Childhood Soft Tissue Sarcoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Childhood Soft Tissue Sarcoma

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1,2,3] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Pediatric soft tissue sarcomas are a heterogenous group of malignant tumors that originate from primitive mesenchymal tissue and account for 6% of all childhood tumors (rhabdomyosarcomas, 3%; other soft tissue sarcomas, 3%).[2] For more information, see the Histopathological Classification of Childhood Soft Tissue Sarcoma section.

Rhabdomyosarcoma, a tumor of striated muscle, is the most common soft tissue sarcoma in children. It accounts for 50% of the soft tissue sarcomas in children aged 0 to 14 years.[2] For more information, see Childhood Rhabdomyosarcoma Treatment.

In pediatrics, the remaining soft tissue sarcomas are commonly referred to as nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS) and account for approximately 3.5% of all childhood tumors.[2,4] This summary discusses the treatment of NRSTS.

NRSTS are often classified according to the normal tissue types from which they are derived. These types include various connective tissues, peripheral nervous system tissue, smooth muscle tissue, and vascular tissue. The classification also includes undifferentiated tumors that are not clearly related to specific tissue types. For more information about vascular tumors in children, see Childhood Vascular Tumors Treatment.

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.

Soft tissue sarcomas include both rhabdomyosarcomas and NRSTS. 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 soft tissue sarcomas 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 soft tissue sarcomas by age according to stage.
Figure 2. The distribution of soft tissue sarcomas by age according to histological subtype.
Figure 3. The distribution of 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 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.[14,15,16]
  • 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.[18,19,20]
  • Adenosine deaminase–deficient severe combined immunodeficiency: Patients with adenosine deaminase–deficient severe combined immunodeficiency are 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.[22,23,24,25,26]
  • 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.[28,29,30] 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 or impact on 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, which was identified as a solitary fibrous tumor and is now included within myofibroma in the revised World Health Organization (WHO) classification. 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 to perform a complete workup, followed by adequate biopsy. 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 may be essential for a surgeon to achieve adequate surgical margins. 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]

Biopsy strategies

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

Needle biopsy techniques must ensure adequate tissue sampling. Given the diagnostic importance of translocations and other molecular changes, a core-needle biopsy or small incisional biopsy that obtains adequate tumor tissue is crucial to allow for conventional histological and immunocytochemical analysis and other studies such as light and electron microscopy, cytogenetics, fluorescence in situ hybridization, and molecular pathology.[37,38]

The acquisition of multiple cores of tissue may be required. Of 530 suspected soft tissue masses in (largely adult) patients who underwent core-needle biopsies, 426 (80%) were proven to be soft tissue tumors, 225 (52.8%) of which were malignant. Core-needle biopsy was able to differentiate soft tissue sarcomas from benign lesions with a sensitivity of 96.3% and a specificity of 99.4%. Tumor subtype was accurately assigned in 89.5% of benign lesions and in 88% of soft tissue sarcomas. The biopsy complication rate was 0.4%.[39]

Considerations related to a biopsy procedure are as follows:

• Core-needle biopsy for a deep-seated tumor can lead to formation of a hematoma, which affects subsequent resection and/or radiation (because the hematoma should be covered in the irradiated volume).
• Fine-needle biopsy is usually not recommended because it is difficult to determine the accurate histological diagnosis and grade of the tumor in this heterogeneous group of tumors.
• Image guidance using ultrasonography, CT scan, or MRI may be necessary to ensure a representative biopsy.[40] Image guidance is particularly helpful in deep lesions and to avoid cystic changes or necrotic tumors.[41]
• Incisional biopsies must not compromise subsequent wide local excision.
• Excisional biopsy of the lesion is only appropriate for small superficial lesions (<3 cm in size) and are discouraged.[42,43] If an excisional biopsy is contemplated, then MRI of the area is recommended to define the area of involvement as subsequent surgery or radiation therapy may be needed.
• Various institutional series have demonstrated the feasibility and effectiveness of sentinel lymph node biopsy as a staging procedure in pediatric patients with soft tissue sarcomas.[44,45,46,47,48,49] The utility of sentinel node biopsy is currently limited to epithelioid sarcoma, clear cell sarcoma, and rhabdomyosarcoma of the trunk and extremities.[50]

  In a prospective study of pediatric patients with sarcoma who underwent sentinel lymph node biopsy, 28 patients were examined. Sentinel lymph node biopsy was positive in 7 of the 28 patients, including 3 patients (43%) who had negative PET-CT scans. PET-CT overestimated and suggested nodal involvement in 14 patients, more than what was confirmed by sentinel lymph node biopsy. The findings from the sentinel lymph node biopsies resulted in altering therapy for all seven patients who were determined to have metastatic disease. As indicated by previous reports, epithelioid sarcoma and clear cell sarcoma were the two NRSTS included in this study.[50]

• In the ARST0332 (NCT00346164) study, patients with epithelioid sarcoma, clear cell sarcoma, or radiographically enlarged nodes underwent regional node sampling. Nodal metastases were identified in 20 patients (3.8%), and all but one of these patients had radiographic evidence of nodal involvement. The most common histologies included epithelioid sarcoma (18%), angiosarcoma (17%), and clear cell sarcoma (14%). Patients with isolated nodal metastases had a similar outcome to those who did not have distant metastases (5-year OS rates, 85% vs. 87%). Sentinel lymph node biopsies were encouraged but not required for this study. A sentinel lymph node biopsy was not done in most patients because they had clinically enlarged nodes. Of note, three patients without clinical evidence of lymph node metastasis at study entry experienced lymph node basin failure. One of these patients had three lymph nodes in two different lymph node basins sampled by sentinel lymph node biopsy that were pathologically negative.[51]

  Transverse extremity incisions are avoided to reduce skin loss at re-excision and because they require a greater cross-sectional volume of tissue to be covered in the radiation field. Other extensive surgical procedures are also avoided before definitive diagnosis.

For these reasons, open biopsy or multiple core-needle biopsies are strongly encouraged so that adequate tumor tissue can be obtained to allow crucial studies to be performed and to avoid limiting future treatment options.

Unplanned resection

In children with unplanned resection of NRSTS, primary re-excision is frequently recommended because many patients will have tumor present in the re-excision specimen.[52,53] A single-institution analysis of adolescents and adults compared patients who had unplanned excisions of soft tissue sarcoma to stage-matched controls. In this retrospective analysis, unplanned initial excision of soft tissue sarcoma resulted in increased risk of local recurrence, metastasis, and death. This increased risk was greatest for high-grade tumors.[54][Level of evidence C1] In this case, a second resection is expected.

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.

Prognosis and Prognostic Factors

The prognosis of NRSTS varies greatly depending on the following factors:[71,72,73]

• 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. This may be a reflection of differences in resectability. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.[74]

Data specific to NRSTS in children and adolescents are difficult to separate. 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 (rhabdomyosarcoma and NRSTS) 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 in a rhabdomyosarcoma study 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 based on 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) given intravenously on days 1 through 3 and five cycles of doxorubicin (37.5 mg/m² per dose) given intravenously on days 1 to 2 every 3 weeks, with the sequence adjusted based on 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.

The COG ARST0332 trial was a risk-based stratification 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).[80]

Pediatric patients with unresected localized NRSTS have a poor outcome. Only about one-third of patients treated with multimodality therapy remain disease free.[71,81]; [82,83][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.[84][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.[85] With a median follow-up of 80 months (interquartile range, 54.3–111.3) for the 467 surviving patients, the 5-year 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.[85]

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.

Treatment failures specifically for the neoadjuvant therapy treatment groups are shown in Table 5.[85]

The authors concluded that adjuvant therapy (radiation therapy and chemotherapy) could safely be omitted in the group of patients assigned to surgery alone. Their criteria included the following:[85]

• Synovial cell: Intergroup Rhabdomyosarcoma Study (IRS) group I tumor size <5 cm.
• Adult-type NRSTS: IRS group I tumor size <5 cm, any grade.
• Adult-type NRSTS: IRS group I tumor size >5 cm, tumor grade I.
• Adult-type NRSTS: IRS group II any tumor size, tumor grade I.

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.[85]

In a pooled analysis from U.S. and European pediatric centers, outcomes were better for patients whose tumor removal procedure was deemed complete than for patients whose tumor removal was incomplete. Outcomes were better for patients who received radiation therapy than for patients who did not.[82][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.[29,86,87,88,89,90]

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