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. The median age was 15.5 years and females were more commonly affected.[3 ] In both reports, the great majority of patients had myxoid liposarcoma.
Histopathologic classification
The World Health Organization (WHO) classification for liposarcoma is as follows:
- Intermediate grade (rarely metastasizing).
- Atypical lipomatous neoplasm/well-differentiated liposarcoma. These tumors do not metastasize unless they undergo dedifferentiation.
- Malignant.
- Liposarcoma, not otherwise specified (NOS).
- 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.[4 ]
- Dedifferentiated liposarcoma.
- Pleomorphic liposarcoma.
Clinical presentation
The majority of liposarcomas in the pediatric and adolescent age range are low grade and located subcutaneously. Metastasis to lymph nodes is very uncommon, and the great majority of metastases are pulmonary. Tumors arising in the periphery are more likely to be low grade and myxoid. Tumors arising centrally are more likely to be high grade, pleomorphic, and present with metastasis or recur with metastasis.
Prognosis
Higher grade or central tumors are associated with a significantly higher risk of death. In a retrospective review, 5-year survival for central tumors was 42%. In the international review, seven of ten patients with pleomorphic myxoid liposarcoma died because of their disease.[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:
- Surgery. If the tumor is not completely removed or locally recurs, a second surgery may be performed.[5 ,6 ,7 ]
- Chemotherapy followed by surgery.
- Surgery preceded or followed by radiation therapy (evidence based on adult studies).[8 ,9 ]
Surgery is the most important treatment for liposarcoma. After surgical resection of myxoid liposarcoma, event-free survival (EFS) and overall survival (OS) are roughly 90%. 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.
There are reports of the use of chemotherapy to decrease the size of liposarcoma before surgery to facilitate complete resection, particularly in central tumors.[10 ,11 ] The role of postoperative chemotherapy for liposarcoma is poorly defined. There does not appear to be a need for any postoperative therapy for completely resected myxoid liposarcoma. Even with the use of postoperative chemotherapy, the survival of pleomorphic liposarcoma remains poor.[12 ]
Trabectedin has produced encouraging responses in adults with advanced myxoid liposarcoma.[13 ] 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.[14 ][Level of evidence: 1iiDiii] There are very limited data to support the use of trabectedin in pediatric patients.[15 ]
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma, excluding myxoid liposarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with liposarcoma are eligible for this trial.
Chondro-osseous Tumors
Chondro-osseous tumors include the following tumor subtypes:
- Extraskeletal mesenchymal chondrosarcoma.
- Extraskeletal osteosarcoma.
- Soft tissue chondroma.
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.[16 ] 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.[17 ]
Prognosis
A retrospective survey of European institutions identified 113 children and adults with mesenchymal chondrosarcoma. Factors associated with better outcome included the following:[18 ][Level of evidence: 3iiiA]
- Lack of metastatic disease at initial presentation.
- Clear resection margins.
- Administration of postoperative chemotherapy following resection for patients with initially localized disease.
Treatment
Treatment options for extraskeletal mesenchymal chondrosarcoma include the following:
- Surgery. If the tumor is not completely removed, radiation therapy may also be given.
- Surgery preceded or followed by radiation therapy.[8 ,9 ]
- 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.[19 ][Level of evidence: 3iiA]
A single-institution, retrospective review identified 12 pediatric patients with mesenchymal chondrosarcoma.[20 ] The presence of the NCOA2 rearrangement in tumors was documented in these patients. It was also confirmed that surgical resection is necessary for cure. Eleven patients presented with localized disease and one presented with pulmonary nodules. All patients received chemotherapy-six patients before and after surgical resection and six patients only after resection. All patients received postoperative chemotherapy (most commonly ifosfamide/doxorubicin) with or without radiation therapy (median dose, 59.4 Gy). At a median follow-up of 4.8 years, 5-year disease-free survival (DFS) was 68.2% (95% CI, 39.8%-96.6%) and OS was 88.9% (95% CI, 66.9%-100%).
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. A 2003 review identified only ten case reports in the medical literature.[21 ]
Prognosis
Extraskeletal osteosarcoma is associated with a high risk of local recurrence and pulmonary metastasis.[22 ]
Treatment
Treatment options for extraskeletal osteosarcoma include the following:
- Surgery followed by chemotherapy.
(Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment for more information.)
Treatment options under clinical evaluation
Information about National Cancer Institute NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with extraskeletal mesenchymal chondrosarcoma and extraskeletal osteosarcoma are eligible for this trial.
Fibroblastic/Myofibroblastic Tumors
Fibroblastic/myofibroblastic tumors include the following tumor subtypes:
- Fibroblastic/myofibroblastic tumors.
- Intermediate grade (locally aggressive).
- Desmoid-type fibromatosis (previously called desmoid tumor or aggressive fibromatoses).
- Giant cell fibroblastoma.
- Lipofibromatosis.
- Palmar/plantar fibromatosis.
- Intermediate grade (rarely metastasizing).
- Dermatofibrosarcoma protuberans.
- Infantile fibrosarcoma.
- Inflammatory myofibroblastic tumor.
- Low-grade myofibroblastic sarcoma.
- Myxoinflammatory fibroblastic sarcoma.
- Solitary fibrous tumor.
- Malignant.
- Adult-type fibrosarcoma.
- Low-grade fibromyxoid sarcoma.
- Myxofibrosarcoma.
- Sclerosing epithelioid fibrosarcoma.
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 adenomatous polyposis coli (APC) gene (associated with intestinal polyps and a high incidence of colon cancer). In a study of 519 patients older than 10 years with a diagnosis of desmoid-type fibromatosis, 39 (7.5%, a possible underestimation) were found to have familial adenomatous polyposis (FAP).[23 ] 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,[24 ,25 ] or location of the desmoid-type fibromatosis in the abdomen or abdominal wall [23 ] 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.[26 ,27 ] (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.
These tumors have a high potential for local recurrence. Desmoid-type fibromatosis has a highly variable natural history, including well documented examples of spontaneous regression.[28 ] Mutations in exon 3 of the beta-catenin gene are seen in over 80% of desmoid-type fibromatosis and the mutation 45F has been associated with an increased risk of disease recurrence.[29 ] Repeated surgical resection can sometimes bring recurrent lesions under control.[30 ]
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. Large adult series and smaller pediatric series have reported long periods of disease stabilization and even regression without systemic therapy.[30 ,31 ]; [32 ][Level of evidence: 3iiiDi]
Treatment options for desmoid-type fibromatosis include the following:
- Surgery.
- 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.[30 ,33 ,34 ,35 ,36 ,37 ,38 ,39 ] Whenever possible, however, the treatment of choice is complete resection.
- Chemotherapy, for unresectable or recurrent tumors.
- Other drug therapy, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or antiestrogen therapy.
- Surgery preceded or followed by radiation therapy, for incompletely resected tumors or to avoid recurrence and subsequent surgery that may result in functional or cosmetic compromise.
- Radiation therapy alone, for unresectable tumors.
The treatment of choice is resection to achieve clear margins. However, a retrospective review of children who underwent surgery for desmoid-type fibromatosis at the St. Jude Children's Research Hospital (SJCRH) reported no correlation between surgical margins and risk of recurrence.[39 ]
When the diagnosis is known and complete surgical excision is not feasible, and if the tumor poses significant potential for mortality or morbidity, preoperative strategies may include the following:[40 ,41 ]
- Observation.
- Chemotherapy.
- Anti-estrogen therapy.
- NSAID therapy.
- External-beam radiation therapy.
Desmoid-type fibromatosis often behaves in a nonaggressive manner. In a study that included mostly adults with extra-abdominal primary fibromatosis, nonsurgical approaches (medical and observation) had similar 3-year EFS compared with surgery.[34 ] In a subsequent study of adolescents and adults with abdominal wall aggressive fibromatosis, 102 patients were treated with a watch and wait approach, of which 65 patients required no further treatment at 3 years. Approximately one-third of patients had regression of the tumor.[33 ]
Chemotherapy regimens may include the following:
- Combination chemotherapy using vinblastine and methotrexate produced objective responses in about one-third of patients with unresectable or recurrent desmoid-type fibromatosis.[40 ]
- 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 (an NSAID) can be safely administered and can induce responses.[42 ]
- Pegylated liposomal doxorubicin has been used with some responses.[43 ] In a series of five patients, a median progression-free interval of 29 months was reported.[44 ]
- Tyrosine kinase inhibitors: A small retrospective study of adults with desmoid-type fibromatosis showed objective responses to the multi-targeted kinase inhibitor sorafenib.[45 ][Level of evidence: 3iiiDiv] Previous studies with imatinib did not support its use.[46 ,47 ]
- The NOTCH pathway has been implicated in the development of desmoid tumors.[48 ] Partial responses to the gamma secretase inhibitor PF-03084014 have been noted in adults with desmoid-type fibromatosis.[49 ][Level of evidence: 3iiiDiv]
- Hydroxyurea has been used successfully to treat a few patients after other treatments, but more data are needed.[50 ,51 ,52 ]
Other drug therapy may include the following:
- NSAIDs such as sulindac have been used in single cases for desmoid-type fibromatosis; the responses seen were usually disease stabilization.[53 ]
- Antiestrogen treatment, usually tamoxifen, plus sulindac has also resulted in disease stabilization.[54 ] 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 progression-free survival (PFS).[55 ][Level of evidence: 2Diii]
Postoperative radiation therapy is a consideration when progression would entail additional surgery that might cause functional or cosmetic compromise and if radiation is considered acceptable in terms of morbidities.
Radiation has been used for unresectable desmoid-type fibromatosis or postoperatively for tumors with inadequate resections. The potential long-term complications of radiation therapy, especially subsequent neoplasms, make using this modality less appealing in a young population.[56 ]
Dermatofibrosarcoma protuberans
Dermatofibrosarcoma is a rare tumor that can be present in all age groups, but many of the reported cases arise in children.[57 ,58 ,59 ] 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).[60 ][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 PDGF-beta gene.
Treatment
Treatment of dermatofibrosarcoma protuberans includes the following:
- Surgery.
- Surgery preceded or followed by radiation therapy.
- 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 or modified Mohs surgery will prevent most tumors from recurring.[61 ] 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.[62 ,63 ]
When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective.[64 ,65 ,66 ] 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.[58 ,60 ]
Guidelines for workup and management of dermatofibrosarcoma protuberans have been published.[67 ]
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-type fibrosarcoma is addressed below.
Infantile fibrosarcoma usually occurs in children younger than 1 year. It occasionally occurs in children up to age 4 years.
Clinical presentation
Infantile fibrosarcoma usually presents with a rapidly growing mass, often noted at birth or even seen in prenatal ultrasound. The tumors are often quite large at the time of presentation.[68 ]
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.
Prognosis
These tumors have a low incidence of metastases at diagnosis.
Treatment
Treatment options for infantile fibrosarcoma include the following:
- Surgery followed by observation.
- Surgery followed by chemotherapy.
- Chemotherapy followed by surgery.
Complete resection is curative in the majority of patients with infantile fibrosarcoma. However, the large size of the lesion frequently makes resection without major functional consequences impossible (for instance, tumors of the extremities often require amputation for complete excision). The European pediatric group has reported that observation may also be an option in patients with group II disease after surgery.[69 ] 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.[70 ][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.[71 ,72 ]; [70 ,73 ][Level of evidence: 3iiA]; [74 ][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.[69 ,70 ,75 ] Two cases with variant LMNA/NTRK1 fusions responded to crizotinib.[76 ,77 ]
A pediatric patient (aged 16 months) with refractory infantile fibrosarcoma with constitutive activation of the tropomyosin-related kinase signaling pathway from an ETS variant gene 6-neurotrophin 3 receptor gene fusion (ETV6-NTRK3) responded to LOXO-101, with a 90% reduction in tumor size after 2 months of treatment.[78 ]
A patient aged 2 months with infantile fibrosarcoma was initially treated with chemotherapy. At disease progression, a response was seen with pazopanib.[79 ]
A rare case of spontaneous regression without treatment has been reported.[80 ][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:
-
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): This is a four-part, open-label, phase I/Ib, dose-escalation study in pediatric patients with: 1) relapsed or refractory solid tumors; 2) primary CNS tumors; 3) neuroblastoma; and 4) non-neuroblastoma, extracranial solid tumors with NTRK1/2/3, ROS1 or ALK gene rearrangements. The study is designed to explore the safety, maximum tolerated dose or recommended phase II dose, pharmacokinetics, and antitumor activity of entrectinib (RXDX-101).
Inflammatory myofibroblastic tumor
Inflammatory myofibroblastic tumor is a rare mesenchymal tumor that has a predilection for children and adolescents.[81 ,82 ,83 ]
Clinical presentation
Inflammatory myofibroblastic tumors are rare tumors that affect soft tissues and visceral organs of children and young adults.[84 ] They rarely metastasize but tend to be locally invasive. Usual anatomical sites of disease include soft tissue, lungs, spleen, colon, and breast.[81 ] A review of 42 cases of pediatric inflammatory myofibroblastic tumor of the bladder was published in 2015.[85 ]
Molecular features
Roughly half of inflammatory myofibroblastic tumors exhibit a clonal mutation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase gene at chromosome 2p23.[86 ]ROS1 and PDGFR-beta kinase fusions have been identified in 8 of 11 cases (73%) who are negative for ALK by immunohistochemistry.[87 ][Level of evidence: 3iiiDiv]
Prognosis
Inflammatory myofibroblastic tumor recurs frequently but is rarely metastatic.[81 ,82 ,83 ]
Treatment
Treatment options for inflammatory myofibroblastic tumor include the following:
- Surgery.
- Chemotherapy.
- Steroid therapy.
- NSAID therapy.
- Targeted therapy (ALK inhibitors).
Complete surgical removal, when feasible, is the mainstay of therapy.[88 ] 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.[89 ][Level of evidence: 3iiA] The benefit of chemotherapy has been noted in case reports.[90 ] There are case reports of response to either steroids or NSAIDs.[91 ,92 ] 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. With complete excision, with or without other treatments such as steroids, there was a high survival rate for patients with this disease.[93 ][Level of evidence: 3iiA]
Inflammatory myofibroblastic tumors respond to crizotinib. Two adults with ALK-rearranged inflammatory myofibroblastic tumor achieved partial response with crizotinib.[94 ][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.[95 ] 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.[96 ] In a phase I trial of ceritinib for adult patients previously treated with ALK inhibitors, one patient with inflammatory myofibroblastic tumor had a partial response.[97 ] Finally, one study included 14 patients with inflammatory myofibroblastic tumor 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.[98 ][Level of evidence: 3iiDiv]
Adult-type fibrosarcoma
These tumors lack the translocation seen in infantile fibrosarcomas. They present like the great majority of nonrhabdomyosarcomas and the management approach is similar.
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.[99 ,100 ]
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) and 15 developed metastases up to 45 years (median, 5 years) from diagnosis, most commonly to the lungs and pleura, emphasizing the need for continued follow-up of these patients.[99 ] Even after metastases occur, the course may be indolent.[101 ]
In another report, 14 of 73 cases were younger than 18 years of age. In this series with a relatively short follow up (median of 24 months), only 8 of 54 patients with adequate follow up developed local (9%) or distant (6%) recurrence. This report suggests that the behavior of this tumor might be significantly better than previously reported.[102 ] 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.[103 ]
Treatment
Treatment options for low-grade fibromyxoid sarcoma include the following:
- Surgery.
The limited treatment information for low-grade fibromyxoid sarcoma suggest that surgery is the treatment of choice as the tumor is not very chemosensitive.[101 ] 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.[104 ]
Myxofibrosarcoma
Myxofibrosarcoma is a rare lesion, especially in childhood. It is typically treated with complete surgical resection.
Sclerosing epithelioid fibrosarcoma
Sclerosing epithelioid fibrosarcoma is a rare malignant sarcoma that commonly harbors EWSR1 gene rearrangements and has an aggressive clinical course.[105 ] It is typically treated with complete surgical excision. Long-term follow-up is recommended because local recurrence and metastases can occur late.
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:
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with infantile fibrosarcoma, inflammatory myofibroblastic tumor, low-grade myofibroblastic tumor, myxoinflammatory fibroblastic sarcoma, solitary fibrous tumor, adult-type fibrosarcoma, low-grade fibromyxoid sarcoma, myxofibrosarcoma, and sclerosing epithelioid fibrosarcoma are eligible for this trial.
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.[106 ] Survivors of hereditary retinoblastoma have a statistically significant increased risk of developing leiomyosarcoma and 78% of these were diagnosed 30 or more years after the initial diagnosis of retinoblastoma.[107 ]
Treatment
Treatment options for leiomyosarcoma include the following:
- Chemotherapy (trabectedin).
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%).[108 ] 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.[14 ] There are no data to support the use of trabectedin in pediatric patients.
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:
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with leiomyosarcoma are eligible for this trial.
So-called Fibrohistiocytic Tumors
So-called fibrohistiocytic tumors include the following tumor subtypes:
- Giant cell tumor of soft tissue.
- Plexiform fibrohistiocytic tumor.
Plexiform fibrohistiocytic tumor
Plexiform histiocytic tumor is a rare, low- to intermediate-grade tumor that most commonly affects children and young adults. Depending on the series, the median age at presentation ranges from 8 to 14.5 years; however, the tumor has been described in patients as young as 3 months.[109 ,110 ]
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.[111 ,112 ,113 ] There are rare reports of spread to regional lymph nodes or the lungs.[109 ,113 ,114 ]
Molecular features
No consistent chromosomal anomalies have been detected but a t(4;15)(q21;q15) translocation has been reported.[115 ]
Prognosis
Plexiform fibrohistiocytic tumor is an intermediate-grade tumor that rarely metastasizes.
Treatment
Surgery is the treatment of choice but local recurrence has been reported in 12% to 50% of cases.[116 ]
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:
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with giant cell tumors of soft tissue and plexiform fibrohistiocytic tumor are eligible for this trial.
Tumors of Peripheral Nerves
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. Elements similar to rhabdomyosarcoma have been identified.
The German Soft Tissue Sarcoma Group (Cooperative Weichteilsarkom Studiengruppe [CWS]) reported on six patients (ages 0.2-13.5 years) registered over 14 years.[117 ][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.[117 ]
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 type 1 neurofibromatosis (NF1).[118 ]
Molecular features
Inactivating mutations of SUZ12 have been described in these tumors and are absent in neurofibromas.[119 ]
Prognosis
Features associated with a favorable prognosis include the following:[118 ,120 ,121 ,122 ]
- Smaller tumor size. In a multivariate analysis, only tumor size and nuclear p53 expression were found to be independent predictors of disease-specific survival.[121 ]
- Male sex and non-Hispanic white race.[123 ]
- 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.[121 ]
- Lower stage.
- Lower histologic grade.
- Extremity as the primary site.
Features associated with an unfavorable prognosis include the following:[124 ]
- High grade.
- Deep tumor location.
- Locally advanced stage at diagnosis.
- Macroscopically incomplete resection (R2).
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.[121 ] 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 [120 ] and unfavorable outcomes.[118 ,120 ,122 ] In the French Sarcoma Group study, NF1 was associated with other adverse prognostic features, but was not an independent predictor of poor outcome.[124 ]
Treatment
Treatment options for malignant peripheral nerve sheath tumor include the following:
- Surgery.
- Surgery preceded or followed by radiation therapy.[8 ,9 ]
- 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.
Chemotherapy has achieved objective responses in childhood malignant peripheral nerve sheath tumor. A large retrospective analysis of the German and Italian experience with malignant peripheral nerve sheath tumor reported that 65% of measurable tumors had objective responses to ifosfamide-containing chemotherapy regimens, but the analysis did not conclusively demonstrate improved survival for chemotherapy.[118 ] This retrospective analysis also noted a trend toward improved outcome with postoperative radiation therapy.[118 ] 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%.[125 ]
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:
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with malignant peripheral nerve sheath tumor are eligible for this trial.
-
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 1 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.
-
ADVL1522 (NCT02452554) (Lorvotuzumab Mertansine in Treating Younger Patients with Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor, or Synovial Sarcoma): This is a phase II study of IMGN901 (lorvotuzumab mertansine) in children with relapsed or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor, and synovial sarcoma. This trial is studying the effects of IMGN901, an antibody-drug conjugate that links a potent antimitotic to antibodies that target CD56.
Malignant triton tumor
Malignant triton tumors are a variant of malignant peripheral nerve sheath tumors. They occur most often in patients with neurofibromatosis type I and consist of neurogenic and rhabdomyoblastic components. Malignant triton tumors are high-grade malignancies. They usually occur before age 35 years and are very rare in children (case reports only).[126 ]
Malignant triton tumors are not usually responsive to chemotherapy and radiation therapy but have been treated with rhabdomyosarcoma therapy.[126 ][Level of evidence: 3iiiA] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)
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:
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with malignant triton tumor are eligible for this trial.
Pericytic (Perivascular) Tumors
Myopericytoma
Infantile hemangiopericytoma is a subtype of myopericytoma.
Hemangiopericytoma is a highly vascularized tumor of uncertain origin.
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.[127 ]
Treatment and outcome
Treatment of infantile hemangiopericytomas includes the following:
- Chemotherapy.
In a series of 17 children, the differences in metastatic potential and response to treatment were clearly demonstrated for adult and infantile hemangiopericytomas.[128 ] Eleven children were older than 1 year. Several of these patients had disease in the lymph nodes or lungs. Six patients with stage II or III disease progressed and died. Three patients with stage I disease survived, although one had recurrence in the lungs. Six patients had infantile hemangiopericytoma, most were greater than stage I (5 of 6). All six patients survived and three had good responses to vincristine, actinomycin, and cyclophosphamide. Hemangiopericytoma in children younger than 1 year seems to have a better prognosis than in children older than 1 year.[129 ,130 ,131 ]
Infantile myofibromatosis
This entity is a fibrous tumor of infancy and childhood that most commonly presents in the first 2 years of life.[132 ] 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).[133 ,134 ,135 ,136 ]
An autosomal dominant form of the disease has been described and it is associated with germline mutations of the PDGFRB gene.[137 ]
Treatment
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.[135 ,136 ,138 ] 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).[135 ,136 ,139 ]
Tumors of Uncertain Differentiation
Tumors of uncertain differentiation include the following tumor subtypes:
- Alveolar soft part sarcoma.
- Clear cell sarcoma of soft tissue.
- Desmoplastic small round cell tumor.
- Epithelioid sarcoma.
- Extrarenal rhabdoid tumor.
- Extraskeletal myxoid chondrosarcoma.
- Neoplasms with perivascular epithelioid cell differentiation (PEComa NOS, malignant)
- Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor.
- Synovial sarcoma (NOS, spindle cell, and biphasic varieties).
Alveolar soft part sarcoma
Alveolar soft parts sarcomas account for 1.4% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
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.[140 ,141 ,142 ] Alveolar soft part sarcoma in children can present with evidence of metastatic disease.[143 ]
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.[144 ,145 ]
Prognosis
Alveolar soft part sarcoma in children may have an indolent course.[143 ] Patients with alveolar soft part sarcoma may relapse several years after a prolonged period of apparent remission.[146 ] Because these tumors are rare, all children with alveolar soft part sarcoma should be considered for enrollment in prospective clinical trials.
In a series of 19 treated patients, one group reported a 5-year OS rate of 80%, a 91% OS rate for patients with localized disease, a 100% OS rate for patients with tumors 5 cm or smaller, and a 31% OS rate for patients with tumors larger than 5 cm.[147 ] 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.[148 ][Level of evidence: 3iiA] Delayed metastases to the brain and lung are uncommon.[140 ]
Treatment
Treatment options for alveolar soft part sarcoma include the following:
- Surgery.
- Surgery preceded or followed by radiation therapy.[8 ,9 ]
- Targeted therapy.
The standard approach is complete resection of the primary lesion.[147 ] If complete excision is not feasible, radiation therapy should be 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.[142 ][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.[140 ][Level of evidence: 3iiiA] There have been sporadic reports of objective responses to interferon-alpha and bevacizumab.[140 ,149 ,150 ]
A small retrospective study of nine adult patients with metastatic alveolar soft part sarcoma treated with sunitinib reported partial response in five patients and stable disease in two patients.[151 ][Level of evidence: 3iiiDiv] In a phase II trial of cediranib, an inhibitor of all three known vascular epidermal growth factor receptors, 15 of 43 adult patients (35%) with metastatic alveolar soft part sarcoma had a partial response.[152 ][Level of evidence: 3iiDiv] There have been no open trials for patients with metastatic alveolar soft part sarcoma.
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 are examples of national and/or institutional clinical trials that are currently being conducted:
-
NCT00942877 (Phase II Study of Cediranib [AZD2171] in Patients With Alveolar Soft Part Sarcoma): A phase II study of cediranib in patients with alveolar soft part sarcoma is being conducted in patients younger than 16 years at the Clinical Center of the National Institutes of Health.
-
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.[153 ]
Clinical presentation
The tumor most commonly affects the lower extremity, particularly the foot, heel, and ankle.[154 ,155 ] It has a high propensity for nodal dissemination, especially metastases to regional lymph nodes (12%-43%).[155 ,156 ] The tumor typically has an indolent clinical course.
Molecular features
Clear cell sarcoma of soft tissue is characterized by an EWS-ATF1 fusion.[157 ]
Treatment
Treatment options for clear cell sarcoma of soft tissue include the following:
- Surgery.
- Surgery preceded or followed by radiation therapy.[8 ,9 ]
In a series of 28 pediatric patients reported by the Italian and German Soft Tissue Cooperative Studies, the median age at diagnosis was 14 years and the lower extremity was the most common primary site (50%). Surgery with or without radiotherapy is the treatment of choice and offers the best chance for cure. In this series, 12 of 13 patients with completely resected tumors were cured. For patients with more advanced disease the outcome is poor and chemotherapy is rarely effective.[158 ]; [159 ][Level of evidence: 3iiDii]
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 abdomen, pelvis, or tissues around the testes, but it may occur in the kidney.[160 ,161 ,162 ,163 ] The tumor occurs more commonly in males and may spread to the lungs and elsewhere. Peritoneal and pelvic lesions frequently have widespread peritoneal implants.[164 ]
In a large, single-institution series of 65 patients, a correlation was made between computed tomography (CT) scans in most patients and positron-emission tomography (PET)/CT scans in 11 patients. PET/CT scans had very few false-negative results and detected metastatic sites missed on conventional CT scans.[164 ]
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 EWS genes.[163 ,165 ] The WT1-EWS 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.[166 ,167 ]
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:
- Surgery.
- Chemotherapy followed by surgery.
- Radiation therapy.
Complete surgical resections are rare, and the overall prognosis for desmoplastic small round cell tumor remains extremely poor, with reported rates of death at 90%. Treatment may include chemotherapy, surgery, and radiation therapy. Multiagent chemotherapy analogous to that used for sarcomas has been used, as well as total abdominal radiation therapy.[160 ,161 ,166 ,168 ,169 ,170 ,171 ]
A single institution 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.[172 ]
The Center for International Blood and Marrow Transplant Research (CIBMTR) analyzed patients with desmoplastic small round cell tumor in their registry who received consolidation with high dose chemotherapy and autologous stem cell reconstitution.[173 ] While this retrospective registry analysis suggested some benefit for this approach, other investigators have abandoned the approach because of excessive toxicity and lack of efficacy.[166 ]
Epithelioid sarcoma
Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis which displays multilineage differentiation.[174 ]
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.[175 ] This abnormality leads to increased dependence on EZH2 and tumor formation.[176 ]
Treatment
Treatment options for epithelioid sarcoma include the following
- Chemotherapy.
- Surgery.
- Surgery preceded or followed by radiation therapy.
Patients should be carefully evaluated for the presence of involved lymph nodes; suspicious lymph nodes should be biopsied. Surgical removal of primary and recurrent tumor(s) is the most effective treatment.[177 ][Level of evidence: 3iiiA]
In a review of 30 pediatric patients with epithelioid sarcoma (median age at presentation, 12 years), responses to chemotherapy were reported in 40% of patients using sarcoma-based regimens, and 60% of patients were alive at 5 years after initial diagnosis.[178 ] A single-institution retrospective review of 20 patients, including children and adults (median age, 27.3 years), found no difference in the probability of recurrence between patients who received chemotherapy and those who did not receive chemotherapy and suggested that radiation therapy may be useful.[177 ]
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:
-
NCT01897571 (An Open-Label, Multicenter, Phase 1/2 Study of E7438 [EZH2 Histone Methyl Transferase (HMT) Inhibitor] as a Single Agent in Subjects With Advanced Solid Tumors or With B-cell Lymphomas): A phase I/II study using the histone methyl transferase inhibitor EPZ6438 is currently enrolling patients aged 18 years and older.
-
NCT02601937 (A Phase 1 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.
Extrarenal (extracranial) rhabdoid tumor
Malignant rhabdoid tumors were first described in children with renal tumors in 1981 (refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information) and were later found in a variety of extrarenal sites. These tumors are uncommon and highly malignant, especially in children younger than 2 years.
Extrarenal (extracranial) rhabdoid tumors account for 2% of soft tissue sarcoma in patients younger than 20 years (refer to Table 1).
Molecular features
The first sizeable series of 26 children with extrarenal extracranial malignant rhabdoid tumor of soft tissues came from patients enrolled on the Intergroup Rhabdomyosarcoma Studies I through III during a review of pathology material. Only five patients (19%) were alive without disease.[179 ] Later, investigation of children with atypical teratoid/rhabdoid tumors of the brain, as well as those with renal and extrarenal malignant rhabdoid tumors, found germline and acquired mutations of the SMARCB1 gene in all 29 tumors tested.[180 ] Rhabdoid tumors may be associated with germline mutations of the SMARCB1 gene and may be inherited from an apparently unaffected parent.[181 ] This observation was extended to 32 malignant rhabdoid tumors at all sites in patients whose mean age at diagnosis was 12 months.[182 ]
Prognosis
In a Surveillance, Epidemiology, and End Results (SEER) study of 229 patients with renal, central nervous system, and extrarenal malignant rhabdoid tumor, patients aged 2 to 18 years, limited extent of tumor, and delivery of radiation therapy were shown to affect the outcome favorably compared with other patients (P < .002 for each comparison). Site of the primary tumor was not prognostically significant. OS at 5 years was 33%.[183 ]
Treatment
Treatment includes surgical removal when possible, chemotherapy as used for soft tissue sarcomas (but no single regimen is currently accepted as best), and radiation therapy.[184 ][Level of evidence: 3iA]; [185 ,186 ][Level of evidence: 3iiiB]
Responses to alisertib have been documented in four patients with central nervous system (CNS) atypical teratoid/rhabdoid tumors.[187 ] (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 is an example of a national and/or institutional clinical trial that is currently being conducted:
-
NCT02601937 (A Phase 1 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 myxoid chondrosarcoma
Extraskeletal myxoid chondrosarcoma is relatively rare among soft tissue sarcomas, representing only 2.3% of all soft tissue sarcoma.[188 ] It has been reported in children and adolescents.[189 ]
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.[190 ]
Prognosis
The tumor has traditionally been considered of low-grade malignant potential.[191 ] However, recent reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are followed for a long time.[192 ,193 ] 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.[193 ]
Treatment
Treatment options for extraskeletal myxoid chondrosarcoma include the following:
- Surgery.
- Radiation therapy.
The therapeutic benefit of chemotherapy has not been established. Aggressive local control and resection of metastases led to OS of 87% at 5 years and 63% at 10 years. Tumors were relatively resistant to radiation therapy.[192 ]
There may be potential genetic targets for small molecules, but these should be studied as part of a clinical trial. In an adult study, six of ten patients who received sunitinib achieved a partial response.[194 ]
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 1 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.
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.[195 ] Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable PEComas with mTOR inhibitors.[196 ,197 ] A small proportion of PEComas have TFE3 rearrangements with fusions involving various genes including SFPQ/PSF and RAD51B.[198 ]
Clinical presentation
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.[199 ] The disease course may be indolent.
Prognosis
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.[200 ]
Treatment
Treatment options have not been defined. Treatment may include surgery or observation followed by surgery when the tumor is large.[201 ]
Clinical activity with mTOR inhibitors, such as sirolimus, in tumors with evidence of mTORC1 activation and TSC loss has been well documented.[202 ]
Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor
(Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)
Synovial sarcoma
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.[203 ]
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.[203 ] Rarely, a synovial sarcoma may arise in the heart or pericardium.[204 ]
The most common site of metastasis is the lung.[205 ,206 ] 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
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.[207 ,208 ] It is thought that the SYT/SSX18 transcript promotes epigenetic silencing of key tumor suppressor genes.[209 ]
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.[210 ]
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.[203 ,211 ] A meta-analysis also suggested that response to chemotherapy was correlated with improved survival.[212 ]
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.[213 ] 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.[214 ][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%.[212 ] 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 Clinical Group III disease (localized, incompletely resected or with biopsy only) and IV (metastases at diagnosis) had decreased OS. Treatment with radiation therapy was related to improved OS (hazard ratio, 0.4; 95% confidence interval, 0.2-0.7). In Intergroup Rhabdomyosarcoma Study 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.[215 ,216 ,217 ]
- 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.[218 ]
- 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).[219 ][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.[220 ][Level of evidence: 3iiA]
Survival after relapse is poor (30% at 5 years). Factors associated with outcome after relapse include duration of first remission (> or ≤ 18 months) and lack of a second remission.[221 ]
Treatment
Treatment options for synovial sarcoma include the following:
- Surgery. Radiation therapy and/or chemotherapy may be given before or after surgery.[8 ,9 ]
- 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.[222 ] 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 salvage 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 when compared with adults.[11 ,206 ,217 ,223 ,224 ,225 ,226 ,227 ] The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[212 ,226 ,228 ] Response rates to the ifosfamide and doxorubicin regimen are higher than in other nonrhabdomyosarcomatous soft tissue sarcomas.[229 ]
Several studies have reported the following chemotherapy-associated treatment findings:
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:
-
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.
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with alveolar soft part sarcoma, clear cell sarcoma of soft tissue, epithelioid sarcoma, extraskeletal myxoid chondrosarcoma, PEComa, and synovial sarcoma are eligible for this trial.
-
NCT02601937 (A Phase 1 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.
-
ADVL1522 (NCT02452554) (Lorvotuzumab Mertansine in Treating Younger Patients with Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor, or Synovial Sarcoma): This is a phase II study of IMGN901 (lorvotuzumab mertansine) in children with relapsed or refractory Wilms tumor, rhabdomyosarcoma, neuroblastoma, pleuropulmonary blastoma, malignant peripheral nerve sheath tumor, and synovial sarcoma. This trial is studying the effects of IMGN901, an antibody-drug conjugate that links a potent antimitotic to antibodies that target CD56.
Undifferentiated/unclassified sarcoma
Patients with undifferentiated soft tissue sarcoma had been eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the COG from 1972 to 2006. The rationale was the observation that patients with undifferentiated soft tissue sarcoma had similar sites of disease and outcome as those with alveolar rhabdomyosarcoma. Therapeutic trials for adults with soft tissue sarcoma include patients with undifferentiated soft tissue sarcoma and other histologies, which are treated similarly, using ifosfamide and doxorubicin, and sometimes with other chemotherapy agents, surgery, and radiation therapy.
In the COG ARST0332 (NCT00346164) trial, patients with high-grade undifferentiated sarcoma were treated with an ifosfamide and doxorubicin-based regimen and were treated with rhabdomyosarcoma-directed therapies in previous Intergroup Rhabdomyosarcoma Study Group studies with a 5-year survival estimate for nonmetastatic patients of 72%.[235 ][Level of evidence: 3iiA] Currently, these patients are eligible for the COG open ARST1321 (NCT02180867) trial for patients with nonrhabdomyosarcomatous soft tissue sarcoma.
Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high-grade)
At one time, malignant fibrous histiocytoma was the single most common histiotype among adults with soft tissue sarcomas. Since it was first recognized in the early 1960s, malignant fibrous histiocytoma has been plagued by controversy in terms of both its histogenesis and its validity as a clinicopathologic entity. The latest WHO classification no longer includes malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[236 ]
This entity accounts for 2% to 6% of all childhood soft tissue sarcomas.[237 ] These tumors can arise in previously irradiated sites or as a second malignancy in patients with retinoblastoma.
These tumors occur mainly in the second decade of life. In a series of ten patients, the median age was 10 years and the tumor was most commonly located in the extremities. In this series, all tumors were localized and five of nine (for whom follow-up was available) were alive and in first remission.[237 ] 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.[238 ] 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.)
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:
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable, intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with undifferentiated epithelial sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, and undifferentiated spindle cell sarcoma are eligible for this trial.
Vascular Tumors
Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant.[239 ] Vascular tumors include the following tumor subtypes:
- Angiosarcoma of the soft tissue.
- Epithelioid hemangioendothelioma.
Angiosarcoma of the soft tissue
Incidence
Angiosarcoma is a rare (accounting for 2% of sarcomas), aggressive, vascular tumor that can arise in any part of the body, but is more common in the soft tissue. Angiosarcoma has an estimated incidence of 2 cases per 1 million; in the United States, it annually affects approximately 600 people who are typically aged 60 to 70 years.[240 ]
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.[241 ,242 ,243 ,244 ] Most angiosarcomas involve the skin and superficial soft tissue, although the liver, spleen, and lung can be affected; bone is rarely affected.
Risk factors
Established risk factors include vinyl chloride exposure, radiation exposure, and chronic lymphedema from any cause, including Stewart-Treves syndrome.[245 ]
Pathology and biology
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%.[245 ]
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).[242 ]
Treatment of angiosarcoma of the soft tissue
Treatment options for angiosarcoma of the soft tissue include the following:
- Surgery (localized disease).
- Radiation therapy (localized cutaneous disease in adults).
- Surgery, chemotherapy, and radiation therapy (metastatic disease).
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.[243 ,246 ,247 ,248 ] 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.[248 ] Data on liver transplantation for localized angiosarcoma are limited.[249 ][Level of evidence: 3iiA]
Localized disease, especially cutaneous angiosarcoma, can be treated with radiation therapy. Most of these reported cases are in adults.[250 ]
Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative.[251 ] Disease control is the objective in metastatic angiosarcoma, with published progression-free survival rates between 3 months and 7 months [252 ] and a median overall survival (OS) rate of 14 months to 18 months.[253 ] In both adults and children, 5-year OS rates between 20% and 35% are reported.[243 ,244 ,254 ]
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.[241 ,251 ] 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.[255 ]
Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcoma.[242 ,254 ]
Treatment options under clinical evaluation for angiosarcoma of the soft tissue
Information about National Cancer Institute (NCI)-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
-
ARST1321 (NCT02180867) (Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery [PAZNTIS]): This study will first determine the feasibility of adding a tyrosine kinase inhibitor in combination with radiation therapy or chemotherapy (ifosfamide/etoposide) and radiation therapy in pediatric and adult patients newly diagnosed with unresected intermediate-risk and high-risk nonrhabdomyosarcomatous soft tissue sarcoma. Subsequently, this trial will compare the rates of near-complete pathologic response (>90% necrosis) of: 1) preoperative pazopanib plus chemoradiation therapy versus preoperative chemoradiation therapy alone for potentially resectable (>5 cm), grade 3 intermediate-risk to high-risk chemotherapy-sensitive adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma; and 2) pazopanib plus preoperative radiation therapy versus preoperative radiation therapy alone for potentially resectable intermediate-risk to high-risk adult and pediatric nonrhabdomyosarcomatous soft tissue sarcoma. Patients with angiosarcoma of the soft tissue are eligible for this trial.
-
NCT01532687 (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma): This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.
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.
Epithelioid hemangioendothelioma
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.[256 ,257 ,258 ,259 ,260 ,261 ,262 ]
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.[258 ]
Pathology and biology
A WWTR1-CAMTA1 gene fusion has been found in a large percentage of patients; less commonly, a YAP1-TFE3 gene fusion has been reported.[256 ] 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.[258 ]
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%).[258 ,263 ,264 ] Clinical presentation depends on site of involvement, as follows:
-
Liver: Hepatic nodules have central vascularity on ultrasound, contrast-enhancing lesions by computed tomography, and low T1 signal and moderate T2 signal on magnetic resonance imaging.
-
Lung: Pulmonary epithelioid hemangioendothelioma may be an asymptomatic finding on chest x-ray or be associated with pleuritic pain, hemoptysis, anemia, and fibrosis.
-
Bone: Bone metastasis may be associated with pathologic fracture. On x-rays, they are well-defined osteolytic lesions and can be multiple or solitary.
-
Soft tissue: Thirty percent of soft tissue cases are associated with metastases, and when present, can have a very aggressive course, with limited response to chemotherapy.
-
Skin: Cutaneous lesions can be raised and nodular or can be warm red-brown plaques.
Treatment of epithelioid hemangioendothelioma
Treatment options for epithelioid hemangioendothelioma include the following:
- Observation.
- Surgery.
- Immunotherapy.
- Targeted therapy.
- Chemotherapy.
For indolent cases, observation is warranted. For more aggressive cases, multiple medications have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus.[265 ] 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.[258 ,266 ,267 ,268 ,269 ]
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.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
-
NCT03148275 (Trametinib in Treating Patients with Epithelioid Hemangioendothelioma That Is Metastatic, Locally Advanced, or Cannot Be Removed by Surgery): This is a phase II trial assessing the efficacy of trametinib, with patient-reported outcomes as secondary aims.
-
NCT01532687 (Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma): This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.
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.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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