Wednesday, August 21, 2019

Childhood Soft Tissue Sarcoma Treatment (PDQ®) 4/5 –Health Professional Version - National Cancer Institute

Childhood Soft Tissue Sarcoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute



Childhood Soft Tissue Sarcoma Treatment (PDQ®)–Health Professional Version





Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma





Adipocytic Tumors

Liposarcoma

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.[1] One retrospective study identified 34 patients younger than 22 years from 1960 to 2011.[2] 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.[3] 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]
Histopathologic classification
The World Health Organization (WHO) classification for liposarcoma is as follows:[4]
  1. Intermediate (locally aggressive).
    • Atypical lipomatous neoplasm/well-differentiated liposarcoma. These tumors do not metastasize unless they undergo dedifferentiation.
  2. Malignant.
    • Dedifferentiated liposarcoma.
    • Myxoid liposarcoma. Pure myxoid liposarcomas are characterized by a t(12;16)(q13;p11) translocation and can metastasize but usually have an excellent outcome in the absence of a round cell component.[5]
    • Pleomorphic liposarcoma.
    • Liposarcoma, not otherwise specified (NOS).
Clinical presentation
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.
Prognosis
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.[3] In a retrospective study of 14 patients, 5-year survival was 78% and tumor grade, histologic subtype, and primary location correlated with survival.[2]
Treatment
Treatment options for liposarcoma include the following:
  1. Surgery. If the tumor is not completely removed or locally recurs, a second surgery may be performed.[6-8]
  2. Chemotherapy followed by surgery.
  3. Surgery preceded or followed by radiation therapy (evidence based on adult studies).[9,10]
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%.[11] 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.[16]
Trabectedin has produced encouraging responses in adults with advanced myxoid liposarcoma.[17] 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.[18][Level of evidence: 1iiDiii] There are very limited data to support the use of trabectedin in pediatric patients.[19]
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.[20][Level of evidence: 1iiA] A pediatric phase I trial of eribulin did not accrue any patients with liposarcoma.[21]

Chondro-osseous Tumors

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.[22] 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.[23]
Prognosis
A retrospective survey of European institutions identified 113 children and adults with mesenchymal chondrosarcoma. Factors associated with better outcome included the following:[24][Level of evidence: 3iiiA]
  • Lack of metastatic disease at initial presentation.
  • Clear resection margins.
  • Administration of postoperative chemotherapy after resection for patients with initially localized disease.
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.[25] The outcomes of skeletal and extraskeletal primary tumors were the same. Factors associated with outcome included the following:
  • Primary site: 5-year OS was 50% for appendicular tumors, 37% for axial tumors, and 74% for cranial tumors.
  • Metastases and tumor size: Presence of metastatic disease and larger tumor size were independently associated with an increased risk of death.
A single-institution retrospective review identified 43 cases of mesenchymal chondrosarcoma from 1979 to 2010.[26] 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
Treatment options for extraskeletal mesenchymal chondrosarcoma include the following:
  1. Surgery. If the tumor is not completely removed, radiation therapy may also be given.
  2. Surgery preceded or followed by radiation therapy.[9,10]
  3. Chemotherapy followed by surgery and additional chemotherapy. Radiation therapy may also be given.
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.[27][Level of evidence: 3iiA]
A single-institution, retrospective review identified 12 pediatric patients with mesenchymal chondrosarcoma.[28] 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.[29] 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.

Extraskeletal osteosarcoma

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.[30]
Molecular features
A review of 32 adult patients with extraskeletal osteosarcomas consistently revealed several alterations.[31] 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.
Prognosis
Extraskeletal osteosarcoma is associated with a high risk of local recurrence and pulmonary metastasis.[32] A single-institution retrospective review identified 43 patients with extraskeletal osteosarcoma; 37 patients had localized disease, and 6 patients presented with metastatic disease.[33] 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.[34][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.[34] 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
Treatment options for extraskeletal osteosarcoma include the following:
  1. Surgery followed by chemotherapy.[32-34]
Typical chemotherapy regimens used for osteosarcoma include some combination of cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide.[32-34]
(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

Fibroblastic/myofibroblastic tumors include the following subtypes:
  1. Fibroblastic/myofibroblastic tumors.
    1. Intermediate (locally aggressive).
      • Palmar/plantar fibromatosis.
      • Desmoid-type fibromatosis (previously called desmoid tumor or aggressive fibromatoses).
      • Lipofibromatosis.
      • Giant cell fibroblastoma.
    2. Intermediate (rarely metastasizing).
    3. Malignant.

Desmoid-type fibromatosis

Desmoid-type fibromatosis has previously been called desmoid tumors or aggressive fibromatoses.
Risk factors
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).[35] 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 [35] 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 CTNNB1mutation 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.)
Prognosis
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.[40] 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.[41] Repeated surgical resection can sometimes bring recurrent lesions under control.[42]
Treatment
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.[43] Large adult series and smaller pediatric series have reported long periods of disease stabilization and even regression without systemic therapy.[42,44]; [45][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.[43]
Treatment options for desmoid-type fibromatosis include the following:
  1. Surgery.
  2. Observation, for tumors that are incompletely resected or recurrent that do not pose a danger to vital organs, if other treatment options are not available.[42,46-52] Whenever possible, however, the treatment of choice is complete resection.
  3. Chemotherapy, for unresectable or recurrent tumors.
    • Methotrexate and vinblastine: This combination produced objective responses in about one-third of patients with unresectable or recurrent desmoid-type fibromatosis.[53]
    • Doxorubicin and dacarbazine: A series of mainly adult patients with FAP and unresectable desmoid-type fibromatosis that were unresponsive to hormone therapy showed that doxorubicin plus dacarbazine followed by meloxicam (a nonsteroidal anti-inflammatory drug [NSAID]) can be safely administered and can induce responses.[54]
    • Pegylated liposomal doxorubicin: Some responses have been reported.[55] In a series of five patients, a median progression-free interval of 29 months was reported.[56]
    • Hydroxyurea: A retrospective analysis reported the results of 16 children with previously treated desmoid tumors who were treated with hydroxyurea. Prior to hydroxyurea, seven patients had tumor progression, two patients had increased pain, and seven patients had both. Tumor shrinkage occurred in 37.5% of patients (with 18.7% partial remissions), and symptom improvement occurred in 68.7% of patients.[57]
  4. Tyrosine kinase inhibitors.
    • Sorafenib: An international prospective phase III double-blind study was conducted through the National Clinical Trials Network (NCTN) to evaluate the efficacy of sorafenib in patients with unresectable progressive or symptomatic desmoid tumors. Adult patients were randomly assigned in a 2:1 fashion (sorafenib: placebo); crossover to sorafenib was permitted after disease progression. Eighty-seven patients were enrolled (aged 18–72 years). The objective response rate was 33% (95% CI, 20%–48%) in the sorafenib arm and 20% (95% CI, 8%–38%) in the placebo arm. The median time to objective response was 9.5 months for patients treated with sorafenib and 13.3 months for patients who received the placebo. The 2-year PFS rate was 81% for patients treated with sorafenib, compared with 36% for patients who received the placebo.[43][Level of evidence: 1iDiii]
    • Pazopanib: A small series reported symptomatic improvement and stable disease in seven patients with desmoid-type fibromatosis who were treated with pazopanib.[58]
  5. NSAIDs: NSAIDs such as sulindac have been used in single cases for desmoid-type fibromatosis; the responses seen were usually disease stabilization.[59]
  6. Antiestrogen treatment: Antiestrogen treatment, usually tamoxifen, plus sulindac has also resulted in disease stabilization.[60] A prospective trial of the combination of tamoxifen and sulindac reported few side effects, although asymptomatic ovarian cysts were common in girls. This combination showed relatively little activity, as measured by rates of response and PFS.[61][Level of evidence: 2Diii]
  7. Radiation therapy.
    • Radiation has been used for unresectable and symptomatic desmoid-type fibromatosis or postoperatively for tumors with inadequate resections if progression would have morbid consequences. The potential long-term complications of radiation therapy, especially subsequent neoplasms, make this modality less appealing in a young population.[62]
    • Postoperative radiation therapy can be considered when recurrence or progression would entail additional surgery that might cause functional or cosmetic compromise and if radiation is considered acceptable in terms of morbidities.
  8. NOTCH pathway inhibitor.
    • The NOTCH pathway has been implicated in the development of desmoid tumors.[63] Partial responses to the gamma secretase inhibitor PF-03084014 have been noted in adults with desmoid-type fibromatosis.[64][Level of evidence: 3iiiDiv]

Dermatofibrosarcoma protuberans

Dermatofibrosarcoma is a rare tumor that can be present in all age groups, but many of the reported cases arise in children.[65-67] 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).[68][Level of evidence: 3iA]
Molecular features
The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGFRB gene.
Treatment
Treatment options for dermatofibrosarcoma protuberans include the following:
  1. Surgery.
  2. Surgery preceded or followed by radiation therapy.
  3. Radiation therapy and imatinib therapy, for unresectable or recurrent tumors.
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.[69] 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.[70,71]
When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective.[72-74] 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.[66,68]
Guidelines for workup and management of dermatofibrosarcoma protuberans have been published.[75]

Inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumor is a rare mesenchymal tumor that has a predilection for children and adolescents.[76-78]
Clinical presentation
Inflammatory myofibroblastic tumors are rare tumors that affect soft tissues and visceral organs of children and young adults.[79] They rarely metastasize but tend to be locally invasive. Usual anatomical sites of disease include soft tissue, lungs, spleen, colon, and breast.[76] A review of 42 cases of pediatric inflammatory myofibroblastic tumor of the bladder was published in 2015.[80]
Molecular features
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.[81] ROS1 and PDGFRB kinase fusions have been identified in 8 of 11 cases (73%) who are negative for ALK by immunohistochemistry.[82][Level of evidence: 3iiiDiv]
Prognosis
Inflammatory myofibroblastic tumor recurs frequently but is rarely metastatic.[76-78]
Treatment
Treatment options for inflammatory myofibroblastic tumor include the following:
  1. Surgery.
  2. Chemotherapy.
  3. Steroid therapy.
  4. NSAID therapy.
  5. Targeted therapy (ALK inhibitors).
Complete surgical removal, when feasible, is the mainstay of therapy.[83] 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.[84][Level of evidence: 3iiA] The benefit of chemotherapy has been noted in case reports.[85]
There are case reports of response to either steroids or NSAIDs.[86,87] 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.[88][Level of evidence: 3iiA]
Inflammatory myofibroblastic tumors respond to ALK inhibitor therapy, as follows:
  • Crizotinib: Two adults with ALK-rearranged inflammatory myofibroblastic tumor achieved partial response with crizotinib.[89][Level of evidence: 3iiiDiv] For pediatric patients with measurable disease, the use of crizotinib achieved partial tumor responses in three of six patients with ALK-translocated inflammatory myofibroblastic tumors.[90] A case report of a patient aged 16 years with metastatic/multifocal ALK-positive inflammatory myofibroblastic tumor demonstrated a complete response and a 3-year disease-free interval with crizotinib therapy.[91] Finally, one study included 14 patients with inflammatory myofibroblastic tumors who were treated with crizotinib. With crizotinib therapy, five patients had a complete response, seven had a partial response, and the remaining two had stable disease; no patient had relapsed at the time the article was published.[92][Level of evidence: 3iiDiv]
  • Ceritinib: In a phase I trial of ceritinib for adult patients previously treated with ALKinhibitors, one patient with inflammatory myofibroblastic tumor had a partial response.[93] Two pediatric patients enrolled in a clinical trial responded to treatment with ceritinib; one patient had a complete response that was durable for multiple years on continuing therapy, and one patient had a partial response when the drug was discontinued for severe liver and renal toxicity.[94]

Infantile fibrosarcoma

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.
Clinical presentation
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.[95] Hypercalcemia secondary to elevated levels of parathyroid hormone–related protein has been reported as a presenting feature of this disease in newborns.[96]
Molecular features
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.[97] BRAF intragenic deletions have been described in cases of infantile fibrosarcoma and co-occur with NTRK3 fusions.[98]
Prognosis
These tumors have a low incidence of metastases at diagnosis.
Treatment
Treatment options for infantile fibrosarcoma include the following:
  1. Surgery followed by observation.
  2. Surgery followed by chemotherapy.
  3. Chemotherapy followed by surgery.
  4. Targeted therapy.
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.[99] 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.[100][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.[101,102]; [100,103][Level of evidence: 3iiA]; [104][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.[99,100,105]
Two cases with variant LMNA-NTRK1 fusions responded to crizotinib.[106,107]
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.[108,109] 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.[110] Pediatric-specific pharmacokinetics and toxicities of larotrectinib were described in a phase I pediatric trial.[111]
A patient aged 2 months with infantile fibrosarcoma was initially treated with chemotherapy. At disease progression, a response was seen with pazopanib.[112]
A rare case of spontaneous regression without treatment has been reported.[113][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:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
    The phase II subprotocol is evaluating LOXO-101 (larotrectinib) in patients with tumors harboring actionable NTRK fusions.
  • LOXO-TRK-15003 (NCT02637687) (Oral TRK Inhibitor LOXO-101 for Treatment of Advanced Pediatric Solid or Primary Central Nervous System [CNS] Tumors): A phase I trial of the pan-TRK inhibitor LOXO-101 is being conducted for children with solid tumors or brain tumors whose disease has progressed or was nonresponsive to available therapies, and for which no standard or available curative therapy exists. LOXO-101 is a highly selective inhibitor of all three TRK family kinases.
  • RXDX-101-03 (NCT02650401) (Study of RXDX-101 in Children With Recurrent or Refractory Solid Tumors and Primary CNS Tumors, With or Without TRK, ROS1, or ALKFusions): This is a five-part, open-label, phase I/Ib, multicenter, dose-escalation study in pediatric patients with relapsed or refractory solid tumors; primary CNS tumors; neuroblastoma; non-neuroblastoma, extracranial solid tumors with NTRK1/2/3, ROS1, or ALK gene rearrangements; and patients who are otherwise eligible but unable to swallow capsules. The study is designed to explore the safety, maximum tolerated dose or recommended phase II dose, pharmacokinetics, and antitumor activity of entrectinib (RXDX-101).
  • NCT03215511 (Phase I/II Study of LOXO-195 in Patients With Previously Treated NTRKFusion Cancers): This is a phase I/II, multicenter, open-label study designed to evaluate the safety and efficacy of LOXO-195 when administered orally to patients aged 1 month and older with NTRK fusion cancers treated with a prior TRK inhibitor.
  • NCT02568267 (Basket Study of Entrectinib [RXDX-101] for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 [Trk A/B/C], ROS1, or ALK Gene Rearrangements [Fusions] [STARTRK-2]): This is an open-label, multicenter, global phase II basket study of entrectinib (RXDX-101) for the treatment of patients 18 years and older with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene fusion. Patients will be assigned to different baskets according to type of tumor and gene fusion.

Adult fibrosarcoma

These tumors lack the translocation seen in infantile fibrosarcomas. They present like most nonrhabdomyosarcomas, and the management approach is similar.

Myxofibrosarcoma

Myxofibrosarcoma is a rare lesion, especially in childhood. It is typically treated with complete surgical resection.

Low-grade fibromyxoid sarcoma

Low-grade fibromyxoid sarcoma is a histologically deceptive soft tissue neoplasm that most commonly affects young and middle-aged adults, is commonly located deep within the extremities, and is characterized by a FUS-CREB3L3 translocation.[114,115]
Prognosis
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.[114] Even after metastases occur, the disease course may be indolent.[116]
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.[117] 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.[118]
Treatment
Treatment options for low-grade fibromyxoid sarcoma include the following:
  1. Surgery.
Because low-grade fibromyxoid sarcoma is not very chemosensitive, the limited treatment information suggests that surgery is the treatment of choice.[116] 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.[119]

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;[120-122] 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

Rhabdomyosarcoma

Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.

Smooth Muscle Tumors

Leiomyosarcoma

Leiomyosarcoma accounts for 2% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
Risk factors
Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma.[123] 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.[124]
Treatment
Treatment options for leiomyosarcoma include the following:
  1. Chemotherapy (trabectedin).
Trabectedin has been studied in adults with leiomyosarcoma. Results from studies include the following:
  • In an open-label study of trabectedin in adult patients with recurrent sarcomas, the best overall response rate (complete remission and partial remission) was seen in patients with leiomyosarcoma (7.5%).[125] The clinical benefit rate (includes stable disease) for leiomyosarcoma was 54%.
  • In another adult study, patients with recurrent liposarcoma and leiomyosarcoma were randomly assigned to receive treatment with either trabectedin or dacarbazine. Patients treated with trabectedin had a 45% reduction in disease progression.[18]
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.[126,127]
Clinical presentation
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.[128-130] There are rare reports of the tumor spreading to regional lymph nodes or the lungs.[126,130,131]
Molecular features
No consistent chromosomal anomalies have been detected but a t(4;15)(q21;q15) translocation has been reported.[132]
Prognosis
Plexiform fibrohistiocytic tumor is an intermediate-grade tumor that rarely metastasizes.
Treatment
Treatment options for plexiform fibrohistiocytic tumor include the following:
  1. Surgery is the treatment of choice but local recurrence has been reported in 12% to 50% of cases.[133]

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).
Risk factors
Malignant peripheral nerve sheath tumor can arise sporadically and in children with neurofibromatosis type 1 (NF1).[134] 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.[135]
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.[136]
Molecular features
Molecular features of malignant peripheral nerve sheath tumor include the following:
  • Inactivating mutations of SUZ12 have been described in these tumors and are absent in neurofibromas.[137]
  • A DNA methylation array for methylome-based and profile-based chromosomal characterization was performed on 171 peripheral nerve sheath tumors.[138] Atypical neurofibromas and low-grade malignant peripheral nerve sheath tumors were indistinguishable, with a common methylation profile and loss of CDKN2A. Epigenomic analysis identified two groups of conventional high-grade malignant peripheral nerve sheath tumor sharing a frequent loss of neurofibromin. The larger group showed an additional loss of trimethylation of H3K27me3. The smaller group of patients with predominantly spinal primary sites showed retention of H3K27me3.
  • Genomic profiling was performed on 201 malignant peripheral nerve sheath tumors.[139] Thirteen of 201 tumors demonstrated BRAF alterations.
Prognosis
Features associated with a favorable prognosis include the following:[134,140-142]
  • Smaller tumor size. In a multivariate analysis, only tumor size and nuclear p53 expression were found to be independent predictors of disease-specific survival.[141]
  • Male sex and non-Hispanic white race.[143]
  • No metastasis at presentation. A retrospective review of 140 patients with malignant peripheral nerve sheath tumor from the MD Anderson Cancer Center included children and adolescents. The disease-specific survival at 10 years was 32%. In this series, presence of metastatic disease was associated with a much worse prognosis.[141]
  • Lower stage.
  • Lower histologic grade.
  • Extremity as the primary site.
Features associated with an unfavorable prognosis include the following:[144]
  • High grade.
  • Deep tumor location.
  • Locally advanced stage at diagnosis.
  • Macroscopically incomplete resection (R2).
  • Inactivation of p53, either by mutation or amplification of MDM2.[145]
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.[141] 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 [140] and unfavorable outcomes.[134,140,142] In the French Sarcoma Group study, NF1 was associated with other adverse prognostic features, but was not an independent predictor of poor outcome.[144]
The Italian Sarcoma Group reported on outcomes after recurrence in 73 children and adolescents with malignant peripheral nerve sheath tumor.[146][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
Treatment options for malignant peripheral nerve sheath tumor include the following:
  1. Surgery.
  2. Surgery preceded or followed by radiation therapy.[9,10]
  3. Chemotherapy, for unresectable tumors.
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.
  1. Chemotherapy has achieved objective responses in childhood malignant peripheral nerve sheath tumor. A large retrospective analysis of the German and Italian experience with malignant peripheral nerve sheath tumor reported that 65% of measurable tumors had objective responses to ifosfamide-containing chemotherapy regimens, but the analysis did not conclusively demonstrate improved survival with chemotherapy.[134] This retrospective analysis also noted a trend toward improved outcome with postoperative radiation therapy.[134]
  2. A series of 37 young patients with malignant peripheral nerve sheath tumor and NF1 showed that most patients had large invasive tumors that were poorly responsive to chemotherapy; PFS was 19%, and 5-year OS was 28%.[147]
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.[146]
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:
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
  • SARC023 (NCT02008877) (Ganetespib and Sirolimus in Patients With Malignant Peripheral Nerve Sheath Tumors): This trial is testing the combination of ganetespib, the heat shock protein inhibitor, and sirolimus, the mammalian target of rapamycin (mTOR) inhibitor, for the treatment of patients with unresectable or metastatic malignant peripheral nerve sheath tumors. Patients with unresectable soft tissue or bone sarcomas are eligible for phase I of the trial. Patients with unresectable malignant peripheral nerve sheath tumors are eligible for phase II of the trial. Eligibility is restricted to patients aged 18 years and older.
  • NCT02601937 (A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.

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).[148]
Treatment
Malignant Triton tumors are not usually responsive to chemotherapy and radiation therapy but have been treated with rhabdomyosarcoma therapy.[148][Level of evidence: 3iiiA] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)

Ectomesenchymoma

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.
  • A retrospective review of six patients with malignant ectomesenchymoma from a single institution identified rhabdomyosarcoma as the mesenchymal element in five of six tumors.[149] Tumors with an alveolar rhabdomyosarcoma morphology exhibited the characteristic translocation. No unifying molecular aberrations were identified.
  • A single-institution retrospective review identified seven cases of malignant ectomesenchymoma.[150] All seven patients were male, with a mean age of 7.5 months (range, 0.6–17.0 months). Most patients showed elements of embryonal rhabdomyosarcoma. The mixed neuroectodermal elements were scattered ganglion cells, ganglioneuroma, or ganglioneuroblastoma. Six of seven cases had HRASmutations. The trimethylation at lysine 27 of histone H3 (H3K27me3), typically lost in malignant peripheral nerve sheath tumor, was retained in all cases. Five of the seven patients in this series were healthy and free of disease at the time of reporting.
Treatment
Treatment options for ectomesenchymoma include the following:
  1. Surgery.
  2. Chemotherapy.
  3. Radiation therapy.
The German Soft Tissue Sarcoma Group (Cooperative Weichteilsarkom Studiengruppe [CWS]) reported on six patients (ages 0.2–13.5 years) registered over 14 years.[151][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.[151]

Pericytic (Perivascular) Tumors

Myopericytoma

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.[152-154]
Histology
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.[155]
Treatment and outcome
Treatment options for infantile hemangiopericytomas include the following:
  1. Chemotherapy.
In a series of 17 children, the differences in metastatic potential and response to treatment were clearly demonstrated for adult and infantile hemangiopericytomas.[156] 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.[107,157] Rather than the ETV6-NTRK3 fusion protein seen in congenital infantile fibrosarcoma, a LMNA-NTRK1 fusion protein was identified.[158] One patient carrying this fusion responded to crizotinib.

Infantile myofibromatosis

This entity is a fibrous tumor of infancy and childhood that most commonly presents in the first 2 years of life.[159]
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).[160-163]
An autosomal dominant form of the disease has been described and it is associated with germline mutations of the PDGFRB gene.[164] Somatic PDGFRB mutations have also been identified without germline mutations.[165]
Treatment and outcome
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.[162,163,166]
Treatment options for infantile myofibromatosis include the following:
  1. Chemotherapy.
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).[162,163,167]

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.[168]
Histologic classification
Synovial sarcoma can be subclassified as the following types:
  • Synovial sarcoma NOS.
  • Synovial sarcoma, spindle cell.
  • Synovial sarcoma, biphasic.
Clinical presentation
The most common tumor location is the extremities, followed by trunk and head and neck.[168] Rarely, a synovial sarcoma may arise in the heart or pericardium.[169]
The most common site of metastasis is the lung.[170,171] 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.[172,173] It is thought that the SYT/SSX18 transcript promotes epigenetic silencing of key tumor suppressor genes.[174]
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.[175]
Prognosis
Patients younger than 10 years have more favorable outcomes and clinical features—including extremity primaries, smaller tumors, and localized disease—than do older patients.[168,176,177] A meta-analysis also suggested that response to chemotherapy was correlated with improved survival.[178]
The following studies have reported multiple factors associated with unfavorable outcomes:
  • In a retrospective analysis of synovial sarcoma in children and adolescents who were treated in Germany and Italy, tumor size (>5 cm or ≤5 cm in greatest dimension) was an important predictor of EFS.[179] In this analysis, local invasiveness conferred an inferior probability of EFS, but surgical margins were not associated with clinical outcome.
  • In a single-institution retrospective analysis of 111 patients with synovial sarcoma who were younger than 22 years at diagnosis, larger tumor size, greater depth in tissue, greater local invasiveness, and more proximal tumor location were associated with poorer OS.[180][Level of evidence: 3iiA]
  • A multicenter analysis of 219 children from various treating centers, including Germany, SJCRH, Instituto Tumori, and MD Anderson Cancer Center, reported an estimated 5-year OS of 80% and EFS rate of 72%.[178] In this analysis, an interaction between tumor size and invasiveness was observed; in multivariate analysis, patients with large or invasive tumors or with Intergroup Rhabdomyosarcoma Study (IRS) group III disease (localized, incompletely resected or with biopsy only) and group IV disease (metastases at diagnosis) had decreased OS. Treatment with radiation therapy was related to improved OS (HR, 0.4; 95% CI, 0.2–0.7). In IRS group III patients, objective response to chemotherapy (18 of 30 [60%]) correlated with improved survival. In adults, factors such as International Union Against Cancer/American Joint Committee on Cancer stage III and stage IVA, tumor necrosis, truncal location, elevated mitotic rate, age, and histologic grade have been associated with a worse prognosis.[181-183]
  • Expression and genomic index prognostic signatures have been studied in synovial sarcoma. Complex genomic profiles, with greater rearrangement of the genome, are more common in adults than in younger patients with synovial sarcoma and are associated with a higher risk of metastasis.[184]
  • A review of 84 patients with localized synovial sarcoma who had information on fusion status (SYT-SSX) and histologic grading found no difference in OS according to these criteria. However, for tumor size at diagnosis, the study showed that patients with tumors between 5 cm and 10 cm had a worse prognosis than those with smaller tumors (P = .02), and patients with tumors larger than 10 cm had even worse OS (P = .0003).[185][Level of evidence: 3iiiA]
  • The German CWS group reviewed 27 evaluable patients younger than 21 years with pulmonary metastases among 296 patients with synovial sarcoma. Metastases involved the lungs in all patients. The 5-year EFS rate was 26%, and the OS rate was 30%. The most important prognostic factor at presentation was that the metastases were limited to one lesion in one lung or one lesion in both lungs (a group they termed oligometastatic). Treatment elements associated with superior survival were adequate local therapy of the primary tumor and, if feasible, for the metastases. The use of whole-lung irradiation did not correlate with better outcomes.[186][Level of evidence: 3iiA]
Treatment
Treatment options for synovial sarcoma include the following:
  1. Surgery. Radiation therapy and/or chemotherapy may be given before or after surgery.[9,10]
  2. Chemotherapy.
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.[187] 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.[15,171,183,188-192] The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[178,191,193] Response rates to the ifosfamide and doxorubicin regimen are higher than in other nonrhabdomyosarcomatous soft tissue sarcomas.[194]
Studies have reported the following chemotherapy-associated treatment findings:
  • Several treatment centers advocate chemotherapy after resection and radiation therapy of synovial sarcoma in children and young adults.[178,179,195-197]
  • The International Society of Pediatric Oncology-Malignant Mesenchymal Tumors studies showed that select patients (young age, <5 cm resected tumors) with nonmetastatic synovial sarcoma can have excellent outcomes in the absence of radiation, but it is still unclear whether that approach obviates an advantage of radiation for local or regional control.[196]
  • A German trial suggested a benefit for postoperative chemotherapy in children with synovial sarcoma.[197]
  • A meta-analysis also suggested that chemotherapy may provide benefit.[178]
  • In the COG ARST0332 (NCT00346164) study, 129 patients with synovial sarcoma were prospectively treated using a risk-based therapy program (as detailed in the prognosis section), of which 43 were categorized as low risk, 66 as intermediate risk, and 20 as high risk. At a median follow-up of 2.6 years, 3-year EFS for low-, intermediate-, and high-risk groups were 83%, 79%, and 16%, respectively. The use of risk factor–directed therapy accurately predicted outcomes.[198]
  • The European Pediatric Soft Tissue Sarcoma Study Group performed a prospective study of patients younger than 21 years with synovial sarcoma (CCLG-EPSSG-NRSTS-2005 [NCT00334854]).[199][Level of evidence: 3iiA] Patients were stratified into the following three risk groups and nonrandomly assigned to treatment by risk group:
    • Low-risk patients had IRS group I tumors less than 5 cm in size and nonaxial primary tumors.
    • Intermediate-risk patients had no axial primary tumors and IRS group I tumors greater than 5 cm or IRS group II tumors.
    • High-risk patients included all patients with axial primary sites (head and neck, lung and pleura, trunk, retroperitoneal), IRS group III tumors, or N1 tumors.
    Outcomes for patients treated on the CCLG-EPSSG-NRSTS-2005 trial are described in Table 9.
    Table 9. Event-Free Survival (EFS) and Overall Survival (OS) in Patients With Low-, Intermediate-, and High-Risk Synovial Sarcoma Treated on the CCLG-EPSSG-NRSTS-2005 Trial
    Risk GroupTreatment3-Year EFS (%)3-Year OS (%)
    IRS = Intergroup Rhabdomyosarcoma Study; RT = radiation therapy.
    aChemotherapy was ifosfamide/doxorubicin, with doxorubicin omitted during radiation therapy.
    b59.4 Gy in cases without the option of secondary resection; 50.4 Gy as preoperative radiation therapy; 50.4, 54, and 59.4 Gy as postoperative radiation therapy, in the case of R0, R1, and R2 resections, respectively (no additional radiation therapy in the case of secondary complete resections with free margins, in children younger than 6 years).
    LowSurgery alone92100
    IntermediateSurgery, 3–6 cycles chemotherapya, ± RTb91100
    High (IRS group III)3 cycles of chemotherapya, surgery, 3 additional cycles of chemotherapy, ± RTb7794
    High (axial primary sites)Surgery, 6 cycles of chemotherapya, RTb78100
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.[200,201] In the German experience, surgical resection of metastatic deposits was the most common way to achieve a second complete remission.[201] 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.[202]
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 is an example of a national and/or institutional clinical trial that is currently being conducted:
  • ADP 04511 (NCT01343043) (A Pilot Study of Genetically Engineered NY-ESO-1 Specific [c259] T Cells in HLA-A2+ Patients With Synovial Sarcoma): Patients with unresectable, metastatic, or recurrent synovial sarcoma undergo apheresis. Cells are shipped to a central laboratory where they undergo NY-ESO-1 transduction, expansion, and cryopreservation. Patients undergo lymphodepletion with fludarabine and cyclophosphamide, followed by an infusion of autologous transfected cells. Eligibility is restricted to patients with HLA type A2+, age older than 4 years, and weight greater than 18 kg.
  • NCT02683148 (Prasterone in Treating Patients With Synovial Sarcoma That Is Metastatic or Cannot Be Removed by Surgery): Prasterone (dehydroepiandrosterone [DHEA]) is a natural allosteric inhibitor of glucose-6-phosphate dehydrogenase (G6PD). G6PD is a key regulatory enzyme needed for the survival of synovial sarcoma. The investigators postulate that treatment with DHEA can inhibit the production of NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) in synovial sarcoma and cause cell death.

Epithelioid sarcoma

Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis that displays multilineage differentiation.[203]
Clinical presentation
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.
Molecular features
Epithelioid sarcoma is characterized by inactivation of the SMARCB1 gene, which is present in both conventional and proximal types of epithelioid sarcoma.[204] This abnormality leads to increased dependence on EZH2 and tumor formation.[205]
Treatment
Treatment options for epithelioid sarcoma include the following:
  1. Chemotherapy.
  2. Surgery.
  3. Surgery preceded or followed by radiation therapy.
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.[206][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.[207]
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.[208] 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.[206]
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.[209][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.[210]
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 is an example of a national and/or institutional clinical trial that is currently being conducted:
  • NCT02601937 (A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.

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).
Clinical presentation
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.[211-213] Alveolar soft part sarcoma in children can present with evidence of metastatic disease.[214] Delayed metastases to the brain and lung are uncommon.[211]
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.[215] 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.[216]
Molecular features
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.[217,218]
Prognosis
Alveolar soft part sarcoma in children may have an indolent course.[214] Patients with alveolar soft part sarcoma may relapse several years after a prolonged period of apparent remission.[215,219] 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.[220] 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.[221][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.[216][Level of evidence: 3iiA] The ASPL-TFE3translocation 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%.[215]
Treatment
Treatment options for alveolar soft part sarcoma include the following:
  1. Surgery.
  2. Surgery preceded or followed by radiation therapy.[9,10]
  3. Targeted therapy (tyrosine kinase inhibitor).
The standard approach is complete resection of the primary lesion.[220] 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.[213][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.[211][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.[215]
There have been sporadic reports of objective responses to interferon-alpha and bevacizumab.[211,222,223]
Studies of tyrosine kinase inhibitors have observed the following:
  • A small retrospective study of nine adult patients with metastatic alveolar soft part sarcoma treated with sunitinib reported partial responses in five patients and stable disease in two patients.[224][Level of evidence: 3iiiDiv]
  • In another study, 15 patients with alveolar soft part sarcoma were treated with sunitinib, and six patients experienced partial responses. The median PFS was 19 months, and the median OS was 56 months. The 5-year OS rate was 49%.[225][Level of evidence: 3iiA] Five patients were treated with sunitinib for longer than 2 years.
  • In a phase II trial of cediranib, an inhibitor of all three known vascular epidermal growth factor receptors, 15 of 43 adult patients (35%) with metastatic alveolar soft part sarcoma had partial responses.[226][Level of evidence: 3iiDiv]
  • An international group performed a double-blind, placebo-controlled, randomized, phase II trial of cediranib in adolescent and adult patients with alveolar soft part sarcoma.[227][Level of evidence: 1iA] Median percentage change in sum of target marker lesion diameters for the evaluable population was -8.3% (interquartile range [IQR], -26.5–5.9) for patients who received cediranib therapy, compared with 13.4% (IQR, 1.1–21.3) for patients who received the placebo (one-sided P = .0010). The authors concluded that cediranib is an active agent in patients with alveolar soft part sarcoma.
  • In an open-label trial that evaluated the efficacy of pazopanib in six adult patients, one patient achieved a partial response and five patients had stable disease.[228] In another trial of 30 adult patients treated with pazopanib, one patient experienced a complete response, seven patients experienced partial responses, and 17 patients had stable disease. The median PFS was 13.6 months.[229]
Treatment options under clinical evaluation for alveolar soft part sarcoma
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 is an example of a national and/or institutional clinical trial that is currently being conducted:
  • NCT01391962 (Sunitinib or Cediranib for Alveolar Soft Part Sarcoma): A phase II trial in which patients with metastatic alveolar soft part sarcoma are randomly assigned to either sunitinib or cediranib monotherapy, with crossover at disease progression. Patients aged 16 years and older are eligible. This study is being conducted at the Clinical Center of the National Institutes of Health.

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.[230]
Clinical presentation
The tumor most commonly affects the lower extremity, particularly the foot, heel, and ankle.[231,232] It has a high propensity for nodal dissemination, especially metastases to regional lymph nodes (12%–43%).[232,233] The tumor typically has an indolent clinical course.
Molecular features
Clear cell sarcoma of soft tissue is characterized by an EWSR1-ATF1 or EWSR1-CREB1 fusion.[234,235]
Treatment
Treatment options for clear cell sarcoma of soft tissue include the following:
  1. Surgery.
  2. Surgery preceded or followed by radiation therapy.[9,10]
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.[236]; [237][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 EWSR1rearrangements were treated with crizotinib.[238] 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.[239] It has been reported in children and adolescents.[240]
Molecular features
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.[241]
Prognosis
The tumor has traditionally been considered of low-grade malignant potential.[242] However, recent reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are monitored for a long time.[243,244] 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.[244]
Treatment
Treatment options for extraskeletal myxoid chondrosarcoma include the following:
  1. Surgery.
  2. Radiation therapy.
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.[243] 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.[245]
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 is an example of a national and/or institutional clinical trial that is currently being conducted:
  • NCT02601937 (A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.

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.
Clinical presentation
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.[246-250] Dozens to hundreds of intraperitoneal implants are often found. The tumor occurs in males (85%) and may spread to the lungs and elsewhere.[250,251]
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.[251]
Molecular features
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.[249,252] The WT1-EWSR1 fusion confirms the diagnosis of desmoplastic small round cell tumor.
Prognosis
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.[253,254]; [255][Level of evidence: 3iiiA] Response to neoadjuvant chemotherapy and complete resection (near 100%) is associated with improved outcome.[250,256]
Treatment
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:
  1. Surgery.
  2. Chemotherapy followed by surgery.
  3. Radiation therapy.
Complete surgical resections are rare, but critical for any improved survival. Treatment may include chemotherapy, surgery, and radiation therapy. Multiagent chemotherapy analogous to that used for sarcomas has been used, as well as total abdominal radiation therapy.[246,247,253,257-260]
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.[261] 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.[253]
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.[262]

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).
Molecular features
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.[263] 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.[264] Rhabdoid tumors may be associated with germline mutations of the SMARCB1gene and may be inherited from an apparently unaffected parent.[265] This observation was extended to 32 malignant rhabdoid tumors at all sites in patients whose mean age at diagnosis was 12 months.[266]
Prognosis
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%.[267]
Treatment
Treatment options for extra-renal (extracranial) rhabdoid tumor include the following:[268][Level of evidence: 3iA]; [269,270][Level of evidence: 3iiiB]
  1. Surgical removal when possible.
  2. Chemotherapy as used for soft tissue sarcomas (but no single regimen is currently accepted as best).
  3. Radiation therapy.
Responses to alisertib have been documented in four patients with CNS atypical teratoid/rhabdoid tumors.[271] (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.)
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:
  • NCT02601937 (A Phase I Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.
  • APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.



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