Distribution of Soft Tissue Sarcoma by Age and Histology

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

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

Nonrhabdomyosarcomatous soft tissue sarcomas are more common in adolescents and adults,[4] and most of the information regarding treatment and natural history of the disease in younger patients has been based on adult studies. The distributions of these tumors by age according to stage (Figure 1), histologic 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 histologic 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 nonrhabdomyosarcomatous soft tissue sarcoma, including the following:

• Genetic factors:

  -

  Li-Fraumeni syndrome: Patients with Li-Fraumeni syndrome (usually due to heritable cancer-associated changes of the TP53 tumor suppressor gene) have an increased risk of developing soft tissue tumors (mostly nonrhabdomyosarcomatous soft tissue sarcomas), bone sarcomas, breast cancer, brain tumors, and acute leukemia.[8,9]

  -

  Familial adenomatous polyposis: Patients with familial adenomatous polyposis are at increased risk of developing desmoid-type fibromatosis.[10]

  -

  RB1 gene: Germline mutations 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 mutations or deletions of the SMARCB1 (INI1) gene are associated with an increased risk of developing extrarenal rhabdoid tumors.[13]

  -

  Neurofibromatosis type 1: Approximately 4% of patients with neurofibromatosis type 1 develop malignant peripheral nerve sheath tumors, which usually develop after a long latency; some patients develop multiple lesions.[14-16]

  -

  Werner syndrome: Werner syndrome is characterized by spontaneous chromosomal instability, resulting in increased susceptibility to cancer and premature aging. An excess of soft tissue sarcomas has been reported in patients with Werner syndrome.[17]

  -

  Tuberous sclerosis complex: Tuberous sclerosis complex is associated with the development of various tumors showing perivascular epithelioid cell differentiation (PEComas), including lymphangioleiomyomatosis and hepatic and renal angiomyolipomas.[18-20]

  -

  Adenosine deaminase-deficient severe combined immunodeficiency: Patients with adenosine deaminase-deficient severe combined immunodeficiency have been reported to be at increased risk of developing multicentric dermatofibrosarcoma protuberans, which usually presents at an average age of 8.9 years.[21]

• External exposures:

  -

  Radiation: Some nonrhabdomyosarcomatous soft tissue sarcomas (particularly malignant fibrous histiocytoma) can develop within a previously irradiated site.[3,22-25]

  -

  Epstein-Barr virus infection in patients with AIDS: Some nonrhabdomyosarcomatous soft tissue sarcomas (e.g., leiomyosarcoma) have been linked to Epstein-Barr virus infection in patients with AIDS.[3,26]

Clinical Presentation

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

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

Diagnostic and Staging Evaluation

When a suspicious lesion is identified, it is crucial that a complete workup, followed by adequate biopsy be performed. 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.
• Chest computed tomography (CT). Chest CT is essential to assess the presence of metastases.
• Abdominal CT or magnetic resonance imaging (MRI). Abdominal CT or MRI can be used to image intra-abdominal tumors, such as liposarcoma.
• Extremity MRI. MRI is essential for extremity lesions.
• Positron emission tomography (PET) scan and bone scan.

  -

  Rhabdomyosarcoma. In children with rhabdomyosarcoma, PET-CT performed better than conventional imaging in identifying nodal, bone, bone marrow, and soft tissue disease. The authors of this imaging comparison study suggested that bone scans with technetium Tc 99m might be eliminated as a staging procedure.[32]

  -

  Other soft tissue sarcomas. In a retrospective study, 46 PET scans were completed in 25 pediatric patients with soft tissue sarcoma.[33] The positive predictive value of finding metastatic disease was 89%, and the negative predictive value was 67%. A small study of nine patients with nonrhabdomyosarcomatous soft tissue sarcoma suggested that PET-CT was more accurate and cost-effective than either modality alone in identifying distant metastatic disease.[34] The use of this modality in pediatric nonrhabdomyosarcomatous soft tissue sarcoma has not been studied prospectively.

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

Prognosis and Prognostic Factors

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

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

In a review of a large adult series of nonrhabdomyosarcomatous soft tissue sarcomas, superficial extremity sarcomas had a better prognosis than did deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.[70]

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.[71] This relationship requires further study to determine the therapeutic implications of the observation.

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

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

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

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

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

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

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

In a pooled analysis from U.S. and European pediatric centers, outcome was better for patients whose tumor removal procedure was deemed complete than for patients whose tumor removal was incomplete. Outcome was better for patients who received radiation therapy than for patients who did not.[75][Level of evidence: 3iiiA]

Because long-term related morbidity must be minimized while disease-free survival is maximized, the ideal therapy for each patient must be carefully and individually determined utilizing these prognostic factors before initiating therapy.[28,78-82]

Related Summaries

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

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

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World Health Organization (WHO) Classification of Soft Tissue Sarcomas

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

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

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

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

1. Adipocytic tumors.

   1. Benign.

      • Lipoma.
      • Lipomatosis.
      • Lipomatosis of nerve.
      • Lipoblastoma/lipoblastomatosis.
      • Angiolipoma.
      • Myolipoma.
      • Chondroid lipoma.
      • Extra-renal angiomyolipoma.
      • Extra-adrenal myelolipoma.
      • Spindle cell/pleomorphic lipoma.
      • Hibernoma.
   2. Intermediate (locally aggressive).

      • Atypical lipomatous tumor/well-differentiated liposarcoma.
   3. Malignant.

      • Dedifferentiated liposarcoma.
      • Myxoid liposarcoma.
      • Pleomorphic liposarcoma.
      • Liposarcoma, not otherwise specified (NOS).
2. Chondro-osseous tumors.

   • Soft tissue chondroma.
   • Extraskeletal mesenchymal chondrosarcoma.[2]
   • Extraskeletal osteosarcoma.
3. Fibroblastic/myofibroblastic tumors.

   1. Benign.

      • Nodular fasciitis.
      • Proliferative fasciitis.
      • Proliferative myositis.
      • Myositis ossificans.
      • Fibro-osseous pseudotumor of digits.
      • Ischemic fasciitis.
      • Elastofibroma.
      • Fibrous hamartoma of infancy.
      • Fibromatosis colli.
      • Juvenile hyaline fibromatosis.
      • Inclusion body fibromatosis.
      • Fibroma of tendon sheath.
      • Desmoplastic fibroblastoma.
      • Mammary-type myofibroblastoma.
      • Calcifying aponeurotic fibroma.
      • Angiomyofibroblastoma.
      • Cellular angiofibroma.
      • Nuchal-type fibroma.
      • Gardner fibroma.
      • Calcifying fibrous tumor.
   2. Intermediate (locally aggressive).

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

      • Dermatofibrosarcoma protuberans.

        -

        Fibrosarcomatous dermatofibrosarcoma protuberans.

        -

        Pigmented dermatofibrosarcoma protuberans.

      • Solitary fibrous tumor.

        -

        Solitary fibrous tumor, malignant.

      • Inflammatory myofibroblastic tumor.
      • Low-grade myofibroblastic sarcoma.
      • Myxoinflammatory fibroblastic sarcoma/atypical myxoinflammatory fibroblastic tumor.
      • Infantile fibrosarcoma.[3]
   4. Malignant.

      • Adult fibrosarcoma.
      • Myxofibrosarcoma.
      • Low-grade fibromyxoid sarcoma.[4]
      • Sclerosing epithelioid fibrosarcoma.
4. Skeletal muscle tumors.

   • Rhabdomyoma.
   • Rhabdomyosarcoma (embryonal, spindle cell/sclerosing, alveolar, and pleomorphic forms). (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)
5. Smooth muscle tumors.

   1. Benign.

      • Deep leiomyoma.
   2. Malignant.

      • Leiomyosarcoma (excluding skin).
      Angioleiomyoma was reclassified under perivascular tumors.
6. So-called fibrohistiocytic tumors.

   1. Benign.

      • Tenosynovial giant cell tumor.

        -

        Localized type.

        -

        Diffuse type.

        -

        Malignant.

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

      • Plexiform fibrohistiocytic tumor.
      • Giant cell tumor of soft tissue.
      The malignant counterpart of so-called fibrohistiocytic tumors, formerly known as malignant fibrous histiocytoma and its subtypes was renamed undifferentiated sarcoma and was previously classified under the undifferentiated/unclassified sarcomas section.
7. Nerve sheath tumors.

   1. Benign.

      • Schwannoma (including variants).
      • Melanotic schwannoma.
      • Neurofibroma (including variants).

        -

        Plexiform neurofibroma.

      • Perineurioma.

        -

        Malignant perineurioma.

      • Granular cell tumor.
      • Dermal nerve sheath myxoma.
      • Solitary circumscribed neuroma.
      • Ectopic meningioma.
      • Nasal glial heterotopia.
      • Benign Triton tumor.
      • Hybrid nerve sheath tumors.
   2. Malignant.

      • Malignant peripheral nerve sheath tumor.
      • Epithelioid malignant peripheral nerve sheath tumor.
      • Malignant Triton tumor.
      • Malignant granular cell tumor.
      • Ectomesenchymoma.
8. Pericytic (perivascular) tumors.

   • Glomus tumor (and variants).

     -

     Glomangiomatosis.

     -

     Malignant glomus tumor.

   • Myopericytoma.

     -

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

     -

     Myofibromatosis.

     -

     Infantile myofibromatosis.

   • Angioleiomyoma.
9. Tumors of uncertain differentiation.

   1. Benign.

      • Acral fibromyxoma.
      • Intramuscular myxoma (including cellular variant).
      • Juxta-articular myxoma.
      • Deep (aggressive) angiomyxoma.
      • Pleomorphic hyalinizing angiectatic tumor.
      • Ectopic hamartomatous thymoma.
   2. Intermediate (locally aggressive).

      • Hemosiderotic fibrolipomatous tumor.
   3. Intermediate (rarely metastasizing).

      • Atypical fibroxanthoma.
      • Angiomatoid fibrous histiocytoma.
      • Ossifying fibromyxoid tumor.

        -

        Ossifying fibromyxoid tumor, malignant.

      • Mixed tumor NOS.
      • Mixed tumor NOS, malignant.
      • Myoepithelioma.
      • Myoepithelial carcinoma.
      • Phosphaturic mesenchymal tumor, benign.
      • Phosphaturic mesenchymal tumor, malignant.
   4. Malignant.

      • Synovial sarcoma NOS.

        -

        Synovial sarcoma, spindle cell.

        -

        Synovial sarcoma, biphasic.

      • Epithelioid sarcoma.
      • Alveolar soft part sarcoma.
      • Clear cell sarcoma of soft tissue.
      • Extraskeletal myxoid chondrosarcoma.
      • Extraskeletal Ewing sarcoma. (Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)
      • Desmoplastic small round cell tumor.
      • Extra-renal rhabdoid tumor.
      • Neoplasms with perivascular epithelioid cell differentiation (PEComa).

        -

        PEComa NOS, benign.

        -

        PEComa NOS, malignant.

      • Intimal sarcoma.
10. Undifferentiated/unclassified sarcomas.

    • Undifferentiated spindle cell sarcoma.
    • Undifferentiated pleomorphic sarcoma.
    • Undifferentiated round cell sarcoma.
    • Undifferentiated epithelioid sarcoma.
    • Undifferentiated sarcoma NOS.[5]
    Genetic subgroups are emerging within this family and this work is ongoing:

    • Undifferentiated round cell and spindle cell sarcoma.
      In this group, EWSR1 is involved in non-ETS fusions with genes such as PATZ1, POU5F1, SMARCA5, NFATC2, or SP3. Another recurrent rearrangement involves the CIC-DUX4 fusion gene resulting in the chimeric CIC-DUX4 protein, which upregulates genes of the PEA3 subclass of ETS family. (Refer to the Genomics of Ewing Sarcoma section of the PDQ summary on Ewing Sarcoma Treatment for more information.)
      It is unclear whether these cases represent one or more separate entities, or whether they are better classified as variants of Ewing sarcoma.
    • Undifferentiated pleomorphic sarcoma.
      Undifferentiated pleomorphic sarcoma was most often called malignant fibrous histiocytoma in the past. Historically, this entity has been difficult to evaluate because of the shifting diagnostic criteria. Analysis of 70 cases diagnosed as malignant fibrous histiocytosis of no specific type, storiform or pleomorphic malignant fibrous histiocytoma, pleomorphic sarcoma or undifferentiated pleomorphic sarcoma showed highly complex karyotype with no specific recurrent aberrations. Undifferentiated sarcomas with 12q13–15 amplification, including MDM2 and CDK4, are best classified as dedifferentiated liposarcomas. The relationship between this tumor and the family of undifferentiated/unclassified tumors with spindle cell morphology remains relatively undefined and is somewhat problematic in application.
11. Vascular tumors.

    1. Benign.

       • Hemangioma. (Refer to the PDQ summary on Childhood Vascular Tumors Treatment for more information.)

         -

         Synovial.

         -

         Venous.

         -

         Arteriovenous hemangioma/malformation.

         -

         Intramuscular.

       • Epithelioid hemangioma.
       • Angiomatosis.
       • Lymphangioma.
    2. Intermediate (locally aggressive).

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

       • Retiform hemangioendothelioma.
       • Papillary intralymphatic angioendothelioma.
       • Composite hemangioendothelioma.
       • Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma.
       • Kaposi sarcoma.
    4. Malignant.

       • Epithelioid hemangioendothelioma.
       • Angiosarcoma of the soft tissue.

References

1. Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013.
2. Dantonello TM, Int-Veen C, Leuschner I, et al.: Mesenchymal chondrosarcoma of soft tissues and bone in children, adolescents, and young adults: experiences of the CWS and COSS study groups. Cancer 112 (11): 2424-31, 2008. [PubMed: 18438777]
3. Steelman C, Katzenstein H, Parham D, et al.: Unusual presentation of congenital infantile fibrosarcoma in seven infants with molecular-genetic analysis. Fetal Pediatr Pathol 30 (5): 329-37, 2011. [PubMed: 21843073]
4. Evans HL: Low-grade fibromyxoid sarcoma: a clinicopathologic study of 33 cases with long-term follow-up. Am J Surg Pathol 35 (10): 1450-62, 2011. [PubMed: 21921785]
5. Alaggio R, Collini P, Randall RL, et al.: Undifferentiated high-grade pleomorphic sarcomas in children: a clinicopathologic study of 10 cases and review of literature. Pediatr Dev Pathol 13 (3): 209-17, 2010 May-Jun. [PubMed: 20055602]

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, histologic grade, and metastasis and by anatomic primary tumor site (head and neck; trunk and extremities; abdomen and thoracic visceral organs; retroperitoneum; and unusual histologies and sites) (refer to Tables 3, 4, 5, and 6).[3-7] For information on unusual histologies and sites, refer to the AJCC Cancer Staging Manual.[7]

Soft Tissue Sarcoma Tumor Pathological Grading System

In most cases, accurate histopathologic classification alone of soft tissue sarcomas does not yield optimal information about their clinical behavior. Therefore, several histologic parameters are evaluated in the grading process, including the following:

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

This process is used to improve the correlation between histologic findings and clinical outcome.[9] In children, grading of soft tissue sarcoma is compromised by the good prognosis of certain tumors, such as infantile fibrosarcoma and hemangiopericytoma, which have a good prognosis in children younger than 4 years, and also angiomatoid fibrous histiocytoma and dermatofibrosarcoma protuberans, which may recur locally if incompletely excised, but usually do not metastasize.

Testing the validity of a grading system within the pediatric population is difficult because of the rarity of these neoplasms. In March 1986, the Pediatric Oncology Group (POG) conducted a prospective study on pediatric soft tissue sarcomas other than rhabdomyosarcoma and devised the POG grading system. Analysis of outcome for patients with localized soft tissue sarcomas other than rhabdomyosarcoma demonstrated that patients with grade 3 tumors fared significantly worse than those with grade 1 or grade 2 lesions. This finding suggests that this system can accurately predict the clinical behavior of nonrhabdomyosarcomatous soft tissue sarcoma.[9-11]

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

Prognostic Significance of Tumor Grading

The POG and FNCLCC grading systems have proven to be of prognostic value in pediatric and adult nonrhabdomyosarcomatous soft tissue sarcomas.[14-18] In a study of 130 tumors from children and adolescents with nonrhabdomyosarcomatous soft tissue sarcoma enrolled in three prospective clinical trials, a correlation was found between the POG-assigned grade and the FNCLCC-assigned grade. However, grading did not correlate in all cases; 44 patients whose tumors received discrepant grades (POG grade 3, FNCLCC grade 1 or 2) had outcomes between concurrent grade 3 and grades 1 and 2. A mitotic index of 10 or greater emerged as an important prognostic factor.[19]

The completed COG-ARST0332 trial will analyze data comparing the POG and FNCLCC pathologic grading systems to determine which system better correlates with clinical outcomes. The closed COG trial (ARST1321 [NCT02180867]) used the FNCLCC system to assign histological grade.

References

1. American Joint Committee on Cancer: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002.
2. Maurer HM, Beltangady M, Gehan EA, et al.: The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 61 (2): 209-20, 1988. [PubMed: 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. New York, NY: Springer, 2017, pp 499-505.
4. Yoon SS, Maki RG, Asare EA, et al.: Soft tissue sarcoma of the trunk and extremities. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 507-15.
5. Raut CP, Maki RG, Baldini EH, et al.: Soft tissue sarcoma of the abdomen and thoracic visceral organs. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 517-21.
6. Pollock RE, Maki RG, Baldini EH, et al.: Soft tissue sarcoma of the retroperitoneum. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 531-7.
7. Maki RG, Folpe AL, Guadagnolo BA, et al.: Soft tissue sarcoma - unusual histologies and sites. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 539-45.
8. Waxweiler TV, Rusthoven CG, Proper MS, et al.: Non-Rhabdomyosarcoma Soft Tissue Sarcomas in Children: A Surveillance, Epidemiology, and End Results Analysis Validating COG Risk Stratifications. Int J Radiat Oncol Biol Phys 92 (2): 339-48, 2015. [PubMed: 25968827]
9. Parham DM, Webber BL, Jenkins JJ 3rd, et al.: Nonrhabdomyosarcomatous soft tissue sarcomas of childhood: formulation of a simplified system for grading. Mod Pathol 8 (7): 705-10, 1995. [PubMed: 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. 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]
13. Guillou L, Coindre JM, Bonichon F, et al.: Comparative study of the National Cancer Institute and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 adult patients with soft tissue sarcoma. J Clin Oncol 15 (1): 350-62, 1997. [PubMed: 8996162]
14. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec. [PubMed: 8284572]
15. Pisters PW, Leung DH, Woodruff J, et al.: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14 (5): 1679-89, 1996. [PubMed: 8622088]
16. Coindre JM, Terrier P, Bui NB, et al.: Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 14 (3): 869-77, 1996. [PubMed: 8622035]
17. Pappo AS, Fontanesi J, Luo X, et al.: Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience. J Clin Oncol 12 (11): 2360-6, 1994. [PubMed: 7964951]
18. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998. [PubMed: 9473754]
19. Khoury JD, Coffin CM, Spunt SL, et al.: Grading of nonrhabdomyosarcoma soft tissue sarcoma in children and adolescents: a comparison of parameters used for the Fédération Nationale des Centers de Lutte Contre le Cancer and Pediatric Oncology Group Systems. Cancer 116 (9): 2266-74, 2010. [PMC free article: PMC2987713] [PubMed: 20166208]

Surgery

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

The timing of surgery depends on an assessment of the feasibility and morbidity of surgery. If the initial operation fails to achieve pathologically negative tissue margins or if the initial surgery was done without the knowledge that cancer was present, a re-excision of the affected area is performed to obtain clear, but not necessarily wide, margins.[1-4] This surgical tenet is true even if no mass is detected by magnetic resonance imaging after initial surgery.[5]; [6][Level of evidence: 3iiA]

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

Radiation Therapy

Considerations for radiation therapy are based on the potential for surgery, with or without chemotherapy, to obtain local control without loss of critical organs or significant functional, cosmetic, or psychological impairment. This will vary according to the following:

• Patient variables (e.g., age and sex).
• Tumor variables (e.g., histopathology, site, size, and grade).
• Use of surgery and margin status.
• Expectations for radiation-induced morbidities (e.g., impaired bone or muscle development, organ damage, or 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.[15] Radiation field size and dose will be based on patient and tumor variables and the surgical procedure.[16] Radiation therapy was associated with improved overall survival (OS) compared with surgery alone when delivered preoperatively or postoperatively.[17]

Preoperative radiation therapy has been associated with excellent local control rates.[18-20] The advantages of this approach include treating smaller tissue volumes without the need to treat a postsurgical bed and somewhat lower radiation doses because relative hypoxia from surgical disruption of vasculature and scarring is not present. Preoperative radiation therapy has been associated with an increased rate of wound complications in adults, primarily in lower extremity tumors; however, the degree of these complications is questionable.[21] Conversely, preoperative radiation therapy may lead to less fibrosis than with postoperative approaches, perhaps because of the smaller treatment volume and dose.[22]

Retroperitoneal sarcomas are unique in that radiosensitivity of the bowel to injury makes postoperative radiation therapy less desirable.[23,24] Postoperative adhesions and bowel immobility can increase the risk of damage from any given radiation dose. This contrasts with the preoperative approach in which the tumor often displaces bowel outside of the radiation field, and any exposed bowel is more mobile, which decreases exposure to specific bowel segments.

Radiation therapy can also be given postoperatively. In general, radiation is indicated for patients with inadequate surgical margins and for larger, high-grade tumors.[25,26] This is particularly important in high-grade tumors with tumor margins smaller than 1 cm.[27,28]; [29][Level of evidence: 3iiDiv] With combined R0 (negative margin) surgery and radiation therapy, local control of the primary tumor can be achieved in about 90% of patients with extremity sarcomas, 70% to 75% of patients with retroperitoneal sarcomas, and 80% of patients overall.[30-34]

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

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

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

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

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

Chemotherapy

The role of postoperative chemotherapy remains unclear.[41]

Evidence (lack of clarity regarding postoperative chemotherapy):

1. A meta-analysis of data from all randomized trials of adults with soft tissue sarcoma observed the following:[42]

   • 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.[43][Level of evidence: 1iiA]

   • Postoperative chemotherapy was not associated with improved event-free survival (EFS) or OS.
   • It is difficult to extrapolate this trial to pediatric patients because the trial included: 1) a wide variety of histologies; 2) a relatively low dose of ifosfamide; 3) patients assigned to chemotherapy had definitive radiation delayed until completion of chemotherapy; and 4) almost one-half of the patients in the trial had intermediate-grade tumors.
   • In the discussion section, the authors merged their patients with previously published series, including those from the European meta-analysis, and concluded that the results suggested a benefit for postoperative chemotherapy.
3. The largest prospective pediatric trial failed to demonstrate any benefit with postoperative vincristine, dactinomycin, cyclophosphamide, and doxorubicin.[30]
4. Doxorubicin and ifosfamide were used in the risk-based COG ARST0332 (NCT00346164) trial.[44][Level of evidence: 3iiiA]

   • Although this was not a randomized study, results at 2.6 years showed that patients with high-risk (>5 cm and high grade), grossly resected, nonmetastatic tumors who were treated with radiation therapy and postoperative doxorubicin and ifosfamide had a 3-year EFS of 68% and OS of 81%.
   • In patients with metastatic disease treated with preoperative chemotherapy and radiation therapy, the estimated 3-year failure-free survival was 52% and OS was 66%.

Targeted Therapy

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

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

1. In a trial of 711 adult patients who achieved a response or stable disease after chemotherapy, patients were randomly assigned to receive ridaforolimus or placebo.[45]

   • 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.[46]

   • The median PFS for the pazopanib arm was 4.6 months compared with 1.6 months for the placebo arm. OS was not different between the two arms.
3. In a 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.[47]

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

Special Considerations for the Treatment of Children With Soft Tissue Sarcoma

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[48] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

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

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[49] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Multidisciplinary evaluation in pediatric cancer centers that have surgical and radiotherapeutic expertise is of critical importance to ensure the best clinical outcome for these patients. Although surgery with or without radiation therapy can be curative for a significant proportion of patients, the addition of chemotherapy might benefit subsets of children with the disease; therefore, enrollment into clinical trials is encouraged. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Many therapeutic strategies for children and adolescents with soft tissue tumors are similar to those for adult patients, although there are important differences. For example, the biology of the neoplasm in pediatric patients may differ dramatically from that of the adult lesion. Additionally, limb-sparing procedures are more difficult to perform in pediatric patients. The morbidity associated with radiation therapy, particularly in infants and young children, may be much greater than that observed in adults.[50]

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

References

1. Sugiura H, Takahashi M, Katagiri H, et al.: Additional wide resection of malignant soft tissue tumors. Clin Orthop (394): 201-10, 2002. [PubMed: 11795735]
2. Cecchetto G, Guglielmi M, Inserra A, et al.: Primary re-excision: the Italian experience in patients with localized soft-tissue sarcomas. Pediatr Surg Int 17 (7): 532-4, 2001. [PubMed: 11666052]
3. Chui CH, Spunt SL, Liu T, et al.: Is reexcision in pediatric nonrhabdomyosarcoma soft tissue sarcoma necessary after an initial unplanned resection? J Pediatr Surg 37 (10): 1424-9, 2002. [PubMed: 12378447]
4. Paulino AC, Ritchie J, Wen BC: The value of postoperative radiotherapy in childhood nonrhabdomyosarcoma soft tissue sarcoma. Pediatr Blood Cancer 43 (5): 587-93, 2004. [PubMed: 15382277]
5. Kaste SC, Hill A, Conley L, et al.: Magnetic resonance imaging after incomplete resection of soft tissue sarcoma. Clin Orthop (397): 204-11, 2002. [PubMed: 11953612]
6. Chandrasekar CR, Wafa H, Grimer RJ, et al.: The effect of an unplanned excision of a soft-tissue sarcoma on prognosis. J Bone Joint Surg Br 90 (2): 203-8, 2008. [PubMed: 18256089]
7. Daigeler A, Kuhnen C, Moritz R, et al.: Lymph node metastases in soft tissue sarcomas: a single center analysis of 1,597 patients. Langenbecks Arch Surg 394 (2): 321-9, 2009. [PubMed: 18594854]
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Adipocytic Tumors

Chondro-osseous Tumors

Chondro-osseous tumors include the following subtypes:

• Soft tissue chondroma.
• Extraskeletal mesenchymal chondrosarcoma.
• Extraskeletal osteosarcoma.

Fibroblastic/Myofibroblastic Tumors

Fibroblastic/myofibroblastic tumors include the following subtypes:

1. Fibroblastic/myofibroblastic tumors.

   1. Intermediate (locally aggressive).

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

      • Dermatofibrosarcoma protuberans.
      • Solitary fibrous tumor.
      • Inflammatory myofibroblastic tumor.
      • Low-grade myofibroblastic sarcoma.
      • Myxoinflammatory fibroblastic sarcoma/atypical myxoinflammatory fibroblastic tumor.
      • Infantile fibrosarcoma.
   3. Malignant.

      • Adult fibrosarcoma.
      • Myxofibrosarcoma.
      • Low-grade fibromyxoid sarcoma.
      • Sclerosing epithelioid fibrosarcoma.

Skeletal Muscle Tumors

Smooth Muscle Tumors

So-called Fibrohistiocytic Tumors

So-called fibrohistiocytic tumors include the following subtypes:

• Plexiform fibrohistiocytic tumor.
• Giant cell tumor of soft tissue.

Nerve Sheath Tumors

Pericytic (Perivascular) Tumors

Tumors of Uncertain Differentiation

Tumors of uncertain differentiation include the following subtypes:

• Synovial sarcoma NOS (spindle cell and biphasic varieties).
• Epithelioid sarcoma.
• Alveolar soft part sarcoma.
• Clear cell sarcoma of soft tissue.
• Extraskeletal myxoid chondrosarcoma.
• Extraskeletal Ewing sarcoma.
• Desmoplastic small round cell tumor.
• Extra-renal rhabdoid tumor.
• Neoplasms with perivascular epithelioid cell differentiation (PEComa) (PEComa NOS, malignant).

Undifferentiated/Unclassified Sarcoma

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

In the COG ARST0332 (NCT00346164) trial, patients with high-grade undifferentiated sarcoma were treated with an ifosfamide and doxorubicin-based regimen and were treated with rhabdomyosarcoma-directed therapies in previous Intergroup Rhabdomyosarcoma Study Group studies, with a 5-year survival estimate for nonmetastatic patients of 72%.[270][Level of evidence: 3iiA]

Vascular Tumors

Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant.[279] Malignant vascular tumors include the following subtypes:

• Epithelioid hemangioendothelioma.
• Angiosarcoma of the soft tissue.

Current Clinical Trials

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

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300. Lezama-del Valle P, Gerald WL, Tsai J, et al.: Malignant vascular tumors in young patients. Cancer 83 (8): 1634-9, 1998. [PubMed: 9781959]
301. Fata F, O'Reilly E, Ilson D, et al.: Paclitaxel in the treatment of patients with angiosarcoma of the scalp or face. Cancer 86 (10): 2034-7, 1999. [PubMed: 10570428]
302. Lahat G, Dhuka AR, Hallevi H, et al.: Angiosarcoma: clinical and molecular insights. Ann Surg 251 (6): 1098-106, 2010. [PubMed: 20485141]
303. Orlando G, Adam R, Mirza D, et al.: Hepatic hemangiosarcoma: an absolute contraindication to liver transplantation--the European Liver Transplant Registry experience. Transplantation 95 (6): 872-7, 2013. [PubMed: 23354302]
304. Sanada T, Nakayama H, Irisawa R, et al.: Clinical outcome and dose volume evaluation in patients who undergo brachytherapy for angiosarcoma of the scalp and face. Mol Clin Oncol 6 (3): 334-340, 2017. [PMC free article: PMC5403362] [PubMed: 28451409]
305. Dickson MA, D'Adamo DR, Keohan ML, et al.: Phase II Trial of Gemcitabine and Docetaxel with Bevacizumab in Soft Tissue Sarcoma. Sarcoma 2015: 532478, 2015. [PMC free article: PMC4446476] [PubMed: 26074722]
306. North PE, Waner M, Mizeracki A, et al.: A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 137 (5): 559-70, 2001. [PubMed: 11346333]
307. Boye E, Yu Y, Paranya G, et al.: Clonality and altered behavior of endothelial cells from hemangiomas. J Clin Invest 107 (6): 745-52, 2001. [PMC free article: PMC208946] [PubMed: 11254674]
308. Ravi V, Patel S: Vascular sarcomas. Curr Oncol Rep 15 (4): 347-55, 2013. [PubMed: 23852636]
309. Grassia KL, Peterman CM, Iacobas I, et al.: Clinical case series of pediatric hepatic angiosarcoma. Pediatr Blood Cancer 64 (11): , 2017. [PubMed: 28521077]

Pulmonary Metastases

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

An alternative approach is focused radiation therapy (fractionated stereotactic radiation therapy), which has been successfully used in adults to control lesions. The estimated 5-year survival rate after thoracotomy for pulmonary metastasectomy has ranged from 10% to 58% in adult studies.[11]

References

1. Demetri GD, Elias AD: Results of single-agent and combination chemotherapy for advanced soft tissue sarcomas. Implications for decision making in the clinic. Hematol Oncol Clin North Am 9 (4): 765-85, 1995. [PubMed: 7490240]
2. Elias A, Ryan L, Sulkes A, et al.: Response to mesna, doxorubicin, ifosfamide, and dacarbazine in 108 patients with metastatic or unresectable sarcoma and no prior chemotherapy. J Clin Oncol 7 (9): 1208-16, 1989. [PubMed: 2504890]
3. Edmonson JH, Ryan LM, Blum RH, et al.: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11 (7): 1269-75, 1993. [PubMed: 8315424]
4. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec. [PubMed: 8284572]
5. deCou JM, Rao BN, Parham DM, et al.: Malignant peripheral nerve sheath tumors: the St. Jude Children's Research Hospital experience. Ann Surg Oncol 2 (6): 524-9, 1995. [PubMed: 8591083]
6. Pappo AS, Rao BN, Jenkins JJ, et al.: Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: the St. Jude Children's Research Hospital experience. Med Pediatr Oncol 33 (2): 76-82, 1999. [PubMed: 10398180]
7. Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999. [PubMed: 10561182]
8. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998. [PubMed: 9473754]
9. Stanelle EJ, Christison-Lagay ER, Wolden SL, et al.: Pulmonary metastasectomy in pediatric/adolescent patients with synovial sarcoma: an institutional review. J Pediatr Surg 48 (4): 757-63, 2013. [PubMed: 23583130]
10. Putnam JB Jr, Roth JA: Surgical treatment for pulmonary metastases from sarcoma. Hematol Oncol Clin North Am 9 (4): 869-87, 1995. [PubMed: 7490246]
11. Dhakal S, Corbin KS, Milano MT, et al.: Stereotactic body radiotherapy for pulmonary metastases from soft-tissue sarcomas: excellent local lesion control and improved patient survival. Int J Radiat Oncol Biol Phys 82 (2): 940-5, 2012. [PubMed: 21277105]

Treatment Options Under Clinical Evaluation

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

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

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

Current Clinical Trials

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

References

1. Bergamaschi L, Bisogno G, Manzitti C, et al.: Salvage rates and prognostic factors after relapse in children and adolescents with malignant peripheral nerve sheath tumors. Pediatr Blood Cancer 65 (2): , 2018. [PubMed: 28926683]
2. 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]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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]
14. Ferrari A, De Salvo GL, Dall'Igna P, et al.: Salvage rates and prognostic factors after relapse in children and adolescents with initially localised synovial sarcoma. Eur J Cancer 48 (18): 3448-55, 2012. [PubMed: 22835783]
15. Soole F, Maupain C, Defachelles AS, et al.: Synovial sarcoma relapses in children and adolescents: prognostic factors, treatment, and outcome. Pediatr Blood Cancer 61 (8): 1387-93, 2014. [PubMed: 24664883]

Purpose of This Summary

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

Reviewers and Updates

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

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

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

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

The lead reviewers for Childhood Soft Tissue Sarcoma Treatment are:

• Denise Adams, MD (Children's Hospital Boston)
• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Holcombe Edwin Grier, MD
• Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• R Beverly Raney, MD (Consultant)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

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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