Childhood Soft Tissue Sarcoma Treatment (PDQ®)

Incidence of Soft Tissue Sarcoma by Age and Histology

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

Table

Table 1. Age Distribution of Soft Tissue Sarcomas in Children Aged 0 to 19 Years (SEER 2000–2015)^a.

NRSTS are more common in adolescents and adults.[6] Most of the information regarding treatment and natural history of the disease in younger patients has been based on studies in adult patients. The distributions of these tumors by age according to stage (Figure 1), histological subtype (Figure 2), and tumor site (Figure 3) are shown below.[7]

Figure 1. The distribution of nonrhabdomyosarcomatous soft tissue sarcomas by age according to stage.

Figure 2. The distribution of nonrhabdomyosarcomatous soft tissue sarcomas by age according to histological subtype.

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 NRSTS, including the following:

• Genetic factors:

  -

  Li-Fraumeni syndrome: Patients with Li-Fraumeni syndrome (usually resulting from heritable cancer-associated changes of the TP53 tumor suppressor gene) have an increased risk of developing soft tissue tumors (mostly NRSTS), 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]

  -

  RB1 gene: Germline variants of the RB1 gene have been associated with an increased risk of developing soft tissue sarcoma, particularly leiomyosarcoma, and the risk appears higher among those younger than 1 year who were treated with alkylating agents.[11,12]

  -

  SMARCB1 gene: Germline variants or deletions of the SMARCB1 (INI1) gene are associated with an increased risk of developing extrarenal rhabdoid tumors.[13] For more information about SMARCB1 and rhabdoid tumor predisposition syndrome type 1, see Rhabdoid Tumor Predisposition Syndrome Type 1.

  -

  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 NRSTS (particularly malignant fibrous histiocytoma) can develop within a previously irradiated site.[22-26]

  -

  Epstein-Barr virus (EBV) infection in patients with AIDS: Some NRSTS (e.g., leiomyosarcoma) have been linked to EBV infection in patients with AIDS.[22,27]

Clinical Presentation

NRSTS can develop in any part of the body, but they arise most commonly in the trunk and extremities.[28-30] Although rare, these tumors can arise in brain tissue and are treated according to the histological type.[31]

NRSTS can present initially as an asymptomatic solid mass, or they may be symptomatic because of local invasion of adjacent anatomical structures. Systemic symptoms (e.g., fever, weight loss, and night sweats) are rare. Hypoglycemia and hypophosphatemic rickets have been reported in cases of hemangiopericytoma (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.[32]

Diagnostic and Staging Evaluation

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

• 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.
• Computed tomography (CT). Chest CT is essential to assess the presence of metastases. An abdominal CT can be used to image intra-abdominal tumors, such as liposarcoma. Patients with NRSTS who were treated in 11 centers as part of the European paediatric Soft Tissue Sarcoma Study Group (EpSSG) were retrospectively assessed to evaluate the impact of indeterminate pulmonary nodules identified on chest CT.[33] Of the 206 patients examined, 109 (52.9%) did not have any nodules, 78 (38%) had at least one indeterminate nodule, and 19 (9.2%) had nodules meeting the definition of metastases. The 5-year event-free survival (EFS) rate was 78.5% (95% confidence interval [CI], 69.4%–85.1%) for patients without nodules and 69.6% (95% CI, 57.9%–78.7%) for patients with indeterminate nodules (P = .135). The 5-year overall survival (OS) rate was 87.4% (95% CI, 79.3%–92.5%) for patients without nodules and 79.0% (95% CI, 67.5%–86.8%) for patients with indeterminate nodules (P = .086).
• Magnetic resonance imaging (MRI). MRI can be used to image intra-abdominal tumors, such as liposarcoma, and is essential for extremity lesions.
• Positron emission tomography (PET) scan and bone scan. In a retrospective study, 46 PET scans were completed in 25 pediatric patients with soft tissue sarcoma.[34] The positive predictive value of finding metastatic disease was 89%, and the negative predictive value was 67%. A small retrospective study of nine patients with NRSTS suggested that PET-CT was more accurate and cost-effective than either modality alone in identifying distant metastatic disease.[35] The use of this modality in pediatric NRSTS has not been studied prospectively.

The imaging characteristics of some tumors can be highly suggestive of that particular 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.[36]

Chromosomal abnormalities

Many NRSTS 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 NRSTS are listed in Table 2.

Table

Table 2. Frequent Chromosomal Aberrations Seen in Nonrhabdomyosarcomatous Soft Tissue Sarcoma^a.

Prognosis and Prognostic Factors

The prognosis of NRSTS varies greatly depending on the following factors:[71-73]

• Site of the primary tumor.
• Tumor size.
• Tumor grade. For more information, see the Soft Tissue Sarcoma Tumor Pathological Grading System section.
• Tumor histology.
• Depth of tumor invasion.
• Presence of metastases and site of the metastatic tumor.
• Resectability of the tumor.
• Use of radiation therapy.

In a review of a large adult series of NRSTS, patients with superficial extremity sarcomas had a better prognosis than did patients with deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.[74]

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.[75] This relationship has been questioned and requires further study to determine the therapeutic implications of the observation.[76]

Some pediatric NRSTS are associated with a better outcome. For instance, patients with infantile fibrosarcoma who present at age 4 years or younger have an excellent prognosis. This excellent outcome occurs because surgery alone can cure a significant number of these patients and infantile fibrosarcoma is highly chemosensitive. This tumor also responds well to larotrectinib, a specific tropomyosin receptor kinase inhibitor.[22,77]

Prognosis based on the Children's Oncology Group (COG) ARST0332 trial

Soft tissue sarcomas in older children and adolescents often behave similarly to those in adult patients.[22,78] A large, prospective, multinational COG study (ARST0332 [NCT00346164]) enrolled newly diagnosed patients younger than 30 years. Patients were assigned to treatment on the basis of their risk group. Risk groups were defined by the presence of metastasis, tumor resectability and margins, and tumor size and grade. For more information, see Figure 4.[79][Level of evidence B4]

Figure 4. Risk group and treatment assignment for the Children’s Oncology Group ARST0332 trial. Reprinted from The Lancet Oncology, Volume 21 (Issue 1), Spunt SL, Million L, Chi YY, et al., A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study, Pages 145–161, Copyright © 2020, with permission from Elsevier.

Each patient was assigned to one of three risk groups and one of four treatment groups. The risk groups were as follows:[79]

1. Low risk: Nonmetastatic R0 (resection was complete with negative microscopic margins) or R1 (microscopically positive margins) low-grade tumor, or ≤5 cm R1 high-grade tumor.
2. Intermediate risk: Nonmetastatic R0 or R1 >5 cm high-grade tumor, or unresected tumor of any size or grade.
3. High risk: Metastatic tumor.

The treatment groups were as follows:

1. Surgery alone (n = 205).
2. Radiation therapy (55.8 Gy) (n = 17).
3. Chemoradiation therapy (chemotherapy and 55.8 Gy radiation therapy) (n = 111).
4. Neoadjuvant chemoradiation therapy (chemotherapy and 45 Gy radiation therapy, then surgery and radiation therapy boost based on margins with continued chemotherapy) (n = 196).

Chemotherapy included six cycles of ifosfamide (3 g/m² per dose) administered intravenously on days 1 through 3 and five cycles of doxorubicin (37.5 mg/m² per dose) administered intravenously on days 1 to 2 every 3 weeks, with the sequence adjusted on the basis of the timing of surgery or radiation therapy.

For the 550 patients enrolled, 529 evaluable patients were included in the analysis; at a median follow-up of 6.5 years (interquartile range [IQR], 4.9–7.9), the survival results are shown in Table 3.

Table

Table 3. Survival Results for the Children's Oncology Group ARST0332 Trial.

Pediatric patients with unresected localized NRSTS have a poor outcome. Only about one-third of patients treated with multimodality therapy remain disease free.[71,80]; [81,82][Level of evidence C1] In an Italian review of 30 patients with NRSTS at visceral sites, only ten patients survived at 5 years. Unfavorable prognostic factors included inability to achieve complete resection, large tumor size, tumor invasion, histological subtype, and lung-pleura sites.[83][Level of evidence C1]

Prognosis based on the European paediatric Soft Tissue Sarcoma Study Group (EpSSG) NRSTS 2005 study

The EpSSG conducted a prospective trial for patients younger than 21 years with NRSTS. They reported an analysis of 206 patients with synovial sarcoma and 363 with adult-type NRSTS. Patients were treated according to assigned risk groups. For more information, see Figure 5.[84] With a median follow-up of 80 months (interquartile range, 54.3–111.3) for the 467 surviving patients, the 5-year event-free survival (EFS) rate was 73.7% (95% CI, 69.7%–77.2%), and the OS rate was 83.8% (95% CI, 80.3%–86.7%). The survival by treatment groups are shown in Table 4.[84]

Figure 5. Treatment plan for patients with synovial sarcoma or adult-type non-rhabdomyosarcoma soft tissue sarcomas. Patients were divided into four treatment groups based on surgical stage, tumour size, nodal involvement, tumour grade (according to the Fédération Nationale des Centres de Lutte Contre le Cancer grading system for adult-type non-rhabdomyosarcoma soft tissue sarcomas), and tumour site (for synovial sarcoma). I+D = ifosfamide (3.0 g/m² per day intravenously for 3 days) plus doxorubicin (37.5 mg/m² per day intravenously for 2 days). I = ifosfamide (3.0 g/m² per day intravenously for 2 days). IRS = Intergroup Rhabdomyosarcoma Study. N1 = nodal involvement. S = delayed surgery. Reprinted from The Lancet Child & Adolescent Health, Volume 5, Issue 8, Ferrari A, van Noesel MM, Brennan B, et al., Paediatric non-rhabdomyosarcoma soft tissue sarcomas: the prospective NRSTS 2005 study by the European paediatric Soft Tissue Sarcoma Study Group (EpSSG), Pages 546-558, Copyright 2021, with permission from Elsevier.

Table

Table 4. Survival Outcomes by Treatment Groups in the EpSSG NRSTS 2005 Study.

Overall, local control after radiation therapy was as follows: R0, 106 of 109 patients (97%); R1, 51 of 60 patients (85%); and R2/unresectable, 2 of 6 patients (33%). Local recurrence predictors included extent of delayed resection (P < .001), imaging response before delayed surgery (P < .001), histological subtype (P < .001), and no radiation therapy (P = .046). The 5-year EFS was significantly lower for patients unable to undergo R0 or R1 resection (P = .0003).[85]

The authors concluded that adjuvant therapy could safely be omitted in the group of patients assigned to surgery alone. They also concluded that improving the outcome for patients with high-risk, initially resected, adult-type NRSTS and those with initially unresected disease remains a major clinical challenge.[84]

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.[81][Level of evidence C1]

Because long-term morbidity must be minimized while disease-free survival is maximized, the ideal therapy for each patient must be carefully and individually determined using these prognostic factors before initiating therapy.[29,86-90]

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70. 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: 27776010]
71. 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: 12149295]
72. 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: 10577841]
73. 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: 15767645]
74. 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: 9524707]
75. 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: 19064986]
76. Rodeberg DA, Stoner JA, Garcia-Henriquez N, et al.: Tumor volume and patient weight as predictors of outcome in children with intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group. Cancer 117 (11): 2541-50, 2011. [PMC free article: PMC3117103] [PubMed: 24048802]
77. Hong DS, DuBois SG, Kummar S, et al.: Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 21 (4): 531-540, 2020. [PMC free article: PMC7497841] [PubMed: 32105622]
78. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. Mosby, 2001.
79. Spunt SL, Million L, Chi YY, et al.: A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study. Lancet Oncol 21 (1): 145-161, 2020. [PMC free article: PMC6946838] [PubMed: 31786124]
80. 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: 12103287]
81. 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. [PMC free article: PMC3539303] [PubMed: 21145727]
82. 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: 21671361]
83. Ferrari A, Magni C, Bergamaschi L, et al.: Pediatric nonrhabdomyosarcoma soft tissue sarcomas arising at visceral sites. Pediatr Blood Cancer 64 (9): , 2017. [PubMed: 28233470]
84. Ferrari A, van Noesel MM, Brennan B, et al.: Paediatric non-rhabdomyosarcoma soft tissue sarcomas: the prospective NRSTS 2005 study by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG). Lancet Child Adolesc Health 5 (8): 546-558, 2021. [PubMed: 34214481]
85. Million L, Hayes-Jordan A, Chi YY, et al.: Local Control For High-Grade Nonrhabdomyosarcoma Soft Tissue Sarcoma Assigned to Radiation Therapy on ARST0332: A Report From the Childrens Oncology Group. Int J Radiat Oncol Biol Phys 110 (3): 821-830, 2021. [PMC free article: PMC8767764] [PubMed: 33548339]
86. 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: 7472928]
87. 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: 7964951]
88. Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997. [PubMed: 9386667]
89. 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: 10561182]
90. 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: 9473754]

World Health Organization (WHO) Classification of Soft Tissue Tumors

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 WHO published a revision to their classification of soft tissue and bone tumors in 2020. The classification had several updates to existing classification, nomenclature, grading, and risk stratification schemes. The revised classification includes newly described entities, and it uses molecular alterations in the classifications.[1]

The grading of soft tissue tumors has always been a controversial issue. The 2020 WHO classification represents the consensus of several soft tissue pathologists and geneticists, as well as a medical oncologist, radiologist, and surgeon. This edition further integrates morphological and genetic information into the classification. For example, a new category of tumors called NTRK-rearranged spindle cell neoplasms was included, but infantile fibrosarcoma was excluded from this group. Ewing sarcoma was removed from the bone tumor section and, instead, is in the undifferentiated small cell sarcomas of bone and soft tissue section. This classification reflects the variable presentation sites and the variety of translocations seen in Ewing sarcoma. This classification also separated Ewing sarcoma from entities such as CIC-rearranged sarcomas, BCOR-rearranged sarcomas, and EWSR1 gene fusions involving non-ETS partner genes.[1]

1. Adipocytic tumors.

   1. Benign.

      • Lipoma not otherwise specified (NOS).
      • Lipomatosis.
      • Lipomatosis of nerve.
      • Lipoblastomatosis.
      • Angiolipoma NOS.
      • Myolipoma.
      • Chondroid lipoma.
      • Spindle cell lipoma.
      • Atypical spindle cell/pleomorphic lipomatous tumor.
      • Hibernoma.
   2. Intermediate (locally aggressive).

      • Atypical lipomatous tumor.
   3. Malignant.

      • Liposarcoma, well-differentiated, NOS.
      • Dedifferentiated liposarcoma.
      • Myxoid liposarcoma.
      • Pleomorphic liposarcoma.
      • Myxoid pleomorphic liposarcoma.
2. Chondro-osseous tumors.

   1. Benign.

      • Chondroma NOS.
   2. Malignant.

      • Osteosarcoma, extraskeletal.
3. Fibroblastic and myofibroblastic tumors.

   1. Benign.

      • Nodular fasciitis.
      • Proliferative fasciitis.
      • Proliferative myositis.
      • Myositis ossificans and 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.
      • Myofibroblastoma.
      • Calcifying aponeurotic fibroma.
      • EWSR1::SMAD3-positive fibroblastic tumor (emerging).
      • Angiomyofibroblastoma.
      • Cellular angiofibroma.
      • Angiofibroma NOS.
      • Nuchal fibroma.
      • Acral fibromyxoma.
      • Gardner fibroma.
   2. Intermediate (locally aggressive).

      • Solitary fibrous tumor, benign.
      • Palmar/plantar-type fibromatosis.
      • Desmoid-type fibromatosis (previously called desmoid tumor or aggressive fibromatoses).
      • Lipofibromatosis.
      • Giant cell fibroblastoma.
   3. Intermediate (rarely metastasizing).

      • Dermatofibrosarcoma protuberans NOS.

        -

        Pigmented dermatofibrosarcoma protuberans.

        -

        Dermatofibrosarcoma protuberans, fibrosarcomatous.

        -

        Myxoid dermatofibrosarcoma protuberans.

        -

        Plaque-like dermatofibrosarcoma protuberans.

      • Solitary fibrous tumor NOS.
      • Inflammatory myofibroblastic tumor.

        • Epithelioid inflammatory myofibroblastic sarcoma.
      • Myofibroblastic sarcoma.
      • Superficial CD34-positive fibroblastic tumor.
      • Myxoinflammatory fibroblastic sarcoma.
      • Infantile fibrosarcoma.[2]
   4. Malignant.

      • Solitary fibrous tumor, malignant.
      • Fibrosarcoma NOS.
      • Myxofibrosarcoma.
      • Low-grade fibromyxoid sarcoma.[3]
      • Sclerosing epithelioid fibrosarcoma.
4. Skeletal muscle tumors.

   1. Benign.

      • Rhabdomyoma NOS.
   2. Malignant.

      • Rhabdomyosarcoma (embryonal, spindle cell/sclerosing, alveolar, and pleomorphic forms). For more information, see Childhood Rhabdomyosarcoma Treatment.
      • Ectomesenchymoma.
5. Smooth muscle tumors.

   1. Benign and intermediate.

      • Leiomyoma NOS.
      • Smooth muscle tumor of uncertain malignant potential.
   2. Malignant.

      • Leiomyosarcoma NOS.
      Angioleiomyoma was reclassified under perivascular tumors.
6. So-called fibrohistiocytic tumors.

   1. Benign.

      • Tenosynovial giant cell tumor NOS.

        -

        Diffuse type.

      • Deep benign fibrous histiocytoma.
   2. Intermediate (rarely metastasizing).

      • Plexiform fibrohistiocytic tumor.
      • Giant cell tumor of soft parts NOS.
   3. Malignant.

      • Malignant tenosynovial giant cell tumor.
7. Peripheral nerve sheath tumors.

   1. Benign.

      • Schwannoma NOS (including variants).
      • Neurofibroma NOS (including variants).

        -

        Plexiform neurofibroma.

      • Perineurioma NOS.
      • Granular cell tumor NOS.
      • Nerve sheath myxoma.
      • Solitary circumscribed neuroma.
      • Meningioma NOS.
      • Benign triton tumor/neuromuscular choristoma.
      • Hybrid nerve sheath tumor.
   2. Malignant.

      • Malignant peripheral nerve sheath tumor NOS.

        • Malignant peripheral nerve sheath tumor, epithelioid.
      • Melanotic malignant peripheral nerve sheath tumor.
      • Granular cell tumor, malignant.
      • Perineurioma, malignant.
8. Pericytic (perivascular) tumors.

   1. Benign and intermediate.

      • Glomus tumor NOS (including variants).

        -

        Glomangiomatosis.

      • Myopericytoma.

        -

        Myofibromatosis.

        -

        Myofibroma (hemangiopericytomas are now included in recent WHO classification).

        -

        Infantile myofibromatosis.

      • Angioleiomyoma.
   2. Malignant.

      • Glomus tumor, malignant.
9. Tumors of uncertain differentiation.

   1. Benign.

      • Myxoma NOS.
      • Aggressive angiomyxoma.
      • Pleomorphic hyalinizing angiectatic tumor.
      • Phosphaturic mesenchymal tumor NOS.
      • Perivascular epithelioid tumor, benign.
      • Angiomyolipoma.
   2. Intermediate (locally aggressive).

      • Hemosiderotic fibrolipomatous tumor.
      • Angiomyolipoma, epithelioid.
   3. Intermediate (rarely metastasizing).

      • Atypical fibroxanthoma.
      • Angiomatoid fibrous histiocytoma.
      • Ossifying fibromyxoid tumor NOS.
      • Mixed tumor NOS.
      • Mixed tumor, malignant, NOS.
      • Myoepithelioma NOS.
   4. Malignant.

      • Phosphaturic mesenchymal tumor, malignant.
      • NTRK-rearranged spindle cell neoplasm (emerging).
      • Synovial sarcoma NOS.

        -

        Synovial sarcoma, spindle cell.

        -

        Synovial sarcoma, biphasic.

        -

        Synovial sarcoma, poorly differentiated.

      • Epithelioid sarcoma.
      • Alveolar soft part sarcoma.
      • Clear cell sarcoma NOS.
      • Extraskeletal myxoid chondrosarcoma.
      • Desmoplastic small round cell tumor.
      • Rhabdoid tumor NOS (extrarenal).
      • Perivascular epithelioid tumor, malignant.
      • Intimal sarcoma.
      • Ossifying fibromyxoid tumor, malignant.
      • Myoepithelial carcinoma.
      • Undifferentiated sarcoma.
      • Spindle cell sarcoma, undifferentiated.
      • Pleomorphic sarcoma, undifferentiated.
      • Round cell sarcoma, undifferentiated.
10. Vascular tumors.

    1. Benign.

       • Hemangioma NOS. For more information, see Childhood Vascular Tumors Treatment.
       • Intramuscular hemangioma.
       • Arteriovenous hemangioma.
       • Venous hemangioma.
       • Epithelioid hemangioma.
       • Lymphangioma NOS.
       • Cystic lymphangioma.
       • Acquired tufted hemangioma.
    2. Intermediate (locally aggressive).

       • Kaposiform hemangioendothelioma.
    3. Intermediate (rarely metastasizing).

       • Retiform hemangioendothelioma.
       • Papillary intralymphatic angioendothelioma.
       • Composite hemangioendothelioma.
       • Kaposi sarcoma.

         • Classic indolent Kaposi sarcoma.
         • Endemic African Kaposi sarcoma.
         • AIDS-associated Kaposi sarcoma.
         • Iatrogenic Kaposi sarcoma.
       • Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma.
    4. Malignant.

       • Epithelioid hemangioendothelioma NOS.

         • Epithelioid hemangioendothelioma with WWTR1::CAMTA1 fusion.
         • Epithelioid hemangioendothelioma with YAP1::TFE3 fusion.
       • Angiosarcoma.

With the increased use of next-generation sequencing techniques and heightened awareness of recently approved tyrosine kinase inhibitors that target NTRK and other genes, newer subgroups of pediatric soft tissue lesions that are characterized by kinase fusions have been identified and share a similar morphological spectrum. Identifying these rare entities is important because some of them might be amenable to therapeutic targeting with novel agents. Some examples of these lesions are described below.[4]

• Lipofibromatosis-like neural tumors are superficial tumors that commonly affect children, and the cells are immunoreactive for S100. These tumors commonly have NTRK1 fusions but rarely harbor RET or ALK fusions.
• Spindle cell tumors with S100 and CD34 positivity that resemble intermediate-grade malignant peripheral nerve sheath tumors predominate in children and young adults and can affect bone and soft tissues. They have fusions in various genes, including RAF1, BRAF, NTRK1, and NTRK2.
• Infantile fibrosarcoma–like lesions morphologically resemble infantile fibrosarcoma and most commonly affect patients younger than 2 years. They have a predilection for intraabdominal sites. They often exhibit alternate fusions, involving genes such as BRAF, NTRK1, and MET.
• Spindle cell sarcomas with hemangiopericytic and myopericytic patterns can affect children and have NTRK1 fusions.
• RAF1 fusion–positive spindle cell sarcomas can be seen in children and adults and often arise in the trunk. They rarely behave aggressively.
• BRAF fusion–positive soft tissue tumors have been associated with infantile fibrosarcoma–like variants or spindle cell sarcomas that resemble malignant peripheral nerve sheath tumors. They have been reported in children and often involve the abdominal cavity.
• RET fusion–positive tumors predominantly affect children and have a similar phenotype to NTRK fusion–positive tumors. They can display fibroblastic and neural-like differentiation. These tumors are sensitive to the highly selective small-molecule RET inhibitor selpercatinib.[5]

References

1. WHO Classification of Tumours Editorial Board: WHO Classification of Tumours. Volume 3: Soft Tissue and Bone Tumours. 5th ed., IARC Press, 2020.
2. 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: 21843073]
3. 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: 21921785]
4. Antonescu CR: Emerging soft tissue tumors with kinase fusions: An overview of the recent literature with an emphasis on diagnostic criteria. Genes Chromosomes Cancer 59 (8): 437-444, 2020. [PMC free article: PMC8323076] [PubMed: 32243019]
5. Ortiz MV, Gerdemann U, Raju SG, et al.: Activity of the Highly Specific RET Inhibitor Selpercatinib (LOXO-292) in Pediatric Patients With Tumors Harboring RET Gene Alterations. JCO Precis Oncol 4: , 2020. [PMC free article: PMC7450975] [PubMed: 32923911]

Intergroup Rhabdomyosarcoma Study Staging System

TNM Staging System

The eighth edition of the AJCC Cancer Staging Manual has designated staging by the four criteria of tumor size, nodal status, histological 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) (see Tables 5, 6, 7, and 8).[3-7] For information about unusual histologies and sites, see the AJCC Cancer Staging Manual.[7]

Table

Table 5. Definition of Primary Tumor (T) for Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneum; Head and Neck; and Abdomen and Thoracic Visceral Organs^a.

Table

Table 6. Definition of Regional Lymph Node (N) for Soft Tissue Sarcoma of the Head and Neck; Trunk and Extremities; Abdomen and Thoracic Visceral Organs; and Retroperitoneum^a.

Table

Table 7. Definition of Distant Metastasis (M) for Soft Tissue Sarcoma of the Head and Neck; Trunk and Extremities; Abdomen and Thoracic Visceral Organs; and Retroperitoneum^a.

Table

Table 8. AJCC Prognostic Stage Groups for Soft Tissue Sarcoma of the Trunk, Extremities, and Retroperitoneum^a.

Soft Tissue Sarcoma Tumor Pathological Grading System

In most cases of soft tissue sarcomas, accurate histopathological classification alone does not yield optimal information about their clinical behavior. Therefore, several histological 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 histological findings and clinical outcome.[9] In children, grading of soft tissue sarcoma is complicated by certain factors, such as prognosis, patient age, extent of surgical resection, and ability to metastasize. For example, children younger than 4 years with infantile fibrosarcoma and hemangiopericytoma have a good prognosis, and angiomatoid fibrous histiocytoma and dermatofibrosarcoma protuberans can 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 NRSTS and devised the POG grading system. Analysis of outcome for patients with localized NRSTS 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 NRSTS.[9-11]

The POG and Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) grading systems have proven to be of prognostic value in pediatric and adult NRSTS.[12-16] The COG uses the FNCLCC clinically. In a study of 130 tumors from children and adolescents with NRSTS 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.[17]

The COG ARST0332 (NCT00346164) trial compared the POG and FNCLCC pathological grading systems as part of a prospective risk-based strategy. The study found that, in addition to tumor depth and invasiveness, the FNCLCC grade was strongly associated with event-free survival and overall survival.[18] The closed COG ARST1321 (NCT02180867) trial used the FNCLCC system to assign histological grade.

The FNCLCC Sarcoma Group is described below. The POG grading system is no longer used.

References

1. American Joint Committee on Cancer: AJCC Cancer Staging Manual. 6th ed. 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: 3275486]
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. 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. 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. 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. 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. 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: 25968827]
9. Parham DM, Webber BL, Jenkins JJ, et al.: Nonrhabdomyosarcomatous soft tissue sarcomas of childhood: formulation of a simplified system for grading. Mod Pathol 8 (7): 705-10, 1995. [PubMed: 8539226]
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: 9872660]
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: 10665717]
12. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec. [PubMed: 8284572]
13. 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: 8622088]
14. 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: 8622035]
15. 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: 7964951]
16. 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: 9473754]
17. 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. [PMC free article: PMC2987713] [PubMed: 20166208]
18. Spunt SL, Million L, Chi YY, et al.: A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study. Lancet Oncol 21 (1): 145-161, 2020. [PMC free article: PMC6946838] [PubMed: 31786124]
19. 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: 11346874]
20. 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: 8996162]

Surgery

Surgical resection of the primary tumor is the predominant therapy for most NRSTS. In the COG ARST0332 (NCT00346164) study, approximately 37% of patients younger than 30 years were treated with surgery alone.[1] Another 36% of patients had surgical resection after neoadjuvant chemoradiation therapy. Involvement of a surgeon with special expertise in the resection of soft tissue sarcomas is highly desirable.

After an appropriate biopsy and pathological diagnosis, every attempt is made to resect the primary tumor. Completeness of resection predicts outcome. In the COG ARST0332 study, complete resections with negative microscopic margins (R0) resulted in the best outcomes.[1]

• The 5-year EFS rates for patients treated with surgery and other modalities were the following:

  • 84% for patients who had R0 resections.
  • 66% for patients who had R1 resections.
  • 49% for patients who had R2 resections.
• The 5-year OS rates for patients treated with surgery and other modalities were the following:

  • 93% for patients who had R0 resections.
  • 80% for patients who had R1 resections.
  • 63% for patients who had R2 resections.
• The 5-year EFS rates for patients treated with surgery only were the following:

  • 96% for patients with low-grade tumors who had R0 resections.
  • 81% for patients with low-grade tumors who had R1 resections.
  • 84% for patients with high-grade tumors that were smaller than 5 cm and had R0 resections.

The COG reported results for the subset of patients with low-grade NRSTS enrolled in the ARST0332 study.[2] Low-risk patients were treated with surgery alone. Intermediate- and high-risk patients received ifosfamide/doxorubicin and radiation therapy, with definitive resection either before or after 12 weeks of chemotherapy and radiation therapy.

Table

Table 9. Survival Results From the ARST0332 Study.

• In low-risk patients, local-only recurrences were seen in 10% of patients. No patients with margins of resection greater than 1 mm had local recurrences.
• Sixteen of 17 intermediate- and high-risk patients who completed neoadjuvant chemotherapy and radiation therapy underwent gross-total tumor resection, and 80% had negative margins.
• In the intermediate- and high-risk group, events included one local recurrence and seven metastatic recurrences.

The timing of surgery depends on an assessment of the feasibility and morbidity of surgery. In the COG ARST0332 study, the outcomes were nearly identical for intermediate-risk patients who achieved an R0 or R1 resection with up-front surgery or surgery after neoadjuvant chemoradiation therapy (70% vs. 71%, respectively). An R0 resection was more likely to occur after neoadjuvant therapy.[1] These observations are true even for high-grade tumors, where ability to achieve R0 or R1 resection was the major predictor of EFS. Treatment with neoadjuvant chemoradiation therapy resulted in lower doses of radiation therapy and achieved greater rates of R0 resection.[3] Resectability should be determined at the time of diagnosis, with an emphasis on achieving negative margins without loss of form or function.

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.[4-7] This surgical tenet is true even if no mass is detected by magnetic resonance imaging after initial surgery.[8]; [9][Level of evidence C1]

Regional lymph node metastases at diagnosis are unusual and are most often seen in patients with epithelioid and clear cell sarcomas.[10,11] Sentinel lymph node biopsy as a staging procedure in soft tissue sarcoma remains controversial. However, it may help manage selected cases in adults with clear cell sarcoma and epithelioid sarcoma. There are insufficient data to support the use of sentinel lymph node biopsy in the management of pediatric patients with other NRSTS.[12-17]

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 functions, or causing 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 subsequent neoplasm).

Radiation therapy can be given preoperatively or postoperatively. It can also be used as definitive therapy in rare situations in which surgical resection is not performed.[18] Radiation field size and dose will be based on patient and tumor variables and the surgical procedure.[19] Radiation therapy was associated with improved OS compared with surgery alone when delivered preoperatively or postoperatively.[20]

Brachytherapy and intraoperative radiation may be applicable in select situations.[21-23]; [24][Level of evidence C2]

Chemotherapy

The role of postoperative chemotherapy remains unclear.[45]

Evidence (lack of clarity regarding postoperative chemotherapy):

1. A meta-analysis of data from all randomized trials of adults with soft tissue sarcoma observed the following:[46]

   • Recurrence-free survival was better with postoperative chemotherapy for patients with high-grade tumors larger than 5 cm.
2. In a European trial, adults with completely resected soft tissue sarcoma were randomly assigned to observation or postoperative chemotherapy with ifosfamide and doxorubicin.[47][Level of evidence A1]

   • Postoperative chemotherapy was not associated with improved 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.[36]
4. Doxorubicin and ifosfamide were used in the risk-based COG ARST0332 (NCT00346164) trial.[1][Level of evidence C1]

   • 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 5-year EFS rate of 67.2% and an OS rate of 78%.
   • In patients with metastatic disease treated with preoperative chemotherapy and radiation therapy, the estimated 5-year EFS rate was 21.2%, and the OS rate was 35.5%.

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 adult patients who achieved a response or stable disease after chemotherapy, patients were randomly assigned to receive ridaforolimus or placebo.[48]

   • The administration of ridaforolimus was associated with a 3-week improvement in progression-free survival (PFS) when compared with placebo.
2. In another trial of 371 randomly assigned adult patients with metastatic soft tissue sarcoma that progressed after chemotherapy, pazopanib was compared with placebo.[49]

   • 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 study of 182 previously treated adult patients with recurrent liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas, patients were randomly assigned to receive regorafenib or placebo.[50]

   • Patients with nonadipocytic tumors who were treated with regorafenib had significant improvements in PFS when compared with patients who were treated with placebo.

The COG and NRG Oncology cancer consortia conducted a randomized trial of pazopanib added to neoadjuvant chemotherapy (doxorubicin and ifosfamide) and preoperative radiation therapy in pediatric and adult patients with NRSTS. Patients whose tumors were larger than 5 cm and had intermediate- or high-grade disease were eligible. The end point of the trial was pathological tumor response after adjuvant therapy. Study entry was closed early because the planned interim analysis showed that the pathological response boundary was crossed. Eighty-one patients were enrolled, but only 42 (52%) were available for response data (17 patients from each group discontinued therapy for either progression, unacceptable toxicity, or patient or physician choice).[51]

• Four of 18 patients (22%) in the control group had greater than 90% necrosis at resection, compared with 14 of 24 patients (58%) in the group treated with pazopanib, meeting the criteria for early stopping of the study.
• Toxicity was greater in the pazopanib group, mainly resulting from increased myelosuppression. Wound complications were also more frequent in the pazopanib group.
• With longer follow-up, the investigators were able to analyze the secondary objectives of OS and EFS.[52] At a median follow-up of 3.3 years (range, 0.1–5.8 years), the 3-year EFS rate for all patients in the intent-to-treat analysis was 52.5% for patients who received pazopanib and 50.6% for those who did not (log-rank P = .8677). The 3-year OS rate was 75.7% for patients who received pazopanib and 65.4% for the control group (log-rank P = .1919).

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Liposarcoma, Well-Differentiated, Not Otherwise Specified (NOS)

Liposarcoma is rare in the pediatric population and accounts for 3% of soft tissue sarcoma in patients younger than 20 years (see Table 1).

In a review of 182 pediatric patients with adult-type sarcomas, only 14 had a diagnosis of liposarcoma.[7] One retrospective study identified 34 patients younger than 22 years from 1960 to 2011.[8] There were roughly equal numbers of male and female patients, and the median age was 18 years. In an international clinico-pathological review, the characteristics of 82 cases of pediatric liposarcoma were reported.[9] The median age was 15.5 years, and females were more commonly affected. In both reports, most patients had myxoid liposarcoma.[8,9]

A literature review of 275 cases of pediatric liposarcoma showed that:[10]

• Myxoid liposarcoma was the most common histology (68%), followed by well-differentiated liposarcoma (10.5%).
• Twelve percent of patients died of disease, and most of the deaths occurred in patients with the pleomorphic and myxoid pleomorphic subtypes.
• About 70% of patients with myxoid and well-differentiated liposarcoma were treated with surgery only. The overall clinical outcomes for these groups of patients were excellent, with no evidence of disease in 114 of 127 patients.
• In contrast, more than 50% of patients with pleomorphic liposarcoma received radiation therapy and chemotherapy in addition to surgery, and their clinical outcome was suboptimal, with no evidence of disease in only 5 of 10 patients.
• Germline TP53 variants were seen in two patients with myxoid pleomorphic liposarcoma and two patients with well-differentiated liposarcoma who had a family history compatible with Li-Fraumeni syndrome.

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23. Sugiura H, Takahashi M, Katagiri H, et al.: Additional wide resection of malignant soft tissue tumors. Clin Orthop (394): 201-10, 2002. [PubMed: 11795735]
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33. Baruchel S, Pappo A, Krailo M, et al.: A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children's Oncology Group. Eur J Cancer 48 (4): 579-85, 2012. [PubMed: 22088484]
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Extraskeletal Mesenchymal Chondrosarcoma

Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcomas in patients younger than 20 years (see Table 1). Mesenchymal chondrosarcoma is more common in the head and neck region.

Osteosarcoma, Extraskeletal

Extraskeletal osteosarcoma is extremely rare in the pediatric and adolescent population. Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcomas in patients younger than 20 years (see Table 1).

References

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Desmoid-Type Fibromatosis

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

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.[1]

Dermatofibrosarcoma Protuberans NOS

Dermatofibrosarcoma is a rare tumor that can be present in all age groups, but many of the reported cases arise in children.[40-42] A review of 451 cases in children younger than 20 years in the SEER Program database found that the incidence was 1 case per 1 million. The incidence was highest among Black patients aged 15 to 19 years. The most common sites were the trunk and extremities, which is similar to what is found in adults.

Ninety-five percent of patients underwent surgery. The overall survival (OS) rate was 100% at 5 years, 98% at 15 years, and 97% at 30 years. Male patients had decreased survival compared with female patients (P < .05).[43][Level of evidence C1]

Inflammatory Myofibroblastic Tumor and Epithelioid Inflammatory Myofibroblastic Sarcoma

Inflammatory myofibroblastic tumor is a rare mesenchymal tumor that is more common in children and adolescents.[53-55]

Infantile Fibrosarcoma

There are two distinct types of fibrosarcoma in children and adolescents, as follows:

1. Infantile fibrosarcoma is a malignant fibroblastic tumor usually characterized by ETV6::NTRK3 gene fusions.
2. Adult-type fibrosarcoma is composed of monomorphic fibroblastic tumor cells. Some of the genomic features of adult-type fibrosarcoma have been recently described.[81]

These are two distinct pathological diagnoses and require different treatments.

Fibrosarcoma NOS

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. It is commonly located deep within the extremities.[105-107]

A Children's Oncology Group (COG) trial (ARST0332 [NCT00346164]) enrolled 11 patients with this tumor type. The median age at diagnosis was 13 years and males were more commonly affected. The most common tumor sites were the lower and upper extremities (n = 9). None of the patients developed local or distant disease recurrence at a median follow up of 2.7 years.[108]

Sclerosing Epithelioid Fibrosarcoma

Sclerosing epithelioid fibrosarcoma is a rare malignant sarcoma that commonly harbors EWSR1 gene fusions and has an aggressive clinical course. The tumor responds poorly to chemotherapy.[114,115]

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84. Kao YC, Fletcher CDM, Alaggio R, et al.: Recurrent BRAF Gene Fusions in a Subset of Pediatric Spindle Cell Sarcomas: Expanding the Genetic Spectrum of Tumors With Overlapping Features With Infantile Fibrosarcoma. Am J Surg Pathol 42 (1): 28-38, 2018. [PMC free article: PMC5730460] [PubMed: 28877062]
85. Wegert J, Vokuhl C, Collord G, et al.: Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants. Nat Commun 9 (1): 2378, 2018. [PMC free article: PMC6006309] [PubMed: 29915264]
86. Tan SY, Al-Ibraheemi A, Ahrens WA, et al.: ALK rearrangements in infantile fibrosarcoma-like spindle cell tumours of soft tissue and kidney. Histopathology 80 (4): 698-707, 2022. [PubMed: 34843129]
87. Motta M, Barresi S, Pizzi S, et al.: RAF1 gene fusions are recurrent driver events in infantile fibrosarcoma-like mesenchymal tumors. J Pathol 263 (2): 166-177, 2024. [PubMed: 38629245]
88. Orbach D, Rey A, Cecchetto G, et al.: Infantile fibrosarcoma: management based on the European experience. J Clin Oncol 28 (2): 318-23, 2010. [PubMed: 19917847]
89. Orbach D, Brennan B, De Paoli A, et al.: Conservative strategy in infantile fibrosarcoma is possible: The European paediatric Soft tissue sarcoma Study Group experience. Eur J Cancer 57: 1-9, 2016. [PubMed: 26849118]
90. Madden NP, Spicer RD, Allibone EB, et al.: Spontaneous regression of neonatal fibrosarcoma. Br J Cancer Suppl 18: S72-5, 1992. [PMC free article: PMC2149666] [PubMed: 1503930]
91. Hawkins DS, Black JO, Orbach D, et al.: Nonrhabdomyosarcoma soft-tissue sarcomas. In: Blaney SM, Helman LJ, Adamson PC, eds.: Pizzo and Poplack's Pediatric Oncology. 8th ed. Wolters Kluwer, 2020, pp 721-46.
92. Loh ML, Ahn P, Perez-Atayde AR, et al.: Treatment of infantile fibrosarcoma with chemotherapy and surgery: results from the Dana-Farber Cancer Institute and Children's Hospital, Boston. J Pediatr Hematol Oncol 24 (9): 722-6, 2002. [PubMed: 12468912]
93. Akyüz C, Küpeli S, Varan A, et al.: Infantile fibrosarcoma: retrospective analysis of eleven patients. Tumori 97 (2): 166-9, 2011 Mar-Apr. [PubMed: 21617710]
94. Gallego S, Pericas N, Barber I, et al.: Infantile fibrosarcoma of the retroperitoneum: a site of unfavorable prognosis? Pediatr Hematol Oncol 28 (5): 451-3, 2011. [PubMed: 21345076]
95. Parida L, Fernandez-Pineda I, Uffman JK, et al.: Clinical management of infantile fibrosarcoma: a retrospective single-institution review. Pediatr Surg Int 29 (7): 703-8, 2013. [PMC free article: PMC4825685] [PubMed: 23708972]
96. Mody RJ, Wu YM, Lonigro RJ, et al.: Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth. JAMA 314 (9): 913-25, 2015. [PMC free article: PMC4758114] [PubMed: 26325560]
97. Wong V, Pavlick D, Brennan T, et al.: Evaluation of a Congenital Infantile Fibrosarcoma by Comprehensive Genomic Profiling Reveals an LMNA-NTRK1 Gene Fusion Responsive to Crizotinib. J Natl Cancer Inst 108 (1): , 2016. [PubMed: 26563356]
98. Laetsch TW, DuBois SG, Mascarenhas L, et al.: Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol 19 (5): 705-714, 2018. [PMC free article: PMC5949072] [PubMed: 29606586]
99. Kummar S, Lassen UN: TRK Inhibition: A New Tumor-Agnostic Treatment Strategy. Target Oncol 13 (5): 545-556, 2018. [PubMed: 30276762]
100. Drilon A, Laetsch TW, Kummar S, et al.: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378 (8): 731-739, 2018. [PMC free article: PMC5857389] [PubMed: 29466156]
101. DuBois SG, Laetsch TW, Federman N, et al.: The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer 124 (21): 4241-4247, 2018. [PMC free article: PMC6263791] [PubMed: 30204247]
102. Hong DS, DuBois SG, Kummar S, et al.: Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 21 (4): 531-540, 2020. [PMC free article: PMC7497841] [PubMed: 32105622]
103. Drilon A, Nagasubramanian R, Blake JF, et al.: A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov 7 (9): 963-972, 2017. [PMC free article: PMC5581710] [PubMed: 28578312]
104. Yanagisawa R, Noguchi M, Fujita K, et al.: Preoperative Treatment With Pazopanib in a Case of Chemotherapy-Resistant Infantile Fibrosarcoma. Pediatr Blood Cancer 63 (2): 348-51, 2016. [PubMed: 26375879]
105. 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: 21921785]
106. Scheer M, Vokuhl C, Veit-Friedrich I, et al.: Low-grade fibromyxoid sarcoma: A report of the Cooperative Weichteilsarkom Studiengruppe (CWS). Pediatr Blood Cancer 67 (2): e28009, 2020. [PubMed: 31736251]
107. Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. IARC Press, 2013.
108. Sargar K, Kao SC, Spunt SL, et al.: MRI and CT of Low-Grade Fibromyxoid Sarcoma in Children: A Report From Children's Oncology Group Study ARST0332. AJR Am J Roentgenol 205 (2): 414-20, 2015. [PMC free article: PMC4570741] [PubMed: 26204295]
109. Guillou L, Benhattar J, Gengler C, et al.: Translocation-positive low-grade fibromyxoid sarcoma: clinicopathologic and molecular analysis of a series expanding the morphologic spectrum and suggesting potential relationship to sclerosing epithelioid fibrosarcoma: a study from the French Sarcoma Group. Am J Surg Pathol 31 (9): 1387-402, 2007. [PubMed: 17721195]
110. Mohamed M, Fisher C, Thway K: Low-grade fibromyxoid sarcoma: Clinical, morphologic and genetic features. Ann Diagn Pathol 28: 60-67, 2017. [PubMed: 28648941]
111. O'Sullivan MJ, Sirgi KE, Dehner LP: Low-grade fibrosarcoma (hyalinizing spindle cell tumor with giant rosettes) with pulmonary metastases at presentation: case report and review of the literature. Int J Surg Pathol 10 (3): 211-6, 2002. [PubMed: 12232578]
112. Folpe AL, Lane KL, Paull G, et al.: Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of high-grade areas. Am J Surg Pathol 24 (10): 1353-60, 2000. [PubMed: 11023096]
113. Maretty-Nielsen K, Baerentzen S, Keller J, et al.: Low-Grade Fibromyxoid Sarcoma: Incidence, Treatment Strategy of Metastases, and Clinical Significance of the FUS Gene. Sarcoma 2013: 256280, 2013. [PMC free article: PMC3683502] [PubMed: 23818812]
114. Prieto-Granada C, Zhang L, Chen HW, et al.: A genetic dichotomy between pure sclerosing epithelioid fibrosarcoma (SEF) and hybrid SEF/low-grade fibromyxoid sarcoma: a pathologic and molecular study of 18 cases. Genes Chromosomes Cancer 54 (1): 28-38, 2015. [PMC free article: PMC4232448] [PubMed: 25231134]
115. Arbajian E, Puls F, Antonescu CR, et al.: In-depth Genetic Analysis of Sclerosing Epithelioid Fibrosarcoma Reveals Recurrent Genomic Alterations and Potential Treatment Targets. Clin Cancer Res 23 (23): 7426-7434, 2017. [PubMed: 28939748]
116. Arbajian E, Puls F, Magnusson L, et al.: Recurrent EWSR1-CREB3L1 gene fusions in sclerosing epithelioid fibrosarcoma. Am J Surg Pathol 38 (6): 801-8, 2014. [PubMed: 24441665]
117. Dewaele B, Libbrecht L, Levy G, et al.: A novel EWS-CREB3L3 gene fusion in a mesenteric sclerosing epithelioid fibrosarcoma. Genes Chromosomes Cancer 56 (9): 695-699, 2017. [PubMed: 28569045]
118. Porteus C, Gan Q, Gong Y, et al.: Sclerosing epithelioid fibrosarcoma: cytologic characterization with histologic, immunohistologic, molecular, and clinical correlation of 8 cases. J Am Soc Cytopathol 9 (6): 513-519, 2020 Nov - Dec. [PubMed: 32624384]
119. Puls F, Agaimy A, Flucke U, et al.: Recurrent Fusions Between YAP1 and KMT2A in Morphologically Distinct Neoplasms Within the Spectrum of Low-grade Fibromyxoid Sarcoma and Sclerosing Epithelioid Fibrosarcoma. Am J Surg Pathol 44 (5): 594-606, 2020. [PubMed: 31913156]
120. Warmke LM, Meis JM: Sclerosing Epithelioid Fibrosarcoma: A Distinct Sarcoma With Aggressive Features. Am J Surg Pathol 45 (3): 317-328, 2021. [PubMed: 32769431]
121. Chew W, Benson C, Thway K, et al.: Clinical Characteristics and efficacy of chemotherapy in sclerosing epithelioid fibrosarcoma. Med Oncol 35 (11): 138, 2018. [PMC free article: PMC6132781] [PubMed: 30187231]

Rhabdomyosarcoma

For more information, see Childhood Rhabdomyosarcoma Treatment.

Ectomesenchymoma

Ectomesenchymoma is a rare skeletal muscle tumor that mainly occurs in children. It is a biphenotypic soft tissue sarcoma with both mesenchymal and ectodermal components.

A single-institution retrospective review identified seven cases of malignant ectomesenchymoma.[1] All seven patients were male, with a mean age of 7.5 months (range, 0.6–17.0 months). Five of the seven patients in this series were healthy and free of disease at the time of reporting.

References

1. Huang SC, Alaggio R, Sung YS, et al.: Frequent HRAS Mutations in Malignant Ectomesenchymoma: Overlapping Genetic Abnormalities With Embryonal Rhabdomyosarcoma. Am J Surg Pathol 40 (7): 876-85, 2016. [PMC free article: PMC4905780] [PubMed: 26872011]
2. Griffin BB, Chou PM, George D, et al.: Malignant Ectomesenchymoma: Series Analysis of a Histologically and Genetically Heterogeneous Tumor. Int J Surg Pathol 26 (3): 200-212, 2018. [PubMed: 28994342]
3. Dantonello TM, Leuschner I, Vokuhl C, et al.: Malignant ectomesenchymoma in children and adolescents: report from the Cooperative Weichteilsarkom Studiengruppe (CWS). Pediatr Blood Cancer 60 (2): 224-9, 2013. [PubMed: 22535600]
4. Milano GM, Orbach D, Casanova M, et al.: Malignant ectomesenchymoma in children: The European pediatric Soft tissue sarcoma Study Group experience. Pediatr Blood Cancer 70 (2): e30116, 2023. [PubMed: 36440693]

Leiomyosarcoma NOS

Leiomyosarcoma accounts for 2% of soft tissue sarcomas in patients younger than 20 years (see Table 1).

References

1. Pollock BH, Jenson HB, Leach CT, et al.: Risk factors for pediatric human immunodeficiency virus-related malignancy. JAMA 289 (18): 2393-9, 2003. [PubMed: 12746363]
2. Kleinerman RA, Tucker MA, Abramson DH, et al.: Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst 99 (1): 24-31, 2007. [PubMed: 17202110]
3. Samuels BL, Chawla S, Patel S, et al.: Clinical outcomes and safety with trabectedin therapy in patients with advanced soft tissue sarcomas following failure of prior chemotherapy: results of a worldwide expanded access program study. Ann Oncol 24 (6): 1703-9, 2013. [PubMed: 23385197]
4. Demetri GD, von Mehren M, Jones RL, et al.: Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol 34 (8): 786-93, 2016. [PMC free article: PMC5070559] [PubMed: 26371143]

Plexiform Fibrohistiocytic Tumor

Plexiform fibrohistiocytic tumor is a rare, low- to intermediate-grade tumor that most commonly affects children and young adults. 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.[1,2]

References

1. Enzinger FM, Zhang RY: Plexiform fibrohistiocytic tumor presenting in children and young adults. An analysis of 65 cases. Am J Surg Pathol 12 (11): 818-26, 1988. [PubMed: 2847569]
2. Black J, Coffin CM, Dehner LP: Fibrohistiocytic tumors and related neoplasms in children and adolescents. Pediatr Dev Pathol 15 (1 Suppl): 181-210, 2012. [PubMed: 22420728]
3. Moosavi C, Jha P, Fanburg-Smith JC: An update on plexiform fibrohistiocytic tumor and addition of 66 new cases from the Armed Forces Institute of Pathology, in honor of Franz M. Enzinger, MD. Ann Diagn Pathol 11 (5): 313-9, 2007. [PubMed: 17870015]
4. Billings SD, Folpe AL: Cutaneous and subcutaneous fibrohistiocytic tumors of intermediate malignancy: an update. Am J Dermatopathol 26 (2): 141-55, 2004. [PubMed: 15024197]
5. Remstein ED, Arndt CA, Nascimento AG: Plexiform fibrohistiocytic tumor: clinicopathologic analysis of 22 cases. Am J Surg Pathol 23 (6): 662-70, 1999. [PubMed: 10366148]
6. Salomao DR, Nascimento AG: Plexiform fibrohistiocytic tumor with systemic metastases: a case report. Am J Surg Pathol 21 (4): 469-76, 1997. [PubMed: 9130995]
7. Redlich GC, Montgomery KD, Allgood GA, et al.: Plexiform fibrohistiocytic tumor with a clonal cytogenetic anomaly. Cancer Genet Cytogenet 108 (2): 141-3, 1999. [PubMed: 9973942]
8. Luzar B, Calonje E: Cutaneous fibrohistiocytic tumours - an update. Histopathology 56 (1): 148-65, 2010. [PubMed: 20055912]

Malignant Peripheral Nerve Sheath Tumor NOS

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

Malignant Triton Tumor

Malignant triton tumors are now classified as a variant of malignant peripheral nerve sheath tumors. They occur most often in patients with NF1 and consist of neurogenic and rhabdomyoblastic components.[25] Most malignant triton tumors are reported in adults, although they may also arise in children and adolescents.[26]

Distinguishing between malignant triton tumors and NF1-altered rhabdomyosarcomas can be difficult. The genomic characteristics of malignant triton tumors can aid in differentiating between the two tumors. CDKN2A deep deletions and loss-of-function alterations in genes of the PRC2 complex (e.g., SUZ12 and EED1) are commonly observed in malignant triton tumors, while they are uncommon in NF1-altered rhabdomyosarcomas. The loss of PRC2 function leads to loss of H3K27me3 expression, a finding that is common in malignant triton tumors. H3K27me3 expression is generally maintained in rhabdomyosarcomas.[26-28]

References

1. Carli M, Ferrari A, Mattke A, et al.: Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. J Clin Oncol 23 (33): 8422-30, 2005. [PubMed: 16293873]
2. Malbari F, Spira M, B Knight P, et al.: Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis: Impact of Family History. J Pediatr Hematol Oncol 40 (6): e359-e363, 2018. [PubMed: 29683959]
3. Agresta L, Salloum R, Hummel TR, et al.: Malignant peripheral nerve sheath tumor: Transformation in a patient with neurofibromatosis type 2. Pediatr Blood Cancer 66 (2): e27520, 2019. [PubMed: 30408304]
4. Agaram NP, Wexler LH, Chi P, et al.: Malignant peripheral nerve sheath tumor in children: A clinicopathologic and molecular study with parallels to the adult counterpart. Genes Chromosomes Cancer 62 (3): 131-138, 2023. [PMC free article: PMC9825640] [PubMed: 36414547]
5. Zhang M, Wang Y, Jones S, et al.: Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet 46 (11): 1170-2, 2014. [PMC free article: PMC4383254] [PubMed: 25305755]
6. Röhrich M, Koelsche C, Schrimpf D, et al.: Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol 131 (6): 877-87, 2016. [PubMed: 26857854]
7. Kaplan HG, Rostad S, Ross JS, et al.: Genomic Profiling in Patients With Malignant Peripheral Nerve Sheath Tumors Reveals Multiple Pathways With Targetable Mutations. J Natl Compr Canc Netw 16 (8): 967-974, 2018. [PubMed: 30099373]
8. Hagel C, Zils U, Peiper M, et al.: Histopathology and clinical outcome of NF1-associated vs. sporadic malignant peripheral nerve sheath tumors. J Neurooncol 82 (2): 187-92, 2007. [PubMed: 17111191]
9. Zou C, Smith KD, Liu J, et al.: Clinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome. Ann Surg 249 (6): 1014-22, 2009. [PubMed: 19474676]
10. Okada K, Hasegawa T, Tajino T, et al.: Clinical relevance of pathological grades of malignant peripheral nerve sheath tumor: a multi-institution TMTS study of 56 cases in Northern Japan. Ann Surg Oncol 14 (2): 597-604, 2007. [PubMed: 17103076]
11. Amirian ES, Goodman JC, New P, et al.: Pediatric and adult malignant peripheral nerve sheath tumors: an analysis of data from the surveillance, epidemiology, and end results program. J Neurooncol 116 (3): 609-16, 2014. [PubMed: 24390465]
12. Valentin T, Le Cesne A, Ray-Coquard I, et al.: Management and prognosis of malignant peripheral nerve sheath tumors: The experience of the French Sarcoma Group (GSF-GETO). Eur J Cancer 56: 77-84, 2016. [PubMed: 26824706]
13. Høland M, Kolberg M, Danielsen SA, et al.: Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53. Mod Pathol 31 (11): 1694-1707, 2018. [PubMed: 29946184]
14. Krawczyk MA, Karpinsky G, Izycka-Swieszewska E, et al.: Immunohistochemical assessment of cyclin D1 and p53 is associated with survival in childhood malignant peripheral nerve sheath tumor. Cancer Biomark 24 (3): 351-361, 2019. [PubMed: 30883338]
15. Akshintala S, Mallory NC, Lu Y, et al.: Outcome of Patients With Malignant Peripheral Nerve Sheath Tumors Enrolled on Sarcoma Alliance for Research Through Collaboration (SARC) Phase II Trials. Oncologist 28 (5): 453-459, 2023. [PMC free article: PMC10166173] [PubMed: 36724001]
16. Martin E, Coert JH, Flucke UE, et al.: Neurofibromatosis-associated malignant peripheral nerve sheath tumors in children have a worse prognosis: A nationwide cohort study. Pediatr Blood Cancer 67 (4): e28138, 2020. [PubMed: 31889416]
17. Meister MT, Scheer M, Hallmen E, et al.: Malignant peripheral nerve sheath tumors in children, adolescents, and young adults: Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. J Surg Oncol 122 (7): 1337-1347, 2020. [PubMed: 32812260]
18. 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. [PMC free article: PMC3646910] [PubMed: 23474110]
19. 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: 26068493]
20. Ferrari A, Bisogno G, Macaluso A, et al.: Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer 109 (7): 1406-12, 2007. [PubMed: 17330850]
21. van Noesel MM, Orbach D, Brennan B, et al.: Outcome and prognostic factors in pediatric malignant peripheral nerve sheath tumors: An analysis of the European Pediatric Soft Tissue Sarcoma Group (EpSSG) NRSTS-2005 prospective study. Pediatr Blood Cancer 66 (10): e27833, 2019. [PubMed: 31241238]
22. Higham CS, Steinberg SM, Dombi E, et al.: SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors. Sarcoma 2017: 8685638, 2017. [PMC free article: PMC5613633] [PubMed: 29138631]
23. 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: 28926683]
24. Al-Ezzi E, Gounder M, Watson G, et al.: Selinexor, a First in Class, Nuclear Export Inhibitor for the Treatment of Advanced Malignant Peripheral Nerve Sheath Tumor. Oncologist 26 (4): e710-e714, 2021. [PMC free article: PMC8018316] [PubMed: 33512749]
25. WHO Classification of Tumours Editorial Board: WHO Classification of Tumours. Volume 3: Soft Tissue and Bone Tumours. 5th ed., IARC Press, 2020.
26. de Traux de Wardin H, Dermawan JK, Vanoli F, et al.: NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor. JCO Precis Oncol 8: e2300597, 2024. [PMC free article: PMC11161258] [PubMed: 38603649]
27. Schaefer IM, Fletcher CD, Hornick JL: Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod Pathol 29 (1): 4-13, 2016. [PubMed: 26585554]
28. Hornick JL, Nielsen GP: Beyond "Triton": Malignant Peripheral Nerve Sheath Tumors With Complete Heterologous Rhabdomyoblastic Differentiation Mimicking Spindle Cell Rhabdomyosarcoma. Am J Surg Pathol 43 (10): 1323-1330, 2019. [PubMed: 31107719]

Myopericytoma

Infantile hemangiopericytoma, a subtype of myopericytoma, is a highly vascularized tumor of uncertain origin.

For children with hemangiopericytomas, those younger than 1 year seem to have a better prognosis than do children older than 1 year.[1-3]

Infantile Myofibromatosis

Infantile myofibromatosis is a fibrous tumor of infancy and childhood that most commonly presents in the first 2 years of life.[9]

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).[10-13]

References

1. Rodriguez-Galindo C, Ramsey K, Jenkins JJ, et al.: Hemangiopericytoma in children and infants. Cancer 88 (1): 198-204, 2000. [PubMed: 10618624]
2. Ferrari A, Casanova M, Bisogno G, et al.: Hemangiopericytoma in pediatric ages: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Cancer 92 (10): 2692-8, 2001. [PubMed: 11745205]
3. Bien E, Stachowicz-Stencel T, Godzinski J, et al.: Retrospective multi-institutional study on hemangiopericytoma in Polish children. Pediatr Int 51 (1): 19-24, 2009. [PubMed: 19371273]
4. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 5th ed. Mosby, 2008.
5. Fernandez-Pineda I, Parida L, Jenkins JJ, et al.: Childhood hemangiopericytoma: review of St Jude Children's Research Hospital. J Pediatr Hematol Oncol 33 (5): 356-9, 2011. [PubMed: 21602721]
6. 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: 26863915]
7. Wong V, Pavlick D, Brennan T, et al.: Evaluation of a Congenital Infantile Fibrosarcoma by Comprehensive Genomic Profiling Reveals an LMNA-NTRK1 Gene Fusion Responsive to Crizotinib. J Natl Cancer Inst 108 (1): , 2016. [PubMed: 26563356]
8. Doebele RC, Davis LE, Vaishnavi A, et al.: An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov 5 (10): 1049-57, 2015. [PMC free article: PMC4635026] [PubMed: 26216294]
9. Wiswell TE, Davis J, Cunningham BE, et al.: Infantile myofibromatosis: the most common fibrous tumor of infancy. J Pediatr Surg 23 (4): 315-8, 1988. [PubMed: 3385581]
10. Chung EB, Enzinger FM: Infantile myofibromatosis. Cancer 48 (8): 1807-18, 1981. [PubMed: 7284977]
11. Modi N: Congenital generalised fibromatosis. Arch Dis Child 57 (11): 881-2, 1982. [PMC free article: PMC1628023] [PubMed: 7149764]
12. Levine E, Fréneaux P, Schleiermacher G, et al.: Risk-adapted therapy for infantile myofibromatosis in children. Pediatr Blood Cancer 59 (1): 115-20, 2012. [PubMed: 22038698]
13. Larralde M, Hoffner MV, Boggio P, et al.: Infantile myofibromatosis: report of nine patients. Pediatr Dermatol 27 (1): 29-33, 2010 Jan-Feb. [PubMed: 20199406]
14. 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: 27776010]
15. Arts FA, Sciot R, Brichard B, et al.: PDGFRB gain-of-function mutations in sporadic infantile myofibromatosis. Hum Mol Genet 26 (10): 1801-1810, 2017. [PubMed: 28334876]
16. Dachy G, de Krijger RR, Fraitag S, et al.: Association of PDGFRB Mutations With Pediatric Myofibroma and Myofibromatosis. JAMA Dermatol 155 (8): 946-950, 2019. [PMC free article: PMC6487901] [PubMed: 31017643]
17. Cheung YH, Gayden T, Campeau PM, et al.: A recurrent PDGFRB mutation causes familial infantile myofibromatosis. Am J Hum Genet 92 (6): 996-1000, 2013. [PMC free article: PMC3675240] [PubMed: 23731537]
18. Martignetti JA, Tian L, Li D, et al.: Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am J Hum Genet 92 (6): 1001-7, 2013. [PMC free article: PMC3675260] [PubMed: 23731542]
19. Murray N, Hanna B, Graf N, et al.: The spectrum of infantile myofibromatosis includes both non-penetrance and adult recurrence. Eur J Med Genet 60 (7): 353-358, 2017. [PubMed: 28286173]
20. Hettmer S, Dachy G, Seitz G, et al.: Genetic testing and surveillance in infantile myofibromatosis: a report from the SIOPE Host Genome Working Group. Fam Cancer 20 (4): 327-336, 2021. [PMC free article: PMC8484085] [PubMed: 32888134]
21. Gopal M, Chahal G, Al-Rifai Z, et al.: Infantile myofibromatosis. Pediatr Surg Int 24 (3): 287-91, 2008. [PubMed: 18074145]
22. Sparber-Sauer M, Vokuhl C, Seitz G, et al.: Infantile myofibromatosis: Excellent prognosis but also rare fatal progressive disease. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry. Pediatr Blood Cancer 69 (3): e29403, 2022. [PubMed: 34636137]
23. Weaver MS, Navid F, Huppmann A, et al.: Vincristine and Dactinomycin in Infantile Myofibromatosis With a Review of Treatment Options. J Pediatr Hematol Oncol 37 (3): 237-41, 2015. [PubMed: 25389917]
24. Weller JM, Keil VC, Gielen GH, et al.: PDGRFB mutation-associated myofibromatosis: Response to targeted therapy with imatinib. Am J Med Genet A 179 (9): 1895-1897, 2019. [PubMed: 31291054]
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Myxoma NOS

Synovial Sarcoma NOS (Poorly Differentiated, Spindle Cell, and Biphasic Varieties)

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

Synovial sarcoma is one of the most common nonrhabdomyosarcomatous soft tissue sarcoma (NRSTS) in children and adolescents. In a review of the Surveillance, Epidemiology, and End Results (SEER) Program database from 1973 to 2005, 1,268 patients with synovial sarcoma were identified. Approximately 17% of these patients were children and adolescents, and the median age at diagnosis was 34 years.[4] In addition, in the Children's Oncology Group (COG) ARST0332 (NCT00346164) and European paediatric Soft Tissue Sarcoma Study Group (EpSSG) 2005 protocols, synovial sarcoma was the single most common histological subtype.[5]

Epithelioid Sarcoma

Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis that displays multilineage differentiation.[53]

Alveolar Soft Part Sarcoma

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

Clear Cell Sarcoma NOS

Clear cell sarcoma (formerly 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.

Extraskeletal Myxoid Chondrosarcoma

Extraskeletal myxoid chondrosarcoma is relatively rare among soft tissue sarcomas, representing only 2.3% of all soft tissue sarcomas.[92] It has been reported in children and adolescents.[93]

The tumor has traditionally been considered to have low-grade malignant potential.[94] However, reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are monitored for a long time.[95,96] 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.[96]

Extraskeletal Ewing Sarcoma

Almost one-fifth of patients with Ewing sarcoma will present with nonbone primary sites (extraosseous). Treatment for this tumor is the same as it is for patients with bone primary tumors.[99] For more information, see Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment.

Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor is a rare primitive sarcoma.

Rhabdoid Tumor NOS (Extrarenal)

Malignant rhabdoid tumors were first described in children with renal tumors in 1981. These tumors were later found in a variety of extrarenal sites. These tumors are uncommon and highly malignant, especially in children younger than 2 years. For more information, see the Rhabdoid Tumors of the Kidney section in Wilms Tumor and Other Childhood Kidney Tumors Treatment.

Extrarenal (extracranial) rhabdoid tumors account for 2% of soft tissue sarcomas in patients younger than 20 years (see Table 1).

PEComa, Malignant

Undifferentiated Sarcoma

From 1972 to 2006, patients with undifferentiated soft tissue sarcoma were eligible for participation in rhabdomyosarcoma trials coordinated by the IRS group and the COG. The rationale was 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. Results for the patients with high-grade undifferentiated sarcoma were reported together with all high-grade soft tissue sarcomas in the trial. The estimated 5-year EFS rate was 64% and the OS rate was 77% for sarcomas classified as high grade by the Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLC).[5][Level of evidence C1]

In a report of 32 patients with undifferentiated soft tissue sarcomas who were enrolled on the ARST0332 (NCT00346164) trial, the median age at enrollment was 13.6 years, and two-thirds of the patients were male. The most common primary sites were the paraspinal region and extremities. Five patients presented with metastatic disease.[146]

• The 5-year EFS rate was 71%, and the OS rate was 83%.
• Of the nine children with low-risk disease (localized low-grade resected disease or localized high-grade disease <5 cm resected with negative margins) who were treated with surgery or radiation therapy only, the 5-year EFS rate was 65% and the OS rate was 100%, suggesting that patients with low-risk disease can be salvaged if the disease recurs.
• The remaining 23 patients had either intermediate-risk disease (resected high-grade tumor >5 cm, unresected high-grade tumor >5 cm) or high-risk disease (metastasis to lymph nodes or distant sites) and were treated with chemoradiation therapy and delayed surgery when feasible. The 5-year EFS rate was 73%, and the OS estimate was 77%.
• Copy number aberrations were common, most frequently involving loss of 1p (25%), gain of 1q (25%), gain of chromosome 8 (25%), and gain of chromosome 2 (16%). These alterations were more commonly seen in patients with intermediate-risk or high-risk tumors, and there was a strong association between loss of chromosome 1p or gain of chromosome 1q and inferior clinical outcomes. Co-occurrence of 1q gain and 1p loss was associated with a particularly poor clinical outcome (5-year EFS and OS rates of 20%). Next-generation sequencing identified oncogenic fusions in eight of ten tumor samples, which included BCOR and CIC rearrangements, as well as COL1A1::PDGFB, KIAA1549::BRAF, and SAMD5::SASH1 gene fusions.

Pleomorphic Sarcoma, Undifferentiated (Malignant Fibrous Histiocytoma)

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 controversial, in terms of both its histogenesis and its validity as a clinico-pathological entity. The World Health Organization (WHO) classification no longer includes malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[147,148]

This entity accounts for 2% to 6% of all childhood soft tissue sarcomas.[149]

Round Cell Sarcoma, Undifferentiated

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Epithelioid Hemangioendothelioma NOS

Angiosarcoma

References

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Pulmonary Metastases

Generally, a surgical procedure, with resection of all gross disease, should be considered for children with isolated pulmonary metastases.[13] 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 who underwent complete resection of all metastatic lung lesions had better survival than did patients who did not undergo complete resections.[13][Level of evidence C1] Formal segmentectomy, lobectomy, and mediastinal lymph node dissection are unnecessary.[14]

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.[9]

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9. 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: 21277105]
10. Howard TP, Boyle PJ, Marcus KJ, et al.: Clinical outcomes for pediatric patients receiving radiotherapy for solid tumor central nervous system metastases. Pediatr Blood Cancer 68 (12): e29331, 2021. [PubMed: 34569132]
11. Cameron AL, Elze MC, Casanova M, et al.: The Impact of Radiation Therapy in Children and Adolescents With Metastatic Rhabdomyosarcoma. Int J Radiat Oncol Biol Phys 111 (4): 968-978, 2021. [PubMed: 34217789]
12. Ferrari A, Merks JHM, Chisholm JC, et al.: Outcomes of metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) treated within the BERNIE study: a randomised, phase II study evaluating the addition of bevacizumab to chemotherapy. Eur J Cancer 130: 72-80, 2020. [PubMed: 32179448]
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: 23583130]
14. Putnam JB, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995. [PubMed: 7490246]

Surgery

Evidence (surgery):

1. Surgical excision of local recurrence.

   1. An Italian review of 73 patients with recurrent malignant peripheral nerve sheath tumors found that most relapses were local.[3][Level of evidence C1]

      • Multivariate analysis showed that the factors associated with improved survival were no tumor invasiveness at initial diagnosis (stage 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.
2. Surgical excision of isolated pulmonary occurrence.

   1. Pulmonary metastasectomy may achieve prolonged disease control for some patients.[4]

      • 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.[5]
      • 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 candidates for metastasectomy.[6][Level of evidence C1]
3. Surgical excision of local recurrence followed by radiation therapy or brachytherapy (if no previous radiation therapy was given).
4. Limb amputation (only for some children with extremity sarcomas that have already received radiation therapy).

Chemotherapy

Chemotherapy agents that have been used to treat recurrent soft tissue sarcomas include the following:

• Gemcitabine and docetaxel.[7]
• Trabectedin.[8-10]

Tyrosine Kinase Inhibitors

Evidence (tyrosine kinase inhibitors):

1. Pazopanib. Pazopanib has been approved for use in patients with recurrent soft tissue sarcoma. The clinical trial that led to the approval was limited to adults. The study demonstrated disease stabilization and prolonged time to progression; it did not demonstrate improved overall survival.[11]

   • 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.[12][Level of evidence B4]
   • 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.[13][Level of evidence C2]

Immune Checkpoint Inhibitors

Evidence (immune checkpoint inhibitors):

1. Pembrolizumab. 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.[14][Level of evidence C3]

   • Seven of 40 patients (18%) with soft tissue sarcoma had an objective response.
   • 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 had objective responses.
   • No patients with leiomyosarcoma (n = 10) had an objective response.

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, see the ClinicalTrials.gov website.

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. 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: 22835783]
2. 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: 24664883]
3. 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: 28926683]
4. 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: 11698958]
5. 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: 14529779]
6. 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: 23583130]
7. 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: 17602081]
8. 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: 22749255]
9. 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: 16110008]
10. 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: 15084621]
11. 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: 22595799]
12. 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. [PMC free article: PMC3739862] [PubMed: 23857966]
13. 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: 27647230]
14. 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. [PMC free article: PMC7939029] [PubMed: 28988646]

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 in the care of their 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-Dixon, MD, FACS, FAAP (Howard University)
• William H. Meyer, MD
• 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)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

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.

Permission to Use This Summary

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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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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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