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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 (rhabdomyosarcomas, 4%; other soft tissue sarcomas, 3%).
The distribution of soft tissue sarcomas by histology and age, on the basis of the Surveillance, Epidemiology, and End Results (SEER) information from 2000 to 2015, is depicted in Table 1. The distribution of histologic subtypes by age is also shown in Figure 2.
Nonrhabdomyosarcomatous soft tissue sarcomas are more common in adolescents and adults, and most of the information regarding treatment and natural history of the disease in younger patients has been based on adult studies. The distributions of these tumors by age according to stage (Figure 1), histologic subtype (Figure 2), and tumor site (Figure 3) are shown below.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 factors and external exposures 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.[27,28,29] These neoplasms can present initially as an asymptomatic solid mass, or they may be symptomatic because of local invasion of adjacent anatomical structures. Although rare, these tumors can arise in brain tissue and are treated according to the histotype.
Systemic symptoms (e.g., fever, weight loss, and night sweats) are rare. Hypoglycemia and hypophosphatemic rickets have been reported in cases of hemangiopericytoma (now identified as a solitary fibrous tumor in the revised World Health Organization classification system), whereas hyperglycemia has been noted in patients with fibrosarcoma of the lung.
Diagnostic and Staging Evaluation
When a suspicious lesion is identified, it is crucial that a complete workup, followed by adequate biopsy be performed. The lesion is imaged before initiating any intervention using the following procedures:
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 pathologically distinct from rhabdomyosarcoma and Ewing sarcoma, the classification of childhood nonrhabdomyosarcomatous soft tissue sarcoma type is often difficult. Core-needle biopsy, incisional biopsy, or excisional biopsy can be used to diagnose a nonrhabdomyosarcomatous soft tissue sarcoma. If possible, the surgeon who will perform the definitive resection needs to be involved in the biopsy decision. Poorly placed incisional or needle biopsies may adversely affect the ability to achieve negative margins.
Given the diagnostic importance of translocations and other molecular changes, a core-needle biopsy or small incisional biopsy that obtains adequate tumor tissue is crucial to allow for conventional histology, immunocytochemical analysis, and other studies such as light and electron microscopy, cytogenetics, fluorescence in situ hybridization, and molecular pathology.[36,37] Needle biopsy techniques must ensure adequate tissue sampling. 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 complication rate was 0.4%. Considerations related to the biopsy procedure are as follows:
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.
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.[50,51] 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] In this case, a second resection is expected.
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.
Prognosis and Prognostic Factors
The prognosis of nonrhabdomyosarcomatous soft tissue sarcoma varies greatly depending on the following factors:[69,70,71]
In a review of a large adult series of nonrhabdomyosarcomatous soft tissue sarcomas, superficial extremity sarcomas had a better prognosis than did deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.
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.
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.[3,74] A large, prospective, multinational Children's Oncology Group study (ARST0332 [NCT00346164]) enrolled newly diagnosed patients younger than 30 years. Patients were assigned to treatment on the basis of their risk group (defined by the presence of metastasis, tumor resectability and margins, and tumor size and grade; refer to Figure 4).[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.[69,76]; [77,78][Level of evidence: 3iiiA] In an Italian review of 30 patients with nonrhabdomyosarcomatous soft tissue sarcoma at visceral sites, only ten patients survived at 5 years. Unfavorable prognostic factors included inability to achieve complete resection, large tumor size, tumor invasion, histologic subtype, and lung-pleura sites.[Level of evidence: 3iiB]
In a pooled analysis from U.S. and European pediatric centers, outcome was better for patients whose tumor removal procedure was deemed complete than for patients whose tumor removal was incomplete. Outcome was better for patients who received radiation therapy than for patients who did not.[Level of evidence: 3iiiA]
Because long-term related morbidity must be minimized while disease-free survival is maximized, the ideal therapy for each patient must be carefully and individually determined utilizing these prognostic factors before initiating therapy.[28,80,81,82,83,84]
Refer to the following PDQ summaries for information about other types of sarcoma:
World Health Organization (WHO) Classification of Soft Tissue Sarcomas
The WHO classification system for cancer represents the common nomenclature for cancer worldwide. In the United States, it has been adopted by the American Joint Committee on Cancer (AJCC) for sarcoma staging and the College of American Pathologists (CAP) cancer protocols for bone and soft tissue sarcomas. The fourth edition of the WHO Classification of Tumors of Soft Tissue and Bone was published in February 2013.
The grading of soft tissue tumors has always been a controversial issue. While the WHO does not strictly state a preference in grading systems, one of the major modifications made to the WHO classification was the designation of two distinct types of intermediate malignancy in terms of biological potential—locally aggressive and rarely metastasizing.
The WHO acknowledged the poorly defined nature of malignant fibrous histiocytoma (also known as undifferentiated pleomorphic sarcoma) and hemangiopericytoma (now considered within the spectrum of solitary fibrous tumors).
With the current advances in molecular and genetic studies, a subset of tumors has been moved into new sections, including angiomatoid malignant fibrous histiocytoma and extraskeletal myxoid chondrosarcoma, which were previously classified as tumors of uncertain differentiation. Multiple entities were newly recognized, and a few entities belonging to tumors of skin were also added to this book. A few entities that were found to most likely represent morphologic variants of other tumors were deleted from the current classification or subsumed into other sections.
Angioleiomyoma was reclassified under perivascular tumors.
The malignant counterpart of so-called fibrohistiocytic tumors, formerly known as malignant fibrous histiocytoma and its subtypes was renamed undifferentiated sarcoma and was previously classified under the undifferentiated/unclassified sarcomas section.
Genetic subgroups are emerging within this family and this work is ongoing:
In this group, EWSR1 is involved in non-ETS fusions with genes such as PATZ1, POU5F1, SMARCA5, NFATC2, or SP3. Another recurrent rearrangement involves the CIC-DUX4 fusion gene resulting in the chimeric CIC-DUX4 protein, which upregulates genes of the PEA3 subclass of ETS family. (Refer to the Genomics of Ewing Sarcoma section of the PDQ summary on Ewing Sarcoma Treatment for more information.)
It is unclear whether these cases represent one or more separate entities, or whether they are better classified as variants of Ewing sarcoma.
Undifferentiated pleomorphic sarcoma was most often called malignant fibrous histiocytoma in the past. Historically, this entity has been difficult to evaluate because of the shifting diagnostic criteria. Analysis of 70 cases diagnosed as malignant fibrous histiocytosis of no specific type, storiform or pleomorphic malignant fibrous histiocytoma, pleomorphic sarcoma or undifferentiated pleomorphic sarcoma showed a highly complex karyotype with no specific recurrent aberrations.
Undifferentiated sarcomas with 12q13–15 amplification, including MDM2 and CDK4, are best classified as dedifferentiated liposarcomas; the relationship between this tumor and the family of undifferentiated/unclassified tumors with spindle cell morphology remains relatively undefined.
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 eighth edition of the AJCC Cancer Staging Manual has designated staging by the four criteria of tumor size, nodal status, histologic grade, and metastasis and by anatomic primary tumor site (head and neck; trunk and extremities; abdomen and thoracic visceral organs; retroperitoneum; and unusual histologies and sites) (refer to Tables 3, 4, 5, and 6).[3,4,5,6,7] For information on unusual histologies and sites, refer to the AJCC Cancer Staging Manual.
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.[9,10,11]
The grading systems developed by the POG and the French Federation of Comprehensive Cancer Centers (Fédération Nationale des Centres de Lutte Contre Le Cancer [FNCLCC]) Sarcoma Group are described below. These grading systems are being compared by the central review pathologists on the COG-ARST0332 study. The study has closed and results are pending.
POG grading system
The POG grading system is described below. 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.[12,13] The system is described in Table 7 and Table 8.
Prognostic Significance of Tumor Grading
The POG and FNCLCC grading systems have proven to be of prognostic value in pediatric and adult nonrhabdomyosarcomatous soft tissue sarcomas.[14,15,16,17,18] In a study of 130 tumors from children and adolescents with nonrhabdomyosarcomatous soft tissue sarcoma enrolled in three prospective clinical trials, a correlation was found between the POG-assigned grade and the FNCLCC-assigned grade. However, grading did not correlate in all cases; 44 patients whose tumors received discrepant grades (POG grade 3, FNCLCC grade 1 or 2) had outcomes between concurrent grade 3 and grades 1 and 2. A mitotic index of 10 or greater emerged as an important prognostic factor.
The completed COG-ARST0332 trial will analyze data comparing the POG and FNCLCC pathologic grading systems to determine which system better correlates with clinical outcomes. The closed COG trial (ARST1321 [NCT02180867]) used the FNCLCC system to assign histological grade.
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 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 the following:
Radiation therapy can be given preoperatively or postoperatively. It can also be used as definitive therapy in rare situations in which surgical resection is not performed. Radiation field size and dose will be based on patient and tumor variables and the surgical procedure. Radiation therapy was associated with improved overall survival (OS) compared with surgery alone when delivered preoperatively or postoperatively.
Preoperative radiation therapy has been associated with excellent local control rates.[18,19,20] The advantages of this approach include treating smaller tissue volumes without the need to treat a postsurgical bed and somewhat lower radiation doses because relative hypoxia from surgical disruption of vasculature and scarring is not present. Preoperative radiation therapy has been associated with an increased rate of wound complications in adults, primarily in lower extremity tumors; however, the degree of these complications is questionable. Conversely, preoperative radiation therapy may lead to less fibrosis than with postoperative approaches, perhaps because of the smaller treatment volume and dose.
Retroperitoneal sarcomas are unique in that radiosensitivity of the bowel to injury makes postoperative radiation therapy less desirable.[23,24] Postoperative adhesions and bowel immobility can increase the risk of damage from any given radiation dose. This contrasts with the preoperative approach in which the tumor often displaces bowel outside of the radiation field, and any exposed bowel is more mobile, which decreases exposure to specific bowel segments.
Radiation therapy can also be given postoperatively. In general, radiation is indicated for patients with inadequate surgical margins and for larger, high-grade tumors.[25,26] This is particularly important in high-grade tumors with tumor margins smaller than 1 cm.[27,28]; [Level of evidence: 3iiDiv] With combined R0 (negative margin) surgery and radiation therapy, local control of the primary tumor can be achieved in about 90% of patients with extremity sarcomas, 70% to 75% of patients with retroperitoneal sarcomas, and 80% of patients overall.[30,31,32,33,34]
Brachytherapy and intraoperative radiation may be applicable in select situations.[31,35,36]; [Level of evidence: 3iiiDii]
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 for R0 resections, up to 65 Gy for R1 resections (microscopic positive margins), and higher when unresectable gross residual disease exists depending on overall treatment goals (e.g., definitive local control vs. palliation).
Radiation margins are typically 2 cm to 4 cm longitudinally and encompass fascial planes axially.[39,40]
The role of postoperative chemotherapy remains unclear.
Evidence (lack of clarity regarding postoperative chemotherapy):
The use of angiogenesis and mammalian target of rapamycin (mTOR) inhibitors has been explored in the treatment of adult soft tissue sarcomas but not in pediatrics.
Evidence (targeted therapy in adults with soft tissue sarcoma):
Special Considerations for the Treatment of Children With Soft Tissue Sarcoma
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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.
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.
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.[2,3]
The World Health Organization (WHO) classification for liposarcoma is as follows:
Most liposarcomas in the pediatric and adolescent age range are low grade and located subcutaneously. Metastasis to lymph nodes is very uncommon, and the great majority of metastases are pulmonary. Tumors arising in the periphery are more likely to be low grade and myxoid. Tumors arising centrally are more likely to be high grade, pleomorphic, and present with metastasis or recur with metastasis.
Higher grade or central tumors are associated with a significantly higher risk of death. In an international retrospective review, 5-year survival for central tumors was 42%. Seven of ten patients with pleomorphic myxoid liposarcoma died of their disease. 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 complete surgical resection of well-differentiated or myxoid liposarcoma, event-free survival (EFS) and overall survival (OS) are roughly 90%. If initial surgery is incomplete, re-excision should be performed to achieve a wide margin of resection. Local recurrences have been seen and are controlled with a second resection of the tumor, particularly for low-grade liposarcomas. Radiation therapy is also considered either preoperatively or postoperatively depending on the cosmetic/functional consequences of additional surgery and radiation therapy.[12,13]
There are reports of the use of chemotherapy to decrease the size of liposarcoma before surgery to facilitate complete resection, particularly in central tumors.[14,15] 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] There are very limited data to support the use of trabectedin in pediatric patients.
Treatment with eribulin, a nontaxane microtubule dynamics inhibitor, significantly improved survival in adult patients with recurrent liposarcoma compared with dacarbazine, with a median OS of 15.6 months versus 8.4 months, respectively. Survival differences were more pronounced in patients with dedifferentiated and pleomorphic liposarcoma. Eribulin was effective in prolonging survival of patients with either high-grade or intermediate-grade tumors.[Level of evidence: 1iiA] A pediatric phase I trial of eribulin did not accrue any patients with liposarcoma.
Chondro-osseous tumors include the following subtypes:
Extraskeletal mesenchymal chondrosarcoma
Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
Histopathology and molecular features
Mesenchymal chondrosarcoma is a rare tumor characterized by small round cells and hyaline cartilage that more commonly affects young adults and has a predilection for involving the head and neck region.
Mesenchymal chondrosarcoma has been associated with consistent chromosomal rearrangement. A retrospective analysis of cases of mesenchymal chondrosarcoma identified a HEY1-NCOA2 fusion in 10 of 15 tested specimens. 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]
A retrospective analysis of Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 2011 identified 205 patients with mesenchymal chondrosarcoma; 82 patients had skeletal primary tumors, and 123 patients had extraskeletal tumors. The outcomes of skeletal and extraskeletal primary tumors were the same. Factors associated with outcome included the following:
A single-institution retrospective review identified 43 cases of mesenchymal chondrosarcoma from 1979 to 2010. Thirty patients with localized disease were evaluated. The mean age at diagnosis was 33 years (range, 11–65 years). Five-year OS was 51%, and 10-year OS was 37%. Younger age (<30 years) and male sex were associated with poorer OS and disease-free survival (DFS). Patients who did not receive adjuvant radiation therapy were more likely to have a local recurrence.
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 DFS was 68.2% (95% confidence interval [CI], 39.8%–96.6%), and OS was 88.9% (95% CI, 66.9%–100%).
A Japanese study of patients with extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma randomly assigned patients to treatment with either trabectedin or best supportive care. The median age of patients was 38 years (range, 21–77 years). OS of the patients assigned to receive trabectedin was superior to that of patients assigned to receive best supportive care.
Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
Extraskeletal osteosarcoma is extremely rare in the pediatric and adolescent age range. An analysis of SEER data identified 256 patients (6%) with extraskeletal osteosarcoma among 4,173 patients with high-grade osteosarcoma from 1973 to 2009. Compared with skeletal osteosarcoma, patients with extraskeletal osteosarcoma were more likely to be older, female, have an axial primary tumor, and have regional lymph node involvement. Adverse prognostic features included presence of metastatic disease, larger tumor size, older age, and axial primary tumor site.
A review of 32 adult patients with extraskeletal osteosarcomas consistently revealed several alterations. Frequent genomic alterations included copy number losses in CDKN2A (70%), TP53 (56%), and RB1 (49%). Mutations were identified that affected methylation/demethylation (40%), chromatin remodeling (27%), and the WNT/SHH pathways (27%). Cases with simultaneous TP53 and RB1 biallelic copy number losses were associated with worse DFS and OS.
Extraskeletal osteosarcoma is associated with a high risk of local recurrence and pulmonary metastasis. A single-institution retrospective review identified 43 patients with extraskeletal osteosarcoma; 37 patients had localized disease, and 6 patients presented with metastatic disease. Median age was 55 years (range, 7–81 years). Median progression-free survival (PFS) was 21 months; median OS was 50 months. Seventy-five percent of patients received chemotherapy. There was a trend toward better survival for patients who received chemotherapy, and a statistically significant improvement in survival for patients who received chemotherapy that included cisplatin.
In a review of 274 patients with a median age of 57 years at diagnosis (range, 12–91 years), 5-year DFS and OS rates were significantly better for those who received chemotherapy, and the use of an osteosarcoma-type regimen was associated with improved response rates.[Level of evidence: 3iiiA]
The European Musculoskeletal Oncology Society performed a retrospective analysis of 266 eligible patients with extraskeletal osteosarcoma treated between 1981 and 2014. Fifty patients (19%) presented with metastatic disease. An analysis of the 211 patients who achieved complete remission after surgical resection of the primary tumor showed a 5-year OS of 51% and a 5-year DFS of 43%. There was a favorable trend for survival among patients who were treated with chemotherapy that is usually employed for patients with osseous osteosarcoma. In a multivariable analysis, factors associated with better prognosis included younger age (<40 years), smaller tumors, and use of chemotherapy.
Treatment options for extraskeletal osteosarcoma include the following:
Typical chemotherapy regimens used for osteosarcoma include some combination of cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide.[32,33,34]
(Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment for more information about treatment, including chemotherapy options, of extraosseous osteosarcoma.)
Fibroblastic/myofibroblastic tumors include the following 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 APC gene (associated with intestinal polyps and a high incidence of colon cancer). In a study of 519 patients older than 10 years with a diagnosis of desmoid-type fibromatosis, 39 patients (7.5%, a possible underestimation) were found to have familial adenomatous polyposis (FAP). 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,[36,37] 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.[38,39] (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.
Desmoid-type fibromatosis has a high potential for local recurrence. These tumors have a highly variable natural history, including well documented examples of spontaneous regression. Mutations in exon 3 of the CTNNB1 gene are seen in over 80% of desmoid-type fibromatosis and the mutation 45F has been associated with an increased risk of disease recurrence. 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, with partial regressions seen in up to 20% of patients. Large adult series and smaller pediatric series have reported long periods of disease stabilization and even regression without systemic therapy.[42,44]; [Level of evidence: 3iiiDi] For instance, in a large placebo-controlled trial of sorafenib in adult patients with desmoid tumor, the patients who received no therapy (observation/placebo) demonstrated a 20% partial regression rate, and 46% of the patients in the placebo group had no progression at 1 year.
Treatment options for desmoid-type fibromatosis include the following:
Dermatofibrosarcoma is a rare tumor that can be present in all age groups, but many of the reported cases arise in children.[68,69,70] A review of 451 cases in children younger than 20 years in the SEER database found that the incidence was 1 case per 1 million, highest among black patients aged 15 to 19 years. The most common sites were trunk and extremities, which is similar to what is found in adults. Ninety-five percent of patients underwent surgery. OS was 100% at 5 years, 98% at 15 years, and 97% at 30 years. Males had decreased survival compared with females (P < .05).[Level of evidence: 3iA]
The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGFRB gene.
Treatment options for dermatofibrosarcoma protuberans include the following:
Most dermatofibrosarcoma tumors can be cured by complete surgical resection. Wide excision with negative margins or Mohs/modified-Mohs surgery will prevent most tumors from recurring. Despite the locally aggressive behavior of the tumor, lymph node or visceral metastasis rarely occurs.
In retrospective reviews, postoperative radiation therapy after incomplete excision may have decreased the likelihood of recurrence.[73,74]
When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective.[75,76,77] Because metastatic disease is more likely after multiple recurrences, radiation or other adjuvant therapy should be considered in patients with recurrence that cannot be managed surgically.[69,71]
Guidelines for workup and management of dermatofibrosarcoma protuberans have been published.
Inflammatory myofibroblastic tumor
Inflammatory myofibroblastic tumor is a rare mesenchymal tumor that has a predilection for children and adolescents.[79,80,81]
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. A review of 42 cases of pediatric inflammatory myofibroblastic tumor of the bladder was published in 2015.
Roughly one-half of inflammatory myofibroblastic tumors exhibit a clonal mutation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase gene at chromosome 2p23.ROS1 and PDGFRB 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.[79,80,81]
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.[89,90] A series of 32 patients aged 18 years and younger found that complete excision was the mainstay of therapy, although some patients were treated with steroids or cytotoxic chemotherapy. OS was 94%; three patients relapsed, and two of them died of the disease. When complete excision was performed, with or without other treatments such as steroids, there was a high survival rate for patients with this disease.[Level of evidence: 3iiA]
Inflammatory myofibroblastic tumors respond to ALK inhibitor therapy, as follows:
There are two distinct types of fibrosarcoma in children and adolescents: infantile fibrosarcoma (also called congenital fibrosarcoma) and fibrosarcoma that is indistinguishable from fibrosarcoma seen in adults. These are two distinct pathologic diagnoses and require different treatments. Adult fibrosarcoma is addressed below.
Infantile fibrosarcoma usually presents with a rapidly growing mass, often noted at birth or even seen in prenatal ultrasound. The tumors are frequently quite large at the time of presentation. Hypercalcemia secondary to elevated levels of parathyroid hormone–related protein has been reported as a presenting feature of this disease in newborns.
The tumor usually has a characteristic cytogenetic translocation t(12;15)(ETV-NTRK3). Infantile fibrosarcoma shares this translocation and a virtually identical histologic appearance with mesoblastic nephroma.
Infantile fibrosarcoma usually occurs in children younger than 1 year. It occasionally occurs in children up to age 4 years. A tumor with similar morphology has been identified in older children; in these older children, the tumors do not have the t(12;15)(ETV-NTRK3) translocation that is characteristic of the younger patients.BRAF intragenic deletions have been described in cases of infantile fibrosarcoma and co-occur with NTRK3 fusions.
These tumors have a low incidence of metastases at diagnosis.
Treatment options for infantile fibrosarcoma include the following:
Complete resection is curative in most patients with infantile fibrosarcoma. However, the large size of the lesion frequently makes resection without major functional consequences impossible. For instance, tumors of the extremities often require amputation for complete excision. The European pediatric group has reported that observation may also be an option in patients with group II disease after surgery. Twelve patients with group II disease received no further therapy and two patients relapsed. One patient obtained a complete remission after chemotherapy. Postoperative chemotherapy was administered to patients with higher group disease and those who progressed. In a subsequent study, only one of seven patients with group II disease progressed during observation; that patient achieved complete remission with chemotherapy.[Level of evidence: 3iiA]
Preoperative chemotherapy has made a more conservative surgical approach possible; agents active in this setting include vincristine, dactinomycin, cyclophosphamide, and ifosfamide.[104,105]; [103,106][Level of evidence: 3iiA]; [Level of evidence: 3iiB] Three studies of patients with infantile fibrosarcoma suggest that an alkylator-free regimen is effective and should be used as the first treatment choice in patients with macroscopic disease.[102,103,108]
Two cases with variant LMNA-NTRK1 fusions responded to crizotinib.[109,110]
In a phase I/II trial of larotrectinib—an oral ATP-competitive inhibitor of TRK A, B, and C—durable objective responses were seen in all eight patients with recurrent infantile fibrosarcoma who harbored an NTRK fusion. Three of five patients who achieved a partial response after neoadjuvant larotrectinib underwent a complete surgical resection with negative margins and achieved an excellent pathologic response (>98% treatment effect) and remained disease free 7 to 15 months after surgery.[111,112]; [Level of evidence: 3iiD] One of eight patients in this trial with an ETV6-NTRK3–rearranged infantile fibrosarcoma developed progressive disease after 8 months of larotrectinib therapy and was found to have a G623R acquired resistance mutation. The patient was treated with LOXO-195, a selective TRK inhibitor designed to overcome acquired resistance mediated by recurrent kinase domain mutations, and experienced a transient partial response. Pediatric-specific pharmacokinetics and toxicities of larotrectinib were described in a phase I pediatric trial.
A patient aged 2 months with infantile fibrosarcoma was initially treated with chemotherapy. At disease progression, a response was seen with pazopanib.
A rare case of spontaneous regression without treatment has been reported.[Level of evidence: 3iiiDiv]
Treatment options under clinical evaluation
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
The phase II subprotocol is evaluating LOXO-101 (larotrectinib) in patients with tumors harboring actionable NTRK fusions.
These tumors lack the translocation seen in infantile fibrosarcomas. They present like most nonrhabdomyosarcomas, and the management approach is similar.
Myxofibrosarcoma is a rare lesion, especially in childhood. It is typically treated with complete surgical resection.
Low-grade fibromyxoid sarcoma
Low-grade fibromyxoid sarcoma is a histologically deceptive soft tissue neoplasm that most commonly affects young and middle-aged adults, is commonly located deep within the extremities, and is characterized by a FUS-CREB3L3 translocation and, rarely, alternative translocations such as FUS-CREB3L1 and EWSR1-CREB3L1.[4,118,119,120,121]
In a review of 33 patients (three were younger than 18 years) with low grade fibromyxoid sarcoma, 21 of 33 patients developed a local recurrence after intervals of up to 15 years (median, 3.5 years); 15 patients developed metastases up to 45 years (median, 5 years) from diagnosis, most commonly to the lungs and pleura, emphasizing the need for continued follow-up of these patients. Even after metastases occur, the disease course may be indolent.
In another report, 14 of 73 patients were younger than 18 years. In this series with a relatively short follow up (median of 24 months), only 8 of 54 patients with adequate follow-up developed local (9%) or distant (6%) recurrence. This report suggests that the behavior of this tumor might be significantly better than previously reported. 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:
Because low-grade fibromyxoid sarcoma is not very chemosensitive, the limited treatment information suggests that surgery is the treatment of choice. The German Cooperative Weichteilsarkom Studiengruppe (CWS) reported study results for 31 patients younger than 21 years with low-grade fibromyxoid sarcoma.[Level of evidence: 3iiDi] The 5-year EFS rate was 71% (95% CI, ±18.6%), the 5-year local relapse-free survival rate was 76% (95% CI, ± 17.6%), and the 5-year OS rate was 100%. Among 24 patients who had R0 resections, 5 patients (21%) suffered relapse (3 local, 1 metastatic, and 1 combined). Among seven patients who had R1 resections, three patients (43%) suffered local relapse.
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.
Sclerosing epithelioid fibrosarcoma
Sclerosing epithelioid fibrosarcoma is a rare malignant sarcoma that commonly harbors EWSR1 gene fusions and has an aggressive clinical course. The tumor is poorly responsive to chemotherapy;[126,127,128] therefore, it is typically treated with complete surgical excision. Long-term follow-up is recommended because late local recurrence and metastases can occur.
Skeletal Muscle Tumors
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 patients were diagnosed 30 or more years after the initial diagnosis of retinoblastoma.
Treatment options for leiomyosarcoma include the following:
Trabectedin has been studied in adults with leiomyosarcoma. Results from studies include the following:
There are no data to support the use of trabectedin in pediatric patients.
So-called Fibrohistiocytic Tumors
So-called fibrohistiocytic tumors include the following subtypes:
Plexiform fibrohistiocytic tumor
Plexiform fibrohistiocytic 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.[132,133]
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.[134,135,136] There are rare reports of the tumor spreading to regional lymph nodes or the lungs.[132,136,137]
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.
Treatment options for plexiform fibrohistiocytic tumor include the following:
Nerve Sheath Tumors
Malignant peripheral nerve sheath tumor
Malignant peripheral nerve sheath tumors account for 5% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
Malignant peripheral nerve sheath tumor can arise sporadically and in children with neurofibromatosis type 1 (NF1). Among patients with NF1, a family history of malignant peripheral nerve sheath tumor is associated with an increased risk of developing early-onset malignant peripheral nerve sheath tumor.
A rare case of a child with documented neurofibromatosis type 2 (NF2) and a benign neurofibroma had five recurrences; during this time, the lesions progressively lost markers (such as S-100) and acquired clear-cut signs of malignant transformation to malignant peripheral nerve sheath tumor, documented by multiple markers, including the first example of NOTCH2 in this disease.
Molecular features of malignant peripheral nerve sheath tumor include the following:
Features associated with a favorable prognosis include the following:[140,146,147,148]
Features associated with an unfavorable prognosis include the following:
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.[140,146,148] In the French Sarcoma Group study, NF1 was associated with other adverse prognostic features, but was not an independent predictor of poor outcome.
The Italian Sarcoma Group reported on outcomes after recurrence in 73 children and adolescents with malignant peripheral nerve sheath tumor.[Level of evidence: 3iiiA] The median OS after first relapse was 11 months, and the survival rates were 39.2% at 1 year and 15.8% at 5 years. The factors associated with a better prognosis for these patients who relapsed were less initial tumor invasiveness, longer time to relapse, and the achievement of a secondary complete remission (which was related to the feasibility of radical surgery).
Treatment options for malignant peripheral nerve sheath tumor include the following:
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.
Recurrent malignant peripheral nerve sheath tumor
Of 120 patients enrolled in Italian pediatric protocols from 1979 to 2004, an analysis identified 73 patients younger than 21 years with relapsed malignant peripheral nerve sheath tumor. The time to relapse from initial diagnosis ranged from 1 month to 204 months, with a median time to relapse of 7 months. Median OS from first relapse was 11 months, with an OS rate of 39% at 1 year and 16% at 5 years. The factors associated with a higher probability of survival after relapse were lower tumor invasiveness at initial presentation, longer time to relapse, and complete surgical resection of the tumor at relapse.
Malignant Triton tumor
Malignant Triton tumors are a variant of malignant peripheral nerve sheath tumors. They occur most often in patients with NF1 and consist of neurogenic and rhabdomyoblastic components. Malignant Triton tumors are high-grade malignancies. They usually occur before age 35 years and are very rare in children (case reports only).
Malignant Triton tumors are not usually responsive to chemotherapy and radiation therapy but have been treated with rhabdomyosarcoma therapy.[Level of evidence: 3iiiA] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)
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.
Treatment options for ectomesenchymoma include the following:
The CWS 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.
Pericytic (Perivascular) Tumors
Infantile hemangiopericytoma, a subtype of myopericytoma, is a highly vascularized tumor of uncertain origin.
Children younger than 1 year with hemangiopericytoma seem to have a better prognosis than do children older than 1 year with hemangiopericytoma.[159,160,161]
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 options for infantile hemangiopericytomas include 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 stage III disease progressed and died. Three patients with stage I disease survived, although one patient had recurrence in the lungs. Six patients had infantile hemangiopericytoma, of which five were greater than stage I. All six patients survived, and three patients had good responses to vincristine, actinomycin, and cyclophosphamide.
Several studies have reported on tumors in children that were more akin to infantile myofibromatosis (refer to the Infantile myofibromatosis section of this summary) or hemangiopericytoma.[110,164] Rather than the ETV6-NTRK3 fusion protein seen in congenital infantile fibrosarcoma, a LMNA-NTRK1 fusion protein was identified. One patient carrying this fusion responded to crizotinib.
This entity is a fibrous tumor of infancy and childhood that most commonly presents in the first 2 years of life.
The lesion can present as a single subcutaneous nodule (myofibroma) most commonly involving the head and neck region, or lesions can affect multiple skin areas, muscle, and bone (myofibromatosis).[167,168,169,170]
An autosomal dominant form of the disease has been described and it is associated with germline mutations of the PDGFRB gene. Somatic PDGFRB mutations have also been identified without germline mutations.
These lesions have an excellent prognosis and can regress spontaneously. About one-third of cases with multicentric involvement will also have visceral involvement, and the prognosis for these patients is poor.[169,170,173]
Treatment options for infantile myofibromatosis include the following:
The use of combination therapy with vincristine/dactinomycin and vinblastine/methotrexate have proven effective in cases of multicentric disease with visceral involvement and in cases in which the disease has progressed and has threatened the life of the patient (e.g., upper airway obstruction).[169,170,174]
Tumors of Uncertain Differentiation
Tumors of uncertain differentiation include the following subtypes:
Synovial sarcoma NOS
Synovial sarcoma accounts for 9% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
Synovial sarcoma is one of the most common nonrhabdomyosarcomatous soft tissue sarcomas in children and adolescents. In a 1973 to 2005 SEER review, 1,268 patients with synovial sarcoma were identified. Approximately 17% of these patients were children and adolescents, and the median age at diagnosis was 34 years.
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.[177,178] The risk of metastases is highly influenced by tumor size; it is estimated that patients with tumors that are larger than 5 cm have a 32-fold risk of developing metastases when compared with other patients.
Diagnostic evaluation and molecular features
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.[179,180] It is thought that the SYT/SSX18 transcript promotes epigenetic silencing of key tumor suppressor genes.
In one report, reduced INI1 nuclear reactivity on immunohistochemical staining was seen in 49 cases of synovial sarcoma, suggesting that this pattern may help distinguish synovial sarcoma from other histologies.
Patients younger than 10 years have more favorable outcomes and clinical features—including extremity primaries, smaller tumors, and localized disease—than do older patients.[175,183,184] 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:
Treatment options for synovial sarcoma include the following:
The COG and the European Pediatric Soft Tissue Sarcoma Study Group reported a combined analysis of 60 patients younger than 21 years with localized synovial sarcoma prospectively assigned to surgery without adjuvant radiation therapy or chemotherapy. Enrollment was limited to patients with initial complete resection with histologically free margins, with a grade 2 tumor of any size or a grade 3 tumor 5 cm or smaller. The 3-year EFS was 90% (median follow-up, 5.2 years; range, 1.9–9.1). All eight events were local tumor recurrence; no metastatic recurrences were seen. All patients with recurrent disease were effectively treated with second-line therapy, resulting in 100% OS.
Synovial sarcoma appears to be more sensitive to chemotherapy than many other soft tissue sarcomas, and children with synovial sarcoma seem to have a better prognosis than do adults with synovial sarcoma.[15,178,190,196,197,198,199,200] The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[185,199,201] Response rates to the ifosfamide and doxorubicin regimen are higher than in other nonrhabdomyosarcomatous soft tissue sarcomas.
Studies have reported the following chemotherapy-associated treatment findings:
Outcomes for patients treated on the CCLG-EPSSG-NRSTS-2005 trial are described in Table 9.
Recurrent synovial sarcoma NOS
Survival after relapse is poor (30%–40% at 5 years). Factors associated with outcome after relapse include duration of first remission (> or ≤ 18 months) and lack of a second remission.[208,209] In the German experience, surgical resection of metastatic deposits was the most common way to achieve a second complete remission. Maintenance chemotherapy with oral trofosfamide, idarubicin, and etoposide or oral cyclophosphamide and intravenous vinblastine was administered on an individual basis.
Radiation therapy (stereotactic body radiation therapy) can be used to target select pulmonary metastases. This is usually considered after at least one resection to confirm metastatic disease. Radiation therapy is particularly appropriate for patients with lesions that threaten air exchange because of their location adjacent to bronchi or cause pain by invading the chest wall.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis that 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 are biopsied. Surgical removal of primary and recurrent tumor(s) is the most effective treatment.[Level of evidence: 3iiiA] Because of the propensity of this disease to have occult metastasis to the lymph nodes, sentinel lymph node biopsy is recommended for epithelioid sarcoma of the extremities or buttocks in the absence of clinically (by imaging or physical examination) enlarged lymph nodes.
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, which included children and adults (median age, 27.3 years), found no difference in the probability of recurrence between patients who received chemotherapy and those who did not receive chemotherapy and suggested that radiation therapy may be useful.
In a German Cooperative Weichteilsarkom Studiengruppe retrospective analysis of 67 children, adolescents, and young adults (median age, 14 years) with epithelioid sarcoma, 53 patients presented with localized disease and 14 patients presented with metastatic disease.[Level of evidence: 3iiA] Fifty-eight of 67 patients were treated with primary resections. Resections were microscopically complete in 35 patients, microscopically incomplete in 12 patients, and macroscopically incomplete in 20 patients. Forty-nine patients received chemotherapy, and 33 patients received radiation therapy. Complete remission was achieved in 45 of 53 patients (85%) with localized disease. Twenty-seven patients relapsed after a median time of 0.9 years (range, 0.1–2.3 years). Patients with localized disease had a 5-year EFS rate of 35% (95% CI, ±12%) and an OS rate of 48% (95% CI, ±14%). Patients with metastatic disease had a 5-year EFS rate of 7% (95% CI, ±14%) and an OS rate of 9% (95% CI, ±16%). Smaller tumor size, lower IRS group, less tumor invasiveness, negative nodal status, and microscopically complete resection correlated with a favorable prognosis in patients with localized disease.
In a phase I trial of the EZH2 inhibitor tazemetostat, two patients with INI1-negative epithelioid sarcoma had prolonged stable disease for more than 20 months after starting therapy.
Alveolar soft part sarcoma
Alveolar soft part sarcomas account for 1.4% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
The median age at presentation is 25 years, and alveolar soft part sarcoma most commonly arises in the extremities but can occur in the oral and maxillofacial region.[219,220,221] Alveolar soft part sarcoma in children can present with evidence of metastatic disease. Delayed metastases to the brain and lung are uncommon.
In a series of 61 patients with alveolar soft part sarcoma who were treated in four consecutive CWS trials and the SoTiSaR registry, 46 patients presented with localized disease and 15 patients had evidence of metastasis at diagnosis. Of the nine children with alveolar soft part sarcoma younger than 30 years who were treated between 1980 and 2014 at four major institutions, the median age at diagnosis was 17 years, and 64% of patients were female. The most common site of disease was the lower extremity, and 26 patients had an ASSPL-TFE3 translocation. The distribution by Intergroup Rhabdomyosarcoma Study (IRS) group was as follows: 19 patients with IRS I disease, 7 patients with IRS II disease, 5 patients with IRS III disease, and 38 patients with IRS IV disease.
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.[225,226]
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.[223,227] Because these tumors are rare, all children with alveolar soft part sarcoma should be considered for enrollment in prospective clinical trials. Information about ongoing clinical trials is available from the NCI website.
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]
A retrospective review of children and young adults younger than 30 years (median age, 17 years; range, 1.5–30 years) from four institutions identified 69 patients treated primarily with surgery between 1980 and 2014.[Level of evidence: 3iiA] The ASPL-TFE3 translocation was present in all 26 patients tested. There were 19 patients with IRS postsurgical staging group I tumors (28%), 7 patients with IRS group II tumors (10%), 5 patients with IRS group III tumors (7%), and 38 patients with IRS group IV tumors (55%). The 5-year EFS was 80% and the OS was 87% for the 31 patients with localized tumors (IRS postsurgical groups I, II, and III). The 5-year EFS was 7% and the OS was 61% for the 38 patients with metastatic tumors (IRS postsurgical group IV).
In patients with alveolar soft part sarcoma, presentation with metastases is common and often has a prolonged indolent course. In a series of patients treated on consecutive studies from Germany, 15 of 61 patients (25%) presented with metastases, often miliary in nature. Despite lack of response to chemotherapy, the 5-year OS was 61%, with an EFS of 20%.
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 is administered. A study from China reported on 18 patients with alveolar soft part sarcoma of the oral and maxillofacial region; 15 patients were younger than 30 years.[Level of evidence: 3iiDii] Surgical removal with negative margins was the primary treatment. All patients survived, and only one patient had metastatic disease recurrence.
A series of 51 pediatric patients aged 0 to 21 years with alveolar soft part sarcoma found an OS rate at 10 years of 78% and an EFS rate of about 63%. Patients with localized disease (n = 37) had a 10-year OS of 87%, and the 14 patients with metastases at diagnosis had a 10-year OS of 44%, partly resulting from surgical removal of primary tumor and lung metastases in some patients. Only 3 of 18 patients (17%) with measurable disease had a response to conventional antisarcoma chemotherapy, but two of four patients treated with sunitinib had a partial response.[Level of evidence: 3iiiA]
In a series of patients treated on consecutive studies from Germany, PFS for patients without metastases on presentation appeared to improve with complete resection of the primary tumor; the 5-year EFS was 100% for patients with completely resected tumors, compared with 50% for patients with microscopic or gross residual disease.
There have been sporadic reports of objective responses to interferon-alpha and bevacizumab.[219,231,232]
Studies of tyrosine kinase inhibitors have observed the following:
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.[241,242] It has a high propensity for nodal dissemination, especially metastases to regional lymph nodes (12%–43%).[242,243] The tumor typically has an indolent clinical course.
Clear cell sarcoma of soft tissue is characterized by an EWSR1-ATF1 or EWSR1-CREB1 fusion.[244,245]
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 radiation therapy is the treatment of choice and offers the best chance for cure. In this series, 12 of 13 patients with completely resected tumors were cured. For patients with more advanced disease, the outcome is poor and chemotherapy is rarely effective.; [Level of evidence: 3iiDii] In a study by the European Organization for Research and Treatment of Cancer, 26 patients with clear cell sarcoma who had metastatic disease and documented EWSR1 rearrangements were treated with crizotinib. One patient achieved a partial response, and 17 patients had stable disease.
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 monitored for a long time.[253,254] 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:
Aggressive local control and resection of metastases led to OS rates of 87% at 5 years and 63% at 10 years. Tumors were relatively resistant to radiation therapy. The therapeutic benefit of chemotherapy has not been established.
There may be potential genetic targets for small molecules, but these should be studied as part of a clinical trial. In an adult study, six of ten patients who received sunitinib achieved partial responses.
Extraskeletal Ewing sarcoma
(Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)
Desmoplastic small round cell tumor
Desmoplastic small round cell tumor is a rare primitive sarcoma.
Desmoplastic small round cell tumor most frequently involves the peritoneum in the abdomen, pelvis, and/or peritoneum into the scrotal sac, but it may occur in the kidney or other solid organs.[256,257,258,259,260] Dozens to hundreds of intraperitoneal implants are often found. The tumor occurs in males (85%) and may spread to the lungs and elsewhere.[260,261]
A large single-institution series of 65 patients compared computed tomography (CT) scans in most patients (n = 54) with positron emission tomography (PET)-CT scans (n = 11). 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 EWSR1 genes.[259,262] The WT1-EWSR1 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.[263,264]; [Level of evidence: 3iiiA] Response to neoadjuvant chemotherapy and complete resection (near 100%) is associated with improved outcome.[260,266]
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 usually performed in highly specialized centers, but are critical for any improved survival. Successful treatment modalities include neoadjuvant Ewing-type chemotherapy, followed by complete surgical resection of the extensive intra-abdominal tumors, followed by total abdominal radiation therapy. With this multimodality therapy, survival can be achieved in 30% to 40% of patients at 5 years.[256,257,263,267,268,269,270]
The Center for International Blood and Marrow Transplant Research analyzed patients with desmoplastic small round cell tumor in their registry who received consolidation with high-dose chemotherapy and autologous stem cell reconstitution. While this retrospective registry analysis suggested some benefit to this approach, other investigators have abandoned the approach because of excessive toxicity and lack of efficacy.
A single-institution study reported that five of five patients with recurrent desmoplastic small round cell tumor had partial responses to treatment with the combination of vinorelbine, cyclophosphamide, and temsirolimus.
Extra-renal (extracranial) rhabdoid tumor
Malignant rhabdoid tumors were first described in children with renal tumors in 1981 (refer to the Rhabdoid Tumors of the Kidney section in the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information) and were later found in a variety of extra-renal sites. These tumors are uncommon and highly malignant, especially in children younger than 2 years.
Extra-renal (extracranial) rhabdoid tumors account for 2% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
The first sizeable series of 26 children with extra-renal extracranial malignant rhabdoid tumor of soft tissues came from patients enrolled on the Intergroup Rhabdomyosarcoma Studies I through III during a review of pathology material. Only five patients (19%) were alive without disease. Later, investigation of children with atypical teratoid/rhabdoid tumors of the brain, as well as those with renal and extra-renal malignant rhabdoid tumors, found germline and acquired mutations of the SMARCB1 gene in all 29 tumors tested. 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 SEER study of 229 patients with renal, central nervous system (CNS), and extra-renal malignant rhabdoid tumor, patients aged 2 to 18 years, limited extent of tumor, and delivery of radiation therapy were shown to affect the outcome favorably compared with other patients (P < .002 for each comparison). Site of the primary tumor was not prognostically significant. OS at 5 years was 33%.
Treatment options for extra-renal (extracranial) rhabdoid tumor include the following:[Level of evidence: 3iA]; [279,280][Level of evidence: 3iiiB]
Responses to alisertib have been documented in four patients with 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.)
Neoplasms with perivascular epithelioid cell differentiation (PEComas)
Risk factors and molecular features
Benign PEComas are common in tuberous sclerosis, an autosomal dominant syndrome that also predisposes to renal cell cancer and brain tumors. Tuberous sclerosis is caused by germline inactivation of either TSC1 (9q34) or TSC2 (16p13.3), and the same tumor suppressor genes are inactivated somatically in sporadic PEComas. Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable tumors with similar genetic inactivation (lymphangioleiomyomatosis and angiomyolipoma) with mTOR inhibitors.[283,284] 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.
In tumors with evidence of mTORC1 activation and TSC loss, including lymphangioleiomyomatosis and angiomyolipoma, clinical activity using mTOR inhibitors, such as sirolimus, has been well documented. Similarly, three adult patients with PEComas responded to sirolimus.
From 1972 to 2006, patients with undifferentiated soft tissue sarcoma were eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the COG. The rationale was the observation that patients with undifferentiated soft tissue sarcoma had sites of disease and outcomes that were similar to those in patients with alveolar rhabdomyosarcoma. Therapeutic trials for adults with soft tissue sarcoma include patients with undifferentiated soft tissue sarcoma and other histologies, which are treated similarly, using ifosfamide and doxorubicin, and sometimes with other chemotherapy agents, surgery, and radiation therapy.
In the COG ARST0332 (NCT00346164) trial, patients with high-grade undifferentiated sarcoma were treated with an ifosfamide and doxorubicin-based regimen and were treated with rhabdomyosarcoma-directed therapies in previous Intergroup Rhabdomyosarcoma Study Group studies, with a 5-year survival estimate for nonmetastatic patients of 72%.[Level of evidence: 3iiA]
In a report of 32 patients with undifferentiated soft tissue sarcomas who were enrolled on the ARST0332 (NCT00346164) trial, the median age at enrollment was 13.6 years, and two-thirds of the patients were male. The most common primary sites were the paraspinal region and extremities. Five patients presented with metastatic disease.
Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high-grade)
At one time, malignant fibrous histiocytoma was the single most common histotype among adults with soft tissue sarcomas. Since it was first recognized in the early 1960s, malignant fibrous histiocytoma has been plagued by controversy in terms of both its histogenesis and its validity as a clinicopathologic entity. The latest WHO classification no longer includes malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[4,292]
This entity accounts for 2% to 6% of all childhood soft tissue sarcomas.
Undifferentiated pleomorphic sarcoma was most often called malignant fibrous histiocytoma in the past. Historically, this entity has been difficult to evaluate because of the shifting diagnostic criteria. Analysis of 70 cases diagnosed as malignant fibrous histiocytosis of no specific type, storiform or pleomorphic malignant fibrous histiocytoma, pleomorphic sarcoma, or undifferentiated pleomorphic sarcoma showed a highly complex karyotype with no specific recurrent aberrations.
Undifferentiated sarcomas with 12q13–15 amplification, including MDM2 and CDK4, are best classified as dedifferentiated liposarcomas; the relationship between this tumor and the family of undifferentiated/unclassified tumors with spindle cell morphology remains relatively undefined.
These tumors can arise in previously irradiated sites or as a second malignancy in patients with retinoblastoma.
Clinical presentation and treatment
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.)
Undifferentiated round cell sarcomas withBCOR-CCNB3rearrangements
(Refer to the Undifferentiated Round Cell Sarcomas With BCOR-CCNB3 Rearrangements and Genomics of Ewing Sarcoma sections of the PDQ summary on Ewing Sarcoma Treatment for more information.)
Undifferentiated round cell sarcomas withCIC-DUX4rearrangements
(Refer to the Undifferentiated Round Cell Sarcomas With CIC-DUX4 Rearrangements and Genomics of Ewing Sarcoma sections of the PDQ summary on Ewing Sarcoma Treatment for more information.)
Undifferentiated round cell sarcomas withCIC-NUTM1rearrangements
(Refer to the Undifferentiated Round Cell Sarcomas With CIC-NUTM1 Rearrangements section of the PDQ summary on Ewing Sarcoma Treatment for more information.)
Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant. Malignant vascular tumors include the following subtypes:
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.[298,299,300,301,302,303,304]
A multi-institutional case series reported on 24 patients aged 2 to 26 years with epithelioid hemangioendothelioma.[Level of evidence: 3iiiDii] Most patients presented with multiorgan disease. Progression was seen in 63% of patients, with a mean time to progression of 18.4 months (range, 0–72 months).
The presence of effusions, tumor size larger than 3 cm, and a high mitotic index (>3 mitoses/50 high-power fields) have been associated with unfavorable outcomes.
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 current medicines. Monoclonality has been described in multiple liver lesions, suggesting a metastatic process.
Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns, with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, one or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.
The number of pediatric patients reported in the literature is limited.
Clinical presentation and diagnostic evaluation
Common sites of involvement are liver alone (21%), liver plus lung (18%), lung alone (12%), and bone alone (14%).[300,306,307] 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.[300,309,310,311,312]
A multi-institutional case series reported on 24 patients aged 2 to 26 years with epithelioid hemangioendothelioma.[Level of evidence: 3iiiDii] Three patients who were treated with sirolimus achieved stable disease or a partial response for more than 2.5 years.
Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Treatment options under clinical evaluation for epithelioid hemangioendothelioma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Angiosarcoma of the soft tissue
Angiosarcoma is a rare (accounting for 2% of sarcomas), aggressive, vascular tumor that can arise in any part of the body, but is more common in the soft tissue. Angiosarcoma has an estimated incidence of 2 cases per 1 million people; in the United States, it annually affects approximately 600 people who are typically aged 60 to 70 years.
Angiosarcomas are extremely rare in children and it is unclear if the pathophysiology of this tumor is different in the pediatric population. Cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive.[314,315,316,317] 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 the following:
Angiosarcomas are largely aneuploid tumors. The rare cases of angiosarcoma that arise from benign lesions such as hemangiomas have a distinct pathway that needs to be investigated. MYC amplification is seen in radiation-induced angiosarcoma. KDR-VEGFR2 mutations and FLT4-VEGFR3 amplifications have been seen with a frequency of less than 50%.
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.[316,319,320,321] 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]
Localized disease, especially cutaneous angiosarcoma, can be treated with radiation therapy. Most of these reported cases are in adults.
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.[316,317,327]
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.[314,324] A report of eight cases of liver angiosarcoma in children highlighted the misuse of the term hemangioendothelioma and the importance of early diagnosis and treatment of these tumors.
Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcoma.[315,327]
Treatment options under clinical evaluation for angiosarcoma of the soft tissue
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 control lesions. The estimated 5-year survival rate after thoracotomy for pulmonary metastasectomy has ranged from 10% to 58% in adult studies.
With the possible exception of infants with infantile fibrosarcoma, the prognosis for patients with progressive or recurrent disease is poor. No prospective trial has demonstrated that enhanced local control of pediatric soft tissue sarcomas will ultimately improve survival. Therefore, treatment should be individualized for the site of recurrence, biologic characteristics of the tumor (e.g., grade, invasiveness, and size), previous therapies, and individual patient considerations. All patients with recurrent tumors should be considered for clinical trials.
Treatment options for progressive or recurrent disease include the following:
Pazopanib has been approved for use in recurrent soft tissue sarcoma. The clinical trial that was used to obtain approval was limited to adults and demonstrated disease stabilization and prolonged time to progression; it did not demonstrate improved overall survival.
One 13-year-old boy and one 14-year-old girl with multiply recurrent synovial sarcoma and lung metastases had responses to pazopanib for 14 and 15 months, respectively.[Level of evidence: 3iiDi]
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.
Published results of two studies addressed the outcomes of children with relapsed synovial sarcoma. Most patients in one study had distant relapse (29 of 44 patients), 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.
Treatment Options Under Clinical Evaluation
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.
Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma
The Treatment subsection of the Desmoid-type fibromatosis section was extensively revised.
Added DuBois et al. as reference 113 and level of evidence 3iiD.
Revised text to state that 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 and, rarely, alternative translocations such as FUS-CREB3L1 and EWSR1-CREB3L1 (cited Scheer et al. and Mohamed et al. as references 120 and 121, respectively).
Added text about the results of the German Cooperative Weichteilsarkom Studiengruppe study of 31 patients younger than 21 years with low-grade fibromyxoid sarcoma (cited Scheer et al. as reference 120 and level of evidence 3iiDi).
Added high expression of p53 and cyclin D1 as features associated with an unfavorable prognosis for patients with malignant peripheral nerve sheath tumor. Also added text to state that these markers were identified as adverse prognostic factors using immunohistochemical staining of diagnostic biopsy tissue (cited Krawczyk et al. as reference 152 and level of evidence 3iiDi).
Added text to state that the European Pediatric Soft Tissue Sarcoma Group designed a genomic index for synovial sarcoma. Genomic index was defined as A2 /C, where A is the total number of alterations and C is the number of involved chromosomes on array comparative genomic hybridization results. In a multivariate analysis of 61 pediatric, adolescent, and young adult patients, high genomic index was an independent predictor of decreased event-free survival and overall survival (cited Orbach et al. as reference 194 and level of evidence 3iiDiii).
Added check point inhibitors as a treatment option for alveolar soft part sarcoma (cited Wilky et al. as reference 230).
Added text to state that in a pediatric phase II trial of cediranib, using 70% of the adult maximum tolerated dose in patients younger than 16 years, five of seven patients had stable disease for 14 months or longer (cited Cohen et al. as reference 236 and level of evidence 2Diii).
Added text about the NCT03141684 trial as a treatment option under clinical evaluation for alveolar soft part sarcoma.
Added targeted therapy as a treatment option for clear cell sarcoma of soft tissue.
Revised text to state that complete surgical resections are rare and usually performed in highly specialized centers, but are critical for any improved survival. Also added text to state that successful treatment modalities include neoadjuvant Ewing-type chemotherapy, followed by complete surgical resection of the extensive intra-abdominal tumors, followed by total abdominal radiation therapy. With this multimodality therapy, survival can be achieved in 30% to 40% of patients at 5 years.
Revised text to state that inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable tumors with similar genetic inactivation (lymphangioleiomyomatosis and angiomyolipoma) with mTOR inhibitors.
Revised text to state that in tumors with evidence of mTORC1 activation and TSC loss, including lymphangioleiomyomatosis and angiomyolipoma, clinical activity using mTOR inhibitors, such as sirolimus, has been well documented. Also added text to state that three adult patients with PEComas responded to sirolimus.
Added Bjerkehagen et al. as reference 295.
Added Undifferentiated round cell sarcomas with CIC-NUTM1 rearrangements as a new subsection.
Added text to state that a multi-institutional case series reported on 24 patients aged 2 to 26 years with epithelioid hemangioendothelioma. Most patients presented with multiorgan disease. Progression was seen in 63% of patients, with a mean time to progression of 18.4 months (cited Cournoyer et al. as reference 305 and level of evidence 3iiiDii).
Added text to state that a multi-institutional case series reported on 24 patients aged 2 to 26 years with epithelioid hemangioendothelioma. Three patients who were treated with sirolimus achieved stable disease or a partial response for more than 2.5 years.
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:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Soft Tissue Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/soft-tissue-sarcoma/hp/child-soft-tissue-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389361]
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Last Revised: 2020-02-06
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