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Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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:
(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. 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.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Rhabdomyosarcoma, a tumor of striated muscle, is the most common soft tissue sarcoma in children aged 0 to 14 years and accounts for 50% of tumors in this age group. (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.) In pediatrics, the remaining soft tissue sarcomas are commonly referred to as nonrhabdomyosarcomatous soft tissue sarcomas and account for approximately 3% of all childhood tumors. This heterogeneous group of tumors includes the following neoplasms:
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.
The distribution of soft tissue sarcomas by histology and age, based on the Surveillance, Epidemiology, and End Results (SEER) information from 1975 to 2012, 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, and most of the information regarding treatment and natural history of the disease in younger patients has been based on adult studies. The distributions of these tumors by age according to stage, histologic subtype, and tumor site are shown in Figures 1, 2, and 3, respectively.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.
Some genetic and environmental factors have been associated with the development of nonrhabdomyosarcomatous soft tissue sarcoma, including the following:
Although nonrhabdomyosarcomatous soft tissue sarcomas can develop in any part of the body, they arise most commonly in the trunk and extremities.[18,19,20] These neoplasms can present initially as an asymptomatic solid mass, or they may be symptomatic because of local invasion of adjacent anatomical structures. Although rare, these tumors can arise primarily in brain tissue and are treated according to the histiotype.
Systemic symptoms (e.g., fever, weight loss, and night sweats) are rare. Hypoglycemia and hypophosphatemic rickets have been reported in cases of hemangiopericytoma, whereas hyperglycemia has been noted in patients with fibrosarcoma of the lung.
Diagnostic and Staging Evaluation
When a suspicious lesion is identified, it is crucial that a complete workup, followed by adequate biopsy be performed. It is best to image the lesion using the following procedures before initiating any intervention:
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.
Although nonrhabdomyosarcomatous soft tissue tumors are fairly readily distinguished pathologically from rhabdomyosarcoma and Ewing sarcoma, the classification of childhood nonrhabdomyosarcomatous soft tissue sarcoma type is often difficult. Core-needle biopsy, incisional biopsy, or excisional biopsy can be used to diagnose a nonrhabdomyosarcomatous soft tissue sarcoma. If possible, the surgeon who will perform the definitive resection needs to be involved in the biopsy decision. Poorly placed incisional or needle biopsies may adversely affect the performance of the primary resection.
Considerations related to the selection of a biopsy procedure are as follows:
In children with unplanned resection of nonrhabdomyosarcomatous soft tissue sarcomas, primary re-excision is frequently recommended because many patients will have tumor present in the re-excision specimen.[31,32] A single-institution analysis of adolescents and adults compared patients with unplanned excision of soft tissue sarcoma to stage-matched controls. In this retrospective analysis, unplanned initial excision of soft tissue sarcoma resulted in increased risk of local recurrence, metastasis, and death; this increase was greatest for high-grade tumors.[Level of evidence: 3iiA]
Many nonrhabdomyosarcomatous soft tissue sarcomas are characterized by chromosomal abnormalities. Some of these chromosomal translocations lead to a fusion of two disparate genes. The resulting fusion transcript can be readily detected by using polymerase chain reaction-based techniques, thus facilitating the diagnosis of those neoplasms that have translocations. Some of the most frequent aberrations seen in nonrhabdomyosarcomatous soft tissue tumors are listed in Table 2.
The prognosis of nonrhabdomyosarcomatous soft tissue sarcoma varies greatly depending on the following factors:[45,46,47]
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.
Soft tissue sarcomas in older children and adolescents often behave similarly to those in adult patients.[4,26] A large, prospective, multinational Children's Oncology Group study (ARST0332 [NCT00346164]) enrolled newly diagnosed patients younger than 30 years. Patients were assigned to treatment on the basis of their risk group (refer to Figure 4).[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.
Of 551 patients enrolled, at a median follow-up of 2.6 years, the preliminary analysis estimated the following 3-year survival rates:
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.[45,49]; [50,51][Level of evidence: 3iiiA]
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.[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.[19,52,53,54,55,56]
Refer to the following PDQ summaries for information about other types of sarcoma:
World Health Organization (WHO) Classification of Soft Tissue Sarcomas
The WHO lists the following cell types in its classification of soft tissue sarcomas:[1,2]
Clinical staging has an important role in predicting the clinical outcome and determining the most effective therapy for pediatric soft tissue sarcomas. As yet, there is no well-accepted staging system that is applicable to all childhood sarcomas. The system from the American Joint Committee on Cancer (AJCC) that is used for adults has not been validated in pediatric studies. Although a standardized staging system for pediatric nonrhabdomyosarcomatous soft tissue sarcoma does not exist, two systems are currently in use for staging pediatric nonrhabdomyosarcomatous soft tissue sarcoma.
Intergroup Rhabdomyosarcoma Study Staging System
TNM Staging System
The seventh edition of the AJCC has designated staging by the four criteria of tumor size, nodal status, histologic grade, and metastasis.
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:
This process is used to improve the correlation between histologic findings and clinical outcome. 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.[5,6,7]
The grading systems developed by the POG and the French Federation of Comprehensive Cancer Centers (Fédération Nationale des Centres de Lutte Contre Le Cancer [FNCLCC]) Sarcoma Group are described below. These grading systems are being compared by the central review pathologists on the COG-ARST0332 study. The study has closed and results are pending.
POG grading system
The POG grading system is described below. It is an older grading system of historical value that is no longer being used for treatment.
Grade I lesions are based on histologic type, well-differentiated cytohistologic features, and/or age of the patient.
Grade II lesions are soft tissue sarcomas not included in grade I or III by histologic diagnosis (with <5 mitoses/10 high-power fields or <15% necrosis):
Grade III lesions are similar to grade II lesions and include certain tumors known to be clinically aggressive by virtue of histologic diagnosis and non-grade I tumors (with >4 mitoses per 10 high-power fields or >15% necrosis):
FNCLCC grading system
The FNCLCC histologic grading system was developed for adults with soft tissue sarcoma. The purpose of the grading system is to predict which patients will develop metastasis and subsequently benefit from postoperative chemotherapy.[8,9] The system is described in Tables 7 and 8.
Prognostic Significance of Tumor Grading
The two grading systems described above have proven to be of prognostic value in pediatric and adult nonrhabdomyosarcomatous soft tissue sarcomas.[10,11,12,13,14] 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. The recently completed COG-ARST0332 trial will analyze data comparing the POG and FNCLCC pathologic grading systems to determine which system better correlates with clinical outcomes.
In a review of a large adult series of nonrhabdomyosarcomatous soft tissue sarcomas, superficial extremity sarcomas had a better prognosis than deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.
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. This relationship requires further study to determine the therapeutic implications of the observation.
Because of the rarity of pediatric nonrhabdomyosarcomatous soft tissue sarcomas, coordination of treatment by a multidisciplinary team comprising oncologists (pediatric or medical), pathologists, surgeons, and radiation oncologists should be considered for all children, adolescents, and young adults with these tumors. In addition, to better define the tumors' natural history and response to therapy, entry into national or institutional treatment protocols should be considered for children with rare neoplasms. Information about ongoing clinical trials is available from the NCI website.
After an appropriate biopsy and pathologic diagnosis, every attempt is made to resect the primary tumor with negative margins before or after chemotherapy and/or radiation therapy. Involvement of a surgeon with special expertise in the resection of soft tissue sarcomas in the decision is highly desirable.
The timing of surgery depends on an assessment of the feasibility and morbidity of surgery. If the initial operation fails to achieve pathologically negative tissue margins or if the initial surgery was done without the knowledge that cancer was present, a re-excision of the affected area is performed to obtain clear, but not necessarily wide, margins.[1,2,3,4] This surgical tenet is true even if no mass is detected by magnetic resonance imaging after initial surgery.; [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.[9,10,11,12,13,14]
Considerations for radiation therapy are based on the potential for surgery, with or without chemotherapy, to obtain local control without loss of critical organs or significant functional, cosmetic or psychological impairment. This will vary according to patient (e.g., age and gender) and tumor variables (e.g., histopathology, site, size, and grade). Radiation therapy considerations also include surgical margin status, and expectations for radiation-induced morbidities such as impaired bone or muscle development, organ damage, or second malignancy. Radiation therapy can be given preoperatively or postoperatively, and the radiation field size and dose will again be based on patient and tumor variables and the operability of the tumor.
In general, radiation is indicated for patients with inadequate surgical margins and for larger, high-grade tumors.[15,16] This is particularly important in high-grade tumors with tumor margins smaller than 1 cm.[17,18]; [Level of evidence: 3iiDiv] With combined surgery and radiation therapy, local control of the primary tumor can be achieved in more than 80% of patients.[20,21]
Preoperative radiation therapy has been associated with excellent local control rates.[22,23] This approach has the advantage of treating smaller tissue volumes because it does not necessitate treating a postsurgical bed; it also has the advantage of somewhat lower radiation doses because relative hypoxia from surgical disruption of vasculature and scarring is not present. Preoperative radiation therapy has been associated with an increased rate of wound complications in adults, primarily in lower extremity tumors, but the degree of this is questionable. Conversely, preoperative radiation therapy may lead to less fibrosis than with postoperative approaches, perhaps due to the smaller treatment volume and dose.
Brachytherapy and intraoperative radiation may be applicable in select situations.[21,26,27]; [Level of evidence: 3iiiDii]
Retroperitoneal sarcomas are unique in that radiosensitivity of the bowel to injury makes postoperative radiation therapy less desirable.[29,30] 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 volume and dose depend on the patient, tumor, and surgical variables noted above, as well as the following:
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. The postoperative radiation dose is 55 Gy to 60 Gy, or rarely, higher when unresectable gross residual disease exists.
Radiation margins are typically 2 cm to 4 cm longitudinally and encompass fascial planes axially.[32,33]
The role of postoperative chemotherapy remains controversial as evidenced by the following studies:
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. In a trial of 711 randomly assigned adult patients who achieved a response or stable disease after chemotherapy, the administration of ridaforolimus was associated with a 3-week improvement in progression-free survival (PFS) when compared with placebo. In another trial of 371 randomly assigned adult patients with metastatic soft tissue sarcoma that progressed after chemotherapy pazopanib was compared with placebo. 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.
Special Treatment Considerations for Children With Soft Tissue Sarcoma
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.
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.
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.
Liposarcoma accounts for 3% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
Liposarcoma is rare in the pediatric population. In a review of 182 pediatric patients with adult-type sarcomas, only 14 had a diagnosis of liposarcoma. One retrospective study identified 34 patients younger than 22 years from 1960 to 2011. There were roughly equal numbers of male and female patients and the median age was 18 years. In an international clinicopathological review, the characteristics of 82 cases of pediatric liposarcoma were reported. The median age was 15.5 years and females were more commonly affected. In both reports, the great majority of patients had myxoid liposarcoma.
The World Health Organization (WHO) classification for liposarcoma is as follows:
The majority of liposarcomas in the pediatric and adolescent age range are low grade and located subcutaneously. Metastasis to lymph nodes is very uncommon, and the great majority of metastases are pulmonary. Tumors arising in the periphery are more likely to be low grade and myxoid. Tumors arising centrally are more likely to be high grade, pleomorphic, and present with metastasis or recur with metastasis.
In a retrospective study of 14 patients, 5-year survival was 78% and tumor grade, histologic subtype, and primary location correlated with survival.
Treatment options for liposarcoma include the following:
Surgery is the most important treatment for liposarcoma. After surgical resection of myxoid liposarcoma, event-free survival (EFS) and overall survival (OS) are roughly 90%. Local recurrences have been seen and are controlled with a second resection of the tumor. Higher grade or central tumors are associated with a significantly higher risk of death. In a retrospective review, 5-year survival for central tumors was 42%. In the international review, seven of ten patients with pleomorphic myxoid liposarcoma died because of their disease. If initial surgery is incomplete, re-excision should be performed to achieve a wide margin of resection.
There are reports of the use of chemotherapy to decrease the size of liposarcoma before surgery to facilitate complete resection, particularly in central tumors.[10,11] The role of postoperative chemotherapy for liposarcoma is poorly defined. There does not appear to be a need for any postoperative therapy for completely resected myxoid liposarcoma. Even with the use of postoperative chemotherapy, the survival of pleomorphic liposarcoma remains poor. Trabectedin has produced encouraging responses in adults with advanced myxoid liposarcoma. In one study, adult patients with recurrent liposarcoma and leiomyosarcoma were randomly assigned to treatment with either trabectedin or dacarbazine. Patients treated with trabectedin had a 45% reduction in disease progression.[Level of evidence: 1iiDiii]
Treatment options under clinical evaluation
Chondro-osseous tumors include the following tumor subtypes:
Extraskeletal mesenchymal chondrosarcoma
Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
Histopathology and molecular features
Mesenchymal chondrosarcoma is a rare tumor characterized by small round cells and hyaline cartilage that more commonly affects young adults and has a predilection for involving the head and neck region.
Mesenchymal chondrosarcoma has been associated with consistent chromosomal rearrangement. A retrospective analysis of cases of mesenchymal chondrosarcoma identified a HEY1-NCOA2 fusion in 10 of 15 tested specimens. This gene fusion was not associated with chromosomal changes that could be detected by karyotyping. In one instance, translocation t(1;5)(q42;q32) was identified in a case of mesenchymal chondrosarcoma and shown to be associated with a novel IRF2BP-CDX1 fusion gene.
A retrospective survey of European institutions identified 113 children and adults with mesenchymal chondrosarcoma. Factors associated with better outcome included the following:[Level of evidence: 3iiiA]
Treatment options for extraskeletal mesenchymal chondrosarcoma include the following:
A review of 15 patients younger than 26 years from the German Cooperative Soft Tissue Sarcoma Study Group (11 with soft-tissue lesions) and the German-Austrian-Swiss Cooperative Osteosarcoma Study Group (four with primary bone lesions) protocols suggests that complete surgical removal, or incomplete resection followed by radiation therapy, is necessary for local control.[Level of evidence: 3iiA]
A single-institution, retrospective review identified 12 pediatric patients with mesenchymal chondrosarcoma. The presence of the NCOA2 rearrangement in tumors was documented in these patients. It was also confirmed that surgical resection is necessary for cure. Eleven patients presented with localized disease and one presented with pulmonary nodules. All patients received chemotherapy—six patients before and after surgical resection and six patients only after resection. All patients received postoperative chemotherapy (most commonly ifosfamide/doxorubicin) with or without radiation therapy (median dose, 59.4 Gy). At a median follow-up of 4.8 years, 5-year disease-free survival (DFS) was 68.2% (95% CI, 39.8–96.6) and OS was 88.9% (95% CI, 66.9–100).
Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
Extraskeletal osteosarcoma is extremely rare in the pediatric and adolescent age range. A 2003 review identified only ten case reports in the medical literature.
Extraskeletal osteosarcoma is associated with a high risk of local recurrence and pulmonary metastasis.
Treatment options for extraskeletal osteosarcoma include the following:
(Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment for more information.)
Fibroblastic/myofibroblastic tumors include the following tumor subtypes:
Desmoid-type fibromatosis has previously been called desmoid tumors or aggressive fibromatoses.
A small number of desmoid-type fibromatosis tumors may occur in association with a mutation in the adenomatous polyposis coli (APC) gene (associated with intestinal polyps and a high incidence of colon cancer). In a study of 519 patients older than 10 years with a diagnosis of desmoid-type fibromatosis, 39 (7.5%, a possible underestimation) were found to have familial adenomatous polyposis (FAP). The patients with FAP and desmoid-type fibromatosis were younger, more often male, and had more abdominal wall or mesenteric tumors than did patients with desmoid-type fibromatosis without FAP.
A family history of colon cancer, the presence of congenital hyperplasia of the retinal pigment epithelium,[23,24] or location of the desmoid-type fibromatosis in the abdomen or abdominal wall  should prompt referral to a genetic counselor. Currently, there are no general recommendations for genetic testing in children with desmoid-type fibromatosis. Pathology and molecular characteristics of the tumor only provide guidance for screening. If the tumor has a somatic CTNNB1 mutation, screening is not necessary, because the APC gene mutation has not been described in this setting. If a CTNNB1 mutation is not identified, screening for the APC mutation may be warranted.[25,26] (Refer to the Familial Adenomatous Polyposis (FAP) section of the PDQ summary on Genetics of Colorectal Cancer for more information.)
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.
These tumors have a high potential for local recurrence. Desmoid-type fibromatosis has a highly variable natural history, including well documented examples of spontaneous regression. Mutations in exon 3 of the beta-catenin gene are seen in over 80% of desmoid-type fibromatosis and the mutation 45F has been associated with an increased risk of disease recurrence. Repeated surgical resection can sometimes bring recurrent lesions under control.
Evaluation of the benefit of interventions for treatment of desmoid-type fibromatosis has been extremely difficult, because desmoid-type fibromatosis has a highly variable natural history. Large adult series and smaller pediatric series have reported long periods of disease stabilization and even regression without systemic therapy.[29,30]; [Level of evidence: 3iiiDi]
Treatment options for desmoid-type fibromatosis include the following:
The treatment of choice is resection to achieve clear margins. However, a retrospective review of children who underwent surgery for desmoid-type fibromatosis at the St. Jude Children's Research Hospital (SJCRH) reported no correlation between surgical margins and risk of recurrence.
When the diagnosis is known and complete surgical excision is not feasible, and if the tumor poses significant potential for mortality or morbidity, preoperative strategies may include the following:[35,36]
Desmoid-type fibromatosis often behaves in a nonaggressive manner. In a study that included mostly adults with extra-abdominal primary fibromatosis, nonsurgical approaches (medical and observation) had similar 3-year EFS compared with surgery. In a subsequent study of adolescents and adults with abdominal wall aggressive fibromatosis, 102 patients were treated with a watch and wait approach, of which 65 patients required no further treatment at 3 years. Approximately one-third of patients had regression of the tumor.
Chemotherapy regimens may include the following:
Other drug therapy may include the following:
Postoperative radiation therapy is a consideration when progression would entail additional surgery that might cause functional or cosmetic compromise and if radiation is considered acceptable in terms of morbidities.
Radiation has been used for unresectable desmoid-type fibromatosis or postoperatively for tumors with inadequate resections. The potential long-term complications of radiation therapy, especially subsequent neoplasms, make using this modality less appealing in a young population.
Partially excised or recurrent lesions that do not pose a significant danger to vital organs may be monitored closely if other treatment alternatives are not available.[29,34,51,52,53,54] Whenever possible, however, the treatment of choice is complete resection.
Dermatofibrosarcoma is a rare tumor, but many of the reported cases arise in children.
The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGF-beta gene.
Treatment of dermatofibrosarcoma protuberans includes the following:
Most dermatofibrosarcoma tumors can be cured by complete surgical resection. Wide excision with negative margins or Mohs or modified Mohs surgery will prevent most tumors from recurring.
In retrospective reviews, postoperative radiation therapy after incomplete excision may have decreased the likelihood of recurrence.[57,58]
When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective.[59,60,61]
Guidelines for workup and management of dermatofibrosarcoma protuberans have been published.
There are two distinct types of fibrosarcoma in children and adolescents: infantile fibrosarcoma (also called congenital fibrosarcoma) and fibrosarcoma that is indistinguishable from fibrosarcoma seen in adults. These are two distinct pathologic diagnoses and require different treatments. Adult-type fibrosarcoma is addressed below.
Infantile fibrosarcoma usually occurs in children younger than 1 year. It occasionally occurs in children up to age 4 years.
Infantile fibrosarcoma usually presents with a rapidly growing mass, often noted at birth or even seen in prenatal ultrasound. The tumors are often quite large at the time of presentation.
The tumor usually has a characteristic cytogenetic translocation t(12;15)(ETV-NTRK3). Infantile fibrosarcoma shares this translocation and a virtually identical histologic appearance with mesoblastic nephroma.
These tumors have a low incidence of metastases at diagnosis.
Treatment options for infantile fibrosarcoma include the following:
Complete resection is curative in the majority of patients with infantile fibrosarcoma. However the large size of the lesion frequently makes resection without major functional consequences impossible (for instance, tumors of the extremities often require amputation for complete excision). The European pediatric group has reported that observation may also be an option in patients with group II disease after surgery. Twelve patients with group II disease received no further therapy and two patients relapsed. One patient obtained a complete remission after chemotherapy. Postoperative chemotherapy was administered to patients with higher group disease and those who progressed.
Preoperative chemotherapy has made a more conservative surgical approach possible; agents active in this setting include vincristine, dactinomycin, cyclophosphamide, and ifosfamide.[65,66]; [Level of evidence: 3iiA]; [Level of evidence: 3iiB]
Two studies of infants with infantile fibrosarcoma suggest that an alkylator-free regimen is effective and should be used as the first treatment choice in patients with macroscopic disease.[64,69] One case of a patient with a variant LMNA/NTRK1 fusion responded to crizotinib.
A rare case of spontaneous regression without treatment has been reported.[Level of evidence: 3iiiDiv]
Inflammatory myofibroblastic tumor
Inflammatory myofibroblastic tumor is a rare mesenchymal tumor that has a predilection for children and adolescents.[72,73,74]
Inflammatory myofibroblastic tumors are rare tumors that affect soft tissues and visceral organs of children and young adults. They rarely metastasize but tend to be locally invasive. Usual anatomical sites of disease include soft tissue, lungs, spleen, colon, and breast.
Roughly half of inflammatory myofibroblastic tumors exhibit a clonal mutation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase gene at chromosome 2p23.ROS1 and PDGFR-beta kinase fusions have been identified in 8 of 11 cases (73%) who are negative for ALK by immunohistochemistry.[Level of evidence: 3iiiDiv]
Inflammatory myofibroblastic tumor recurs frequently but is rarely metastatic.[72,73,74]
Treatment options for inflammatory myofibroblastic tumor include the following:
Complete surgical removal, when feasible, is the mainstay of therapy. In a series of nine patients, four patients achieved continuous remission after complete resection, three patients with residual disease recurred but later achieved continuous remission, and one patient with metastatic disease responded to multiagent chemotherapy.[Level of evidence: 3iiA] The benefit of chemotherapy has been noted in case reports. There are case reports of response to either steroids or NSAIDs.[81,82]
Two adults with ALK-rearranged inflammatory myofibroblastic tumor achieved partial response with crizotinib.[Level of evidence: 3iiiDiv] For pediatric patients with measurable disease the use of crizotinib achieved partial tumor responses in three of six patients with ALK-translocated inflammatory myofibroblastic tumors. The use of crizotinib for ROS1-rearranged non-small cell lung carcinoma suggests that this agent may be efficacious in ROS1-rearranged tumors. In a phase I trial of ceritinib for adult patients previously treated with ALK inhibitors, one patient with inflammatory myofibroblastic tumor had a partial response.
These tumors lack the translocation seen in infantile fibrosarcomas. They present like the great majority of nonrhabdomyosarcomas and the management approach is similar.
(Refer to the PDQ summary on Adult Soft Tissue Sarcoma Treatment for more information.)
Low-grade fibromyxoid sarcoma
Low-grade fibromyxoid sarcoma is a histologically deceptive soft tissue neoplasm that most commonly affects young and middle-aged adults, is commonly located deep within the extremities, and is characterized by a FUS/CREB3L3 translocation.[87,88]
In a review of 33 patients (three were younger than 18 years) with low grade fibromyxoid sarcoma, 21 of 33 patients developed a local recurrence after intervals of up to 15 years (median, 3.5 years) and 15 developed metastases up to 45 years (median, 5 years) from diagnosis, most commonly to the lungs and pleura, emphasizing the need for continued follow-up of these patients. Even after metastases occur, the course may be indolent.
In another report, 14 of 73 cases were younger than 18 years of age. In this series with a relatively short follow up (median of 24 months), only 8 of 54 patients with adequate follow up developed local (9%) or distant (6%) recurrence. This report suggests that the behavior of this tumor might be significantly better than previously reported. However, because of the occurrence of late metastases, careful monitoring of these patients is warranted.
The most recent Children's Oncology Group (COG) trial (ARST0332 [NCT00346164]) enrolled 11 patients with this tumor entity. The median age at diagnosis was 13 years and males were more commonly affected. The most common sites were the lower and upper extremity (n = 9) and none of the patients had developed local or distant disease recurrence at a median follow up of 2.7 years.
Treatment options for low-grade fibromyxoid sarcoma include the following:
The limited treatment information for low-grade fibromyxoid sarcoma suggest that surgery is the treatment of choice as the tumor is not very chemosensitive. There are little data regarding the use of chemotherapy and/or radiation therapy in this disease. One report suggests that trabectedin may be effective in the treatment of low-grade fibromyxoid sarcoma.
Myxofibrosarcoma is a rare lesion, especially in childhood. It is typically treated with complete surgical resection.
Sclerosing epithelioid fibrosarcoma
Sclerosing epithelioid fibrosarcoma is a rare malignant sarcoma that commonly harbors EWSR1 gene rearrangements and has an aggressive clinical course. It is typically treated with complete surgical excision. Long-term follow-up is recommended because local recurrence and metastases can occur late.
Skeletal Muscle Tumors
Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.
Smooth Muscle Tumors
Leiomyosarcoma accounts for 2% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma. Survivors of hereditary retinoblastoma have a statistically significant increased risk of developing leiomyosarcoma and 78% of these were diagnosed 30 or more years after the initial diagnosis of retinoblastoma.
Treatment options for leiomyosarcoma include the following:
In an open-label study of trabectedin in adult patients with recurrent sarcomas, the best overall response rate (complete remission and partial remission) was seen in patients with leiomyosarcoma (7.5%). The clinical benefit rate (includes stable disease) for leiomyosarcoma was 54%. In another adult study, patients with recurrent liposarcoma and leiomyosarcoma were randomly assigned to receive treatment with either trabectedin or dacarbazine. Patients treated with trabectedin had a 45% reduction in disease progression.
So-called Fibrohistiocytic Tumors
So-called fibrohistiocytic tumors include the following tumor subtypes:
Plexiform fibrohistiocytic tumor
Plexiform histiocytic tumor is a rare, low- to intermediate-grade tumor that most commonly affects children and young adults. Depending on the series, the median age at presentation ranges from 8 to 14.5 years; however, the tumor has been described in patients as young as 3 months.[97,98]
The tumor commonly arises as a painless mass in the skin or subcutaneous tissue and most often involves the upper extremities, including the fingers, hand, and wrist.[99,100,101] There are rare reports of spread to regional lymph nodes or the lungs.[97,101,102]
No consistent chromosomal anomalies have been detected but a t(4;15)(q21;q15) translocation has been reported.
Plexiform fibrohistiocytic tumor is an intermediate-grade tumor that rarely metastasizes.
Surgery is the treatment of choice but local recurrence has been reported in 12% to 50% of cases.
Tumors of Peripheral Nerves
Ectomesenchymoma is a rare nerve sheath tumor that mainly occurs in children. It is a biphenotypic soft tissue sarcoma with both mesenchymal and ectodermal components. Elements similar to rhabdomyosarcoma have been identified.
The German Soft Tissue Sarcoma Group (Cooperative Weichteilsarkon Studiengruppe) reported on six patients (ages 0.2–13.5 years) registered over 14 years.[Level of evidence: 3iiA] The tumors were located in various sites including the extremities, abdomen, and orbit. All six patients were treated with surgery and chemotherapy directed at rhabdomyosarcoma. Two patients received radiation therapy. Three patients recurred with rhabdomyosarcoma features. Although data are scant, it appears that the tumor may respond to chemotherapy.
Malignant peripheral nerve sheath tumor
Malignant peripheral nerve sheath tumors account for 5% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
Malignant peripheral nerve sheath tumor can arise sporadically and in children with type 1 neurofibromatosis (NF1).
Inactivating mutations of SUZ12 have been described in these tumors and are absent in neurofibromas.
Features with favorable prognosis include the following:[106,108,109,110]
For patients with localized disease in the MD Anderson Cancer Center study, there was no significant difference in outcome between patients with and without NF1. In other studies, it was not clear whether the absence of NF1 is a favorable prognostic factor as it has been associated with both favorable  and unfavorable outcomes.[106,108,110]
Treatment options for malignant peripheral nerve sheath tumor include the following:
There is agreement that complete surgical removal of the tumor, whenever possible, is the mainstay of treatment.
The role of radiation therapy is difficult to assess, but durable local control of known postoperative microscopic residual tumor is not assured after radiation therapy.
Chemotherapy has achieved objective responses in childhood malignant peripheral nerve sheath tumor. A large retrospective analysis of the German and Italian experience with malignant peripheral nerve sheath tumor reported that 65% of measurable tumors had objective responses to ifosfamide-containing chemotherapy regimens, but the analysis did not conclusively demonstrate improved survival for chemotherapy. This retrospective analysis also noted a trend toward improved outcome with postoperative radiation therapy. A series of 37 young patients with malignant peripheral nerve sheath tumor and NF1 showed that most patients had large invasive tumors that were poorly responsive to chemotherapy; PFS was 19% and 5-year OS was 28%.
The following are examples of a national and/or institutional clinical trial that are currently being conducted. Information about ongoing clinical trials is available from the NCI website.
Malignant triton tumor
Malignant triton tumors are a variant of malignant peripheral nerve sheath tumors. They occur most often in patients with neurofibromatosis type I and consist of neurogenic and rhabdomyoblastic components. Malignant triton tumors are high-grade malignancies. They usually occur before age 35 years and are very rare in children (case reports only).
Malignant triton tumors are not usually responsive to chemotherapy and radiation therapy but have been treated with rhabdomyosarcoma therapy.[Level of evidence: 3iiiA]
Pericytic (Perivascular) Tumors
Infantile hemangiopericytoma is a subtype of myopericytoma.
Hemangiopericytoma is a highly vascularized tumor of uncertain origin.
Histologically, hemangiopericytomas are composed of packed round or fusiform cells that are arranged around a complex vasculature, forming many branch-like structures. Hyalinization is often present. Infantile hemangiopericytomas have similar histology but many are multilobular with vasculature outside the tumor mass.
Treatment and outcome
Treatment of infantile hemangiopericytomas includes the following:
In a series of 17 children, the differences in metastatic potential and response to treatment were clearly demonstrated for adult and infantile hemangiopericytomas. Eleven children were older than 1 year. Several of these patients had disease in the lymph nodes or lungs. Six patients with stage II or III disease progressed and died. Three patients with stage I disease survived, although one had recurrence in the lungs. Six patients had infantile hemangiopericytoma, most were greater than stage I (5 of 6). All six patients survived and three had good responses to vincristine, actinomycin, and cyclophosphamide. Hemangiopericytoma in children younger than 1 year seems to have a better prognosis than in children older than 1 year.[116,117,118]
Tumors of Uncertain Differentiation
Tumors of uncertain differentiation include the following tumor subtypes:
Alveolar soft part sarcoma
Alveolar soft parts sarcomas account for 1.4% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
The median age at presentation is 25 years and most commonly arises in the extremities.[119,120] Alveolar soft part sarcoma in children can present with evidence of metastatic disease.
This tumor of uncertain histogenesis is characterized by a consistent chromosomal translocation t(X;17)(p11.2;q25) that fuses the ASPSCR1 gene with the TFE3 gene.[122,123]
Alveolar soft part sarcoma in children may have an indolent course. Patients with alveolar soft part sarcoma may relapse several years after a prolonged period of apparent remission. Because these tumors are rare, all children with alveolar soft part sarcoma should be considered for enrollment in prospective clinical trials.
In a series of 19 treated patients, one group reported a 5-year OS rate of 80%, a 91% OS rate for patients with localized disease, a 100% OS rate for patients with tumors 5 cm or smaller, and a 31% OS rate for patients with tumors larger than 5 cm. In another series of 33 patients, OS was 68% at 5 years from diagnosis and 53% at 10 years from diagnosis. Survival was better for smaller tumors (≤5 cm) and completely resected tumors.[Level of evidence: 3iiA] Delayed metastases to the brain and lung are uncommon.
Treatment options for alveolar soft part sarcoma include the following:
The standard approach is complete resection of the primary lesion. If complete excision is not feasible, radiation therapy should be administered.
A series of 51 pediatric patients aged 0 to 21 years with alveolar soft part sarcoma found an OS rate at 10 years of 78% and an EFS rate of about 63%. Patients with localized disease (n = 37) had a 10-year OS of 87%, and the 14 patients with metastases at diagnosis had a 10-year OS of 44%, partly resulting from surgical removal of primary tumor and lung metastases in some patients. Only 3 of 18 patients (17%) with measurable disease had a response to conventional antisarcoma chemotherapy, but two of four patients treated with sunitinib had a partial response.[Level of evidence: 3iiiA] There have been sporadic reports of objective responses to interferon-alpha and bevacizumab.[119,127,128]
A small retrospective study of nine adult patients with metastatic alveolar soft part sarcoma treated with sunitinib reported partial response in five patients and stable disease in two patients.[Level of evidence: 3iiiDiv] In a phase II trial of cediranib, an inhibitor of all three known vascular epidermal growth factor receptors, 15 of 43 adult patients (35%) with metastatic alveolar soft part sarcoma had a partial response.[Level of evidence: 3iiDiv] Trials in pediatric patients have not been reported.
Treatment options under clinical evaluation for alveolar soft part sarcoma
Clear cell sarcoma of soft tissue
Clear cell sarcoma (formerly and inappropriately called malignant melanoma of soft parts) is a rare soft tissue sarcoma that typically involves the deep soft tissues of the extremities. It is also called clear cell sarcoma of tendons and aponeuroses. The tumor often affects adolescents and young adults.
Patients who have small, localized tumors with low mitotic rate and intermediate histologic grade fare best.
The tumor most commonly affects the lower extremity, particularly the foot, heel, and ankle.[132,133] It has a high propensity for nodal dissemination, especially metastases to regional lymph nodes (12%–43%).[133,134] The tumor typically has an indolent clinical course.
Clear cell sarcoma of soft tissue is characterized by an EWS-ATF1 fusion.
Treatment options for clear cell sarcoma of soft tissue include the following:
In a series of 28 pediatric patients reported by the Italian and German Soft Tissue Cooperative Studies, the median age at diagnosis was 14 years and the lower extremity was the most common primary site (50%). Surgery with or without radiotherapy is the treatment of choice and offers the best chance for cure. In this series, 12 of 13 patients with completely resected tumors were cured. For patients with more advanced disease the outcome is poor and chemotherapy is rarely effective.; [Level of evidence: 3iiDii]
Desmoplastic small round cell tumor
Desmoplastic small round cell tumor is a rare primitive sarcoma.
Desmoplastic small round cell tumor most frequently involves the abdomen, pelvis, or tissues around the testes.[138,139,140] The tumor occurs more commonly in males and may spread to the lungs and elsewhere. Peritoneal and pelvic lesions frequently have widespread peritoneal implants.
In a large, single-institution series of 65 patients, a correlation was made between computed tomography (CT) scans in most patients and positron-emission tomography (PET)/CT scans in 11 patients. PET/CT scans had very few false-negative results and detected metastatic sites missed on conventional CT scans.
Cytogenetic studies of these tumors have demonstrated the recurrent translocation t(11;22)(p13;q12), which has been characterized as a fusion of the WT1 and EWS genes. The WT1-EWS fusion confirms the diagnosis of desmoplastic small round cell tumor.
The overall prognosis for desmoplastic small round cell tumor remains extremely poor, with reported rates of death at 90%. Greater than 90% tumor resection either at presentation or after preoperative chemotherapy may be a favorable prognostic factor for OS.[143,144]
There is no standard approach to the treatment of desmoplastic small round cell tumor.
Treatment options for desmoplastic small round cell tumor include the following:
Complete surgical resections are rare, and the overall prognosis for desmoplastic small round cell tumor remains extremely poor, with reported rates of death at 90%.
Treatment may include chemotherapy, surgery, and radiation therapy. Multiagent chemotherapy analogous to that used for sarcomas has been used, as well as total abdominal radiation therapy.[138,139,143,145,146]
The Center for International Blood and Marrow Transplant Research (CIBMTR) analyzed patients with desmoplastic small round cell tumor in their registry who received consolidation with high dose chemotherapy and autologous stem cell reconstitution. While this retrospective registry analysis suggested some benefit for this approach, other investigators have abandoned the approach because of excessive toxicity and lack of efficacy.
Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis which displays multilineage differentiation.
Epithelioid sarcoma commonly presents as a slowly growing firm nodule based in the deep soft tissue; the proximal type predominantly affects adults and involves the axial skeleton and proximal sites. The tumor is highly aggressive and has a propensity for lymph node metastases.
Epithelioid sarcoma is characterized by inactivation of the SMARCB1 gene, which is present in both conventional and proximal types of epithelioid sarcoma. This abnormality leads to increased dependence on EZH2 and tumor formation.
Treatment options for epithelioid sarcoma include the following
Patients should be carefully evaluated for the presence of involved lymph nodes; suspicious lymph nodes should be biopsied. Surgical removal of primary and recurrent tumor(s) is the most effective treatment.[Level of evidence: 3iiiA]
In a review of 30 pediatric patients with epithelioid sarcoma (median age at presentation, 12 years), responses to chemotherapy were reported in 40% of patients using sarcoma-based regimens, and 60% of patients were alive at 5 years after initial diagnosis. A single-institution retrospective review of 20 patients, including children and adults (median age, 27.3 years), found no difference in the probability of recurrence between patients who received chemotherapy and those who did not receive chemotherapy and suggested that radiation therapy may be useful.
Extrarenal (extracranial) rhabdoid tumor
Malignant rhabdoid tumors were first described in children with renal tumors in 1981 (refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information) and were later found in a variety of extrarenal sites. These tumors are uncommon and highly malignant, especially in children younger than 2 years.
Extrarenal (extracranial) rhabdoid tumors account for 2% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
The first sizeable series of 26 children with extrarenal extracranial malignant rhabdoid tumor of soft tissues came from patients enrolled on the Intergroup Rhabdomyosarcoma Studies I through III during a review of pathology material. Only five patients (19%) were alive without disease. Later, investigation of children with atypical teratoid/rhabdoid tumors of the brain, as well as those with renal and extrarenal malignant rhabdoid tumors, found germline and acquired mutations of the SMARCB1 gene in all 29 tumors tested. Rhabdoid tumors may be associated with germline mutations of the SMARCB1 gene and may be inherited from an apparently unaffected parent. This observation was extended to 32 malignant rhabdoid tumors at all sites in patients whose mean age at diagnosis was 12 months.
In a Surveillance, Epidemiology, and End Results (SEER) study of 229 patients with renal, central nervous system, and extrarenal malignant rhabdoid tumor, patients aged 2 to 18 years, limited extent of tumor, and delivery of radiation therapy were shown to affect the outcome favorably compared with other patients (P < .002 for each comparison). Site of the primary tumor was not prognostically significant. OS at 5 years was 33%.
Treatment includes surgical removal when possible, chemotherapy as used for soft tissue sarcomas (but no single regimen is currently accepted as best), and radiation therapy.[Level of evidence: 3iA]; [159,160][Level of evidence: 3iiiB]
Responses to alisertib have been documented in four patients with central nervous system (CNS) atypical teratoid/rhabdoid tumors. (Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment summary for more information about CNS atypical teratoid/rhabdoid tumors.)
Extraskeletal myxoid chondrosarcoma
Extraskeletal myxoid chondrosarcoma is relatively rare among soft tissue sarcomas, representing only 2.3% of all soft tissue sarcoma. It has been reported in children and adolescents.
Extraskeletal myxoid chondrosarcoma is a multinodular neoplasm. The rounded cells are arranged in cords and strands in a chondroitin sulfate myxoid background. Several cytogenetic abnormalities have been identified (refer to Table 2), with the most frequent being the translocation t(9;22)(q22;q12), involving the EWSR1/NR4A3 genes.
The tumor has traditionally been considered of low-grade malignant potential. However, recent reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are followed for a long time.[166,167] 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.
Treatment options for extraskeletal myxoid chondrosarcoma include the following:
The therapeutic benefit of chemotherapy has not been established. Aggressive local control and resection of metastases led to OS of 87% at 5 years and 63% at 10 years. Tumors were relatively resistant to radiation therapy.
There may be potential genetic targets for small molecules, but these should be studied as part of a clinical trial. In an adult study, six of ten patients who received sunitinib achieved a partial response.
Perivascular epithelioid cell differentiation (PEComas)
Risk factors and molecular features
Benign PEComas are common in tuberous sclerosis, an autosomal dominant syndrome that also predisposes to renal cell cancer and brain tumors. Tuberous sclerosis is caused by germline inactivation of either TSC1 (9q34) or TSC2 (16p13.3), and the same tumor suppressor genes are inactivated somatically in sporadic PEComas. Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable PEComas with mTOR inhibitors.[170,171] A small proportion of PEComas have TFE3 rearrangements with fusions involving various genes including SFPQ/PSF and RAD51B.
PEComas occur in various rare gastrointestinal, pulmonary, gynecologic, and genitourinary sites. Soft tissue, visceral, and gynecologic PEComas are more commonly seen in middle-aged female patients and are usually not associated with the tuberous sclerosis complex. The disease course may be indolent.
Most PEComas have a benign clinical course, but malignant behavior has been reported and can be predicted based on the size of the tumor, mitotic rate, and presence of necrosis.
Treatment options have not been defined. Treatment may include surgery or observation followed by surgery when the tumor is large.
Clinical activity with mTOR inhibitors, such as sirolimus, in tumors with evidence of mTORC1 activation and TSC loss has been well documented.
Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor
(Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)
Synovial sarcoma accounts for 9% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
Synovial sarcoma is one of the most common nonrhabdomyosarcomatous soft tissue sarcomas in children and adolescents. In a 1973 to 2005 SEER review, 1,268 patients with synovial sarcoma were identified. Approximately 17% of these patients were children and adolescents and the median age at diagnosis was 34 years.
Synovial sarcoma can be subclassified as the following types:
The most common tumor location is the extremities, followed by trunk and head and neck. Rarely, a synovial sarcoma may arise in the heart or pericardium.
The most common site of metastasis is the lung.[179,180] The risk of metastases is highly influenced by tumor size; it is estimated that patients with tumors that are larger than 5 cm have a 32-fold risk of developing metastases when compared with other patients.
The diagnosis of synovial sarcoma is made by immunohistochemical analysis, ultrastructural findings, and demonstration of the specific chromosomal translocation t(x;18)(p11.2;q11.2). This abnormality is specific for synovial sarcoma and is found in all morphologic subtypes. Synovial sarcoma results in rearrangement of the SYT gene on chromosome 18 with one of the subtypes (1, 2, or 4) of the SSX gene on chromosome X.[181,182] It is thought that the SYT/SSX18 transcript promotes epigenetic silencing of key tumor suppressor genes. Reduced INI1 nuclear reactivity on immunohistochemical staining is typical of most synovial sarcomas examined and does not occur with other similar histologies, thus providing a fast diagnosis while awaiting genetic studies.
Patients younger than 10 years have more favorable outcomes and clinical features, including extremity primaries, smaller tumors, and localized disease, than do older patients. A meta-analysis also suggested that response to chemotherapy was correlated with improved survival.
The following studies have reported multiple factors associated with unfavorable outcomes:
Survival after relapse is poor (30% at 5 years). Factors associated with outcome after relapse include duration of first remission (> or ≤ 18 months) and lack of a second remission.
Treatment options for synovial sarcoma include the following:
Synovial sarcoma appears to be more sensitive to chemotherapy than many other soft tissue sarcomas, and children with synovial sarcoma seem to have a better prognosis when compared with adults.[11,180,190,193,194,195,196,197] The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[185,196,198] Response rates to the ifosfamide and doxorubicin regimen are higher than in other nonrhabdomyosarcomatous soft tissue sarcomas.
Several studies have reported the following chemotherapy-associated treatment results:
Patients with undifferentiated soft tissue sarcoma had been eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the COG from 1972 to 2006. The rationale was the observation that patients with undifferentiated soft tissue sarcoma had similar sites of disease and outcome as those 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%.[Level of evidence: 3iiA] Currently, these patients are eligible for the COG open ARST1321 (NCT02180867) trial for patients with nonrhabdomyosarcomatous soft tissue sarcoma.
Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high-grade)
At one time, malignant fibrous histiocytoma was the single most common histiotype among adults with soft tissue sarcomas. Since it was first recognized in the early 1960s, malignant fibrous histiocytoma has been plagued by controversy in terms of both its histogenesis and its validity as a clinicopathologic entity. The latest WHO classification no longer includes malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.
This entity accounts for 2% to 6% of all childhood soft tissue sarcomas. These tumors can arise in previously irradiated sites or as a second malignancy in patients with retinoblastoma.
These tumors occur mainly in the second decade of life. In a series of ten patients, the median age was 10 years and the tumor was most commonly located in the extremities. In this series, all tumors were localized and five of nine (for whom follow-up was available) were alive and in first remission. In another series of 17 pediatric patients with malignant fibrous histiocytoma, the median age at diagnosis was 5 years and the extremities were involved in eight cases. All patients with metastatic disease died and two patients experienced a clinical response to a doxorubicin-based regimen.
(Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment for more information about the treatment of malignant fibrous histiocytoma of bone.)
Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant. Vascular tumors include the following tumor subtypes:
Angiosarcoma of the soft tissue
Angiosarcoma is a rare (accounting for 2% of sarcomas), aggressive, vascular tumor that can arise in any part of the body, but is more common in the soft tissue. Angiosarcoma has an estimated incidence of 2 cases per 1 million; in the United States, it annually affects approximately 600 people who are typically aged 60 to 70 years.
Angiosarcomas are extremely rare in children. However, cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive.[210,211,212,213] Most angiosarcomas involve the skin and superficial soft tissue, although the liver, spleen, and lung can be affected; bone is rarely affected.
Established risk factors include vinyl chloride exposure, radiation exposure, and chronic lymphedema from any cause, including Stewart-Treves syndrome.
Pathology and biology
Angiosarcomas are largely aneuploidy tumors. The rare cases of angiosarcoma that arise from benign lesions such as hemangiomas have a distinct pathway that needs to be investigated. MYC amplification is seen in radiation-induced angiosarcoma. KDR-VEGFR2 mutations and FLT4-VEGFR3 amplifications have been seen with a frequency of less than 50%.
Histopathologic diagnosis can be very difficult because there can be areas of varied atypia. The common feature is an irregular network of channels in a dissective pattern along dermal collagen bundles. There is varied cellular shape, size, mitosis, endothelial multilayering, and papillary formation. Epithelioid cells can also be present. Necrosis and hemorrhage are common. Tumors stain for factor VIII, CD31, and CD34. Some liver lesions can mimic infantile hemangiomas and have focal GLUT1 positivity. Nomenclature of these liver lesions has been difficult and confusing with use of terminology from 1971 (e.g., type I hemangioendothelioma: infantile hemangioma; type II hemangioendothelioma: low-grade angiosarcoma; type III hemangioendothelioma: high-grade angiosarcoma).
Treatment of angiosarcoma of the soft tissue
Treatment options for angiosarcoma of the soft tissue include the following:
Localized disease is cured by aggressive surgery. Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients who were treated with local or systemic therapy.[212,215,216,217] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis. Data on liver transplantation for localized angiosarcoma are limited.[Level of evidence: 3iiA]
Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative. Disease control is the objective in metastatic angiosarcoma, with published progression-free survival rates between 3 months and 7 months  and a median overall survival (OS) rate of 14 months to 18 months. In both adults and children, 5-year OS rates between 20% and 35% are reported.[212,213,222]
In a child diagnosed with angiosarcoma secondary to malignant transformation from infantile hemangioma, response to treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, combined with systemic chemotherapy, has been reported.
Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcoma.[211,222]
Current Clinical Trials
Check the list of NCI-supported cancer clinical trials that are now accepting patients with childhood angiosarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
Incidence and outcome
This tumor was first described in soft tissue by Weiss and Enzinger in 1982. Epithelioid hemangioendotheliomas can occur at younger ages, but the peak incidence is in the fourth and fifth decades of life. The tumors can have an indolent or very aggressive course, with overall survival of 73% at 5 years. There are case reports of patients with untreated multiple lesions who have a very benign course compared with other patients who have a very aggressive course. Some pathologists have tried to stratify patients to evaluate risks and adjust treatment, but more research is needed.[223,224,225,226,227,228,229]
A WWTR1-CAMTA1 gene fusion has been found in a large percentage of patients; less commonly, a YAP1-TFE3 gene fusion has been reported. These fusions are not directly targetable with medicines. Monoclonality has been described in multiple liver lesions, suggesting a metastatic process. Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns, with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, one or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.
Clinical presentation and diagnostic evaluation
Common sites of involvement are liver alone (21%), liver plus lung (18%), lung alone (12%), and bone alone (14%).[225,230,231] Clinical presentation depends on site of involvement, as follows:
Treatment of epithelioid hemangioendothelioma
Treatment options for epithelioid hemangioendothelioma include the following:
For indolent cases, observation is warranted. For more aggressive cases, multiple medications have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus. The most aggressive cases are treated with angiosarcoma-type chemotherapy. Surgery is used when possible. Liver transplantation has been used with aggressive liver lesions, both with and without metastases.[225,232,233,234,235]
Check the list of NCI-supported cancer clinical trials that are now accepting patients with childhood epithelioid hemangioendothelioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with nonmetastatic childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Standard treatment options for metastatic childhood soft tissue sarcoma include the following:
For treatment options, refer to the individual tumor type sections of the summary.
The prognosis for children with metastatic soft tissue sarcomas is poor,[1,2,3,4,5,6] and these children should receive combined treatment with chemotherapy, radiation therapy, and surgical resection of pulmonary metastases. In a prospective randomized trial, chemotherapy with vincristine, dactinomycin, doxorubicin, and cyclophosphamide, with or without dacarbazine, led to tumor responses in one-third of patients with unresectable or metastatic disease. The estimated 4-year survival rate, however, was poor, with fewer than one-third of children surviving.[6,7,8]
Generally, children with isolated pulmonary metastases should be considered for a surgical procedure in an attempt to resect all gross disease. For patients with multiple or recurrent pulmonary metastases, additional surgical procedures can be performed if the morbidity is deemed acceptable. 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.[Level of evidence: 3iiiA] Formal segmentectomy, lobectomy, and mediastinal lymph node dissection are unnecessary.
An alternative approach is focused radiation therapy (fractionated stereotactic radiation therapy), which has been successfully used in adults to sterilize lesions. The estimated 5-year survival rate after thoracotomy for pulmonary metastasectomy has ranged from 10% to 58% in adult studies. Emerging data suggest a similar outcome after the administration of focused radiation therapy.
With the possible exception of infants with infantile fibrosarcoma, the prognosis for patients with recurrent or progressive disease is poor. No prospective trial has been able to prove that enhanced local control of pediatric soft tissue sarcomas will ultimately improve survival. Therefore, treatment should be individualized for the site of recurrence and biologic characteristics (e.g., grade, invasiveness, and size) of the tumor.
Decisions about treatment options for progressive or recurrent childhood soft tissue sarcoma are based on many factors, including the following:
Treatment options for recurrent or progressive disease include the following:
Resection is the standard treatment for recurrent pediatric nonrhabdomyosarcomatous soft tissue sarcomas. If the patient has not yet received radiation therapy, postoperative radiation should be considered after local excision of the recurrent tumor. Limb-sparing procedures with postoperative brachytherapy have been evaluated in adults but have not been studied extensively in children. For some children with extremity sarcomas who have received previous radiation therapy, amputation may be the only therapeutic option.
Pulmonary metastasectomy may achieve prolonged disease control for some patients. 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. In 31 children and adolescents younger than 23 years with pulmonary metastases from synovial sarcoma, complete resection of lung metastases appeared to prolong survival when compared with ten other patients who were not considered candidates for metastasectomy.[Level of evidence: 3iiiA] All patients with recurrent tumors should be considered for current clinical trials.
Published results of two studies addressed the outcomes for children with relapsed synovial sarcoma. Most patients in one study had distant relapse (29 of 44 patients), while most patients in the second study had local relapse (27 of 37 patients). Distant recurrence was a poor prognostic variable, while tumor resectability at relapse (as manifested by extremity recurrence) was associated with a better outcome in both studies.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
General Information About Childhood Soft Tissue Sarcoma
Added Figures 1, 2, and 3 depicting the distribution of nonrhabdomyosarcomatous soft tissue sarcomas by stage, histologic subtype, and tumor site (cited Ferrari et al. as reference 7).
Added text to state that a large, prospective, multinational Children's Oncology Group (COG) study (ARST0332) enrolled newly diagnosed patients younger than 30 years. Patients were assigned to treatment on the basis of their risk group (cited Spunt et al. as reference 47 and level of evidence 2A).
Added Figure 4 depicting the risk stratification and treatment assignment for the COG ARST0332 trial.
Added text about the treatment options for each arm of the COG ARST0332 trial.
Added text about the estimated 3-year event-free survival and overall survival rates for each arm of the COG ARST0332 trial.
Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma
Added text to state that the SARC023 trial is testing the combination of ganetespib, the heat shock protein inhibitor, and sirolimus, the mammalian target of rapamycin inhibitor, for the treatment of patients with unresectable or metastatic malignant peripheral nerve sheath tumors. Eligibility is restricted to patients aged 18 years and older.
Added text to state that the disease course for perivascular epithelioid cell differentiation (PEComas) may be indolent.
Added text to state that treatment options have not been defined for PEComas. Treatment may include surgery or observation followed by surgery when the tumor is large (cited Alaggio et al. as reference 175).
Added Treatment options under clinical evaluation as a new subsection.
The Angiosarcoma of the soft tissue subsection was extensively revised.
The Epithelioid hemangioendothelioma subsection was extensively revised.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
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:
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:
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: http://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-soft-tissue-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389361]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
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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Last Revised: 2016-04-26
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