Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma
Extraskeletal chondrosarcoma (mesenchymal and other variants)
Inflammatory myofibroblastic tumor
Low-grade fibromyxoid sarcoma
Myxofibrosarcoma, low grade
Sclerosing epithelioid fibrosarcoma
Skeletal Muscle Tumors
Smooth Muscle Tumors
So-called Fibrohistiocytic Tumors
Plexiform fibrohistiocytic tumor
Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high-grade)
Tumors of Peripheral Nerves
Malignant peripheral nerve sheath tumor
Tumors of Uncertain Differentiation
Alveolar soft part sarcoma
Clear cell sarcoma of soft tissue
Desmoplastic small round cell tumor
Extrarenal (extracranial) rhabdoid tumor
Extraskeletal myxoid chondrosarcoma
Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor
Undifferentiated sarcoma; sarcoma, NOS
Current Clinical Trials
Liposarcoma is rare in the pediatric population. In a review of 182 pediatric patients with adult-type sarcomas, only 14 had a diagnosis of liposarcoma. One retrospective study identified 34 patients younger than 22 years from 1960 to 2011. There were roughly equal numbers of male and female patients and the median age was 18 years. In an international clinicopathological review, the characteristics of 82 cases of pediatric liposarcoma were reported. The median age was 15.5 years and females were more commonly affected. In both reports, the great majority of patients had myxoid liposarcoma.
Liposarcomas can be roughly divided into the following four large groups:
- Atypical lipomatous neoplasm/well-differentiated liposarcoma. These tumors do not metastasize unless they undergo dedifferentiation.
- 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.
- Dedifferentiated liposarcoma.
- Pleomorphic liposarcoma.
The great majority of liposarcomas in the pediatric and adolescent age range are low grade. Myxoid liposarcoma is typically low grade. Pleomorphic liposarcoma is typically high grade and much more likely to develop metastasis. 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.Treatment
Surgery is the most important treatment for liposarcoma. After surgical resection of myxoid liposarcoma, event-free survival (EFS) and overall survival (OS) are roughly 90%. Local recurrences have been seen and are controlled with a second resection of the tumor. Higher grade or central tumors are associated with a significantly higher risk of death. In a retrospective review, 5-year survival for central tumors was 42%. In the international review, seven of ten patients with pleomorphic myxoid liposarcoma died because of their disease. If initial surgery is incomplete, re-excision should be performed to achieve a wide margin of resection. There are reports of the use of chemotherapy to decrease the size of liposarcoma before surgery to facilitate complete resection, particularly in central tumors.[4,5] The role of adjuvant chemotherapy for liposarcoma is poorly defined. There does not appear to be a need for any adjuvant therapy for completely resected myxoid liposarcoma. Even with the use of adjuvant chemotherapy, the survival of pleomorphic liposarcoma remains poor.Chondro-osseous Tumors
Chondro-osseous tumors include the following tumor subtypes:
- Extraskeletal chondrosarcoma (mesenchymal and other variants).
- Extraskeletal osteosarcoma.
Mesenchymal chondrosarcoma is a highly malignant tumor with a propensity to spread to the lungs.Treatment
A review of 15 patients younger than 26 years from the German Cooperative Soft Tissue Sarcoma Study Group (11 with soft-tissue lesions) and the German-Austrian-Swiss Cooperative Osteosarcoma Study Group (four with primary bone lesions) protocols suggests that complete surgical removal, or incomplete resection followed by radiation therapy, is necessary for local control.[Level of evidence: 3iiA]
Multiagent chemotherapy may decrease the likelihood of lung metastases: OS at 10 years was 67%, compared with approximately 20% in an earlier series of young patients.Extraskeletal osteosarcoma
Extraskeletal osteosarcoma is extremely rare in the pediatric and adolescent age range. A 2003 review identified only ten case reports in the medical literature.
Extraskeletal osteosarcoma is associated with a high risk of local recurrence and pulmonary metastasis.Treatment
The primary therapy for extraskeletal osteosarcoma is surgical resection of the primary tumor. Chemotherapy for extraskeletal osteosarcoma has not been well studied. It has been recommended that the treatment for extraskeletal osteosarcoma abide by the soft tissue sarcoma (STS) guidelines, rather than the guidelines for osteosarcoma of bone. A report of a series of adult patients with extraskeletal osteosarcoma suggested that adjuvant chemotherapy reduced the risk of recurrence. Extraskeletal osteosarcoma may be more chemosensitive in young patients than in adults. A retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraskeletal osteosarcoma treated with surgery and conventional osteosarcoma chemotherapy. (Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment for more information.)Fibroblastic/Myofibroblastic Tumors
Fibroblastic/myofibroblastic tumors include the following tumor subtypes:
- Desmoid tumor.a
- Infant fibrosarcoma.
- Adult-type fibrosarcoma.
- Inflammatory myofibroblastic tumor.a
- Low-grade fibromyxoid sarcoma.
- Sclerosing epithelioid fibrosarcoma.
[Note: aNot a high-grade tumor.]Desmoid tumors
Desmoid tumors are also known as aggressive fibromatoses.
Desmoid tumors are low-grade malignancies with 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 also have a high potential for local recurrence. Desmoid tumors have a highly variable natural history, including well documented examples of spontaneous regression. Mutations in exon 3 of the beta-catenin gene are seen in over 80% of desmoid tumors and the mutation 45F has been associated with an increased risk of disease recurrence. Repeated surgical resection can sometimes bring recurrent lesions under control.
A small number of desmoid 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%) were found to have familial adenomatous polyposis (FAP) (a possible underestimation). The patients with FAP and desmoid tumors were younger, more often male, and had more abdominal wall or mesenteric tumors than did patients with desmoid tumors without FAP. A family history of colon cancer or the presence of congenital hyperplasia of the retinal pigment epithelium [16,17] or location of the desmoid tumor in the abdomen or abdominal wall  should prompt referral to a genetic counselor. Currently, there are no general recommendations for genetic testing in children with desmoid tumors. 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.[18,19]Treatment
The treatment of choice is resection to achieve clear margins. However, a retrospective review of children who underwent surgery for desmoid tumors at the St. Jude Children’s Research Hospital reported no correlation between surgical margins and risk of recurrence. 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. 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:[21,22]
- Antiestrogen therapy.
- Nonsteroidal anti-inflammatory agent therapy.
- External-beam radiation therapy.
Evaluation of the benefit of interventions for treatment of desmoid tumors has been extremely difficult, because desmoid tumors have 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.[14,23]; [Level of evidence: 3iiiDi] Combination chemotherapy using vinblastine and methotrexate produced objective responses in about one-third of patients with recurrent or unresectable desmoid tumors. A small series of mainly adult patients (N = 19) with desmoid tumors were treated with imatinib mesylate and showed infrequent objective responses. A series of mainly adult patients with familial adenomatous polyposis and unresectable desmoid tumors that were unresponsive to hormone therapy showed that doxorubicin plus dacarbazine followed by meloxicam (a nonsteroidal anti-inflammatory agent) can be safely administered and can induce responses. Pegylated liposomal doxorubicin has also been used with some responses. Hydroxyurea may be useful, but more data are needed.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac have been used in single cases for desmoid tumors; the responses seen were usually disease stabilization. Similar results have been seen with antiestrogen treatment, usually tamoxifen. 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.[Level of evidence: 2Diii]
Radiation has been used for unresectable desmoid tumors or adjuvantly for tumors with inadequate resections. The potential long-term complications of radiation therapy, especially subsequent neoplasms, make using this modality less appealing in a young population.
Partially excised or recurrent lesions that do not pose a significant danger to vital organs may be monitored closely if other treatment alternatives are not available.[14,20,32-35] Whenever possible, however, the treatment of choice is complete resection.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.Infantile fibrosarcoma
Infantile fibrosarcoma usually occurs in children younger than 1 year. It occasionally occurs in children up to age 4 years. It usually presents with a rapidly growing mass, often noted at birth or even seen in prenatal ultrasound. The tumors are often quite large at the time of presentation. The tumor usually has a characteristic cytogenetic translocation t(12;15)(ETV-NTRK3). Infantile fibrosarcoma shares this translocation and a virtually identical histologic appearance with mesoblastic nephroma. These tumors have a low incidence of metastases at diagnosis.Treatment
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). Preoperative chemotherapy has made a more conservative surgical approach possible; agents active in this setting include vincristine, dactinomycin, cyclophosphamide, and ifosfamide.[37-39]; [Level of evidence: 3iiA]; [Level of evidence: 3iiB]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.Dermatofibrosarcoma protuberans
Dermatofibrosarcoma is a rare tumor, but many of the reported cases arise in children. The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGF-beta gene.Treatment
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.
Guidelines for workup and management of dermatofibrosarcoma protuberans have been published.Inflammatory myofibroblastic tumor
Inflammatory myofibroblastic tumor is an incompletely characterized neoplasm of intermediate biologic potential. It recurs frequently but metastasizes rarely.[50-52] Roughly half of inflammatory myofibroblastic tumors exhibit a clonal mutation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase gene at chromosome 2p23.
Complete surgical removal, when feasible, is the mainstay of therapy. In a series of nine patients, four patients who had a complete resection achieved continuous remission, three patients who had residual disease had a high recurrence rate and achieved continuous remission, and one patient who had metastatic disease responded to multiagent chemotherapy.[Level of evidence: 3iiA] There are case reports of response to either steroids or NSAIDs.[56,57]Low-grade fibromyxoid sarcoma
Low-grade fibromyxoid sarcoma is somewhat misnamed, because its appearance is deceptively benign, but its behavior is malignant, although rather indolent. In a review, 21 of 33 patients had local recurrences after intervals of up to 15 years (median, 3.5 years) and 15 had metastases, mostly in the lungs and pleura, after periods of up to 45 years (median, 5 years), indicating that follow-up must be lifelong. Even after metastases occur, the course may be indolent.
The limited treatment information for low-grade fibromyxoid sarcoma is summarized in the review above. This tumor is not very chemosensitive and there are little data regarding the use of chemotherapy and/or radiation therapy.Myxofibrosarcoma, low grade
Myxofibrosarcoma, low grade, is a rare lesion, especially in childhood. It is typically treated with complete surgical resection.Sclerosing epithelioid fibrosarcoma
Sclerosing epithelioid fibrosarcoma is another rare, usually low-grade, sarcoma. It is typically treated with complete surgical excision.Skeletal Muscle Tumors
There are three forms of rhabdomyosarcoma:
- Embryonal, plus subtypes of botryoid and spindle cells.
- Pleomorphic, also known as anaplastic sarcoma.
Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.Smooth Muscle Tumors
A 24-year retrospective analysis of the Italian cooperative group identified one child with leiomyosarcoma. A retrospective analysis of the St. Jude Children’s Research Hospital (SJCRH) experience from 1962 to 1996 identified 40 children with nonrhabdomyosarcomatous STS; none had leiomyosarcoma. Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma. Survivors of hereditary retinoblastoma have a statistically significant increased risk of developing leiomyosarcoma and 78% of these were diagnosed 30 or more years after the initial diagnosis of retinoblastoma.So-called Fibrohistiocytic Tumors
So-called fibrohistiocytic tumors include the following tumor subtypes:
- Plexiform fibrohistiocytic tumor.
- Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma.
- Giant cell.
- Myxoid/high-grade myxofibrosarcoma.
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.[63,64]
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.[65-67] There are rare reports of spread to regional lymph nodes or the lungs.[63,67,68]
No consistent chromosomal anomalies have been detected but a t(4;15)(q21;q15) has been reported.Treatment
Surgery is the treatment of choice but local recurrence has been reported in 12% to 50% of cases.Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high-grade)
At one time, malignant fibrous histiocytoma was the single most common histiotype among adults with STSs. 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 World Health Organization classification no longer includes malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.
This entity accounts for 2% to 6% of all childhood STSs. 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 in first remission. In another series of 17 pediatric patients with malignant fibrous histiocytoma, the median age at diagnosis was 5 years and the extremities were involved in eight cases. All patients with metastatic disease died and two patients experienced a clinical response to a doxorubicin-based regimen.Tumors of Peripheral Nerves
Malignant peripheral nerve sheath tumor
Malignant peripheral nerve sheath tumor arises in children with type 1 neurofibromatosis (NF1), and it arises sporadically.
- Smaller tumor size—In a multivariate analysis, only tumor size and nuclear p53 expression were found to be independent predictors of disease-specific survival.
- Localized disease; 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. For patients with localized disease, there was no significant difference in outcome between patients with and without NF1.
- Lower stage.
- Lower histologic grade.
- Extremity as the primary site.
There is agreement that complete surgical removal of the tumor, whenever possible, is the mainstay of treatment. The role of radiation therapy is difficult to assess, but durable local control of known postsurgical microscopic residual tumor is not assured after radiation therapy. Chemotherapy has achieved objective responses in childhood malignant peripheral nerve sheath tumor. A large retrospective analysis of the German and Italian experience with malignant peripheral nerve sheath tumor reported that 65% of measurable tumors had objective responses to ifosfamide-containing chemotherapy regimens, but the analysis did not conclusively demonstrate improved survival for chemotherapy. This retrospective analysis also noted a trend toward improved outcome with adjuvant radiation therapy. A series of 37 young patients with malignant peripheral nerve sheath tumor and NF1 showed that most patients had large invasive tumors that were poorly responsive to chemotherapy; progression-free survival was 19% and 5-year OS was 28%. The role of adjuvant chemotherapy after resection of malignant peripheral nerve sheath tumor has not been prospectively evaluated.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.
- Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor.
- Synovial sarcoma.
- Undifferentiated sarcoma; sarcoma, not otherwise specified (NOS).
This is a tumor of uncertain histogenesis. A consistent chromosomal translocation t(X;17)(p11.2;q25) juxtaposes the ASPSCR1 gene with the TFE3 gene.[79,80] In children, alveolar soft part sarcoma often presents with metastases  and sometimes has a very indolent course. A subset of renal tumors found in young people was previously considered to be renal cell carcinoma, but the subset now appears to be genetically related to alveolar soft part sarcoma.
In a series of 19 treated patients, one group reported a 5-year OS rate of 80%, a 91% OS rate for patients with localized disease, a 100% OS rate for patients with tumors 5 cm or smaller, and a 31% OS rate for patients with tumors larger than 5 cm. In another series of 33 patients, OS was 68% at 5 years from diagnosis and 53% at 10 years from diagnosis. Survival was better for smaller tumors (≤5 cm) and completely resected tumors.[Level of evidence: 3iiA]Treatment
The standard approach is complete resection of the primary lesion. If complete excision is not feasible, radiation therapy should be administered.
A series of 51 pediatric patients aged 0 to 21 years with alveolar soft part sarcoma found an OS rate at 10 years of 78% and an EFS rate of about 63%. Patients with localized disease (n = 37) had a 10-year OS of 87%, and the 14 patients with metastases at diagnosis had a 10-year OS of 44%, partly resulting from surgical removal of primary tumor and lung metastases in some patients. Only 3 of 18 patients (17%) with measurable disease had a response to conventional antisarcoma chemotherapy, but two of four patients treated with sunitinib had a partial response.[Level of evidence: 3iiiA] There have been sporadic reports of objective responses to interferon-alpha and bevacizumab.[85-87] In a phase II trial of cediranib, an inhibitor of all three known vascular epidermal growth factor receptors, 15 of 43 patients (35%) with metastatic alveolar soft part sarcoma had a partial response.[Level of evidence: 3iiDiv]
Patients with alveolar soft part sarcoma may relapse several years after a prolonged period of apparent remission. Because these tumors are rare, all children with alveolar soft part sarcoma should be considered for prospective clinical trials.Treatment options under clinical evaluation for alveolar soft part sarcoma
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- NCT00942877 (Phase II Study of Cediranib in Patients With Alveolar Soft Part Sarcoma): This phase II study of cediranib in patients with alveolar soft part sarcoma is being conducted at the Clinical Center of the National Institutes of Health. Patients aged 18 years and older are eligible to participate.
- 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 (formerly and inappropriately called malignant melanoma of soft parts), also called clear cell sarcoma of tendons and aponeuroses, is somewhat similar to cutaneous malignant melanoma but is cytogenetically distinct; most cases have a t(12;22)(q13;q12) translocation that has not been reported in melanoma. In one series, clear cell sarcoma demonstrated a propensity to metastasize to regional lymph nodes (12%–43%).
Patients who have small, localized tumors with low mitotic rate and intermediate histologic grade fare best.
The primary treatment for clear cell sarcoma is complete surgical resection, with the addition of radiation therapy for uncertain or involved margins. Chemotherapy is rarely effective.; [Level of evidence: 3iiDii]Desmoplastic small round cell tumor
Desmoplastic small round cell tumor is a primitive sarcoma that most frequently involves the abdomen, pelvis, or tissues around the testes.[95-97] The tumor occurs more commonly in males and may spread to the lungs and elsewhere. Peritoneal and pelvic lesions frequently have widespread peritoneal implants. In a large, single-institution series of 65 patients, a correlation was made between computed tomography (CT) scans in most patients and positron-emission tomography (PET)/CT scans in 11 patients. PET/CT scans had very few false-negative results and detected metastatic sites missed on conventional CT scans.
Cytogenetic studies of these tumors have demonstrated the recurrent translocation t(11;22)(p13;q12), which has been characterized as a fusion of the WT1 and EWS genes.Treatment
There is no standard approach to the treatment of desmoplastic small round cell tumor. 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%. A small series of patients who were treated with hyperthermic intraperitoneal chemotherapy with acceptable toxicity has been reported.
Greater than 90% tumor resection either at presentation or after neoadjuvant chemotherapy may be a favorable prognostic factor for OS.[101,102] 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.[95,96,101,103,104]Epithelioid sarcoma
Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis which displays multilineage differentiation. It is characterized by inactivation of the SMARC gene, which is present in both conventional and proximal types of epithelioid sarcoma.
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.
In a review of 30 pediatric patients with epithelioid sarcoma (median age at presentation, 12 years), responses to chemotherapy were reported in 40% of patients using sarcoma-based regimens, and 60% of patients were alive at 5 years after initial diagnosis. A single-institution retrospective review of 20 patients, including children and adults, 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. Surgical removal of primary and recurrent tumor(s) was most effective.[Level of evidence: 3iiiA]Perivascular epithelioid cell tumors (PEComas)
PEComas (tumors showing perivascular epithelioid cell differentiation) include the following:
- Clear cell "sugar" tumor.
Benign PEComas are common in tuberous sclerosis, an autosomal dominant syndrome that also predisposes to renal cell cancer and brain tumors. Tuberous sclerosis is caused by germline inactivation of either TSC1 (9q34) or TSC2 (16p13.3), and the same tumor suppressor genes are inactivated somatically in sporadic PEComas. Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable PEComas with mTOR inhibitors.[110,111]
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. 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.Extrarenal (extracranial) rhabdoid tumor
Malignant rhabdoid tumors were first described in children with renal tumors in 1981 (refer to the Wilms Tumor and Other Childhood Kidney Tumors Treatment summary for more information) and were later found in a variety of extrarenal sites. They are uncommon and highly malignant, especially in children younger than 2 years. The first sizeable series of 26 childhood patients with extrarenal extracranial malignant rhabdoid tumor of soft tissues came from patients enrolled on the Intergroup Rhabdomyosarcoma Studies I through III during a review of pathology material. Only five patients (19%) were alive without disease. Later, investigation of children with atypical teratoid/rhabdoid tumors of the brain, as well as those with renal and extrarenal malignant rhabdoid tumors, found germline and acquired mutations of the SMARCB1 gene in all 29 tumors tested. Rhabdoid tumors may be associated with germline mutations of the SMARCB1 gene and may be inherited from an apparently unaffected parent. This observation was extended to 32 malignant rhabdoid tumors at all sites in patients whose mean age at diagnosis was 12 months. The disease can occur congenitally  and is uncommon in older children and adults.
In a Surveillance, Epidemiology, and End Results (SEER) study of 229 patients with renal, central nervous system, and extrarenal malignant rhabdoid tumor, patients aged 2 to 18 years, limited extent of tumor, and delivery of radiation therapy were shown to affect the outcome favorably compared with other patients (P < .002 for each comparison). Site of the primary tumor was not prognostically significant. OS at 5 years was 33%.
Treatment includes surgical removal when possible, chemotherapy as used for STSs (but no single regimen is currently accepted as best), and radiation therapy.[Level of evidence: 3iA]; [121,122][Level of evidence: 3iiiB]Extraskeletal myxoid chondrosarcoma
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 (see Table 2), with the most frequent being the translocation t(9;22)(q22;q12), involving the EWSR1/NR4A3 genes. The tumor has traditionally been considered of low-grade malignant potential. However, recent reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are followed for a long time.[127,128] Patients tend to have slow protracted courses. Nodal involvement has been well described. Local recurrence (57%) and metastatic spread to lungs (26%) have been reported.Treatment
The therapeutic benefit of chemotherapy has not been established. Aggressive local control and aggressive resection of metastases led to OS of 87% at 5 years and 63% at 10 years. There may be potential genetic targets for small molecules, but these should be studied as part of a clinical trial.Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor
(Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)Synovial sarcoma
Synovial sarcoma is one of the most common nonrhabdomyosarcomatous STSs in children and adolescents. In a SEER review from 1973 to 2005, 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. The most common location is the extremities, followed by trunk and head and neck. Patients younger than 10 years have more favorable outcomes and clinical features, including extremity primaries, smaller tumors, and localized disease, than do older patients.
Synovial sarcoma can be subclassified as the following types:
- Monophasic fibrous type.
- Biphasic type with distinct epithelial and spindle cell components.
- Poorly differentiated. Poorly differentiated synovial sarcoma has features of monophasic or biphasic synovial sarcoma but also has a variable proportion of poorly differentiated areas characterized by high cellularity, pleomorphism, and polygonal or small round-cell morphology, numerous mitoses, and often necrosis.
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.[131,132] It is thought that the SYT/SSX18 transcript promotes epigenetic silencing of key tumor suppressor genes. Reduced INI1 nuclear reactivity on immunohistochemical staining is typical of most synovial sarcomas examined and does not occur with other similar histologies, thus providing a fast diagnosis while awaiting genetic studies.
The most common site of metastasis is the lung.[135,136] The risk of metastases is highly influenced by tumor size; it is estimated that patients with tumors that measure greater than 5 cm have a 32-fold risk of developing metastases when compared with other patients.
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. 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.[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%. 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 and IV disease 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.[139-141] Expression and genomic index prognostic signatures have been studied in synovial sarcoma. More 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 for metastasis.Treatment
Synovial sarcoma appears to be more sensitive to chemotherapy than many other STSs, and children with synovial sarcoma seem to have a better prognosis when compared with adults.[5,136,141,143-148] The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[146,149,150] Response rates to the ifosfamide and doxorubicin regimen are higher than in other nonrhabdomyosarcomatous STSs. A meta-analysis also suggested that response to chemotherapy was correlated with improved survival.
Several treatment centers advocate adjuvant chemotherapy after resection and radiation therapy of synovial sarcoma in children and young adults.[137,147,150,152-154] The International Society of Pediatric Oncology-Malignant Mesenchymal Tumors studies showed that select patients (young age, < 5 cm resected tumors) with nonmetastatic synovial sarcoma can have excellent outcome in the absence of radiation, but it is still unclear whether that approach obviates an advantage of radiation for local or regional control. A German trial suggested a benefit for adjuvant chemotherapy in children with synovial sarcoma. A meta-analysis also suggested that chemotherapy may provide benefit. However, unequivocal proof of the value of adjuvant chemotherapy from prospective, randomized clinical trials is lacking and the results of COG-ARST0332 are pending. 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.Undifferentiated sarcoma; sarcoma, NOS
Patients with undifferentiated STS had been eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the Children’s Oncology Group (COG) from 1972 to 2006. The rationale was the observation that patients with undifferentiated STS had similar sites of disease and outcome as those with alveolar rhabdomyosarcoma. Therapeutic trials for adults with STS include patients with undifferentiated STS and other histologies, which are treated similarly, using ifosfamide and doxorubicin, and sometimes with other chemotherapy agents, surgery, and radiation therapy. Currently in the COG, they are treated on clinical trials for patients with nonrhabdomyosarcomatous STSs.Vascular Tumors
Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant. Vascular tumors include the following tumor subtypes:
- Epithelioid hemangioendothelioma.
- Angiosarcoma (deep).
- Hemangiopericytoma (infantile).
Hemangioendotheliomas are tumors found in infants that arise within the liver or elsewhere and usually remain benign.[157,158] Liver hemangioendotheliomas may regress then enlarge. These tumors may also become malignant. The tumors are sometimes associated with consumptive coagulopathy, also known as the Kasabach-Merritt syndrome (or phenomenon).[159-162] Chemotherapy and interferon have had some benefit in isolated cases of hemangioendothelioma associated with Kasabach-Merritt syndrome.[160,161] A report from Spain indicated good control of severe thrombocytopenia of less than 30,000/mm3 in 11 patients with hemangioendothelioma or tufted angioma treated with weekly vincristine, and daily low-dose aspirin and ticlodipine.[Level of evidence: 3iiiA]
In older children and adults, hemangioendotheliomas may occur elsewhere in the body and can metastasize to lungs, lymph nodes, bones, and within the pleural or peritoneal cavities. The preferred pathologic designation for these lesions in older persons is epithelioid hemangioendothelioma, which connotes the possibility of distant spread. These latter lesions are considered to be of intermediate malignant potential, between benign hemangioma and angiosarcoma.[164,165] Epithelioid hemangioendothelioma of the liver is usually managed surgically. Some patients may need orthotopic liver transplantation because this disease does not respond to radiation therapy or chemotherapy. In more extensive hemangioendothelioma, inhibition of the mTOR pathway may be helpful. However, this should be investigated as part of a clinical trial before use in the clinical setting.
Treatment of asymptomatic liver hemangioendothelioma in a child younger than 1 year may include close observation, because some tumors will regress. Symptomatic lesions require urgent medical or surgical management, especially if coagulopathy is present.[157,159-161,163]Angiosarcoma (deep)
Angiosarcomas may arise in a setting of benign vascular anomalies or vascular malformations.[167-169] Angiosarcomas have also been described in previously benign hemangiomas and hemangioendotheliomas. Of five girls, three infants younger than 4 months with cutaneous hemangiomas and two girls with multinodular liver hemangiomas developed angiosarcomas. All three girls initially diagnosed with cutaneous hemangiomas died. Liver size initially decreased; however, at age 2.5 to 5 years, their livers enlarged, and all three girls died of angiosarcoma. The other two girls presented with vascular liver tumors at age 2 and 3.5 years, without previous histories. The younger girl had a benign unifocal hemangioendothelioma on biopsy; 3 months later, another biopsy showed both benign and malignant histology, and she died. The older girl had multinodular angiosarcomas without metastases, underwent liver transplantation, and was recurrence free 2 years later. The authors recommend liver ultrasound surveillance every 6 months for infants with multinodular liver hemangiomas.
Complete surgical excision appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence of tumor shrinkage in some patients in response to local or systemic therapy.[170-173] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis. Data on liver transplantation for localized angiosarcoma are limited.[Level of evidence: 3iiA]
Chemotherapy may be effective for the treatment of angiosarcoma. A review of 20 years of experience in the Italian and German Soft Tissue Sarcoma Cooperative Group identified 12 children with angiosarcoma. One objective response to chemotherapy was observed, and the overall behavior of this tumor was identical to angiosarcoma in adults. A subsequent retrospective study of 14 children with angiosarcoma performed by the Polish and German Cooperative Paediatric Soft Tissue Sarcoma Study Groups identified four chemotherapy responses in ten children. Another review of 15 patients demonstrated a 33% survival rate.
Anti-angiogenesis therapy may prove useful in the treatment of this group of neoplasms.Hemangiopericytoma (infantile)
Hemangiopericytoma is a highly vascularized tumor of uncertain origin. Hemangiopericytoma in children younger than 1 year seems to have a better prognosis than in children older than 1 year.[177-179] 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.
In a series of 17 children, the differences in metastatic potential and response to treatment were clearly demonstrated for adult and infantile hemangiopericytomas. Eleven children were older than 1 year. Several of these patients had disease in the lymph nodes or lungs. Six patients with stage II and 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 survived and three had good responses to vincristine, actinomycin, and cyclophosphamide.Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with nonmetastatic childhood soft tissue sarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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