Treatment of Tumors of Uncertain Differentiation
Tumors of uncertain differentiation have many subtypes, including the following:
- Myxoma not otherwise specified (NOS) (benign).
- Synovial sarcoma NOS (poorly differentiated, spindle cell, and biphasic varieties).
- Epithelioid sarcoma.
- Alveolar soft part sarcoma.
- Clear cell sarcoma NOS.
- Extraskeletal myxoid chondrosarcoma.
- Desmoplastic small round cell tumor.
- Rhabdoid tumor NOS (extrarenal).
- Perivascular epithelioid tumor (PEComa), malignant.
- Undifferentiated sarcoma.
- Pleomorphic sarcoma, undifferentiated.
- Round cell sarcoma, undifferentiated.
Myxoma NOS
Carney complex
Carney complex is an autosomal dominant syndrome caused by variants in the PRKAR1A gene, located on chromosome 17.[1] The syndrome is characterized by cardiac and cutaneous myxomas, pale brown to brown lentigines, blue nevi, primary pigmented nodular adrenocortical disease causing Cushing syndrome, and a variety of endocrine and nonendocrine tumors, including pituitary adenomas, thyroid tumors, and large cell calcifying Sertoli cell tumor of the testis.[1,2,3] There are published surveillance guidelines for patients with Carney complex that include cardiac, testicular, and thyroid ultrasonography.
For patients with the Carney complex, prognosis depends on the frequency of recurrences of cardiac and skin myxomas and other tumors.
For more information about the treatment of conditions related to Carney complex, see the following summaries:
- Childhood Cardiac Tumors Treatment.
- Childhood Testicular Cancer Treatment.
- Childhood Thyroid Cancer Treatment.
Synovial Sarcoma NOS (Poorly Differentiated, Spindle Cell, and Biphasic Varieties)
Synovial sarcoma accounts for 9% of soft tissue sarcomas in patients younger than 20 years (see Table 1).
Synovial sarcoma is one of the most common nonrhabdomyosarcomatous soft tissue sarcoma (NRSTS) in children and adolescents. In a review of the Surveillance, Epidemiology, and End Results (SEER) Program database 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.[4] In addition, in the Children's Oncology Group (COG) ARST0332 (NCT00346164) and European paediatric Soft Tissue Sarcoma Study Group (EpSSG) 2005 protocols, synovial sarcoma was the single most common histological subtype.[5]
Clinical presentation
The most common primary tumor location is the extremities, followed by trunk and head and neck.[4] Rarely, a synovial sarcoma may arise in the heart or pericardium or appear with a pleuropulmonary presentation.[6,7,8,9]
The most common site of metastasis is the lung.[10,11] 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.
The Cooperative Weichteilsarkom Studiengruppe (CWS) reported on 432 patients younger than 21 years diagnosed with synovial sarcoma between 1981 and 2018.[12] 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).
Histological features, diagnostic evaluation, and genomic alterations
Synovial sarcoma can be subclassified as the following types:
- Synovial sarcoma, spindle cell.
- Synovial sarcoma, biphasic.
- Synovial sarcoma, poorly differentiated.
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 SS18 gene on chromosome 18 with one of the subtypes (1, 2, or 4) of the SSX gene on chromosome X.[13,14] It is thought that the SS18::SSX fusion transcript promotes epigenetic silencing of key tumor suppressor genes.[15]
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.[16]
Prognostic factors
Favorable prognostic factors
Patients younger than 10 years have more favorable outcomes and clinical features than do older patients.
Favorable clinical features include the following:[4,17,18,19]
- Extremity primary tumors.
- Smaller tumors.
- Localized disease.
- Response to chemotherapy was correlated with improved survival in one meta-analysis.
Unfavorable prognostic factors
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 event-free survival (EFS).[20] 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 overall survival (OS).[21][Level of evidence C1]
- A multicenter analysis of 219 children from various treating centers, including Germany, St. Jude Children's Research Hospital (SJCRH), Instituto Tumori, and MD Anderson Cancer Center, reported an estimated 5-year OS rate of 80% and an EFS rate of 72%.[19] In this analysis, an interaction between tumor size and invasiveness was observed. In multivariate analysis, patients with large or invasive tumors or with Intergroup Rhabdomyosarcoma Study (IRS) group III disease (localized, incompletely resected or with biopsy only) and group IV disease (metastases at diagnosis) had decreased OS. Treatment with radiation therapy was related to improved OS (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2–0.7). In IRS group III patients, objective response to chemotherapy (18 of 30 [60%]) correlated with improved survival.
- 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.[22]
- A review of 84 patients with localized synovial sarcoma who had information on fusion status (SS18::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). Patients with tumors larger than 10 cm had an even worse OS (P = .0003).[23][Level of evidence C1]
- The German CWS group reviewed 27 evaluable patients younger than 21 years with pulmonary metastases among 296 patients with synovial sarcoma. All patients had metastasis to the lungs. 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.[24][Level of evidence C1]
- The EpSSG designed a genomic index for synovial sarcoma.[25][Level of evidence C2] 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.
- In adults, factors such as International Union Against Cancer/American Joint Committee on Cancer stage III and stage IVA, poor tumor necrosis, truncal location, elevated mitotic rate, older age, and higher histological grade have been associated with a worse prognosis.[26,27,28]
Treatment of synovial sarcoma
Treatment options for synovial sarcoma include the following:
- Surgery alone.
- Surgery and chemotherapy, with or without radiation therapy.[29,30]
Surgery alone
Evidence (surgery alone):
- 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.[31] 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 patients who achieved an R0 resection (complete resection with negative microscopic margins) and had tumors smaller than 5 cm, regardless of grade.
Surgery and chemotherapy, with or without radiation therapy
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.[11,28,32,33,34,35,36,37]
The most commonly used chemotherapy regimens for the treatment of synovial sarcoma incorporate ifosfamide and doxorubicin.[19,35,38] Response rates to the ifosfamide and doxorubicin regimen are higher than in other NRSTS.[39]
Evidence (surgery and chemotherapy with or without radiation therapy):
- Several treatment centers advocate chemotherapy after resection and radiation therapy for children and young adults with synovial sarcoma.[19,20,40,41,42]
- The International Society of Pediatric Oncology-Malignant Mesenchymal Tumors studies showed that select patients (young age, <5 cm resected tumors) with nonmetastatic synovial sarcoma treated with chemotherapy can have excellent outcomes in the absence of radiation therapy. However, it is still unclear whether that approach obviates an advantage of radiation for local or regional control.[41]
- A German trial suggested a benefit for postoperative chemotherapy in children with synovial sarcoma.[42]
- A meta-analysis also suggested that chemotherapy may provide benefit.[19]
- The COG reported an analysis of the subset of patients with synovial sarcoma treated on the ARST0332 (NCT00346164) trial. This was a prospective treatment assignment trial for patients younger than 30 years with NRSTS.[43] They analyzed the outcomes of 138 eligible patients.
- Overall, R0 resection or R1 resection (microscopically positive margins) of the primary tumor was achieved in 129 patients (93.5%): 69 patients (53.5%) at study entry and 60 patients (46.5%) after neoadjuvant chemotherapy. Of these, 104 patients (80.6%) had an R0 resection: 55 patients (53%) at study entry and 49 patients (47%) after neoadjuvant chemotherapy.
- In the 60 patients who received neoadjuvant chemotherapy, response was evaluable in 55 patients. Two patients (3.6%) had a complete response, 9 (16.4%) had a partial response, 41 (74.6%) had stable disease, and 3 (5.5%) had progressive disease. The tissue from 57 tumors was centrally reviewed after definitive resection. Forty-one tumors (72%) had less than 90% necrosis, and 16 tumors (28%) had 90% necrosis or more.
- For the 46 patients in the low-risk group, the 5-year EFS rate was 81.9% (95% CI, 69%–94.8%), and the OS rate was 97.7% (95% CI, 92.7%–100%).
- For the 23 patients in the intermediate-risk group (treatment arm C), the 5-year EFS rate was 64% (95% CI, 42.4%–85.8%), and the OS rate was 89.5% (95% CI, 75.3%–100%).
- For the 49 patients in the intermediate-risk group (treatment arm D), the 5-year EFS rate was 71.2% (95% CI, 56.5%–85.9%), and the OS rate was 86.5% (95% CI, 75.6%–97.3%).
- For the 21 patients in the high-risk group, the 5-year EFS rate was 7.6% (95% CI, 0%–22%), and the OS rate was 12.5% (95% CI, 0%–28.7%).
- The EpSSG performed a prospective study of patients younger than 21 years with synovial sarcoma (CCLG-EPSSG-NRSTS-2005 [NCT00334854]).[44][Level of evidence C1] Patients were stratified into the following three risk groups and nonrandomly assigned to treatment by risk group:
- Low-risk patients had IRS group I tumors less than 5 cm in size and nonaxial primary tumors.
- Intermediate-risk patients had no axial primary tumors and IRS group I tumors greater than 5 cm or IRS group II tumors.
- High-risk patients included all patients with axial primary sites (head and neck, lung and pleura, trunk, retroperitoneal), IRS group III tumors, or N1 tumors.
Outcomes for patients treated on the CCLG-EPSSG-NRSTS-2005 trial are described in Table 10.
Table 10. Event-Free Survival (EFS) and Overall Survival (OS) in Patients With Low-, Intermediate-, and High-Risk Synovial Sarcoma Treated on the CCLG-EPSSG-NRSTS-2005 Trial
| Risk Group |
Treatment |
3-Year EFS (%) |
3-Year OS (%) |
| IRS = Intergroup Rhabdomyosarcoma Study; RT = radiation therapy. |
| a Chemotherapy was ifosfamide/doxorubicin, with doxorubicin omitted during radiation therapy. |
| b 59.4 Gy in cases without the option of secondary resection; 50.4 Gy as preoperative radiation therapy; 50.4, 54, and 59.4 Gy as postoperative radiation therapy, in the case of R0, R1, and R2 resections, respectively (no additional radiation therapy in the case of secondary complete resections with free margins, in children younger than 6 years). |
| Low |
Surgery alone |
92 |
100 |
| Intermediate |
Surgery, 3–6 cycles chemotherapya, ± RTb |
91 |
100 |
| High (IRS group III) |
3 cycles of chemotherapya, surgery, 3 additional cycles of chemotherapy, ± RTb |
77 |
94 |
| High (axial primary sites) |
Surgery, 6 cycles of chemotherapya, RTb |
78 |
100 |
- The CWS reported results from a prospective trial for the treatment of patients with synovial sarcoma. Eligibility was restricted to patients with localized tumors with macroscopic residual disease after first surgery, before the initiation of systemic therapy (IRS III) and no clinically detectable metastatic disease. There were 145 patients in the study with a median age of 14.5 years (range, 0.2–33.2 years). The protocols recommended but did not require radiation therapy to be given before definitive tumor resection. Radiation therapy was administered to 115 patients (79%), and 23 patients did not receive radiation therapy (no information documented for 7 patients). Of the 115 irradiated patients, 57 were irradiated before tumor excision and 52 after tumor excision.[45]
- In this nonrandomized comparison, the sequencing of radiation therapy before definitive resection was associated with a statistically significant improvement in local recurrence-free survival rates, compared with definitive surgery before radiation therapy.
- Omission of radiation therapy was associated with an inferior outcome.
- Outcomes for patients are described in Table 11.
Table 11. Effects of Radiation Therapy Timing on Outcomes of Patients With Synovial Sarcoma
| Radiation Therapy |
# Patients |
5-Year EFS Rate |
5-Year OS Rate |
5-Year Local Recurrence-Free Survival Rate |
| EFS= event-free survival; OS = overall survival. |
| No radiation therapy |
23 |
44% |
57% |
76% |
| Radiation therapy before surgery |
57 |
70% |
83% |
98% |
| Radiation therapy after surgery |
52 |
73% |
82% |
86% |
Recurrent synovial sarcoma NOS
For patients with recurrent synovial sarcoma, the survival rate 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.[46,47]
In a German experience, surgical resection of metastatic disease was the most common way to achieve a second complete remission.[47] 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.[48]
Between 70% to 80% of synovial sarcomas express NY-ESO-1, an immunogenic cancer testis antigen.[49] 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.[50] 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.[51]
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Epithelioid Sarcoma
Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis that displays multilineage differentiation.[52]
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.
Genomic alterations
Epithelioid sarcoma is characterized by inactivation of the SMARCB1 gene, which is present in both conventional and proximal types of epithelioid sarcoma.[53] This abnormality leads to increased dependence on EZH2 and tumor formation.[54]
Treatment of epithelioid sarcoma
Treatment options for epithelioid sarcoma include the following:
- Surgery with or without chemotherapy and/or radiation therapy.
- Targeted therapy.
Surgery with or without chemotherapy and/or radiation therapy
Surgical removal of primary and recurrent tumor(s) is the most effective treatment.[55][Level of evidence C1] 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.[56]
Evidence (surgery with or without chemotherapy and/or radiation therapy):
- 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.[57][Level of evidence C1] 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.[58][Level of evidence B4] 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.
- A review of 30 pediatric patients with epithelioid sarcoma (median age at presentation, 12 years) reported the following results:[59]
- Responses to chemotherapy were reported in 40% of patients using sarcoma-based treatment regimens.
- Sixty percent of patients were alive at 5 years after initial diagnosis.
- A single-institution retrospective review of 20 patients, which included children and adults (median age, 27.3 years), reported the following:[55]
- There was 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.
Targeted therapy
Evidence (tazemetostat):
- 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.[60]
- 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 (FDA) 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.
Treatment options under clinical evaluation for epithelioid sarcoma
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
- PEPN2121 (NCT05286801) (Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1- or SMARCA4-Deficient Tumors): This study is evaluating the combination of a PD-L1 targeting antibody (atezolizumab) with a TIGIT targeting antibody (tiragolumab) for patients with SMARCB1- or SMARCA4-deficient tumors. Patients with epithelioid sarcoma may be eligible for this study.
Alveolar Soft Part Sarcoma
Alveolar soft part sarcomas account for 1.4% of soft tissue sarcomas in patients younger than 20 years (see 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.[61,62,63] Alveolar soft part sarcoma in children can present with evidence of metastatic disease.[64] Delayed metastases to the brain and lung are uncommon.[61]
In a series of 61 patients with alveolar soft part sarcoma who were treated in four consecutive CWS trials and the Soft Tissue Sarcoma Registry (SoTiSaR), 46 patients presented with localized disease and 15 patients had evidence of metastasis at diagnosis.[65]
Sixty-nine patients younger than 30 years with alveolar soft part sarcoma were treated between 1980 and 2014 at four major institutions. The median age at diagnosis was 17 years, and 64% of patients were female. The most common site of disease was the lower extremity, and 26 patients had an ASPSCR1::TFE3 gene translocation.[66]
Genomic alterations
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.[67,68]
Prognosis
In patients with alveolar soft part sarcoma, presentation with metastases is common and often has a prolonged indolent course.
Alveolar soft part sarcoma in children may have an indolent course.[64] Patients with alveolar soft part sarcoma may relapse several years after a prolonged period of apparent remission.[65,69]
- 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.[70]
- 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.[71][Level of evidence C1]
- 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.[66][Level of evidence C1] The ASPSCR1::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 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%.[65]
Treatment of alveolar soft part sarcoma
Treatment options for alveolar soft part sarcoma include the following:
- Surgery with or without radiation therapy and chemotherapy.[29,30]
- Targeted therapy (tyrosine kinase inhibitors and checkpoint inhibitors).[72]
Surgery with or without radiation therapy and chemotherapy
The standard treatment approach is complete resection of the primary lesion.[70] If complete excision is not feasible, radiation therapy is administered.
Evidence (surgery with or without chemotherapy):
- 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. Surgical removal with negative margins was the primary treatment.[63][Level of evidence C2]
- All patients survived, and only one patient had metastatic disease recurrence.
- In a series of patients treated on consecutive studies from Germany, the following was reported:[65]
- Progression-free survival (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.
- In a series of 51 pediatric patients aged 0 to 21 years with alveolar soft part sarcoma, the following was reported:[61][Level of evidence C1]
- 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 the surgical removal of the 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.
Targeted therapy
Studies of targeted therapy (tyrosine kinase inhibitors and checkpoint inhibitors) have been done.
Sunitinib
Evidence (sunitinib):
- 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.[73][Level of evidence C3]
- In another study, 15 adult patients with alveolar soft part sarcoma were treated with sunitinib. Five patients were treated with sunitinib for longer than 2 years.[74][Level of evidence C1]
- 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%.
Cediranib
Cediranib is an inhibitor of all three known vascular epidermal growth factor receptors.
Evidence (cediranib):
- In a pediatric phase II trial of cediranib, using 70% of the adult maximum tolerated dose in patients younger than 16 years, the following was reported:[75][Level of evidence B4]
- Five of seven patients had stable disease for 14 months or longer.
- 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.[76][Level of evidence A1]
- 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 a phase II trial of cediranib, 15 of 43 adult patients (35%) with metastatic alveolar soft part sarcoma had partial responses.[77][Level of evidence C3]
Pazopanib
Evidence (pazopanib):
- 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.[78]
- Another trial included 30 adult patients who were treated with pazopanib.[79]
- One patient experienced a complete response, seven patients experienced partial responses, and 17 patients had stable disease.
- The median PFS was 13.6 months.
Axitinib and pembrolizumab
Axitinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Pembrolizumab is an anti–programmed cell death protein 1 immune checkpoint inhibitor.
Evidence (axitinib and pembrolizumab):
- In one trial, adult patients with advanced sarcomas were treated with a combination of axitinib and pembrolizumab.[72]
- 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.
Other therapies
There have been sporadic reports of objective responses to treatment with interferon-alpha and bevacizumab.[61,80,81]
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.
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, see 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 NOS
Clear cell sarcoma (formerly 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.
Clinical presentation
The tumor most commonly affects the lower extremity, particularly the foot, heel, and ankle.[82,83] It has a high propensity for nodal dissemination, especially metastases to regional lymph nodes (12%–43%).[83,84]
The tumor typically has an indolent clinical course. Patients who have small, localized tumors with low mitotic rate and intermediate histological grade have the best outcomes.[85]
Genomic alterations
Clear cell sarcoma of soft tissue is characterized by EWSR1::ATF1 or EWSR1::CREB1 gene fusions.[86,87]
Treatment of clear cell sarcoma of soft tissue
Treatment options for clear cell sarcoma of soft tissue include the following:
- Surgery with or without radiation therapy.[29,30]
- Targeted therapy.
Surgery with or without radiation therapy
Surgery with or without radiation therapy is the treatment of choice and offers the best chance for cure.
Evidence (surgery with or without radiation 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%).[88]; [89][Level of evidence C2]
- 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.
Targeted therapy
Evidence (targeted therapy):
- 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.[90]
- 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.[91] It has been reported in children and adolescents.[92]
The tumor has traditionally been considered to have low-grade malignant potential.[93] However, reports from large institutions showed that extraskeletal myxoid chondrosarcoma has significant malignant potential, especially if patients are monitored for a long time.[94,95] 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.[95]
Genomic alterations
Extraskeletal myxoid chondrosarcoma is a multinodular neoplasm. The rounded cells are arranged in cords and strands in a chondroitin sulfate myxoid background. Several cytogenetic abnormalities have been identified (see Table 2), with the most frequent being the EWSR1::NR4A3 gene fusion.[96]
Treatment of extraskeletal myxoid chondrosarcoma
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.[94] The therapeutic benefit of chemotherapy has not been established.
There may be potential genetic targets for small molecules, but these need to be studied as part of a clinical trial. In an adult study, six of ten patients who received sunitinib achieved partial responses.[97]
Extraskeletal Ewing Sarcoma
Almost one-fifth of patients with Ewing sarcoma will present with nonbone primary sites (extraosseous). Treatment for this tumor is the same as it is for patients with bone primary tumors.[98] For more information, see Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment.
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.[99,100,101,102,103] Dozens to hundreds of intraperitoneal implants are often found. The tumor occurs predominantly in males (85%) and may spread to the lungs and elsewhere.[103,104]
Diagnostic evaluation
A large single-institution series of 65 patients compared computed tomography (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.[104]
Genomic alterations
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.[102,105] The EWSR1::WT1 fusion confirms the diagnosis of desmoplastic small round cell tumor. The average tumor variant burden is low for desmoplastic small round cell tumor (<1 variant per megabase), and recurring gene alterations other than the EWSR1::WT1 fusion are uncommon.[106] A small percentage of cases (approximately 3%) have activating variants in FGFR4, with amplification of FGFR4 observed at similar frequency.[106,107] Inactivating variants in TP53 and ARID1A are observed in a small percentage of desmoplastic small round cell tumor cases.[106,107]
Prognosis
The overall prognosis for patients with 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.[108,109]; [110][Level of evidence C1] Response to neoadjuvant chemotherapy and complete resection (near 100%) is associated with improved outcome.[103,111]
Treatment of desmoplastic small round cell tumor
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:
- Multimodality therapy (chemotherapy, surgery, and radiation therapy).
- Surgery with hyperthermic intraperitoneal chemotherapy (HIPEC).
- Other treatment options.
Multimodality 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 approach, survival can be achieved in 30% to 40% of patients at 5 years.[99,100,108,112,113,114,115]
Surgery with HIPEC
HIPEC is a local treatment method that may control more of the microscopic intra-abdominal disease. The theory is that the heated 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.[116]
The addition of 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 more than 12 hours, and technical aspects of this unique tumor resection should be considered.[116]
Evidence (surgery with HIPEC):
- 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. They also received adjuvant total-abdominal radiation therapy followed by adjuvant chemotherapy.[116]
- 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.
- 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 tumor types. A complete macroscopic resection (CC-0, where CC is completeness of cytoreduction) was achieved in 16 cases (73%). Four of the seven patients with desmoplastic small round cell tumors had complete resections.[117][Level of evidence C1]
- Sixteen patients (72%) relapsed after a median time of 9.6 months (range, 1.4–86.4 months).
- Nine patients (41%) died of relapsed disease after a median time of 5.3 months (range, 0.1–36.1 months).
- 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 (mean age, 22 years), 38 (79%) received preoperative and/or postoperative chemotherapy, and 23 (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.[118]
- 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 disease-free survival (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.
- A single-institutional retrospective study reported on nine patients (median age, 19 years) with desmoplastic small round cell tumor. Most patients had widespread disease, including four patients with extra-abdominal 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 transplant.[119]
- 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).
Other treatment options
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.[120] 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.[108]
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.[121]
Rhabdoid Tumor NOS (Extrarenal)
Malignant rhabdoid tumors were first described in children with renal tumors in 1981. 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. For more information, see the Rhabdoid Tumors of the Kidney section in Wilms Tumor and Other Childhood Kidney Tumors Treatment.
Extrarenal (extracranial) rhabdoid tumors account for 2% of soft tissue sarcomas in patients younger than 20 years (see Table 1).
Genetic and genomic alterations
The first sizeable series of children with extrarenal extracranial malignant rhabdoid tumor of soft tissues came from 26 patients enrolled on the IRS I through III studies during a review of pathology material. Only five patients (19%) were alive without disease beyond 2 years.[122]
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 variants of the SMARCB1 gene in all 29 tumors tested.[123] Rhabdoid tumors may be associated with germline variants of the SMARCB1 gene and may be inherited from an apparently unaffected parent.[124] This observation was extended to 32 malignant rhabdoid tumors at all sites in patients whose mean age at diagnosis was 12 months.[125]
Genetic testing and surveillance
Germline analysis should be considered for individuals of all ages with rhabdoid tumors. Genetic counseling is also part of the treatment plan, given the low-but-actual risk of familial recurrence. In cases of variants, parental screening should be considered, although such screening carries a low probability of positivity. Prenatal diagnosis can be performed in situations where a specific SMARCB1 variant or deletion has been documented in the family.[124]
To date, there is little evidence regarding the effectiveness of surveillance for patients with rhabdoid tumor predisposition syndrome type 1 caused by loss-of-function germline SMARCB1 variants. However, because of the aggressive nature of the tumors with significant lethality and young age of onset in SMARCB1 carriers with truncating variants, consensus recommendations have been developed. These recommendations were developed by a group of pediatric cancer genetic experts (including oncologists, radiologists, and geneticists). They have not been formally studied to confirm the benefit of monitoring patients with germline SMARCB1 variants. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve OS.[126,127,128]
Surveillance for patients with germline SMARCB1 variants includes the following:
- Brain magnetic resonance imaging (MRI) every 3 months from birth (or diagnosis) until age 5 years.
- Abdominal ultrasonography with a focus on the kidneys every 3 months.
For information about SMARCB1 and rhabdoid tumor predisposition syndrome type 1, see Rhabdoid Tumor Predisposition Syndrome Type 1.
Prognosis and clinical presentation
Young age and metastatic disease at presentation are associated with poor outcome in children with extracranial rhabdoid tumors.
One study that used data from the National Cancer Database identified 202 patients (aged younger than 18 years) with non–central nervous system (CNS) malignant rhabdoid tumors. The primary site of the malignant rhabdoid tumor was soft tissue (46%), kidney (45%), and liver (9%).[129]
- The 1-year OS rate was 48.8%, and the 5-year OS rate was 35.9%.
- The multivariate analysis demonstrated that age younger than 1 year and presence of metastasis were negative prognostic indications (P = .058).
- In the cohort of surgical patients (n = 143), there was a trend for an association between the presence of residual disease and a clinically significant worse outcome (HR, 1.54; 95% CI, 0.88–2.69; P = .13).
A SEER study examined 229 patients with renal, 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.[130]
A European registry for extracranial rhabdoid tumors identified 100 patients from 14 countries between 2009 and 2018.[131] 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 variants 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 variant, metastasis, and lack of a gross-total resection were the strongest significant negative predictors of outcome.
Treatment of extrarenal (extracranial) rhabdoid tumor
Treatment options for extrarenal (extracranial) rhabdoid tumor include the following:[132,133,134][Level of evidence C1]
- 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.[135] For more information about CNS atypical teratoid/rhabdoid tumors, see Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment.
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, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
- PEPN2121 (NCT05286801) (Tiragolumab and Atezolizumab for the Treatment of Relapsed or Refractory SMARCB1- or SMARCA4-Deficient Tumors): This study is evaluating the combination of a PD-L1 targeting antibody (atezolizumab) with a TIGIT targeting antibody (tiragolumab) for patients with SMARCB1- or SMARCA4-deficient tumors. Patients with extrarenal (extracranial) rhabdoid tumors may be eligible for this study.
PEComa, Malignant
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.[136] The disease course may be indolent.
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.[137] 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.[138,139] A small proportion of PEComas have TFE3 rearrangements with fusions involving various genes, including SFPQ and RAD51B.[140]
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.[141]
Treatment of PEComas
There are no standard treatment options. Treatment may include surgery or observation followed by surgery when the tumor is large.[142]
In tumors with evidence of mTORC1 activation and TSC1 or TSC2 loss, including lymphangioleiomyomatosis and angiomyolipoma,[138] clinical activity using mTOR inhibitors, such as sirolimus, has been well documented. In a small case series, three adult patients with PEComas responded to sirolimus.[143]
In a phase II trial, 34 patients with metastatic or locally advanced malignant PEComas were treated with sirolimus protein-bound particles for injectable suspension (albumin-bound) (nab-sirolimus). Of the 31 patients eligible for efficacy analysis, 12 (39%) had a response (1 complete response and 11 partial responses), 16 (52%) had stable disease, and 3 (10%) had progressive disease. Responses were rapid and durable. The median duration of response was not reached after a median follow-up of 2.5 years. Treatment was ongoing for 7 of 12 patients who responded to treatment (range, 5.6 months to longer than 47.2 months). Tumor variant profiling was completed for 25 specimens. Eight of nine patients with TSC2 variants responded to treatment, while only 2 of 16 patients without TSC2 variants responded. In addition, responses were noted in 10 of 17 patients with phospho-S6 (pS6) expression. No response was noted in eight patients without pS6 expression. The absence of pS6 expression reflects the lack of mTORC1 activation.[144][Level of evidence C1] In 2021, the FDA approved nab-sirolimus for adult patients with PEComas.
Undifferentiated 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 (FNCLC).[5][Level of evidence C1]
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.[145]
- 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 low-risk disease can be salvaged if the disease recurs.
- 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 tumor samples, which included BCOR and CIC rearrangements, as well as COL1A1::PDGFB, KIAA1549::BRAF, and SAMD5::SASH1 gene fusions.
Pleomorphic Sarcoma, Undifferentiated (Malignant Fibrous Histiocytoma)
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 clinico-pathological entity. The World Health Organization (WHO) classification no longer includes malignant fibrous histiocytoma as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[146,147]
This entity accounts for 2% to 6% of all childhood soft tissue sarcomas.[148]
Clinical presentation
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.[148]
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.[149] All patients with metastatic disease died, and two patients experienced a clinical response to a doxorubicin-based regimen.
For more information about the treatment of malignant fibrous histiocytoma of bone, see Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment.
Risk factors
These tumors can arise in previously irradiated sites or as a second malignancy in patients with retinoblastoma.[150]
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.[151]
Undifferentiated sarcomas with 12q13–15 amplification, including MDM2 and CDK4, are best classified as dedifferentiated liposarcomas.[151] The relationship between this tumor and the family of undifferentiated/unclassified tumors with spindle cell morphology remains relatively undefined.
Treatment of newly diagnosed pleomorphic sarcoma
For information about the treatment of undifferentiated pleomorphic sarcoma of bone, see Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment.
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.[152][Level of evidence C3]
- 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.
Round Cell Sarcoma, Undifferentiated
Undifferentiated small round cell sarcomas withBCORgenetic alterations
See the sections on Undifferentiated Small Round Cell Sarcomas With BCOR Genetic Alterations and Genomics of Ewing Sarcoma in Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment.
Undifferentiated small round cell sarcomas withCICgenetic alterations
See the sections on Undifferentiated Small Round Cell Sarcomas With CIC Genetic Alterations and Genomics of Ewing Sarcoma in Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment.
Undifferentiated small round cell sarcomas withEWSR1::non-ETS fusions
See the Undifferentiated Small Round Cell Sarcomas With EWSR1::non-ETS Fusions section in Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment.
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