Treatment of Newly Diagnosed Childhood Soft Tissue Sarcoma
Adipocytic Tumors
Adipocytic tumors account for less than 10% of soft tissue lesions in patients younger than 20 years. The most common adipocytic tumors in children are lipomas and lipoblastomas.
Table 11 summarizes the adipocytic neoplasms seen in pediatric patients and includes information about their corresponding clinico-pathological and molecular features.[1]
Table 11. Adipocytic Neoplasms in Pediatric Populationa
| Adipocytic Tumors |
Frequency[2,3] |
Epidemiology |
Predilection Site(s) |
Histology |
Cytogenetic/Molecular Alterations |
| M = male; F = female;HGMA2= high-mobility group AT-hook 2;PLAG1= pleomorphic adenoma gene 1;MDM2= mouse double minute 2 homolog;FUS= fused in sarcoma;DDIT3= DNA damage inducible transcript 3. |
| a Reprinted fromSeminars in Diagnostic Pathology, Volume 36, Issue 2, Putra J, Al-Ibraheemi A, Adipocytic tumors in Children: A contemporary review, Pages 95–104, Copyright 2019, with permission from Elsevier.[1] |
| Benign |
| Lipoma |
64%–70% (including variants) |
• Solitary: M = F |
Trunk. |
Monotonous sheets of mature adipocytes. |
Chromosomes 12q (HMGA2), 13q and 6p. |
| • Multiple: M > F |
| • Uncommon in the first 2 decades of life. |
| • Most common seen between the age 40–60 years. |
| Angiolipoma |
4%–28% |
• M > F |
Trunk and extremities. |
• Mature adipocytic proliferation. |
— |
| • Most common in late teens or early twenties. |
• Vascular proliferation (capillary proliferation with fibrin thrombi). |
| Lipoblastoma |
18%–30% |
• M > F |
Trunk and extremities. |
• Lobular architecture. |
Chromosome 8q (PLAG1) rearrangement. |
| • Zones of maturation. |
| • <3 years old (90%) |
• Primitive stellate cells. |
| • Multivacuolated lipoblasts. |
| • Myxoid area with prominent plexiform vessels. |
| Hibernoma |
2% |
• M = F |
Back (scapular area), chest wall, axilla and inguinal regions. |
• Lobular architecture. |
Chromosome 11q13-21 rearrangement. |
| • Rare in the first 2 decades of life (5%). |
• Different type of cells: brown fat cells, multivacuolated lipoblasts, mature fat cells. |
| • 60% occur in the 3rd and 4th decades of life. |
• Prominent capillary network (less pronounced than lipoblastoma and myxoid liposarcoma). |
| Intermediate |
| Atypical lipomatous tumor/well-differentiated liposarcoma |
Rare |
• M = F |
Extremities, head and neck, trunk. |
• Mature adipocytic proliferation. |
Supernumary ring and giant marker chromosome 12q14-15 (MDM2). |
| • Extremely rare in children (associated with Li-Fraumeni syndrome). |
• Significant variation in size. |
| • Peak incidence is 6th decade of life. |
• Hyperchromatic nuclei with atypia. |
| Malignant |
| Myxoid liposarcoma |
4% |
• F > M |
Extremities, trunk, head and neck and abdominal regions. |
• Nodular architecture. |
Recurrent t(12;16)(q13;p11) resulting inFUS-DDIT3gene fusion. |
| • Mixture of round to spindle nonlipogenic cells and lipoblasts. |
| • The most common liposarcoma in children (2nd decade of life), but less frequent than adults. |
• Prominent myxoid stroma with chicken-wire vasculature. |
| • Variants seen in children: pleomorphic and spindle cell subtypes. |
| • Peak incidence is 4th and 5th decades of life. |
• Progression to round cell morphology is uncommon in children. |
| Dedifferentiated liposarcoma |
Rare |
• Reported in an 8-year old with a well-differentiated liposarcoma.[4] |
• Lower extremity in a single case report of pediatric patient.[4] |
• Transition from a well-differentiated liposarcoma to nonlipogenic, high-grade sarcoma. |
Supernumary ring and giant marker chromosome 12q14-15 (MDM2). |
| • Dedifferentiation occurs in up to 10% of well-differentiated liposarcomas in adults. |
• Retroperitoneum (adults). |
• Heterologous differentiation (5%–10%). |
| • Peak incidence is 6th decade of life. |
| Pleomorphic liposarcoma |
Rare/not reported |
• Peak incidence of pleomorphic liposarcoma is 7th decade of life. |
• Extremities (adults). |
• Pleomorphic lipoblasts. |
— |
| • The subtype has been reported in the settings of Li-Fraumeni[5]and Muir-Torre syndromes.[6] |
• Background of a high-grade, pleomorphic sarcoma (non-lipogenic). |
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.[7] One retrospective study identified 34 patients younger than 22 years from 1960 to 2011.[8] 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.[9] The median age was 15.5 years, and females were more commonly affected. In both reports, most patients had myxoid liposarcoma.[8,9]
A literature review of 275 cases of pediatric liposarcoma showed that myxoid liposarcoma was the most common histology (68%), followed by well-differentiated liposarcoma (10.5%). Twelve percent of patients died of disease, and most of the deaths occurred in patients with the pleomorphic and myxoid pleomorphic subtypes. About 70% of patients with myxoid and well-differentiated liposarcoma were treated with surgery only. The overall clinical outcomes for these groups of patients were excellent, with no evidence of disease in 114 of 127 patients. In contrast, more than 50% of patients with pleomorphic liposarcoma received radiation therapy and chemotherapy in addition to surgery, and their clinical outcome was suboptimal, with no evidence of disease in only 5 of 10 patients. Germline TP53 mutations were seen in two patients with myxoid pleomorphic liposarcoma and two patients with well-differentiated liposarcoma who had a family history compatible with Li-Fraumeni syndrome.[10]
Histopathological classification
The World Health Organization (WHO) classification for liposarcoma is as follows:[11]
- Intermediate (locally aggressive).
- Atypical lipomatous tumor/well-differentiated liposarcoma. These tumors do not metastasize unless they undergo dedifferentiation.
- Malignant.
- Dedifferentiated liposarcoma.
- Myxoid liposarcoma. Pure myxoid liposarcomas are characterized by a t(12;16)(q13;p11) translocation and can metastasize but usually have an excellent outcome in the absence of a round cell component.[12] Myxoid liposarcoma is the most common subtype of liposarcoma in the pediatric population.[8,9]
- Pleomorphic liposarcoma. This is an uncommon type of liposarcoma and primarily arises in older adults.
- Myxoid pleomorphic liposarcoma. This rare entity occurs primarily in children, adolescents, and young adults. It presents commonly in the mediastinum and is clinically aggressive.
- Liposarcoma, not otherwise specified (NOS).
Clinical presentation
Most liposarcomas in the pediatric and adolescent age range are low grade and located subcutaneously. Metastasis to lymph nodes is uncommon, and most 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.
Genomic characteristics
- Atypical lipomatous tumor/well-differentiated liposarcoma. This entity is characterized by supernumerary ring and giant marker chromosomes that contain chromosomal region 12q14-q15, which includes MDM2. MDM2 amplification can be detected in virtually all cases of atypical lipomatous tumor/well-differentiated liposarcoma, with nearby genes such as CDK4 and FRS2 commonly being coamplified with MDM2.[13]
- Dedifferentiated liposarcoma. This entity, like atypical lipomatous tumor/well-differentiated liposarcoma, is characterized by MDM2 amplification and the supernumerary ring and giant marker chromosomes containing the chromosomal region 12q14-q15. Dedifferentiated liposarcoma contains a high number of segmental copy number alterations, but has few gene mutations.[14]
- Myxoid liposarcoma. This entity is characterized by the t(12;16)(q13;p11) translocation that produces the FUS-DDIT3 gene fusion.[14] In a small percentage of cases, EWSR1 substitutes for FUS, producing the EWSR1-DDIT3 gene fusion (t(12;22)(q13;q12)). DDIT3 (previously called CHOP and GADD153) is a stress-induced gene that has an inhibitory effect on adipogenesis.[15] Myxoid liposarcoma is the most common subtype of liposarcoma in the pediatric population. Most pediatric cases show the FUS-DDIT3 gene fusion.[8,9,16]
- Pleomorphic liposarcoma. This entity is primarily a disease of older adults and lacks either DDIT3 gene rearrangements or MDM2 amplification. Cases of pleomorphic liposarcoma typically have multiple chromosomal imbalances, including mutations in TP53 and NF1 observed in some cases.[17]
- Pleomorphic myxoid liposarcoma. This entity most commonly presents in the adolescent and young adult population and lacks the DDIT3 gene rearrangement of myxoid liposarcoma and the MDM2 amplification of atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma.[9,16,18] Instead, pleomorphic myxoid liposarcoma presents with multiple chromosomal gains and losses. Loss of Rb expression is commonly observed, sometimes in association with loss of chromosome 13q14 where RB1 is located.[18,19] Although most cases of pleomorphic myxoid liposarcoma lack TP53 mutations, a minority have TP53 mutations that are associated with Li-Fraumeni syndrome in some cases.[20,21,22]
Prognosis
Higher grade or central tumors are associated with a significantly higher risk of death. In an international retrospective review, the 5-year survival rate was 42% for patients with central tumors. Seven of ten patients with pleomorphic myxoid liposarcoma died of their disease.[9] In a retrospective study of 14 patients, the 5-year survival rate was 78%. Tumor grade, histological subtype, and primary location correlated with survival.[8]
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.[23,24,25]
- Chemotherapy followed by surgery.
- Surgery preceded or followed by radiation therapy (evidence based on adult studies).[26,27]
Surgery is the most important treatment for liposarcoma. After complete surgical resection of well-differentiated or myxoid liposarcoma, the event-free survival (EFS) and overall survival (OS) rates are roughly 90%.[28] If initial surgery is incomplete, re-excision should be performed to achieve a wide margin of resection. Local recurrences have been seen and are controlled with a second resection of the tumor, particularly for low-grade liposarcomas. Radiation therapy is also considered either preoperatively or postoperatively depending on the cosmetic/functional consequences of additional surgery and radiation therapy.[29,30]
Chemotherapy has been used to decrease the size of liposarcoma before surgery to facilitate complete resection, particularly in central tumors.[31,32] The role of postoperative chemotherapy for liposarcoma is poorly defined. Postoperative therapy for completely resected myxoid liposarcomas does not appear to be needed. Even with the use of postoperative chemotherapy, the survival of pleomorphic liposarcoma remains poor.[33]
Trabectedin has produced encouraging responses in adults with advanced myxoid liposarcoma.[34] 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.[35][Level of evidence: 1iiDiii] There are very limited data to support the use of trabectedin in pediatric patients.[36]
Treatment with eribulin, a nontaxane microtubule dynamics inhibitor, significantly improved survival in adult patients with recurrent liposarcoma compared with dacarbazine. The median OS was 15.6 months for patients who received eribulin, versus 8.4 months for patients who received dacarbazine. Survival differences were more pronounced in patients with dedifferentiated and pleomorphic liposarcoma. Eribulin was effective in prolonging survival of patients with either high-grade or intermediate-grade tumors.[37][Level of evidence: 1iiA] A pediatric phase I trial of eribulin did not accrue any patients with liposarcoma.[38]
In a phase II, single-arm, multicenter study, 41 adult patients with unresectable or metastatic high-grade or intermediate-grade liposarcoma were treated with pazopanib at a dose of 800 mg daily. The progression-free survival (PFS) rate at 12 weeks was 68.3%, which was significantly greater than the null hypothesis value of 40%. Forty-four percent of patients experienced tumor control. One patient had a partial response, and 17 patients had stable disease. At 24 weeks, 39% of the patients remained progression free. The median progression-free survival was 4.4 months, and median OS was 12.6 months.[10][Level of evidence: 2Diii]
Chondro-osseous Tumors
Chondro-osseous tumors include the following subtypes:
- Soft tissue chondroma.
- Extraskeletal mesenchymal chondrosarcoma.
- Extraskeletal osteosarcoma.
Extraskeletal mesenchymal chondrosarcoma
Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcomas 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.[39] 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.[40]
Prognosis
A retrospective survey of European institutions identified 113 children and adults with mesenchymal chondrosarcoma. Factors associated with better outcome included the following:[41][Level of evidence: 3iiiA]
- Lack of metastatic disease at initial presentation.
- Clear resection margins.
- Administration of postoperative chemotherapy after resection for patients with initially localized disease.
A retrospective analysis of Surveillance, Epidemiology, and End Results (SEER) Program data from 1973 to 2011 identified 205 patients with mesenchymal chondrosarcoma; 82 patients had skeletal primary tumors, and 123 patients had extraskeletal tumors.[42] The outcomes of skeletal and extraskeletal primary tumors were the same. Factors associated with outcome included the following:
- Primary site: The 5-year OS rate was 50% for patients with appendicular tumors, 37% for patients with axial tumors, and 74% for patients with cranial tumors.
- Metastases and tumor size: Presence of metastatic disease and larger tumor size were independently associated with an increased risk of death.
A single-institution retrospective review identified 43 cases of mesenchymal chondrosarcoma from 1979 to 2010.[43] Thirty patients with localized disease were evaluated. The mean age at diagnosis was 33 years (range, 11–65 years). The 5-year OS rate was 51%, and the 10-year OS rate was 37%. Younger age (<30 years) and male sex were associated with poorer OS and disease-free survival (DFS). Patients who did not receive adjuvant radiation therapy were more likely to have a local recurrence.
Treatment
Treatment options for extraskeletal mesenchymal chondrosarcoma include the following:
- Surgery. If the tumor is not completely removed, radiation therapy may also be given.
- Surgery preceded or followed by radiation therapy.[26,27]
- 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.[44][Level of evidence: 3iiA]
A single-institution, retrospective review identified 12 pediatric patients with mesenchymal chondrosarcoma.[45] 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 patient 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, the 5-year DFS rate was 68.2% (95% confidence interval [CI], 39.8%–96.6%), and the OS rate was 88.9% (95% CI, 66.9%–100%).
A Japanese study of patients with extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma randomly assigned patients to treatment with either trabectedin or best supportive care.[46] The median age of patients was 38 years (range, 21–77 years). The OS was higher for the patients assigned to receive trabectedin than for patients assigned to receive best supportive care.
Extraskeletal osteosarcoma
Osseous and chondromatous neoplasms account for 0.8% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
Extraskeletal osteosarcoma is extremely rare in the pediatric and adolescent population. An analysis of SEER data identified 256 patients (6%) with extraskeletal osteosarcoma among 4,173 patients with high-grade osteosarcoma from 1973 to 2009. Compared with skeletal osteosarcoma, patients with extraskeletal osteosarcoma were more likely to be older, female, have an axial primary tumor, and have regional lymph node involvement. Adverse prognostic features included presence of metastatic disease, larger tumor size, older age, and axial primary tumor site.[47]
Molecular features
A review of 32 adult patients with extraskeletal osteosarcomas consistently revealed several alterations.[48] Frequent genomic alterations included copy number losses in CDKN2A (70%), TP53 (56%), and RB1 (49%). Mutations were identified that affected methylation/demethylation (40%), chromatin remodeling (27%), and the WNT/SHH pathways (27%). Cases with simultaneous TP53 and RB1 biallelic copy number losses were associated with worse DFS and OS.
Prognosis
Extraskeletal osteosarcoma is associated with a high risk of local recurrence and pulmonary metastasis.[49] A single-institution retrospective review identified 43 patients with extraskeletal osteosarcoma; 37 patients had localized disease, and 6 patients presented with metastatic disease.[50] The median age was 55 years (range, 7–81 years). The median PFS was 21 months; the median OS was 50 months. Seventy-five percent of patients received chemotherapy. There was a trend toward better survival for patients who received chemotherapy, and a statistically significant improvement in survival for patients who received chemotherapy that included cisplatin.
In a review of 274 patients, with a median age of 57 years at diagnosis (range, 12–91 years), the 5-year DFS and OS rates were significantly better for those who received chemotherapy. The use of an osteosarcoma-type regimen was associated with improved response rates.[51][Level of evidence: 3iiiA]
The European Musculoskeletal Oncology Society performed a retrospective analysis of 266 eligible patients with extraskeletal osteosarcoma treated between 1981 and 2014.[51] Fifty patients (19%) presented with metastatic disease. An analysis of the 211 patients who achieved complete remission after surgical resection of the primary tumor showed a 5-year OS rate of 51% and a 5-year DFS rate of 43%. There was a favorable trend for survival among patients who were treated with chemotherapy that is usually employed for patients with osseous osteosarcoma. In a multivariable analysis, factors associated with better prognosis included younger age (<40 years), smaller tumors, and use of chemotherapy.
Treatment
Treatment options for extraskeletal osteosarcoma include the following:
- Surgery followed by chemotherapy.[49,50,51]
Typical chemotherapy regimens used for osteosarcoma include some combination of cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide.[49,50,51]
(Refer to the PDQ summary on Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment for more information about treatment, including chemotherapy options, of extraosseous osteosarcoma.)
Fibroblastic/Myofibroblastic Tumors
Fibroblastic/myofibroblastic tumors include the following subtypes:
- Fibroblastic/myofibroblastic tumors.
- Intermediate (locally aggressive).
- Palmar/plantar fibromatosis.
- Desmoid-type fibromatosis (previously called desmoid tumor or aggressive fibromatoses).
- Lipofibromatosis.
- Giant cell fibroblastoma.
- Intermediate (rarely metastasizing).
- Dermatofibrosarcoma protuberans.
- Solitary fibrous tumor.
- Inflammatory myofibroblastic tumor.
- Low-grade myofibroblastic sarcoma.
- Myxoinflammatory fibroblastic sarcoma/atypical myxoinflammatory fibroblastic tumor.
- Infantile fibrosarcoma.
- Malignant.
- Adult fibrosarcoma.
- Myxofibrosarcoma.
- Low-grade fibromyxoid sarcoma.
- Sclerosing epithelioid fibrosarcoma.
Desmoid-type fibromatosis
Desmoid-type fibromatosis has previously been called desmoid tumors or aggressive fibromatoses.
Risk factors
Most desmoid tumors are sporadic, but a small proportion may occur in association with a mutation in the APC gene (associated with intestinal polyps and a high incidence of colon cancer). In a study of 519 patients older than 10 years with a diagnosis of desmoid-type fibromatosis, 39 patients (7.5%, a possible underestimation) were found to have familial adenomatous polyposis (FAP).[52] 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,[53,54] or location of the desmoid-type fibromatosis in the abdomen or abdominal wall [52] 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.[55,56] Pediatric desmoid tumors can harbor additional mutations in the AKT, BRAF V600E, TP53, and RET genes.[10] (Refer to the Familial Adenomatous Polyposis [FAP] section of the PDQ summary on Genetics of Colorectal Cancer for more information.)
Prognosis
Desmoid-type fibromatosis has an extremely low potential to metastasize. The tumors are locally infiltrating, and surgical control can be difficult because of the need to preserve normal structures.
Desmoid-type fibromatosis has a high potential for local recurrence. These tumors have a highly variable natural history, including well documented examples of spontaneous regression.[57] Mutations in exon 3 of the CTNNB1 gene are seen in more than 80% of desmoid-type fibromatosis cases. The 45F mutation in exon 3 of the CTNNB1 gene has been associated with an increased risk of disease recurrence.[58] Repeated surgical resection can sometimes bring recurrent lesions under control.[59]
Treatment
Evaluating the benefit of treatment interventions for desmoid-type fibromatosis has been extremely difficult, because desmoid-type fibromatosis has a highly variable natural history, with partial regressions seen in up to 20% of patients.[60] Large adult series and smaller pediatric series have reported long periods of disease stabilization and even regression without systemic therapy.[59,61]; [62][Level of evidence: 3iiiDi] For instance, in a large placebo-controlled trial of sorafenib in adult patients with desmoid tumor, the patients who received no therapy (observation/placebo) demonstrated a 20% partial regression rate, and 46% of the patients in the placebo group had no progression at 1 year.[60]
Treatment options for desmoid-type fibromatosis include the following:
- Observation. Because of the variable natural history of desmoid tumors, as outlined above, observation is sometimes a viable option. This is particularly the case for asymptomatic lesions, lesions that do not pose a danger to vital organs, and tumors that are incompletely resected.[59,63,64,65,66,67,68,69] A global consensus meeting that involved sarcoma experts with experience in both adult and pediatric desmoid tumor was organized to define the appropriate management of desmoid tumor. The Desmoid Tumor Working Group suggested that an initial active surveillance approach does not influence the efficacy of subsequent treatments. They suggest that active therapy should only be considered in cases of persistent progression. Active surveillance includes continuous monitoring with a first magnetic resonance imaging (MRI) within 1 to 2 months of diagnosis, followed by scans in 3- to 6-month intervals. When the disease is located in critical structures that may pose significant morbidity, such as the mesentery and head and neck region, earlier decisions toward an active therapy should be undertaken.[70]
- In a prospective study of 771 patients with desmoid-type fibromatosis that compared initial surgery with initial observation, there was no difference in EFS rates between the two groups (53% vs. 58%; P = .415). Among patients with favorable tumor locations, defined as abdominal wall, intra-abdominal, breast, digestive viscera, and lower limb, the 2-year EFS rate was similar in patients who underwent surgery (70%) or were observed (63%; P = .41). Among patients with tumors in unfavorable locations, defined as chest wall, head and neck, and upper limb, the 2-year EFS rate was significantly better for those treated nonsurgically (52%) compared with those who underwent initial surgery (25%; P = .001).[71][Level of evidence: 3iiiD]
- Of 173 patients with desmoid-type fibromatosis who were treated on European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) studies since 2005, all patients were alive at the time of analysis. Thirteen patients (8%) had biopsies only (no further treatment), 65 patients (42%) received chemotherapy only, 31 patients (20%) underwent surgery only, 36 patients (23%) had both chemotherapy and surgery, and 9 patients (6%) received radiation therapy in addition to other therapies. The authors concluded that the conservative nonsurgical approach did not compromise outcome in pediatric patients.[72][Level of evidence: 3iiiDi]
- The lack of intervention, surgical or otherwise, has been questioned. The Toronto Hospital for Sick Children evaluated the emotional impact on patients with desmoid tumors of continuing to return, on a regular basis, to a cancer center for ongoing computed tomography (CT) or MRI scans and follow-up. For individuals with desmoid tumors, higher levels of anxiety were found, even when compared with sarcoma patients, which did not ease with treatment and continued throughout surveillance.[73][Level of evidence: 3iiiC]
- Chemotherapy, for unresectable or recurrent tumors.
- Methotrexate and vinblastine: This combination produced objective responses in about one-third of patients with unresectable or recurrent desmoid-type fibromatosis.[74]
- Doxorubicin and dacarbazine: A series of mainly adult patients with FAP and unresectable desmoid-type fibromatosis that were unresponsive to hormone therapy showed that doxorubicin plus dacarbazine followed by meloxicam (a nonsteroidal anti-inflammatory drug [NSAID]) can be safely administered and can induce responses.[75]
- Pegylated liposomal doxorubicin: Some responses have been reported.[76] In a series of five patients, a median progression-free interval of 29 months was reported.[77]
- Hydroxyurea: A retrospective analysis reported the results of 16 children with previously treated desmoid tumors who were treated with hydroxyurea. Prior to hydroxyurea, seven patients had tumor progression, two patients had increased pain, and seven patients had both. Tumor shrinkage occurred in 37.5% of patients (with 18.7% partial remissions), and symptom improvement occurred in 68.7% of patients.[78]
- Tyrosine kinase inhibitors.
- Sorafenib: An international prospective phase III double-blind study was conducted through the National Clinical Trials Network to evaluate the efficacy of sorafenib in patients with unresectable progressive or symptomatic desmoid tumors. Adult patients were randomly assigned in a 2:1 fashion (sorafenib: placebo); crossover to sorafenib was permitted after disease progression. Eighty-seven patients were enrolled (aged 18–72 years). The objective response rate was 33% (95% CI, 20%–48%) in the sorafenib arm and 20% (95% CI, 8%–38%) in the placebo arm. The median time to objective response was 9.5 months for patients treated with sorafenib and 13.3 months for patients who received the placebo. The 2-year PFS rate was 81% for patients treated with sorafenib, compared with 36% for patients who received the placebo.[60][Level of evidence: 1iDiii]
- Pazopanib: A small series reported symptomatic improvement and stable disease in seven patients with desmoid-type fibromatosis who were treated with pazopanib.[79] A randomized noncomparative study in adults with desmoid tumors treated patients with either pazopanib or methotrexate/vinblastine. About 84% of the patients who received pazopanib had no progression at 6 months.[80]
- Gamma-secretase inhibitor. The gamma-secretase inhibitor nirogacestat was administered to four children and young adults (three with FAP) with desmoid tumors.[81] Three patients had a durable benefit; one patient had a complete response, one patient had a partial response, and one patient had stable disease. The fourth patient had disease progression after a partial response.
- NSAIDs. NSAIDs such as sulindac have been used in single cases for desmoid-type fibromatosis; the responses seen were usually disease stabilization.[82]
- Antiestrogen treatment. Antiestrogen treatment, usually tamoxifen, plus sulindac has also resulted in disease stabilization.[83] A prospective trial of the combination of tamoxifen and sulindac reported few side effects, although asymptomatic ovarian cysts were common in girls. This combination showed relatively little activity, as measured by rates of response and PFS.[84][Level of evidence: 2Diii]
- Surgery. If surgery is chosen, the intent is to achieve clear margins. However, a retrospective review of children who underwent surgery for desmoid-type fibromatosis at St. Jude Children's Research Hospital (SJCRH) reported no correlation between surgical margins and risk of recurrence.[69] In this study, 10 of 39 patients experienced a recurrence after surgery, with a median interval time of 2.5 years.
- Surgical resection should be used judiciously in patients with desmoid tumors because spontaneous regression can occur in up to 20% of cases. Surgical resection is recommended when tumor enlargement threatens the airway or when symptoms such as pain are persistent. A watch-and-wait strategy is otherwise preferred.
- Radiation therapy.
- Radiation has been used for unresectable and symptomatic desmoid-type fibromatosis or postoperatively for tumors with inadequate resections if progression would have morbid consequences. The potential long-term complications of radiation therapy, especially subsequent neoplasms, make this modality less appealing in a young population.[85]
- Postoperative radiation therapy can be considered when recurrence or progression would entail additional surgery that might cause functional or cosmetic compromise and if radiation is considered acceptable in terms of morbidities.
- NOTCH pathway inhibitor.
- The NOTCH pathway has been implicated in the development of desmoid tumors.[86] The gamma secretase inhibitor nirogacestat has been evaluated in adult and pediatric patients. In a study of 17 adult patients with desmoid tumors, 15 of whom had mutations in the APC or CTNNB1 genes, 5 patients (29%) achieved a confirmed partial response.[87][Level of evidence: 3iiDiv] In a small series of four patients younger than 20 years who received nirogacestat on a compassionate basis, three had a durable benefit, defined as a complete response (n = 1), partial response (n = 1), or stable disease (n = 1). No patients experienced grades 3 or 4 adverse events.[81][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 is an example of a national and/or institutional clinical trial that is currently being conducted:
- ARST1921 (NCT04195399) (A Safety, Pharmacokinetic, and Efficacy Study of a Gamma-Secretase Inhibitor, Nirogacestat [PF-03084014] in Children and Adolescents With Progressive, Surgically Unresectable Desmoid Tumors): This phase II trial studies the toxicities and pharmacokinetics of nirogacestat in patients with progressive, surgically unresectable desmoid tumors.
Dermatofibrosarcoma protuberans
Dermatofibrosarcoma is a rare tumor that can be present in all age groups, but many of the reported cases arise in children.[88,89,90] 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. The incidence was highest among Black patients aged 15 to 19 years. The most common sites were the trunk and extremities, which is similar to what is found in adults. Ninety-five percent of patients underwent surgery. The OS rate was 100% at 5 years, 98% at 15 years, and 97% at 30 years. Male patients had decreased survival compared with female patients (P < .05).[91][Level of evidence: 3iA]
Molecular features
The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGFRB gene.
Treatment
Treatment options for dermatofibrosarcoma protuberans include the following:
- Surgery.
- Surgery preceded or followed by radiation therapy.
- Radiation therapy and imatinib therapy, for unresectable or recurrent tumors.
Most patients with dermatofibrosarcoma tumors can be cured by complete surgical resection. Wide excision with negative margins or Mohs/modified-Mohs surgery will prevent most tumors from recurring.[92] Despite the locally aggressive behavior of the tumor, lymph node or visceral metastasis rarely occurs.
The EpSSG prospective NRSTS 2005 (NCT00334854) trial identified 46 patients with dermatofibrosarcoma protuberans.[93] The median age at diagnosis was 6.9 years (range, 0.4–17.5 years). All patients had localized disease, 93% of patients had small tumors (<5 cm), and 76% of patients had Intergroup Rhabdomyosarcoma Study (IRS) group I tumors. All patients underwent upfront surgery, and 32 patients required two procedures. There were 11 patients with IRS group II tumors, 2 of whom went on to have a local recurrence. After a median follow-up of 49 months (range, 4.2–130.9 months), all patients were alive at the time of this report. The 5-year EFS rate was 92.6% (95% CI, 78.8%–97.6%), and the OS rate was 100%.
In retrospective reviews, postoperative radiation therapy after incomplete excision may have decreased the likelihood of recurrence.[94,95]
When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective.[96,97,98] Because metastatic disease is more likely after multiple recurrences, radiation or other adjuvant therapy should be considered in patients with recurrences that cannot be managed surgically.[89,91]
A systematic review of nine studies examined 152 adult patients with histologically proven dermatofibrosarcoma protuberans who were treated with imatinib. The study demonstrated a complete response rate of 5.2%, a partial response rate of 55.2%, and a stable disease rate of 27.6%. There were no differences in the response rates based on imatinib dosing of either 400 mg or 800 mg per day.[99]
Guidelines for workup and management of dermatofibrosarcoma protuberans have been published.[100]
Inflammatory myofibroblastic tumor and epithelioid inflammatory myofibroblastic sarcoma
Inflammatory myofibroblastic tumor is a rare mesenchymal tumor that has a predilection for children and adolescents.[101,102,103]
Clinical presentation
Inflammatory myofibroblastic tumors are rare tumors that affect soft tissues and visceral organs of children and young adults.[104] They rarely metastasize but tend to be locally invasive. Usual anatomical sites of disease include soft tissue, lungs, spleen, colon, and breast.[101] A review of 42 cases of pediatric inflammatory myofibroblastic tumor of the bladder was published in 2015.[105]
Epithelioid inflammatory myofibroblastic sarcoma is an uncommon subtype of inflammatory myofibroblastic tumors. This subtype shows epithelioid morphology and a perinuclear or nuclear membrane pattern of immunostaining for ALK.[106] The most common site of presentation is the abdomen, although other primary sites have been reported.[106,107,108] Epithelioid inflammatory myofibroblastic sarcoma shows a male predominance, and it can present from infancy through adulthood.[106,107,108]
Molecular features
Roughly one-half of inflammatory myofibroblastic tumors exhibit a clonal mutation that activates the ALK gene (encodes a receptor tyrosine kinase) at chromosome 2p23.[109]ROS1 and PDGFRB kinase fusions have been identified in 8 of 11 cases (73%) who are negative for ALK by immunohistochemistry.[110][Level of evidence: 3iiiDiv]
Most cases of epithelioid inflammatory myofibroblastic sarcoma have a RANBP2-ALK gene fusion. A RRBP1-ALK gene fusion has also been reported.[106,107,108] Because RANBP2 localizes to the nuclear pore, this likely explains the perinuclear or nuclear membrane pattern of staining noted for ALK in epithelioid inflammatory myofibroblastic sarcoma.
Prognosis
Inflammatory myofibroblastic tumor recurs frequently but is rarely metastatic.[101,102,103] Studies of children with inflammatory myofibroblastic tumor show 5-year survival rates higher than 80%.[111]
Epithelioid inflammatory myofibroblastic sarcoma is an aggressive tumor, and before the availability of ALK inhibitors, disease progression and high mortality rates were common.[106,107,112] Epithelioid inflammatory myofibroblastic sarcoma generally responds to ALK inhibitors but progression on therapy has been observed, which is consistent with the aggressive clinical behavior of the tumor.[108]
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.[113] 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.[114][Level of evidence: 3iiA] In another study of 31 patients who underwent complete surgical resection, 4 patients had local recurrences, and all patients were alive after surgical re-resection (3 patients) or adjuvant chemotherapy and resection (1 patient).[111] A review of German studies identified 37 patients younger than 21 years with inflammatory myofibroblastic tumors.[115][Level of evidence: 3iiA] The overall 5-year EFS rate was 75%, and the OS rate was 91%. Of 20 patients, 17 had complete resections with no recurrences. All other patients were treated with a combination of surgery and various chemotherapy regimens. Surgical resections can be limited to those procedures that preserve form and function.
The benefit of chemotherapy has been noted in case reports.[116] A prospective registry of children with inflammatory myofibroblastic tumor from the European Soft Tissue Sarcoma Group (2005–2016) found an EFS rate of 82.9% and an OS rate of 98.1% at 5 years in all patients. The response rate for patients who received systemic therapy was 63% when used as front-line therapy and 66% when used as second-line therapy. Eight of ten patients who received vinblastine and low-dose methotrexate and all five patients who received ALK inhibitors (all of whom had ALK-positive tumors) responded to treatment.[111]
There are case reports of response to either steroids or NSAIDs.[117,118] 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. The OS rate was 94%. Three patients relapsed, two of whom died of the disease. When complete excision was performed, with or without other treatments such as steroids, there was a high survival rate for these patients.[119][Level of evidence: 3iiA]
Inflammatory myofibroblastic tumors respond to ALK inhibitor therapy, as follows:
- Crizotinib: Two adults with ALK-rearranged inflammatory myofibroblastic tumor achieved partial responses with crizotinib.[120][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.[121] 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.[122] Finally, one study included 14 patients with inflammatory myofibroblastic tumors who were treated with crizotinib. 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.[123][Level of evidence: 3iiDiv]
- Ceritinib: 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.[124] Two pediatric patients enrolled in a clinical trial responded to treatment with ceritinib. One patient had a complete response that was durable for multiple years on continuing therapy, and one patient had a partial response when the drug was discontinued for severe liver and renal toxicity.[125]
Patients with epithelioid inflammatory myofibroblastic sarcoma are generally treated with surgery. ALK inhibitors are often able to induce responses, although progression on therapy may occur.[106,108,112]
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 pathological diagnoses and require different treatments. Adult fibrosarcoma is addressed below.
Clinical presentation
Infantile fibrosarcoma usually presents with a rapidly growing mass, often noted at birth or even seen in the prenatal ultrasound. The tumors are frequently quite large at the time of presentation.[126] Hypercalcemia secondary to elevated levels of parathyroid hormone–related protein has been reported as a presenting feature of this disease in newborns.[127]
Molecular features
The tumor usually has a characteristic cytogenetic translocation t(12;15)(ETV-NTRK3). Infantile fibrosarcoma shares this translocation and a virtually identical histological appearance with mesoblastic nephroma.
Infantile fibrosarcoma usually occurs in children younger than 1 year. It occasionally occurs in children up to age 4 years. A tumor with similar morphology has been identified in older children; in these older children, the tumors do not have the t(12;15)(ETV-NTRK3) translocation that is characteristic of the younger patients.[128]BRAF intragenic deletions have been described in cases of infantile fibrosarcoma and co-occur with NTRK3 fusions.[129]
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.
- Targeted therapy.
Complete resection is curative in most patients with infantile fibrosarcoma. However, the large size of the lesion frequently makes resection without major functional consequences impossible. For instance, tumors of the extremities often require amputation for complete excision. The European pediatric group has reported that observation may also be an option in patients with group II disease after surgery.[130] 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.[131][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.[132,133]; [131,134][Level of evidence: 3iiA]; [135][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.[130,131,136]
Two cases with variant LMNA-NTRK1 fusions responded to crizotinib.[137,138]
A phase I/II trial of larotrectinib was completed in patients with recurrent infantile fibrosarcoma who harbored an NTRK fusion. Larotrectinib is an oral ATP-competitive inhibitor of TRK A, B, and C. Durable objective responses were seen in all eight patients, and responses occurred at a median of 1.7 months. Most toxicities were grades 1 and 2, which included transaminitis, leukopenia, neutropenia, and vomiting. There were no grade 4 or grade 5 events attributed to larotrectinib.[139] Three of five patients who achieved a partial response after neoadjuvant larotrectinib underwent a complete surgical resection with negative margins. These three patients achieved an excellent pathologic response (>98% treatment effect) and remained disease free 7 to 15 months after surgery.[140,141]; [142][Level of evidence: 3iiD] In a follow-up report, 159 patients with TRK fusion–positive tumors were enrolled in three phase I/II trials. In 28 patients with infantile fibrosarcoma who received single-agent larotrectinib, the response rate was 96%.[143][Level of evidence: 3iiD]
One of eight pediatric patients in this trial with an ETV6-NTRK3–rearranged infantile fibrosarcoma developed progressive disease after 8 months of larotrectinib therapy and was found to have a G623R acquired resistance mutation. The patient was treated with LOXO-195, a selective TRK inhibitor designed to overcome acquired resistance mediated by recurrent kinase domain mutations, and experienced a transient partial response.[144]
A patient aged 2 months with infantile fibrosarcoma was initially treated with chemotherapy. At disease progression, a response was seen with pazopanib therapy.[145]
A rare case of spontaneous regression without treatment has been reported.[146][Level of evidence: 3iiiDiv]
Treatment options under clinical evaluation
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
- APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified in a patient's tumor (refractory or recurrent). Children and adolescents aged 1 to 21 years are eligible for the trial.
Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
The phase II subprotocol is evaluating larotrectinib in patients with tumors harboring actionable NTRK fusions.
- LOXO-TRK-15003 (NCT02637687) (A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK Fusions in Children): A phase I trial of the pan-TRK inhibitor larotrectinib 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. Larotrectinib is a highly selective inhibitor of all three TRK family kinases.
- RXDX-101-03 (NCT02650401) (Study Of Entrectinib [RXDX-101] in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors and/or Who Have No Satisfactory Treatment Options): This is a five-part, open-label, phase I/Ib, multicenter, dose-escalation study in pediatric patients with relapsed or refractory solid tumors; primary CNS tumors; neuroblastoma; non-neuroblastoma, extracranial solid tumors with NTRK1/2/3, ROS1, or ALK gene rearrangements; and patients who are otherwise eligible but unable to swallow capsules. The study is designed to explore the safety, maximum tolerated dose or recommended phase II dose, pharmacokinetics, and antitumor activity of entrectinib.
- NCT03215511 (A Study to Test the Safety of the Investigational Drug Selitrectinib in Children and Adults): This is a phase I/II, multicenter, open-label study designed to evaluate the safety and efficacy of selitrectinib when administered orally to patients aged 1 month and older with NTRK fusion cancers treated with a previous TRK inhibitor.
- NCT02568267 (Basket Study of Entrectinib [RXDX-101] for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 [Trk A/B/C], ROS1, or ALK Gene Rearrangements [Fusions]): This is an open-label, multicenter, global phase II basket study of entrectinib (RXDX-101) for the treatment of patients 18 years and older with solid tumors that harbor an NTRK1/2/3, ROS1, or ALK gene fusion. Patients will be assigned to different baskets according to type of tumor and gene fusion.
- ADVL1823 (NCT03834961) (Larotrectinib in Treating Patients With Previously Untreated TRK-Fusion Solid Tumors and TRK-Fusion Relapsed Acute Leukemia): This phase II trial aims to study the side effects and efficacy of larotrectinib in treating patients with previously untreated TRK-fusion solid tumors and TRK-fusion acute leukemia that has recurred.
Adult fibrosarcoma
These tumors lack the translocation seen in infantile fibrosarcomas. They present like most nonrhabdomyosarcomas, and the management approach is similar.
Myxofibrosarcoma
Myxofibrosarcoma is a rare lesion, especially in childhood. It is typically treated with complete surgical resection.
Low-grade fibromyxoid sarcoma
Low-grade fibromyxoid sarcoma is a histologically deceptive soft tissue neoplasm that most commonly affects young and middle-aged adults. It is commonly located deep within the extremities, and it is characterized by a FUS-CREB3L2 translocation and, rarely, alternative translocations such as FUS-CREB3L1 and EWSR1-CREB3L1.[11,147,148,149,150]
Prognosis
In a review of 33 patients (3 were younger than 18 years) with low-grade fibromyxoid sarcoma, 21 patients developed a local recurrence after intervals of up to 15 years (median, 3.5 years). Fifteen patients developed metastases up to 45 years (median, 5 years) from diagnosis, most commonly to the lungs and pleura. This finding emphasizes the need for continued follow-up of these patients.[147] Even after metastases occur, the disease course may be indolent.[151]
In another report, 14 of 73 patients were younger than 18 years. In this series with a relatively short follow up (median of 24 months), only 8 of 54 patients with adequate follow-up developed local (9%) or distant (6%) recurrence. This report suggests that the behavior of this tumor might be significantly better than previously reported.[152] However, because late metastases can occur, careful monitoring of these patients is warranted.
A 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 tumor sites were the lower and upper extremity (n = 9). None of the patients developed local or distant disease recurrence at a median follow up of 2.7 years.[153]
Treatment
Treatment options for low-grade fibromyxoid sarcoma include the following:
- Surgery.
Because low-grade fibromyxoid sarcoma is not very chemosensitive, the limited treatment information suggests that surgery is the treatment of choice.[151] The German Cooperative Weichteilsarkom Studiengruppe (CWS) reported study results for 31 patients younger than 21 years with low-grade fibromyxoid sarcoma.[149][Level of evidence: 3iiDi] The 5-year EFS rate was 71% (95% CI, ±18.6%), the 5-year local relapse-free survival rate was 76% (95% CI, ±17.6%), and the 5-year OS rate was 100%. Among 24 patients who had R0 resections, 5 patients (21%) suffered relapse (3 local, 1 metastatic, and 1 combined). Among seven patients who had R1 resections, three patients (43%) suffered local relapse.
There are little data regarding the use of chemotherapy and/or radiation therapy in this disease. One report suggests that trabectedin may be effective in the treatment of low-grade fibromyxoid sarcoma.[154]
Sclerosing epithelioid fibrosarcoma
Sclerosing epithelioid fibrosarcoma is a rare malignant sarcoma that commonly harbors EWSR1 gene fusions and has an aggressive clinical course. The tumor is poorly responsive to chemotherapy.[155,156,157] Therefore, it is typically treated with complete surgical excision. Long-term follow-up is recommended because late local recurrence and metastases can occur.
Genomic characteristics
Sclerosing epithelioid fibrosarcoma most commonly has the EWSR1-CREB3L1 gene fusion. However, EWSR1 may have other partners, including CREB3L2 and CREB3L3.[158,159] Gene fusions involving FUS (including the FUS-CREB3L2 fusion associated with low-grade fibromyxoid sarcoma) and PAX5 (e.g., PAX5-CREB3L1) are uncommon but can occur.[159,160] For cases of sclerosing epithelioid fibrosarcoma that lack MUC4 expression, EWSR1 gene fusions are generally absent, while a gene fusion involving YAP1 and KMT2A is commonly observed.[155,158,161,162] Sclerosing epithelioid fibrosarcoma has more structural and chromosomal segmental alterations than low-grade fibromyxoid fibrosarcoma.[158]
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 sarcomas in patients younger than 20 years (refer to Table 1).
Risk factors
Among 43 children with HIV/AIDS who developed tumors, 8 developed Epstein-Barr virus–associated leiomyosarcoma.[163] Survivors of hereditary retinoblastoma have a statistically significant increased risk of developing leiomyosarcoma, and 78% of these patients were diagnosed 30 or more years after the initial diagnosis of retinoblastoma.[164]
Treatment
Treatment options for leiomyosarcoma include the following:
- Chemotherapy (trabectedin).
Trabectedin has been studied in adults with leiomyosarcoma. Results from studies include the following:
- In an open-label study of trabectedin in adult patients with recurrent sarcomas, the best overall response rate (complete remission and partial remission) was seen in patients with leiomyosarcoma (7.5%).[165] The clinical benefit rate (includes stable disease) was 54% for patients with leiomyosarcoma.
- 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.[35]
There are no data to support the use of trabectedin in pediatric patients.
So-called Fibrohistiocytic Tumors
So-called fibrohistiocytic tumors include the following subtypes:
- Plexiform fibrohistiocytic tumor.
- Giant cell tumor of soft tissue.
Plexiform fibrohistiocytic tumor
Plexiform fibrohistiocytic tumor is a rare, low- to intermediate-grade tumor that most commonly affects children and young adults. Depending on the series, the median age at presentation ranges from 8 to 14.5 years; however, the tumor has been described in patients as young as 3 months.[166,167]
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.[168,169,170] There are rare reports of the tumor spreading to regional lymph nodes or the lungs.[166,170,171]
Molecular features
No consistent chromosomal anomalies have been detected but a t(4;15)(q21;q15) translocation has been reported.[172]
Prognosis
Plexiform fibrohistiocytic tumor is an intermediate-grade tumor that rarely metastasizes.
Treatment
Treatment options for plexiform fibrohistiocytic tumor include the following:
- Surgery is the treatment of choice, but local recurrence has been reported in 12% to 50% of cases.[173]
Nerve Sheath Tumors
Malignant peripheral nerve sheath tumor
Malignant peripheral nerve sheath tumors account for 5% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
Risk factors
Malignant peripheral nerve sheath tumor can arise sporadically and in children with neurofibromatosis type 1 (NF1).[174] Among patients with NF1, a family history of malignant peripheral nerve sheath tumor is associated with an increased risk of developing early-onset malignant peripheral nerve sheath tumor.[175]
A rare case of a child with documented neurofibromatosis type 2 (NF2) and a benign neurofibroma had five recurrences. During this time, the lesions progressively lost markers (such as S-100) and acquired clear-cut signs of malignant transformation to malignant peripheral nerve sheath tumor, documented by multiple markers, including the first example of NOTCH2 in this disease.[176]
Molecular features
Molecular features of malignant peripheral nerve sheath tumor include the following:
- Inactivating mutations of SUZ12 have been described in these tumors and are absent in neurofibromas.[177]
- A DNA methylation array for methylome-based and profile-based chromosomal characterization was performed on 171 peripheral nerve sheath tumors.[178] Atypical neurofibromas and low-grade malignant peripheral nerve sheath tumors were indistinguishable, with a common methylation profile and loss of CDKN2A. Epigenomic analysis identified two groups of conventional high-grade malignant peripheral nerve sheath tumor sharing a frequent loss of neurofibromin. The larger group showed an additional loss of trimethylation of H3K27me3. The smaller group of patients with predominantly spinal primary sites showed retention of H3K27me3.
- Genomic profiling was performed on 201 malignant peripheral nerve sheath tumors.[179] Thirteen of 201 tumors demonstrated BRAF alterations.
Prognosis
Features associated with a favorable prognosis include the following:[174,180,181,182]
- Smaller tumor size. In a multivariate analysis, only tumor size and nuclear p53 expression were found to be independent predictors of disease-specific survival.[181]
- Male sex and non-Hispanic White race.[183]
- 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.[181]
- Lower stage.
- Lower histological grade.
- Extremity as the primary site.
Features associated with an unfavorable prognosis include the following:[184]
- High grade.
- Deep tumor location.
- Locally advanced stage at diagnosis.
- Macroscopically incomplete resection (R2).
- Inactivation of p53, either by mutation or amplification of MDM2.[185]
- High expression of p53 and cyclin D1. These markers were identified as adverse prognostic factors using immunohistochemical staining of diagnostic biopsy tissue.[186][Level of evidence: 3iiDi]
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.[181] 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 [180] and unfavorable outcomes.[174,180,182] In the French Sarcoma Group study, NF1 was associated with other adverse prognostic features, but was not an independent predictor of poor outcome.[184] A retrospective analysis of cancer registry data from the Netherlands identified 784 patients with malignant peripheral nerve sheath tumor; 70 of the patients were aged 18 years or younger.[187][Level of evidence: 3iA] In children with NF1, large tumor size was more common (>5 cm, 92.3% vs. 59.1%). Overall, the estimated 5-year survival rate was 52.4% (standard error [SE], 10.1%) for patients with localized malignant peripheral nerve sheath tumor and NF1, compared with 75.8% (SE, 7.1%) for non-NF1 patients.
The Italian Sarcoma Group reported on outcomes after recurrence in 73 children and adolescents with malignant peripheral nerve sheath tumor.[188][Level of evidence: 3iiiA] The median OS after first relapse was 11 months, and the survival rates were 39.2% at 1 year and 15.8% at 5 years. The factors associated with a better prognosis for these patients who relapsed were less initial tumor invasiveness, longer time to relapse, and the achievement of a secondary complete remission (which was related to the feasibility of radical surgery).
The CWS reported a retrospective review of patients with malignant peripheral nerve sheath tumor who were treated on five consecutive CWS trials.[189] A total of 159 patients were analyzed. NF1 was reported in 38 patients (24%). Nodal involvement was documented in 15 patients (9%) at diagnosis, and distant metastases was noted in 15 patients (9%) at diagnosis. Overall, the EFS rate was 40.5% at 5 years and 36.3% at 10 years. The OS rate was 54.6% at 5 years and 47.1% at 10 years. Older age, positive NF1 status, primary tumor site other than extremity, larger tumor size, higher IRS group, presence of metastatic disease, and failure to achieve first complete remission were identified as adverse prognostic factors for EFS and/or OS in the univariate analysis.
Treatment
Treatment options for malignant peripheral nerve sheath tumor include the following:
- Surgery.
- Surgery preceded or followed by radiation therapy.[26,27]
- 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 this tumor reported that 65% of measurable tumors had objective responses to ifosfamide-containing chemotherapy regimens, but the analysis did not conclusively demonstrate improved survival with chemotherapy.[174] This retrospective analysis also noted a trend toward improved outcome with postoperative radiation therapy.[174]
- 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. The PFS rate was 19%, and the 5-year OS rate was 28%.[190]
- The EpSSG performed a prospective study in patients aged 21 years and younger with malignant peripheral nerve sheath tumor.[191] Surgical resection of primary tumors was classified as R0 if the resection was complete with negative microscopic margins, R1 if the margins were microscopically positive, and R2 if the resection left macroscopic residual tumor. Patients were nonrandomly assigned to one of the following four treatment groups:
- Cohort 1: Patients with completely resected tumors (R0) who received surgery only (n = 13); the 5-year EFS rate was 92%.
- Cohort 2: Patients with incompletely resected tumors (R1/R2) who received adjuvant radiation therapy (n = 4); the 5-year EFS rate was 33%.
- Cohort 3: Patients with incompletely resected tumors (R1/R2) who received adjuvant chemotherapy (n = 7); the 5-year EFS rate was 29%.
- Cohort 4: Patients who received either chemotherapy before surgical resection and/or who had nodal involvement (n = 27); the 5-year EFS rate was 52%.
For patients who received chemotherapy, treatment consisted of four courses of ifosfamide/doxorubicin and two courses of ifosfamide concomitant with radiation therapy (50.4–54 Gy). The response rate to chemotherapy (partial response + complete response) in patients with measurable disease was 46%. The presence of NF1 (51% of patients) was an independent poor prognostic factor for OS and EFS.
- In a study of pediatric and adult patients with either sporadic (n = 14) or chemotherapy-naïve, NF1-associated (n = 34), malignant peripheral nerve sheath tumors, patients were treated with two cycles of ifosfamide and doxorubicin and two cycles of ifosfamide and etoposide.[192]
- Response rates were lower in patients with NF1-associated tumors than in patients with sporadic tumors (17.9% vs. 44.4%). However, the premature closure of the study did not allow sufficient power to detect meaningful differences in objective responses between the two groups.
- The rates of stable disease were similar between the two groups.
Recurrent malignant peripheral nerve sheath tumor
Of 120 patients enrolled in Italian pediatric protocols from 1979 to 2004, an analysis identified 73 patients younger than 21 years with relapsed malignant peripheral nerve sheath tumor. The time to relapse from initial diagnosis ranged from 1 month to 204 months, with a median time to relapse of 7 months. Median OS from first relapse was 11 months, with an OS rate of 39% at 1 year and 16% at 5 years. The factors associated with a higher probability of survival after relapse were lower tumor invasiveness at initial presentation, longer time to relapse, and complete surgical resection of the tumor at relapse.[188]
A retrospective study evaluated nine patients with unresectable or metastatic malignant peripheral nerve sheath tumor (seven patients were previously treated) who were treated with selinexor with or without doxorubicin. Three patients experienced a partial response that lasted for 3 months to longer than 8 months, and four patients had stable disease.[193]
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:
Malignant triton tumor
Malignant triton tumors are a variant of malignant peripheral nerve sheath tumors. They occur most often in patients with NF1 and consist of neurogenic and rhabdomyoblastic components. Malignant triton tumors are high-grade malignancies. They usually occur before age 35 years and are very rare in children (case reports only).[194]
Treatment
Malignant triton tumors are not usually responsive to chemotherapy and radiation therapy but have been treated with rhabdomyosarcoma therapy.[194][Level of evidence: 3iiiA] (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)
Ectomesenchymoma
Ectomesenchymoma is a rare nerve sheath tumor that mainly occurs in children. It is a biphenotypic soft tissue sarcoma with both mesenchymal and ectodermal components.
- A retrospective review of six patients with malignant ectomesenchymoma from a single institution identified rhabdomyosarcoma as the mesenchymal element in five of six tumors.[195] Tumors with an alveolar rhabdomyosarcoma morphology exhibited the characteristic translocation. No unifying molecular aberrations were identified.
- A single-institution retrospective review identified seven cases of malignant ectomesenchymoma.[196] All seven patients were male, with a mean age of 7.5 months (range, 0.6–17.0 months). Most patients showed elements of embryonal rhabdomyosarcoma. The mixed neuroectodermal elements were scattered ganglion cells, ganglioneuroma, or ganglioneuroblastoma. Six of seven cases had HRAS mutations. The trimethylation at lysine 27 of histone H3 (H3K27me3), typically lost in malignant peripheral nerve sheath tumor, was retained in all cases. Five of the seven patients in this series were healthy and free of disease at the time of reporting.
Treatment
Treatment options for ectomesenchymoma include the following:
- Surgery.
- Chemotherapy.
- Radiation therapy.
The CWS reported on six patients (ages 0.2–13.5 years) registered over 14 years.[197][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 experienced tumor recurrences with rhabdomyosarcoma features. Although data are scant, it appears that the tumor may respond to chemotherapy.[197]
Pericytic (Perivascular) Tumors
Myopericytoma
Infantile hemangiopericytoma, a subtype of myopericytoma, is a highly vascularized tumor of uncertain origin.
Children younger than 1 year with hemangiopericytoma seem to have a better prognosis than do children older than 1 year with hemangiopericytoma.[198,199,200]
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.[201]
Treatment and outcome
Treatment options for infantile hemangiopericytomas include 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.[202] Eleven children were older than 1 year. Several of these patients had disease in the lymph nodes or lungs. Six patients with stage II or stage III disease progressed and died. Three patients with stage I disease survived, although one patient had recurrence in the lungs. Six patients had infantile hemangiopericytoma, five of which were greater than stage I. All six patients survived, and three patients had good responses to vincristine, actinomycin, and cyclophosphamide.
Several studies have reported on tumors in children that were more akin to infantile myofibromatosis (refer to the Infantile myofibromatosis section of this summary) or hemangiopericytoma.[138,203] Rather than the ETV6-NTRK3 fusion protein seen in congenital infantile fibrosarcoma, a LMNA-NTRK1 fusion protein was identified.[204] One patient carrying this fusion responded to crizotinib.
Infantile myofibromatosis
This entity is a fibrous tumor of infancy and childhood that most commonly presents in the first 2 years of life.[205]
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).[206,207,208,209]
An autosomal dominant form of infantile myofibromatosis has been described. It is associated with germline mutations of the PDGFRB gene, with the R561C variant being most commonly observed.[210,211,212] The R561C variant is a relatively weak activator of PDGFRB, which may explain the presence of additional PDGFRB mutations with stronger activity in some familial infantile myofibromatosis cases.[210,213]
The European Society for Paediatric Oncology Host Genome Working Group developed counseling and germline testing guidelines for these groups of children. This group recommends germline analysis for children with infantile myofibromatosis who have at least one of the following criteria:[214]
- Multicentric disease.
- First- or second-degree relatives with infantile myofibromatosis or soft tissue nodules during childhood.
- A known PDGFR germline variant in the family.
- Suspected germline mosaic PDGFR variants.
Somatic gain-of-function PDGFRB mutations have been identified in sporadic cases of infantile myofibromatosis, including activating point mutations and in-frame indels and duplications.[215,216]PDGFRB mutations are observed in most cases with multicentric nodules, but are less common in cases with solitary myofibroma.[213,216] Some PDGFRB mutations that cause infantile myofibromatosis are sensitive to tyrosine kinase inhibitors like imatinib.[213,216]
Treatment and outcome
These lesions have an excellent prognosis and can regress spontaneously. About one-third of cases with multicentric involvement will also have visceral involvement, and the prognosis for these patients is poor.[208,209,217]
Treatment options for infantile myofibromatosis include the following:
- Chemotherapy.
- Tyrosine kinase inhibitors effective against PDGFRB.
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).[208,209,218]
Case reports have described prompt tumor regression in patients with infantile myofibromatosis that have PDGFRB mutations when treated with tyrosine kinase inhibitors like imatinib and sunitinib, which inhibit the gain-of-function mutated PDGFRB in the tumor.[219,220,221,222]
Tumors of Uncertain Differentiation
Tumors of uncertain differentiation include the following subtypes:
- Synovial sarcoma NOS (spindle cell and biphasic varieties).
- Epithelioid sarcoma.
- Alveolar soft part sarcoma.
- Clear cell sarcoma of soft tissue.
- Extraskeletal myxoid chondrosarcoma.
- Extraskeletal Ewing sarcoma.
- Desmoplastic small round cell tumor.
- Extrarenal rhabdoid tumor.
- Neoplasms with perivascular epithelioid cell differentiation (PEComa) (PEComa NOS, malignant).
Synovial sarcoma NOS
Synovial sarcoma accounts for 9% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
Synovial sarcoma is one of the most common nonrhabdomyosarcomatous soft tissue sarcomas in children and adolescents. In a 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.[223] In addition, in the COG ARST0332 (NCT00346164) and EpSSG 2005 protocols, synovial sarcoma was the single most common histological subtype.[224]
Histological 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.[223] Rarely, a synovial sarcoma may arise in the heart or pericardium or appear with a pleuropulmonary presentation.[225,226,227,228]
The CWS reported on 432 patients younger than 21 years with synovial sarcoma between 1981 and 2018.[229] The study compared three age groups of patients: children (aged 0–12 years; n = 176), adolescents (aged 13–16 years; n = 178), and young adults (aged 17–21 years; n = 78). The proportion of invasive tumors was significantly higher in older patients (children, 33%; adolescents, 39%; and young adults, 54%; P = .009). The proportion of tumors larger than 10 cm (children, 13%; adolescents, 21%; and young adults, 31%; P = .006) and the presence of metastasis at first diagnosis were also higher in older patients (children, 6%; adolescents, 10%; and young adults, 21%; P = .001).
The most common site of metastasis is the lung.[230,231] The risk of metastases is highly influenced by tumor size. Patients with tumors that are larger than 5 cm have an estimated 32-fold higher risk of developing metastases compared with other patients.
Diagnostic evaluation and molecular features
The diagnosis of synovial sarcoma is made by immunohistochemical analysis, ultrastructural findings, and demonstration of the specific chromosomal translocation t(x;18)(p11.2;q11.2). This abnormality is specific for synovial sarcoma and is found in all morphological 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.[232,233] It is thought that the SYT/SSX18 transcript promotes epigenetic silencing of key tumor suppressor genes.[234]
In one report, reduced SMARCB1 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.[235]
Prognosis
Patients younger than 10 years have more favorable outcomes and clinical features than do older patients. Favorable clinical features include extremity primary tumors, smaller tumors, and localized disease.[223,236,237] A meta-analysis also suggested that response to chemotherapy was correlated with improved survival.[238]
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.[239] 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.[240][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 rate of 80% and an EFS rate of 72%.[238] In this analysis, an interaction between tumor size and invasiveness was observed. In multivariate analysis, patients with large or invasive tumors or with IRS group III disease (localized, incompletely resected or with biopsy only) and group IV disease (metastases at diagnosis) had decreased OS. Treatment with radiation therapy was related to improved OS (HR, 0.4; 95% CI, 0.2–0.7). In IRS group III patients, objective response to chemotherapy (18 of 30 [60%]) correlated with improved survival. In adults, factors such as International Union Against Cancer/American Joint Committee on Cancer stage III and stage IVA, tumor necrosis, truncal location, elevated mitotic rate, age, and histologic grade have been associated with a worse prognosis.[241,242,243]
- 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.[244]
- A review of 84 patients with localized synovial sarcoma who had information on fusion status (SYT-SSX) and histological 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).[245][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.[246][Level of evidence: 3iiA]
- The EpSSG designed a genomic index for synovial sarcoma.[247][Level of evidence: 3iiDiii] Genomic index was defined as A2 /C, where A is the total number of alterations (segmental gains and losses) and C is the number of involved chromosomes on array comparative genomic hybridization results. In a multivariate analysis of 61 pediatric, adolescent, and young adult patients (aged <25 years), high genomic index was an independent predictor of decreased EFS and OS.
Treatment
Treatment options for synovial sarcoma include the following:
- Surgery. Radiation therapy and/or chemotherapy may be given before or after surgery.[26,27]
- Chemotherapy.
The COG and the EpSSG 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.[248] 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 rate was 90% (median follow-up, 5.2 years; range, 1.9–9.1). All eight events were local tumor recurrence; no metastatic recurrences were seen. All patients with recurrent disease were effectively treated with second-line therapy, resulting in an OS rate of 100%. Therefore, the authors concluded that a surgery-only approach was optimal for all synovial sarcomas smaller than 5 cm, regardless of grade, and in patients who achieved an R0 resection.
Synovial sarcoma appears to be more sensitive to chemotherapy than many other soft tissue sarcomas. Children with synovial sarcoma seem to have a better prognosis than do adults with synovial sarcoma.[32,231,243,249,250,251,252,253] The most commonly used regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[238,252,254] Response rates to the ifosfamide and doxorubicin regimen are higher than in other nonrhabdomyosarcomatous soft tissue sarcomas.[255]
Studies have reported the following chemotherapy-associated treatment findings:
Recurrent synovial sarcoma NOS
Survival after relapse is poor (30%–40% at 5 years). Factors associated with outcome after relapse include duration of first remission (> or ≤ 18 months) and lack of a second remission.[261,262] In the German experience, surgical resection of metastatic disease was the most common way to achieve a second complete remission.[262] Maintenance chemotherapy with oral trofosfamide, idarubicin, and etoposide or oral cyclophosphamide and intravenous vinblastine was administered on an individual basis.
Radiation therapy (stereotactic body radiation therapy) can be used to target select pulmonary metastases. This is usually considered after a minimum of one resection to confirm metastatic disease. Radiation therapy is particularly appropriate for patients with lesions that threaten air exchange because of their location adjacent to bronchi or cause pain by invading the chest wall.[263]
Between 70% to 80% of synovial sarcomas express NY-ESO-1, an immunogenic cancer testis antigen.[264] NY-ESO-1 can be targeted with adoptive transfer of T cells engineered to express NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) targeting NY-ESO-1/LAGE1a.[265] The procedure to produce the genetically engineered T cells restricts their reactivity to a single HLA type. All clinical trials of this technology chose HLA-A*02 as the initial target and limited eligibility to patients whose tumors expressed NY-ESO-1 and who had HLA-A*02. In a multi-institutional trial, confirmed antitumor responses occurred in 50% of patients (6 of 12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1c259T cells were present postinfusion in all patients, and the cells persisted for at least 6 months in all responders.[266]
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:
- NCT03967223 (Master Protocol to Assess the Safety and Antitumor Activity of Genetically Engineered T Cells in NY-ESO-1 and/or LAGE-1a Positive Solid Tumors): This trial will evaluate the safety and efficacy of human engineered T-cell therapies in participants with advanced tumors.
Epithelioid sarcoma
Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis that displays multilineage differentiation.[267]
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.[268] This abnormality leads to increased dependence on EZH2 and tumor formation.[269]
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 are biopsied. Surgical removal of primary and recurrent tumor(s) is the most effective treatment.[270][Level of evidence: 3iiiA] Because of the propensity of this disease to have occult metastasis to the lymph nodes, sentinel lymph node biopsy is recommended for epithelioid sarcoma of the extremities or buttocks in the absence of clinically (by imaging or physical examination) enlarged lymph nodes.[271]
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. Sixty percent of patients were alive at 5 years after initial diagnosis.[272] A single-institution retrospective review of 20 patients, which included children and adults (median age, 27.3 years), found no difference in the probability of recurrence between patients who received chemotherapy and those who did not receive chemotherapy. The authors suggested that radiation therapy may be useful.[270]
In a German CWS retrospective analysis of 67 children, adolescents, and young adults (median age, 14 years) with epithelioid sarcoma, 53 patients presented with localized disease and 14 patients presented with metastatic disease.[273][Level of evidence: 3iiA] Fifty-eight of 67 patients were treated with primary resections. Resections were microscopically complete in 35 patients, microscopically incomplete in 12 patients, and macroscopically incomplete in 20 patients. Forty-nine patients received chemotherapy, and 33 patients received radiation therapy. Complete remission was achieved in 45 of 53 patients (85%) with localized disease. Twenty-seven patients relapsed after a median time of 0.9 years (range, 0.1–2.3 years). Patients with localized disease had a 5-year EFS rate of 35% (95% CI, ±12%) and an OS rate of 48% (95% CI, ±14%). Patients with metastatic disease had a 5-year EFS rate of 7% (95% CI, ±14%) and an OS rate of 9% (95% CI, ±16%). Smaller tumor size, lower IRS group, less tumor invasiveness, negative nodal status, and microscopically complete resection correlated with a favorable prognosis in patients with localized disease.
A retrospective analysis reviewed COG and EpSSG prospective clinical trials that enrolled patients younger than 30 years with epithelioid sarcoma.[274][Level of evidence: 2A] The analysis identified 63 patients who were treated between July 2005 and November 2015. Patients were stratified into three risk groups using a combination of clinical features and treatment received. Low-risk patients (n = 34) underwent surgery with or without radiation therapy and included predominantly patients with nonmetastatic widely or marginally resected tumors 5 cm or smaller. The intermediate-risk group included patients (n = 16) with nonmetastatic, high-grade, and larger than 5 cm tumors or unresectable tumors. Patients with nodal or distant metastatic disease were at high risk (n = 13) , regardless of tumor grade or size. Partial response was observed in 11 of 22 patients (50%) who received neoadjuvant therapy. Events were local recurrence (n = 10) and distant recurrence (n = 15). The estimated 5-year OS rates were 86.4% for low-risk patients, 63.5% for intermediate-risk patients, and 0% for high-risk patients. Locoregional nodal involvement, invasive tumor, high grade, and lesser extent of resection predicted poorer EFS in patients without metastases.
In a phase II trial of 62 adult patients with epithelioid sarcoma and documented loss of INI1 by immunohistochemistry or biallelic SMARCB1 (the gene that encodes INI1) alterations, tazemetostat showed clinical activity. There were 9 of 62 confirmed partial responses, with an objective response rate of 15% and a disease control rate of 26%. In January 2020, the U.S. Food and Drug Administration granted accelerated approval for tazemetostat for adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma who were not eligible for complete resection.[275]
Alveolar soft part sarcoma
Alveolar soft part sarcomas account for 1.4% of soft tissue sarcomas in patients younger than 20 years (refer to Table 1).
Clinical presentation
The median age at presentation is 25 years for patients with alveolar soft part sarcoma. This tumor most commonly arises in the extremities but can occur in the oral and maxillofacial region.[276,277,278] Alveolar soft part sarcoma in children can present with evidence of metastatic disease.[279] Delayed metastases to the brain and lung are uncommon.[276]
In a series of 61 patients with alveolar soft part sarcoma who were treated in four consecutive CWS trials and the SoTiSaR registry, 46 patients presented with localized disease and 15 patients had evidence of metastasis at diagnosis.[280] Of the nine children younger than 30 years with alveolar soft part sarcoma treated between 1980 and 2014 at four major institutions, the median age at diagnosis was 17 years, and 64% of patients were female. The most common site of disease was the lower extremity, and 26 patients had an ASSPL-TFE3 translocation. The distribution by IRS group was as follows: 19 patients with IRS I disease, 7 patients with IRS II disease, 5 patients with IRS III disease, and 38 patients with IRS IV disease.[281]
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.[282,283]
Prognosis
Alveolar soft part sarcoma in children may have an indolent course.[279] Patients with alveolar soft part sarcoma may relapse several years after a prolonged period of apparent remission.[280,284] Because these tumors are rare, all children with alveolar soft part sarcoma should be considered for enrollment in prospective clinical trials. Information about ongoing clinical trials is available from the NCI website.
In a series of 19 treated patients with alveolar soft part sarcoma, one study reported a 5-year OS rate of 80%. The OS rate was 91% for patients with localized disease, 100% for patients with tumors 5 cm or smaller, and 31% for patients with tumors larger than 5 cm.[285] In another series of 33 patients, the OS rate was 68% at 5 years from diagnosis and 53% at 10 years from diagnosis. Survival was better for patients with smaller tumors (≤5 cm) and completely resected tumors.[286][Level of evidence: 3iiA]
A retrospective review of children and young adults younger than 30 years (median age, 17 years; range, 1.5–30 years) from four institutions identified 69 patients treated primarily with surgery between 1980 and 2014.[281][Level of evidence: 3iiA] The ASPL-TFE3 translocation was present in all 26 patients tested. There were 19 patients with IRS group I tumors (28%), 7 patients with IRS group II tumors (10%), 5 patients with IRS group III tumors (7%), and 38 patients with IRS group IV tumors (55%). The 5-year EFS rate was 80%, and the OS rate was 87% for the 31 patients with localized tumors (IRS postsurgical groups I, II, and III). The 5-year EFS rate was 7%, and the OS rate was 61% for the 38 patients with metastatic tumors (IRS group IV).
In patients with alveolar soft part sarcoma, presentation with metastases is common and often has a prolonged indolent course. In a series of patients treated on consecutive studies from Germany, 15 of 61 patients (25%) presented with metastases, often miliary in nature. Despite lack of response to chemotherapy, the 5-year OS rate was 61%, with an EFS rate of 20%.[280]
Treatment
Treatment options for alveolar soft part sarcoma include the following:
- Surgery.
- Surgery preceded or followed by radiation therapy.[26,27]
- Targeted therapy (tyrosine kinase inhibitors).
- Checkpoint inhibitors.[287]
The standard treatment approach is complete resection of the primary lesion.[285] If complete excision is not feasible, radiation therapy is administered. A study from China reported on 18 patients with alveolar soft part sarcoma of the oral and maxillofacial region. Fifteen patients were younger than 30 years.[278][Level of evidence: 3iiDii] Surgical removal with negative margins was the primary treatment. All patients survived, and only one patient had metastatic disease recurrence.
In a series of patients treated on consecutive studies from Germany, PFS for patients without metastases on presentation appeared to improve with complete resection of the primary tumor. The 5-year EFS rate was 100% for patients with completely resected tumors, compared with 50% for patients with microscopic or gross residual disease.[280]
In a series of 51 pediatric patients aged 0 to 21 years with alveolar soft part sarcoma, the OS rate was 78% at 10 years and the EFS rate was about 63%. Patients with localized disease (n = 37) had a 10-year OS rate of 87%. The 14 patients with metastases at diagnosis had a 10-year OS rate 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.[276][Level of evidence: 3iiiA]
There have been sporadic reports of objective responses to treatment with interferon-alpha and bevacizumab.[276,288,289]
Studies of tyrosine kinase inhibitors have observed the following:
- A small retrospective study of nine adult patients with metastatic alveolar soft part sarcoma treated with sunitinib reported partial responses in five patients and stable disease in two patients.[290][Level of evidence: 3iiiDiv]
- In another study, 15 patients with alveolar soft part sarcoma were treated with sunitinib, and six patients experienced partial responses. The median PFS was 19 months, and the median OS was 56 months. The 5-year OS rate was 49%.[291][Level of evidence: 3iiA] Five patients were treated with sunitinib for longer than 2 years.
- In a phase II trial of cediranib, an inhibitor of all three known vascular epidermal growth factor receptors, 15 of 43 adult patients (35%) with metastatic alveolar soft part sarcoma had partial responses.[292][Level of evidence: 3iiDiv] In a pediatric phase II trial of cediranib, using 70% of the adult maximum tolerated dose in patients younger than 16 years, five of seven patients had stable disease for 14 months or longer.[293][Level of evidence: 2Diii]
- An international group performed a double-blind, placebo-controlled, randomized, phase II trial of cediranib in adolescent and adult patients with alveolar soft part sarcoma.[294][Level of evidence: 1iA] Median percentage change in sum of target marker lesion diameters for the evaluable population was -8.3% (interquartile range [IQR], -26.5 to 5.9) for patients who received cediranib therapy, compared with 13.4% (IQR, 1.1–21.3) for patients who received the placebo (one-sided P = .0010). The authors concluded that cediranib is an active agent in patients with alveolar soft part sarcoma.
- In an open-label trial that evaluated the efficacy of pazopanib in six adult patients, one patient achieved a partial response and five patients had stable disease.[295] In another trial of 30 adult patients treated with pazopanib, one patient experienced a complete response, seven patients experienced partial responses, and 17 patients had stable disease. The median PFS was 13.6 months.[296]
- In one trial, patients with advanced sarcomas were treated with a combination of axitinib (a vascular endothelial growth factor receptor tyrosine kinase inhibitor) and pembrolizumab (an anti–programmed cell death protein 1 immune checkpoint inhibitor).[287] For the 12 patients with alveolar soft part sarcoma, the 3-month PFS rate was 73%. Six of eleven patients with evaluable disease had partial responses to axitinib.
Treatment options under clinical evaluation for alveolar soft part sarcoma
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
- NCT03141684 (Atezolizumab in Treating Patients With Newly Diagnosed and Metastatic Alveolar Soft Part Sarcoma That Cannot Be Removed by Surgery): This phase II trial studies how well atezolizumab works in treating patients with alveolar soft part sarcoma that has not been treated, has spread from where it started to other places in the body, and cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Patients aged 2 years and older are eligible for this trial.
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 histological grade have the best outcomes.[297]
Clinical presentation
The tumor most commonly affects the lower extremity, particularly the foot, heel, and ankle.[298,299] It has a high propensity for nodal dissemination, especially metastases to regional lymph nodes (12%–43%).[299,300] The tumor typically has an indolent clinical course.
Molecular features
Clear cell sarcoma of soft tissue is characterized by an EWSR1-ATF1 or EWSR1-CREB1 fusion.[301,302]
Treatment
Treatment options for clear cell sarcoma of soft tissue include the following:
- Surgery.
- Surgery preceded or followed by radiation therapy.[26,27]
- Targeted therapy.
In a series of 28 pediatric patients reported by the Italian and German Soft Tissue Cooperative Studies, the median age at diagnosis was 14 years and the lower extremity was the most common primary site (50%). Surgery with or without radiation therapy is the treatment of choice and offers the best chance for cure. In this series, 12 of 13 patients with completely resected tumors were cured. For patients with more advanced disease, the outcome is poor and chemotherapy is rarely effective.[303]; [304][Level of evidence: 3iiDii] In a study by the European Organization for Research and Treatment of Cancer, 26 patients with clear cell sarcoma who had metastatic disease and documented EWSR1 rearrangements were treated with crizotinib.[305] One patient achieved a partial response, and 17 patients had stable disease.
Extraskeletal myxoid chondrosarcoma
Extraskeletal myxoid chondrosarcoma is relatively rare among soft tissue sarcomas, representing only 2.3% of all soft tissue sarcomas.[306] It has been reported in children and adolescents.[307]
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.[308]
Prognosis
The tumor has traditionally been considered to have low-grade malignant potential.[309] However, recent reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are monitored for a long time.[310,311] 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.[311]
Treatment
Treatment options for extraskeletal myxoid chondrosarcoma include the following:
- Surgery.
- Radiation therapy.
Aggressive local control and resection of metastases led to OS rates of 87% at 5 years and 63% at 10 years. Tumors were relatively resistant to radiation therapy.[310] The therapeutic benefit of chemotherapy has not been established.
There may be potential genetic targets for small molecules, but these should be studied as part of a clinical trial. In an adult study, six of ten patients who received sunitinib achieved partial responses.[312]
Extraskeletal Ewing sarcoma
(Refer to the PDQ summary on Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment for more information.)
Desmoplastic small round cell tumor
Desmoplastic small round cell tumor is a rare primitive sarcoma.
Clinical presentation
Desmoplastic small round cell tumor most frequently involves the peritoneum in the abdomen, pelvis, and/or peritoneum into the scrotal sac, but it may occur in the kidney or other solid organs.[313,314,315,316,317] Dozens to hundreds of intraperitoneal implants are often found. The tumor occurs predominantly in males (85%) and may spread to the lungs and elsewhere.[317,318]
A large single-institution series of 65 patients compared CT scans (n = 54) with positron emission tomography (PET)-CT scans (n = 11). PET-CT scans had very few false-negative results and detected metastatic sites missed on conventional CT scans.[318]
Molecular features
Cytogenetic studies of these tumors have demonstrated the recurrent translocation t(11;22)(p13;q12), which has been characterized as a fusion of the WT1 and EWSR1 genes.[316,319] The EWSR1-WT1 fusion confirms the diagnosis of desmoplastic small round cell tumor. The average tumor mutational burden is low for desmoplastic small round cell tumor (<1 mutation per megabase), and recurring gene alterations other than the EWSR1-WT1 fusion are uncommon.[320] A small percentage of cases (approximately 3%) have activating mutations in FGFR4, with amplification of FGFR4 observed at similar frequency.[320,321] Inactivating mutations in TP53 and ARID1A are observed in a small percentage of desmoplastic small round cell tumor cases.[320,321]
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.[322,323]; [324][Level of evidence: 3iiiA] Response to neoadjuvant chemotherapy and complete resection (near 100%) is associated with improved outcome.[317,325]
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 usually performed in highly specialized centers, but are critical for any improved survival. Successful treatment modalities include neoadjuvant Ewing-type chemotherapy, followed by complete surgical resection of the extensive intra-abdominal tumors, followed by total abdominal radiation therapy. With this multimodality therapy, survival can be achieved in 30% to 40% of patients at 5 years.[313,314,322,326,327,328,329]
The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to complete surgical resection (cytoreductive surgery) is a new technique first applied to children in 2006 in a phase I clinical trial. Cytoreductive surgery and HIPEC for desmoplastic small round cell tumors is part of a multidisciplinary approach and is only being done in highly specialized centers. Surgeries can last over 12 hours in duration, and technical aspects of this unique tumor resection should be considered. HIPEC is a method of local treatment that may provide more control of the microscopic intra-abdominal disease. The theory is that heat plus the chemotherapy that is instilled in the abdominal cavity after surgical resection (at the time of surgery) provides synergistic cytotoxicity to any microscopic cells remaining in the abdomen.[330]
A single-institution phase II study showed HIPEC to be a potentially promising addition to complete surgical resection. Fourteen patients with desmoplastic small round cell tumor and five patients with other sarcomas were enrolled. These highly selected patients had tumor limited to the abdominal cavity. They demonstrated a partial response to neoadjuvant Ewing-type chemotherapy, had complete surgical resections and received HIPEC using cisplatin, and received adjuvant total-abdominal radiation therapy followed by adjuvant chemotherapy. With this standardized approach, patients with desmoplastic small round cell tumors had an OS rate of 80% at 30 months and 40% at 50 months. Patients with desmoplastic small round cell tumors without liver metastasis had no intra-abdominal recurrences, whereas 87% of patients with liver metastasis or portal disease had a recurrence.[330]
Other centers have used this approach of cytoreductive surgery and HIPEC in patients with desmoplastic small round cell tumors. In a retrospective study from centers in France, patients were treated with cytoreductive surgery and HIPEC. Twenty-two patients were selected, and the median age at diagnosis was 14.8 years (range, 4.2–17.6 years). Seven patients had peritoneal mesotheliomas, seven patients had desmoplastic small round cells tumors, and eight patients had other histological types. A complete macroscopic resection (CC-0, where CC is completeness of cytoreduction) was achieved in 16 cases (73%). Sixteen patients (72%) relapsed after a median time of 9.6 months (range, 1.4–86.4 months). Nine patients (41%) died of disease relapse after a median time of 5.3 months (range, 0.1–36.1 months). Not all of the seven patients with desmoplastic small round cell tumors had complete resections.[331][Level of evidence: 3iii]
Another study from France reviewed the use of cytoreductive surgery and HIPEC for the treatment of patients with desmoplastic small round cell tumors who had disease limited to the abdomen. In 107 patients with desmoplastic small round cell tumors, 48 had no extraperitoneal metastasis and underwent cytoreductive surgery. Of 48 patients, 38 patients (79%) received preoperative and/or postoperative chemotherapy, and 23 patients (48%) received postoperative whole-abdominopelvic radiation therapy. Intraperitoneal chemotherapy was administered to 11 patients (23%); two patients received early postoperative intraperitoneal chemotherapy (EPIC) and nine patients received HIPEC. After a median follow-up of 30 months, the median OS of the entire cohort was 42 months. The 2-year OS rate was 72%, and the 5-year OS rate was 19%. The 2-year DFS rate was 30%, and the 5-year DFS rate was 12%. Whole-abdominopelvic radiation therapy was the only variable associated with longer peritoneal recurrence-free survival and DFS after cytoreductive surgery. Of 11 patients who received intraperitoneal chemotherapy (HIPEC or EPIC), six different chemotherapy regimens were used. The survival or outcome of this group is not reported in the manuscript. The influence of HIPEC/EPIC on OS and DFS was not statistically significant, but standardized regimens were not used in all patients, making results difficult to determine.[332]
A single-institutional retrospective study reported on nine patients with desmoplastic small round cell tumor. Most patients had widespread disease, including four patients with extraabdominal disease and five patients with liver involvement. These nine patients underwent ten cytoreductive and HIPEC treatments. Additionally, seven patients also received radiation therapy, and three patients underwent stem cell transplantation. The 3-year relapse-free survival rate was 13%, and the OS rate was 55%. Therapy was often associated with prolonged hospitalizations. Long-term parenteral nutrition was required in eight patients for a median of 261 days. Other long-term complications included gastroparesis (n = 1), small bowel obstruction (n = 3), and hemorrhagic cystitis (n = 2).[333]
The Center for International Blood and Marrow Transplant Research analyzed patients with desmoplastic small round cell tumor in their registry who received consolidation with high-dose chemotherapy and autologous stem cell reconstitution.[334] While this retrospective registry analysis suggested some benefit to this approach, other investigators have abandoned the approach because of excessive toxicity and lack of efficacy.[322]
A single-institution study reported that five of five patients with recurrent desmoplastic small round cell tumor had partial responses to treatment with the combination of vinorelbine, cyclophosphamide, and temsirolimus.[335]
Extrarenal (extracranial) rhabdoid tumor
Malignant rhabdoid tumors were first described in children with renal tumors in 1981 (refer to the Rhabdoid Tumors of the Kidney section in the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information). These tumors 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 sarcomas 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.[336] 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.[337] Rhabdoid tumors may be associated with germline mutations of the SMARCB1 gene and may be inherited from an apparently unaffected parent.[338] This observation was extended to 32 malignant rhabdoid tumors at all sites in patients whose mean age at diagnosis was 12 months.[339]
Prognosis
A SEER study examined 229 patients with renal, central nervous system (CNS), and extrarenal malignant rhabdoid tumor. Patient age of 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. The OS rate was 33% at 5 years.[340]
A European registry for extracranial rhabdoid tumors identified 100 patients from 14 countries between 2009 and 2018.[341] Half of the patients were younger than 1 year at diagnosis. In 30 patients (30%), the tumor was located in the kidneys. Extracranial, extrarenal malignant rhabdoid tumor was found in 70% of patients (70 of 100), and the most common locations were in the cervical region, thoracic region, and liver. Nine patients demonstrated synchronous tumors. Distant metastases at diagnosis were present in 35% of patients (35 of 100). SMARCB1 germline mutations were detected in 21% of patients (17 of 81 evaluable). The 5-year OS rate was 45.8% (± 5.4%), and the EFS rate was 35.2% (± 5.1%). In an adjusted multivariate model, presence of a germline mutation, metastasis, and lack of a gross-total resection were the strongest significant negative predictors of outcome.
Treatment
Treatment options for extrarenal (extracranial) rhabdoid tumor include the following:[342][Level of evidence: 3iA]; [343,344][Level of evidence: 3iiiB]
- Surgical removal when possible.
- Chemotherapy as used for soft tissue sarcomas (but no single regimen is currently accepted as best).
- Radiation therapy.
Responses to alisertib have been documented in four patients with CNS atypical teratoid/rhabdoid tumors.[345] (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:
Neoplasms with perivascular epithelioid cell differentiation (PEComas)
Risk factors and molecular features
Benign PEComas are common in patients with 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.[346] Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of nonsurgically curable tumors with similar genetic inactivation (lymphangioleiomyomatosis and angiomyolipoma) with mTOR inhibitors.[347,348] A small proportion of PEComas have TFE3 rearrangements with fusions involving various genes, including SFPQ/PSF and RAD51B.[349]
Clinical presentation
PEComas occur in various rare gastrointestinal, pulmonary, gynecological, and genitourinary sites. Soft tissue, visceral, and gynecological PEComas are more commonly seen in middle-aged female patients and are usually not associated with the tuberous sclerosis complex.[350] 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.[351]
Treatment
Treatment options have not been defined. Treatment may include surgery or observation followed by surgery when the tumor is large.[352]
In tumors with evidence of mTORC1 activation and TSC loss, including lymphangioleiomyomatosis and angiomyolipoma,[347] clinical activity using mTOR inhibitors, such as sirolimus, has been well documented. Similarly, three adult patients with PEComas responded to sirolimus.[353]
Undifferentiated/Unclassified Sarcoma
From 1972 to 2006, patients with undifferentiated soft tissue sarcoma were eligible for participation in rhabdomyosarcoma trials coordinated by the IRS group and the COG. The rationale was that patients with undifferentiated soft tissue sarcoma had sites of disease and outcomes that were similar to those in patients with alveolar rhabdomyosarcoma. Therapeutic trials for adults with soft tissue sarcoma include patients with undifferentiated soft tissue sarcoma and other histologies, which are treated similarly, using ifosfamide and doxorubicin, and sometimes with other chemotherapy agents, surgery, and radiation therapy.
In the COG ARST0332 (NCT00346164) trial, patients with high-grade undifferentiated sarcoma were treated with an ifosfamide- and doxorubicin-based regimen. Results for the patients with high-grade undifferentiated sarcoma were reported together with all high-grade soft tissue sarcomas in the trial. The estimated 5-year EFS rate was 64% and the OS rate was 77% for sarcomas classified as high grade by the Fédération Nationale des Centres de Lutte Contre le Cancer.[224][Level of evidence: 3iiA]
In a report of 32 patients with undifferentiated soft tissue sarcomas who were enrolled on the ARST0332 (NCT00346164) trial, the median age at enrollment was 13.6 years, and two-thirds of the patients were male. The most common primary sites were the paraspinal region and extremities. Five patients presented with metastatic disease.[354]
- The 5-year EFS rate was 71%, and the OS rate was 83%.
- Of the nine children with low-risk disease (localized low-grade resected disease or localized high-grade disease <5 cm resected with negative margins) who were treated with surgery or radiation therapy only, the 5-year EFS rate was 65% and the OS rate was 100%, suggesting that patients with recurrent disease can be salvaged with additional therapy.
- The remaining 23 patients had either intermediate-risk disease (resected high-grade tumor >5 cm, unresected high-grade tumor >5 cm) or high-risk disease (metastasis to lymph nodes or distant sites) and were treated with chemoradiation therapy and delayed surgery when feasible. The 5-year EFS rate was 73%, and the OS estimate was 77%.
- Copy number aberrations were common, most frequently involving loss of 1p (25%), gain of 1q (25%), gain of chromosome 8 (25%), and gain of chromosome 2 (16%). These alterations were more commonly seen in patients with intermediate-risk or high-risk tumors, and there was a strong association between loss of chromosome 1p or gain of chromosome 1q and inferior clinical outcomes. Co-occurrence of 1q gain and 1p loss was associated with a particularly poor clinical outcome (5-year EFS and OS rates of 20%). Next-generation sequencing identified oncogenic fusions in eight of ten samples, which included BCOR and CIC rearrangements, as well as COL1A1-PDGFB, KIAA1549-BRAF, and SAMD-SASH1 fusions.
Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (high-grade)
At one time, malignant fibrous histiocytoma was the single most common histotype among adults with soft tissue sarcomas. Since it was first recognized in the early 1960s, malignant fibrous histiocytoma has been controversial, in terms of both its histogenesis and its validity as a clinicopathological 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.[11,355]
This entity accounts for 2% to 6% of all childhood soft tissue sarcomas.[356]
Molecular features
An analysis of 70 patients who were diagnosed with malignant fibrous histiocytosis of no specific type, storiform or pleomorphic malignant fibrous histiocytoma, pleomorphic sarcoma, or undifferentiated pleomorphic sarcoma showed a highly complex karyotype with no specific recurrent aberrations.[357]
Undifferentiated sarcomas with 12q13–15 amplification, including MDM2 and CDK4, are best classified as dedifferentiated liposarcomas.[357] The relationship between this tumor and the family of undifferentiated/unclassified tumors with spindle cell morphology remains relatively undefined.
Risk factors
These tumors can arise in previously irradiated sites or as a second malignancy in patients with retinoblastoma.[358]
Clinical presentation and treatment
These tumors occur mainly in the second decade of life. In a series of ten patients, the median age was 10 years and the tumor was most commonly located in the extremities. In this series, all tumors were localized, and five of nine patients (for whom follow-up was available) were alive and in first remission.[356] 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.[359] 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 Undifferentiated Pleomorphic Sarcoma of Bone Treatment for more information about the treatment of malignant fibrous histiocytoma of bone.)
Treatment of recurrent or refractory pleomorphic sarcoma
Treatment options for recurrent or refractory pleomorphic sarcoma include the following:
- Pembrolizumab.
The Sarcoma Alliance for Research through Collaboration conducted a phase II trial of the checkpoint inhibitor pembrolizumab in patients aged 18 years and older with recurrent soft tissue sarcoma.[360][Level of evidence: 3iiDiv] Seven of 40 patients (18%) with soft tissue sarcoma had an objective response. Four of ten patients (40%) with undifferentiated pleomorphic sarcoma, two of ten patients (20%) with liposarcoma, and one of ten patients (10%) with synovial sarcoma had objective responses. No patients with leiomyosarcoma (n = 10) had an objective response.
Undifferentiated small round cell sarcomas withBCORgenetic alterations
(Refer to the Undifferentiated Small Round Cell Sarcomas With BCOR Genetic Alterations and Genomics of Ewing Sarcoma sections of the PDQ summary on Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment for more information.)
Undifferentiated small round cell sarcomas withCICgenetic alterations
(Refer to the Undifferentiated Small Round Cell Sarcomas With CIC Genetic Alterations and Genomics of Ewing Sarcoma sections of the PDQ summary on Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment for more information.)
Undifferentiated small round cell sarcomas withEWSR1–non-ETS fusions
(Refer to the Undifferentiated Small Round Cell Sarcomas With EWSR1–non-ETS Fusions section of the PDQ summary on Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment for more information.)
Vascular Tumors
Vascular tumors vary from hemangiomas, which are always considered benign, to angiosarcomas, which are highly malignant.[361] Malignant vascular tumors include the following subtypes:
- Epithelioid hemangioendothelioma.
- Angiosarcoma of the soft tissue.
Epithelioid hemangioendothelioma
Incidence and outcome
Epithelioid hemangioendothelioma was first described in soft tissue by Weiss and Enzinger in 1982. These tumors can occur in younger patients, but the peak incidence is in the fourth and fifth decades of life. The tumors can have an indolent or very aggressive course, with an overall survival rate of 73% at 5 years. There are case reports of patients with untreated multiple lesions who have a very benign course. However, other patients have a very aggressive course. Some pathologists have tried to stratify patients to evaluate risks and adjust treatment, but more research is needed.[362,363,364,365,366,367,368]
A multi-institutional case series reported on 24 patients aged 2 to 26 years with epithelioid hemangioendotheliomas.[369][Level of evidence: 3iiiDii] Most patients presented with multiorgan disease. Progression was seen in 63% of patients, with a mean time to progression of 18.4 months (range, 0–72 months).
The presence of effusions, tumor size larger than 3 cm, and a high mitotic index (>3 mitoses/50 high-power fields) have been associated with unfavorable outcomes.[364]
Clinical presentation and diagnostic evaluation
Common sites of involvement are liver alone (21%), liver plus lung (18%), lung alone (12%), and bone alone (14%).[364,370,371] Clinical presentation depends on the 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. These may be incidental findings in asymptomatic patients, but most patients commonly present with signs or symptoms of cholestasis, including pruritus, jaundice, or scleral icterus.
- 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.
Histopathology and molecular features
A WWTR1-CAMTA1 gene fusion has been found in most patients. Less commonly, a YAP1-TFE3 gene fusion has been reported.[362] These fusions are not directly targetable with current medications. 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.[364]
The number of pediatric patients reported in the literature is limited.
Treatment of epithelioid hemangioendothelioma
Treatment options for epithelioid hemangioendothelioma include the following:
- Observation.
- Surgery.
- Immunotherapy.
- Targeted therapy.
- Chemotherapy.
- Radiation therapy.
For indolent cases, observation is warranted. Surgery is performed when resection is possible. Liver transplant has been used with aggressive liver lesions, both with and without metastases.[364,372,373,374]
For more aggressive cases, multiple medications have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus.[372,375,376] The most aggressive cases are treated with angiosarcoma-type chemotherapy.
A multi-institutional case series reported on 24 patients aged 2 to 26 years with epithelioid hemangioendothelioma.[369][Level of evidence: 3iiiDii] Three patients who were treated with sirolimus achieved stable disease or a partial response for more than 2.5 years. A report from 2020 that investigated sirolimus treatment in children aimed to add to the previous experience of sirolimus in adults. A retrospective review identified six pediatric patients with disseminated epithelioid hemangioendothelioma who were treated with sirolimus. Four of the six patients demonstrated partial responses or disease stabilization.[377]
Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Treatment options under clinical evaluation for epithelioid hemangioendothelioma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is 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.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Angiosarcoma of the soft tissue
Incidence and clinical presentation
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 soft tissues. Angiosarcoma has an estimated incidence of 2 cases per 1 million people. In the United States, it affects approximately 600 people annually, who are typically aged 60 to 70 years.[378]
Angiosarcomas are extremely rare in children. It is unclear if the pathophysiology of angiosarcomas in children differs from that of angiosarcomas in adults. Cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive.[379,380,381,382] 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 the following:[383]
- Vinyl chloride exposure.
- Radiation exposure.
- Chronic lymphedema from any cause, including Stewart-Treves syndrome.
Histopathology and molecular features
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%.[383]
Histopathological diagnosis can be very difficult because there can be areas of varied atypia. A common feature of angiosarcoma 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 outdated terminology proposed in 1971 (e.g., type I hemangioendothelioma: infantile hemangioma; type II hemangioendothelioma: low-grade angiosarcoma; type III hemangioendothelioma: high-grade angiosarcoma).[380]
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 can be cured by aggressive surgery. Complete surgical excision appears to be crucial for the long-term survival of patients with angiosarcomas and lymphangiosarcomas, despite evidence of tumor shrinkage in some patients who were treated with local or systemic therapy.[381,384,385,386] A review of 222 patients (median age, 62 years; range, 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. The 5-year DSS rate was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.[386] Data on liver transplant for localized angiosarcomas are limited.[387][Level of evidence: 3iiA]
Localized disease, especially cutaneous angiosarcomas, can be treated with radiation therapy. Most of these reported cases are in adults.[388]
Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative.[389,390] Disease control is the objective in patients with metastatic angiosarcomas. Published progression-free survival is between 3 months and 7 months,[391] and the median overall survival (OS) is 14 to 18 months.[392] In both adults and children, the 5-year OS rates are between 20% and 35%.[381,382,393]
One child who was diagnosed with angiosarcoma secondary to malignant transformation from infantile hemangioma responded to treatment with bevacizumab (a monoclonal antibody against vascular endothelial growth factor) combined with systemic chemotherapy.[379,389] A report of eight cases of liver angiosarcomas in children highlighted the misuse of the term hemangioendothelioma and the importance of early diagnosis and treatment of these tumors.[394]
Biologic agents that inhibit angiogenesis have shown activity in adults with angiosarcomas.[380,393]
There is one case report of a pediatric patient with metastatic cardiac angiosarcoma who was successfully treated with conventional chemotherapy, radiation, surgery, and targeted therapies, including pazopanib.[395]
Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.
Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Treatment options under clinical evaluation for 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:
- NCT02834013 (Nivolumab and Ipilimumab in Treating Patients With Rare Tumors): This is a phase II study of nivolumab and ipilimumab to treat patients with rare tumors. Immunotherapy with monoclonal antibodies such as nivolumab and ipilimumab may help the body's immune system attack the cancer and may interfere with the ability of the tumor cells to grow and spread.
- Alliance A091902 (NCT04339738) (Testing the Addition of Nivolumab to Chemotherapy in Treatment of Soft Tissue Sarcoma): This trial is for patients who have histologically confirmed cutaneous or visceral angiosarcoma, where curative treatment is either not possible or curative modality therapy has been declined by the patient. Patients must be aged 18 years or older. Taxane-naïve patients will be randomly assigned to receive either paclitaxel and nivolumab or paclitaxel. If patients progress on the paclitaxel arm, they can cross over to the cabozantinib and nivolumab arm. Patients who were previously treated with a taxane will be treated on the cabozantinib and nivolumab arm.
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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