlando G, Adam R, Mirza D, et al.: Hepatic hemangiosarcoma: an absolute contraindication to liver transplantation--the European Liver Transplant Registry experience. Transplantation 95 (6): 872-7, 2013. [PUBMED Abstract]
  303. Sanada T, Nakayama H, Irisawa R, et al.: Clinical outcome and dose volume evaluation in patients who undergo brachytherapy for angiosarcoma of the scalp and face. Mol Clin Oncol 6 (3): 334-340, 2017. [PUBMED Abstract]
  304. Dickson MA, D'Adamo DR, Keohan ML, et al.: Phase II Trial of Gemcitabine and Docetaxel with Bevacizumab in Soft Tissue Sarcoma. Sarcoma 2015: 532478, 2015. [PUBMED Abstract]
  305. North PE, Waner M, Mizeracki A, et al.: A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 137 (5): 559-70, 2001. [PUBMED Abstract]
  306. Boye E, Yu Y, Paranya G, et al.: Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest 107 (6): 745-52, 2001. [PUBMED Abstract]
  307. Ravi V, Patel S: Vascular sarcomas. Curr Oncol Rep 15 (4): 347-55, 2013. [PUBMED Abstract]
  308. Grassia KL, Peterman CM, Iacobas I, et al.: Clinical case series of pediatric hepatic angiosarcoma. Pediatr Blood Cancer 64 (11): , 2017. [PUBMED Abstract]

Treatment of Metastatic Childhood Soft Tissue Sarcoma

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

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

For treatment options, refer to the individual tumor type sections of the summary.

The prognosis for children with metastatic soft tissue sarcomas is poor,[1-6] 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.[6-8]

Pulmonary Metastases

Generally, children with isolated pulmonary metastases should be considered for a surgical procedure in an attempt to resect all gross disease.[9] For patients with multiple or recurrent pulmonary metastases, additional surgical procedures can be performed if the morbidity is deemed acceptable. In a retrospective review, patients with synovial sarcoma and pulmonary metastases for whom it was possible to completely resect all metastatic lung lesions had better survival than did patients for whom it was not possible to achieve complete resections.[9][Level of evidence: 3iiiA] Formal segmentectomy, lobectomy, and mediastinal lymph node dissection are unnecessary.[10]

An alternative approach is focused radiation therapy (fractionated stereotactic radiation therapy), which has been successfully used in adults to control 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 after the administration of focused radiation therapy.[11]

References
  1. Demetri GD, Elias AD: Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematol Oncol Clin North Am 9 (4): 765-85, 1995. [PUBMED Abstract]
  2. Elias A, Ryan L, Sulkes A, et al.: Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 7 (9): 1208-16, 1989. [PUBMED Abstract]
  3. Edmonson JH, Ryan LM, Blum RH, et al.: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11 (7): 1269-75, 1993. [PUBMED Abstract]
  4. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec. [PUBMED Abstract]
  5. deCou JM, Rao BN, Parham DM, et al.: Malignant peripheral nerve sheath tumors: the St. Jude Children's Research Hospital experience. Ann Surg Oncol 2 (6): 524-9, 1995. [PUBMED Abstract]
  6. Pappo AS, Rao BN, Jenkins JJ, et al.: Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: the St. Jude Children's Research Hospital experience. Med Pediatr Oncol 33 (2): 76-82, 1999. [PUBMED Abstract]
  7. Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999. [PUBMED Abstract]
  8. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998. [PUBMED Abstract]
  9. Stanelle EJ, Christison-Lagay ER, Wolden SL, et al.: Pulmonary metastasectomy in pediatric/adolescent patients with synovial sarcoma: an institutional review. J Pediatr Surg 48 (4): 757-63, 2013. [PUBMED Abstract]
  10. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995. [PUBMED Abstract]
  11. Dhakal S, Corbin KS, Milano MT, et al.: Stereotactic body radiotherapy for pulmonary metastases from soft-tissue sarcomas: excellent local lesion control and improved patient survival. Int J Radiat Oncol Biol Phys 82 (2): 940-5, 2012. [PUBMED Abstract]

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 will ultimately improve survival. Therefore, treatment should be individualized for the site of recurrence, biologic characteristics of the tumor (e.g., grade, invasiveness, and size), previous therapies, and individual patient considerations.

Treatment options for recurrent or progressive disease include the following:

  1. Surgery.
    • Surgical excision of local recurrence or isolated pulmonary recurrence.
      • An Italian review of 73 patients with recurrent malignant peripheral nerve sheath tumors found that most relapses were local. Multivariate analysis showed that the factors associated with improved survival were no tumor invasiveness at initial diagnosis (T1), time of recurrence more than 12 months after initial diagnosis, and achievement of a second complete response with surgical removal of the recurrence(s). Only 15.8% of patients who had complete surgical excisions of local recurrence(s) were alive at 5 years.[1][Level of evidence: 3iiiA]
    • Surgical excision of local recurrence followed by radiation therapy or brachytherapy (if no previous radiation therapy was given).
    • Limb amputation (only for some children with extremity sarcomas that have already received radiation therapy).
  2. Chemotherapy.
    • Gemcitabine and docetaxel.[2]
    • Trabectedin.[3-5]
    • A clinical trial of new chemotherapeutic regimens.
  3. Tyrosine kinase inhibitors.
    • Pazopanib. A phase I trial of pazopanib reported one partial response in a patient with desmoplastic small round cell tumor and prolonged disease stabilization in eight patients with recurrent sarcoma.[6][Level of evidence: 2Diii] Pazopanib has been approved for use in recurrent soft tissue sarcoma. The clinical trial that was used to obtain approval was limited to adults and demonstrated disease stabilization and prolonged time to progression; it did not demonstrate improved overall survival.[7] One 13-year-old boy and one 14-year-old girl with multiply recurrent synovial sarcoma and lung metastases had responses to pazopanib for 14 and 15 months, respectively.[8][Level of evidence: 3iiDi]
  4. Immune checkpoint inhibitors.
    • The Sarcoma Alliance for Research through Collaboration conducted a phase II trial of the checkpoint inhibitor pembrolizumab in patients aged 18 years and older with recurrent soft tissue sarcoma.[9][Level of evidence: 3iiDiv] Seven of 40 patients (18%) with soft tissue sarcoma had an objective response, including four of ten patients (40%) with undifferentiated pleomorphic sarcoma, two of ten patients (20%) with liposarcoma, and one of ten patients (10%) with synovial sarcoma. No patients with leiomyosarcoma (n = 10) had an objective response.
  5. Radiation therapy.
    • Targeted (stereotactic body) radiation therapy is an option for sites of metastasis, particularly the lung.[10]

Resection is the standard treatment for recurrent pediatric nonrhabdomyosarcomatous soft tissue sarcomas. If the patient has not yet received radiation therapy, postoperative radiation should be considered after local excision of the recurrent tumor. Limb-sparing procedures with postoperative 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.[11] A large, retrospective analysis of patients with recurrent soft tissue sarcoma showed that isolated local relapse had a better prognosis and that resection of pulmonary metastases improved the probability of survival.[12] In 31 children and adolescents younger than 23 years with pulmonary metastases from synovial sarcoma, complete resection of lung metastases appeared to prolong survival when compared with ten other patients who were not considered candidates for metastasectomy.[13][Level of evidence: 3iiiA] Targeted radiation therapy is also an option for local control or palliation of pulmonary metastases, particularly in patients for whom the morbidity of resection is a concern or whose life expectancy is limited.[10] All patients with recurrent tumors should be considered for current clinical trials.

Published results of two studies addressed the outcomes of children with relapsed synovial sarcoma. Most patients in one study had distant relapse (29 of 44 patients),[14] while most patients in the second study had local relapse (27 of 37 patients).[15] Distant recurrence was a poor prognostic variable, while tumor resectability at relapse (as manifested by extremity recurrence) was associated with a better outcome in both studies.

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Bergamaschi L, Bisogno G, Manzitti C, et al.: Salvage rates and prognostic factors after relapse in children and adolescents with malignant peripheral nerve sheath tumors. Pediatr Blood Cancer 65 (2): , 2018. [PUBMED Abstract]
  2. 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. [PUBMED Abstract]
  3. Le Cesne A, 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. [PUBMED Abstract]
  4. 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. [PUBMED Abstract]
  5. 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. [PUBMED Abstract]
  6. Glade Bender JL, Lee A, Reid JM, et al.: Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children's oncology group phase I consortium report. J Clin Oncol 31 (24): 3034-43, 2013. [PUBMED Abstract]
  7. van der Graaf WT, Blay JY, Chawla SP, et al.: Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379 (9829): 1879-86, 2012. [PUBMED Abstract]
  8. Casanova M, Basso E, Magni C, et al.: Response to pazopanib in two pediatric patients with pretreated relapsing synovial sarcoma. Tumori 103 (1): e1-e3, 2017. [PUBMED Abstract]
  9. Tawbi HA, Burgess M, Bolejack V, et al.: Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 18 (11): 1493-1501, 2017. [PUBMED Abstract]
  10. Dhakal S, Corbin KS, Milano MT, et al.: Stereotactic body radiotherapy for pulmonary metastases from soft-tissue sarcomas: excellent local lesion control and improved patient survival. Int J Radiat Oncol Biol Phys 82 (2): 940-5, 2012. [PUBMED Abstract]
  11. 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. [PUBMED Abstract]
  12. 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. [PUBMED Abstract]
  13. Stanelle EJ, Christison-Lagay ER, Wolden SL, et al.: Pulmonary metastasectomy in pediatric/adolescent patients with synovial sarcoma: an institutional review. J Pediatr Surg 48 (4): 757-63, 2013. [PUBMED Abstract]
  14. Ferrari A, De Salvo GL, Dall'Igna P, et al.: Salvage rates and prognostic factors after relapse in children and adolescents with initially localised synovial sarcoma. Eur J Cancer 48 (18): 3448-55, 2012. [PUBMED Abstract]
  15. Soole F, Maupain C, Defachelles AS, et al.: Synovial sarcoma relapses in children and adolescents: prognostic factors, treatment, and outcome. Pediatr Blood Cancer 61 (8): 1387-93, 2014. [PUBMED Abstract]

Changes to This Summary (11/21/2018)

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:

  • Denise Adams, MD (Children's Hospital Boston)
  • Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
  • Holcombe Edwin Grier, MD
  • Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center 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 NCI website's Email Us. 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:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Soft Tissue Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-soft-tissue-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389361]

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  • Updated: November 21, 2018

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