Nonrhabdomyosarcoma Soft Tissue Sarcomas

Soft tissue sarcomas, the fifth most common solid tumors in children, are relatively rare and account for about 6-7% of all childhood malignancies. About half of these tumors are rhabdomyosarcomas, and nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) account for the remainder (ie, about 4% of childhood malignancies).

NRSTSs are heterogeneous tumors that have varied biology and histology. The most common types in the pediatric population include fibrosarcoma, synovial cell sarcoma, fibrosarcoma, and malignant peripheral nerve sheath tumor. Other histologic types include hemangiopericytoma, alveolar soft part sarcoma, leiomyosarcoma, liposarcoma, epithelioid sarcoma, and desmoplastic small round cell tumor.

Childhood NRSTs are not well studied. Because soft tissue sarcomas are most common in adults, many treatment modalities are extrapolated from experiences in adult patients. However, many pediatric tumors differ from their adult counterparts in terms of clinical behaviors and outcomes. The prognoses of infants and young children with NRSTSs tend to be better than those of adolescents and adults with similar diagnoses.[1]

The soft tissues comprise various structural and supportive tissues in the body, including muscle, connective tissues, endothelium, synovium, fat, lymphatics, and fascias. Soft tissue sarcomas may arise in any part of the body. The most common sites are the trunk and the extremities.

Approximately 15-30% of patients have metastatic disease at presentation. The most common metastatic site is the lung. Other common sites for metastases include the skin, bone, liver, and lymph nodes. Spread to the brain and to the omentum and/or peritoneum is described as well. A brief discussion of the most common NRSTSs follows.

Fibrosarcoma

Fibrosarcoma is the most common NRSTS in children, in whom 2 peaks in incidence are observed. The first is in children younger than 5 years, and the second is in children and adolescents aged 10-15 years.

On histologic analysis, fibrosarcomas are spindle-shaped tumors with a characteristic herringbone pattern. Aggressive fibromatosis, nodular fasciitis, myositis ossificans, and inflammatory pseudotumor are among the most important differential diagnoses.

Infantile fibrosarcoma (IFS) is almost exclusively observed in children younger than 2 years. Many of these sarcomas are congenital. This tumor is locally aggressive, but rarely metastatic, and occurs in the extremity in 70% of patients. IFSs are characterized by the unique cytogenetic translocation t(12;15)(p13;q25) that results in the fusion of the gene TEL/ETV6 to TRKC/NTRK3.

Childhood fibrosarcoma, including IFS, has classically been treated with surgery alone or with preoperative chemotherapy and surgery in cases that are not amenable surgical resection upfront.[2]  However, larotrectinib, a highly selective tropomyosin‐related kinase (TRK) inhibitor, has shown impressive antitumor activity in TRK positive cancers including IFS and may change the treatment paradigm for IFS.[3, 4] Patients with IFS have an excellent prognosis, with survival rates of more than 90% in some series. 

The adult form of fibrosarcoma is rare in children and usually occurs in individuals aged 10-15 years, most often affects the extremity, and has greater metastatic potential than its infantile counterpart (usually involving the lung). In contrast to IFS, the adult form of fibrosarcoma is not associated with a characteristic cytogenetic translocation. The adult form of fibrosarcoma is treated with aggressive surgical resection with or without radiation therapy; chemotherapy is considered in some patients that are considered unresectable at diagnosis. Overall, the survival rate is approximately 60% in the adult type.

Dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans is also a common NRSTS in children. Dermatofibrosarcoma protuberans are cutaneous soft tissue sarcomas that clinically present as plaquelike areas of cutaneous thickening that are usually fixed to the dermis but are freely mobile over deeper soft tissues. The most common sites of presentation are the trunk and extremities.

Histologically, dermatofibrosarcoma protuberans is composed of benign spindle cells arranged in a storiform pattern. Most dermatofibrosarcoma protuberans stain positive for CD34; this is useful in differentiating this tumor from normal fibroblasts and dermatofibromas. Cytogenetic analysis reveals the presence of chromosomal abnormalities, either supernumerary ring chromosomes or t(17,22) that causes a fusion of the genes for collagen 1A1 (COL1A1) and platelet-derived growth factor B (PDGF-B). This results in constitutive expression of PDGF-B, and stimulation of the PDGF receptor in tumor cells.

Most dermatofibrosarcoma protuberans are classified as low-grade sarcomas; however, 10-15% are intermediate-grade to high-grade sarcomas. They rarely metastasize, although they can locally recur. The treatment of dermatofibrosarcoma protuberans is comparable to the treatment of most NRSTSs and involves wide resection with negative margins. Mohs micrographic surgery is increasing in popularity as a method of resection for these tumors. Adjuvant radiation therapy is used postoperatively for tumors that have close or microscopically positive margins if further surgery cannot be performed.

The role of adjuvant chemotherapy in the treatment of dermatofibrosarcoma protuberans is currently under investigation. Imatinib targets the PDGF receptor, which is activated in dermatofibrosarcoma protuberans. Several series have shown a benefit of imatinib in patients with advanced or metastatic dermatofibrosarcoma protuberans;[5] it is now approved for the treatment of adults with dermatofibrosarcoma protuberans.

Malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNSTs) account for approximately 5-10% of NRSTSs in children. These tumors are associated with neurofibromatosis type I (NF1), and they have a common chromosomal deletion on chromosome 17q.

Malignant peripheral nerve sheath tumors most frequently arise from a large peripheral nerve or a neurofibroma in patients with NF1. Their pathologic appearance is similar to that of fibrosarcomas, with dense cellular proliferations of spindle shaped cells with irregular wavy nuclei.

Surgery and radiation therapy are the major modalities of treatment. Malignant peripheral nerve sheath tumors are considered chemoresponsive. However, the role of adjuvant chemotherapy in the overall outcome of patients is still under investigation. Factors associated with a poor outcome include large tumor size, age greater than 7 years, presence of NF1, and tumor necrosis greater than 25%.

Synovial sarcoma

Synovial sarcoma is one of the most common NRSTSs, comprising approximately 40% of these malignancies, although it is rarely observed in children younger than 10 years. One third of these tumors occur in individuals younger than 20 years.

Over 90% of synovial sarcomas have the presence of a fusion of the SYT/SSX genes t(x;18)(p11,q11). This gene fusion results in aberrant transcription. The detection of the SYT/SSX fusion using real-time polymerase chain reaction (RT-PCR) or fluorescence in-situ hybridization (FISH) techniques is very useful in the pathologic diagnosis of this malignancy. Synovial sarcomas are usually found on an extremity, with lower-extremity lesions more common than upper-extremity lesions, followed by the trunk, abdomen, and head and neck. In terms of pathologic features, the 2 forms of tumor are a spindle-cell fibrous form and a glandular form with epithelial differentiation. Metastasis develop in about 40% of patients. The most common site for metastasis is the lung (90%), followed by the lymph nodes (5-15%) and bone (5-10%).

Complete surgical resection alone has been found to be sufficient for localized synovial sarcomas < 5 cm in size.[6]  For incompletely resected tumors, adjuvant radiation of residual disease is the best therapy.[7] Chemotherapy may have a role in unresectable and metastatic disease, as well as in adjuvant therapy after resection.[8] Several series have demonstrated efficacy with the use of doxorubicin and high-dose ifosfamide in combination with surgery and radiation therapy. Low-stage disease is associated with a 70% survival rate. Patients with advanced stage disease have a poor prognosis.

Alveolar soft part sarcoma

Alveolar soft part sarcomas are rare and usually arise in individuals aged 15-35 years. Among children, the primary site of occurrence is the head and neck; tumors of the orbit or tongue are most common.

Patients with alveolar soft part sarcomas usually present with an indolent, slow-growing mass. Alveolar soft part sarcoma often arises in skeletal muscle tissue. Children frequently present with metastases, most commonly in the lung, followed by the brain, bone, and lymph nodes.

Cytogenetics reveal der(17) t(X;17)(p11;q25) causing the fusion protein ASPL-TFE3. Pathologic classification of this tumor is uncertain, but evidence suggests myogenic or epithelioid differentiation.

The primary treatment modality is surgery, with irradiation and chemotherapy reserved for recurrences. Surgical resection is also indicated for select metastatic sites.

The short-term prognosis is good, with 80% of patients surviving 2 years after diagnosis. However, the long-term survival rate is poor regardless of the initial stage of disease.

McCarville et al performed an assessment of the imaging characteristics of alveolar soft-part sarcomas (ASPS) to determine whether there are features that suggest the diagnosis. The study concluded that the imaging features of ASPS include flow voids, large peripheral vessels, internal nodularity, and lobulated margins. Contrast administration produces intense to moderate enhancement, sometimes with a thick enhancing peripheral rim around central necrosis. Extremity tumors with these imaging features in a child or young adult should suggest the diagnosis of ASPS.[9]

Leiomyosarcoma

Leiomyosarcoma accounts for about 2% of NRSTSs.

These tumors are pathologically derived from smooth muscle tissue. Leiomyosarcomas are associated with human immunodeficiency virus (HIV) disease, infection with the Epstein-Barr virus (EBV), and immunosuppressive states.

The most common site for these tumors is the GI tract (20-30%), particularly the stomach. An important clinical presentation is the occurrence of leiomyosarcoma with extrarenal or adrenal paraganglioma and pulmonary chondroma; this Carney triad is most commonly observed in young women.

Surgical resection has been the most common treatment for this NRSTS. In general, patients with tumors in the GI tract have a poor prognosis. The prognosis is good with complete resection of tumors outside the GI tract. The role of radiation therapy and chemotherapy in the management of leiomyosarcoma is still under investigation.

Liposarcoma

Although liposarcoma is primarily a disease of adults, it can occur in older children. This NRSTS rarely occurs in young children and infants; when it does, it usually carries an excellent prognosis if completely resected. A consistent cytogenetic abnormality observed in myxoid liposarcoma tumors is the t(12;16)(q13;p11) translocation. The genes involved are FUS-CHOP.

The lower extremity and the trunk are the 2 most common sites of involvement. Liposarcoma rarely metastasizes. For this reason, the treatment of choice is wide local excision. The role of radiation therapy and chemotherapy in the setting of gross residual disease is under investigation.

Desmoid tumors

These tumors are low-grade malignancies that tend to be locally infiltrating and have a high likelihood of recurring locally; they have a very low potential for metastasis. The natural history varies; in fact, several examples of spontaneous regression have been noted. Over 80% of desmoid tumors exhibit a mutation in exon 3 of the beta-catenin gene; the mutation 45F has been associated with an increased risk of recurrence.[10]

Desmoid tumors that are not actively progressing and are asymptomatic may be managed with close observation. For desmoid tumors that are progressing and/or symptomatic, surgical resection with clear margins is the treatment of choice, if feasible. Surgical resection with clear margins can be difficult due to the infiltrative nature of these tumors. Partially excised or recurrent tumors that do not pose a risk to vital organs and are no longer symptomatic may simply be monitored closely. For those desmoid tumors that are progressing and/or symptomatic and the tumor is unresectable or surgery is potentially morbid, interventions such as systemic therapy or radiation therapy are often undertaken. The choice of the systemic therapy regimen depends on the degree of symptomatology and urgency of management. Non-cytotoxic systemic therapy options include sulidac, tamoxifen, the combination of sulidac and tamoxifen, hydroxyurea, and tyrosine kinase inhibitors (TKIs) such as imatinib, sorafenib or pazopanib.[11, 12, 13, 14, 15, 16, 17, 18]  Additionally, nirogacestat (previously called PF-03084014), an inhibitor of γ-secretase involved in the NOTCH pathway, has had encouraging results in phase 1 and 2 trials of adults with desmoid tumors.[19, 20] A phase 3 trial of nirogacestat is planned. Cytotoxic chemotherapy options include vinblastine/methotrexate and adriamycin/dacarbazine (DTIC).[21, 22, 23]

Hemangioendothelioma

In infants, these tumors are typically found within the liver and usually remain benign. However, they can be associated with a consumptive coagulopathy (ie, Kasabach-Merritt phenomenon). Treatment of asymptomatic lesions may consist of observation alone because some tumors spontaneously regress. Symptomatic lesions, especially those associated with a coagulopathy, require urgent medical or surgical management.[24]

In older children, hemangioendotheliomas behave similarly to adults. They occur in other locations in the body in addition to the liver and can metastasize to the lungs, lymph nodes, bones, and within the pleural or peritoneal cavities. Treatment of these tumors involves surgical resection; they do not respond to either irradiation or chemotherapy.

Undifferentiated pleomorphic sarcomas

There was previously an entity termed Malignant Fibrous Histiocytoma (MFH). MFH were once the most commonly diagnosed soft tissue sarcoma in the adult population. These pleomorphic tumors were initially given the name MFH because they were presumed to be derived from histiocytes capable of fibroblastic transformation. More critical histochemical, immunohistochemical, and ultrastructural studies of cases previously diagnosed as MFH have found that neoplastic histiocytes are in fact not present in these tumors and that many of these cases could be classified as another subtype of NRSTS. Therefore, the World Health Organization (WHO) now no longer recognizes MFH as a distinct diagnostic category. Instead, Undifferentiated Pleomorphic Sarcomas is now the term used for NRSTS for which specific lines of differentiation cannot be identified.[25, 26]

Epithelioid sarcoma

Epithelioid sarcoma (ES) is a rare soft tissue sarcoma in adolescents and young adults. The most common site of ES involvement is the upper extremity. There are two histopathological subtypes of ES – distal (also called classic/conventional) ES and proximal ES – each with distinct clinical behavior. The distal subtype typically presents in the distal extremity while the proximal subtype typically presents in the proximal extremities or midline and is a more rapidly growing tumor with worse outcomes.[27, 28]  ES is notable for a high rate of local recurrence, regional lymph node involvement and distal metastasis. The reported rates of lymphatic spread range from approximately 20-50% of cases.[29, 30, 31, 32]  Although sentinel lymph node biopsy is controversial, evaluation for lymphatic spread with imaging of regional draining lymph nodes and biopsy of concerning sites is typically recommended. Studies on treatment of ES are limited due to the rarity of the tumor.[33]  The primary treatment of ES is surgical resection with wide local excision. This is often combined with radiation. Additionally, systemic chemotherapy is typically given in metastatic disease although its role in localized disease is less clear. Importantly, the majority of ES tumors lack SMARCB1/INI1 protein expression and are termed INI1 negative.[34]  Results from phase 1 and 2 clinical trials of tazemetostat, an EZH2 inhibitor involved in the INI1 pathway, show encouraging anti-tumor activity in ES and other INI1 negative tumors. The results of the phase 1 clinical trial in adults has been completed and the phase 1 trial in pediatric patients and phase 2 trial in adults are ongoing (clinical trial identifiers NCT02601937 and NCT02601950).[35, 36, 37, 38, 39]  The reported 5-year overall survival of ES is approximately 60-70% although some publications report higher survival rates in children and adolescents.[32, 40]

Malignant rhabdoid tumor 

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive pediatric malignancy. The majority of MRT cases occur in children less than 2 years of age. The most common site of extracranial MRT is the kidney but they can occur in nearly any location. Most MRTs have a biallelic inactivation mutation in the tumor suppressor gene SMARCB1/INI1 and are termed INI1 negative.[41]  Approximately 15-30% of patients with MRTs have a germline perturbation of INI1 (also called SMARCB1).[42, 43]  Of note, in addition to evaluation for pulmonary metastases, bone scan and head imaging are indicated in all MRTs to evaluate for bone metastases and a synchronous primary or metastatic brain tumor. Treatment includes surgery, chemotherapy and radiation.[44]  The chemotherapy regimen used in the most recent European Paediatric Soft Tissue Sarcoma Group protocol for MRT was Cyclophosphamide-carboplatin-etoposide (Cy*CE) alternating with vincristine-doxorubicin-cyclophosphamide (VDCy).[33]  Other chemotherapy regimens that have been used include VDC alternating with Ifosfamide, cyclophosphamide and etoposide or alternating with ifosfamide and etoposide.[45]  Preliminary results from phase 1 and 2 clinical trials of tazemetostat, a EZH2 inhibitor acting on the INI1 pathway, show encouraging anti-tumor activity in INI1 negative MRTs (clinical trial identifiers NCT02601937 and NCT02601950).[35, 36, 38, 39] . Survival rates for extracranial MRT are approximately 30%.[33]

United States statistics

NRSTSs account for approximately 3% of childhood malignancies. The most common NRSTS is fibrosarcoma, which accounts for 23.9%. Among individuals younger than 20 years, approximately 500-600 cases of NRSTS are diagnosed yearly.

Race-, sex-, and age-related demographics

The prevalence is slightly higher in Blacks than in Whites (14 vs 10 cases per 1 million population).

The prevalence is slightly higher in male individuals than in female individuals (12 vs 10 cases per 1 million population).

Among young children, rates for NRSTS are highest in infancy, when the disease affects approximately 15 per 1 million infants. Rates decrease in the second year of life to a fairly stable rate until about the age of 10 years, when approximately 8-10 per 1 million children are affected. For individuals older than 10 years, the incidence rate increases to about 15 cases per 1 million population per year.

Morbidity/mortality

The most important prognostic factors associated with a poor outcome in children with NRSTS are the histologic grade, tumors larger than 5 cm, presence of metastases, and extent of resection. Except for fibrosarcoma, most NRSTSs in children are immature and poorly differentiated, with a highly malignant histologic grade. For patients with low-grade localized disease, the survival rate is 90%, compared with less than 15% for patients with high-grade, invasive, or metastatic disease.

Patients with nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) usually present with painless, asymptomatic masses. The tumors may come to attention because of an episode of trauma in the affected area. Mass effect due to the tumor may cause specific signs or symptoms depending on the location of the mass. For instance, invasion of local neurovascular bundles in an involved extremity may lead to pain, swelling, numbness, or loss of function. Large masses in the chest wall may cause pulmonary dysfunction.

If advanced metastatic disease is present, systemic symptoms with fever, sweats, and weight loss may be observed.

Hemangiopericytomas have been associated with hypoglycemia and hypophosphatemic rickets. Hyperglycemia has been observed with fibrosarcoma of the lung.

Physical findings depend on the location of the mass. A mass is palpable in many, if not most, patients.

Specific tumors may be associated with specific findings. Malignant peripheral nerve sheath tumors may be associated with neurofibromatosis type 1 (NF1), which is characterized by café au lait spots, axillary freckling, neurofibromas, skeletal dysplasias, learning disabilities, and various neoplasms. CNS tumors may cause an abnormal neurologic findings depending on the location of the mass and the structures affected.

Genetic conditions such as Li-Fraumeni syndrome associated with P53 mutations, NF1, and germline mutation of the retinoblastoma susceptibility gene, RB, are known genetic risk factors for NRSTS. Gorlin syndrome has been associated with an increased risk of development of fibrosarcoma and leiomyosarcoma. NF1 is strongly associated with the development of malignant peripheral nerve sheath tumors.

Other factors with an association with the development of NRSTs include exposure to previous radiation, childhood cancer survival, and infection with retroviruses in immunocompromised children (eg, those with HIV or Epstein-Barr virus [EBV] infection). Individuals with HIV have an increased risk of developing leiomyosarcoma related to EBV infection.

In patients with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS), a baseline CBC count with differential provides parameters before therapy and is useful in evaluating for involvement of the bone marrow.

Chemical tests to assess renal function and creatinine clearance provide baseline parameters before chemotherapy is given and further testing is performed.

Liver function testing provides baseline parameters before chemotherapy and is helpful in evaluating for hepatic involvement.

Primary site imaging:

Plain radiography of the involved areas may be useful in the initial evaluation of a mass, depending on its location and suspected involvement of bony structures. 

CT and MRI are used to determine the size of the mass and the extent of local involvement and impingement on adjacent structures. CT and MRI also help in defining options for surgical resection. Contrast-enhanced studies are most helpful. Abdominal CT scanning is important for assessing abdominal primary lesions and to determine hepatic involvement.

Staging imaging:

For NRSTSs with a predisposition for lymphatic spread (including epithelioid sarcoma and synovial sarcoma), imaging of draining lymph nodes should be performed, preferably with MRI.

A non-contrast chest CT is generally preferred over chest plain radiography to evaluate for pulmonary metastatic disease. When feasible these studies should be performed prior to general anesthesia as atelectasis can make interpretation more difficult. 

Radionucleotide bone scanning is necessary to rule out bony involvement.

The roles of positive emission tomography (PET)-CT and of18 F-fluorodeoxyglucose (FDG) PET to image NRSTS in children have not been well established. However, PET-CT may prove beneficial in distinguishing normal from pathologic processes, in the initial staging of a sarcoma, in monitoring responses to therapy, and in detecting recurrences.[46, 47]

A cardiologist may need to be consulted to perform cardiac ECG and echocardiography in patients who will receive anthracycline-based chemotherapy or radiation therapy to the chest.

Testing of renal glomerular filtration or creatinine clearance may be necessary before renal-toxic chemotherapy agents (eg, cisplatin, ifosfamide) are administered.

Carefully planned and executed biopsy of the mass lesion is required for diagnosis.

Whatever technique is used, adequate tissue must be obtained to allow for histology, immunostaining, and other studies including cytogenetics, fluorescent in situ hybridization (FISH), and molecular pathology. 

If possible, the biopsy should be accomplished in a manner that does not compromise the possibility for later local surgical control of the tumor. The definitive surgical procedure should be delayed until after the biopsy because neoadjuvant chemotherapy, radiation therapy, or both may be needed.

Fine-needle aspiration is not recommended as this procedure may often yield insufficient diagnostic material.

Percutaneous image-guided core needle biopsy may be feasible and the preferred procedure for obtaining diagnostic material in many cases. However, this should be performed by a skilled interventional radiologist.[48]  

An open procedure is required if core-needle biopsy yields nondiagnostic pathologic material. A surgeon with expertise in oncologic surgery should perform this procedure. The surgeon's specific discipline depends on the location of the mass. Minimally invasive surgical techniques using fiberoptic surgical procedures may be appropriate in certain biopsy situations. The best approach for small lesions in accessible areas may be excisional biopsy. Large masses involving critical organs or structures may require incisional biopsy for diagnosis.

Sentinel lymph node biopsy in the diagnosis and staging evaluation of NRSTS is controversial. For NRSTS with predilection for lymphatic metastases we recommend MRI of regional draining lymph nodes and biopsy if concern for metastatic spread on imaging.

Consider long-term venous access. In cases where adjuvant and/or neoadjuvant chemotherapy is planned, placement of an implanted or externalized central venous catheter is useful for monitoring laboratory results and for delivering chemotherapy and supportive care.

Routine bilateral bone marrow aspirates and biopsy is not recommended in the standard staging of children with NRSTS due to the unlikelihood of bone marrow metastatic spread. However, we recommend examination of the bone marrow if there are unexplained cytopenias or other findings that raise the clinical suspicion for bone marrow involvement. In children, these procedures are best performed in the posterior iliac crests.

These tests should be accomplished in conjunction with another procedure requiring sedation, if possible.

If there is a high clinical suspicion for central nervous system involvement (e.g. parameningeal tumors or tumors involving the CNS), lumbar puncture may be considered to rule out contamination of the cerebrospinal fluid (CSF) with tumor cells though not routinely performed.

Diagnosis of an NRSTS can be confirmed only with biopsy of the mass. Diagnosis of a specific tumor depends on the mesenchymal and/or support tissue it most closely represents. Immunostaining, electron microscopy, cytogenetic analysis, and tests for molecular markers of genetic rearrangements may all be used for final diagnosis, depending on the differentiation of the specific tumor. Many of the NRSTSs are characterized by chromosomal translocations that lead to a fusion of two genes. The resultant fusion gene can be detected by FISH, polymerase chain reaction (PCR)-based techniques, and newer next generation DNA/RNA sequencing diagnostic platforms. NRSTSs possess a wide range of histologic features.

A tumor is classified as low-grade or high-grade on the basis of its potential to metastasize. Low-grade lesions are unlikely to metastasize. Certain types of tumors are arbitrarily considered high grade; examples are synovial cell sarcomas and malignant peripheral nerve sheath tumors. Malignant and metastatic potential are based on the degree of anaplasia and mitotic activity the tumor specimen exhibits.

No staging system is validated for NRSTSs in children. Two systems are currently in use: the surgicopathologic grouping system used by the Intergroup Rhabdomyosarcoma Study (IRS), which is based on the amount of tumor remaining after initial surgery, and the American Joint Commission for Cancer (AJCC) staging system for Soft Tissue Sarcomas.[49]  This is the staging system that is being used in the current COG trial for NRSTS.

Table. American Joint Commission for Cancer Staging (Tumor, Node, and Metastases [TNM] System) (Open Table in a new window)

G1 = well differentiated; G2 = moderately differentiated; G3 = poorly differentiated; M0 = no distant mets; M1 = distant mets; N0 = no regional LN mets; N1 = regional LN mets

Intergroup Rhabdomyosarcoma Study (IRS) groups staging is as follows:

• Group I - Complete resection with negative margins

• Group II - Microscopic residual disease after resection

• Group III - Incomplete resection or biopsy with gross residual tumor

• Group IV - Metastatic disease present at time of diagnosis

General treatment considerations for nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) vary depending on the anatomic site of the tumor, its histologic features, and the extent of local and metastatic disease. Most of the data have been extrapolated from trials involving adults. The standard of care for most NRSTSs is to achieve local control by complete surgical resection, if possible, preferably limb-preserving. In general, the roles of radiation and chemotherapy depend on tumor resectability, histological grade, and tumor extent (size and stage).

The role of radiation therapy in children with NRSTSs has yet to be fully defined. In the recent Children's Oncology Group (COG) ARST0332 study, radiation therapy was used less frequently and at lower doses with similar or better outcomes compared with historical controls.[50]  For low-grade NRSTSs, the use of radiation therapy after complete surgical excision is controversial. Thus, in these tumors, radiation therapy is generally used adjuvantly only when surgical margins are involved and re-resection is not possible.[51, 52] Radiation is also indicated for use in large, high-grade tumors.[53]  Radiation therapy may also have a role in the control and palliative treatment of certain metastatic diseases.

Radiation therapy must be approached differently in children than in adults, who typically require a large treatment volume. This places the adjacent tissues of children at risk for decreased bone growth, loss of joint function, and soft tissue and muscle fibrosis. Devastating lifelong complications, including secondary malignancies, are also a concern. The efficacy of focal limited margin external radiation therapy in patients with high-grade NRSTSs has been tested; preliminary results show a high rate of local control.[54, 55]  Radiation therapy may also have a role in the control and palliative treatment of certain metastatic diseases.

Large and unresectable primary tumors, metastatic disease, and disease of high metastatic potential may require chemotherapy as part of the treatment plan. Neoadjuvant chemotherapy may allow for a less aggressive surgical approach by achieving tumor shrinkage. Adjuvant chemotherapy may aid in local control and treatment of metastatic disease. The chemotherapy agents with the most activity in NRSTSs are doxorubicin and ifosfamide. These agents were the backbone chemotherapy regimen utilized in the most recent COG-ARST0332 study. Other chemotherapeutic agents that have shown activity either alone or in combination are cyclophosphamide, vincristine, etoposide, cisplatin, and dactinomycin.

The role of each component of multimodal therapy in NRSTSs has been studied in prospective clinical trials, and studies are ongoing. The recent COG trial ARST0332 was designed to elucidate a risk-based strategy for treating NRSTSs, with the goals of limiting toxicity in low-risk patients and maximizing efficacy in intermediate- and high-risk patients. Stratification into these risk-based groups was based on tumor grade and extent (size, resectability, and presence of metastatic disease). Patients at low risk were treated with surgery with or without adjuvant radiation therapy, depending on the histologic grade of the tumor and the surgical margin status. Intermediate and high-risk patients in whom the primary tumor was not excised, received combined neoadjuvant chemoradiotherapy prior to definitive resection. Intermediate and high risk patients in whom the primary tumor was able to be excised, were treated with adjuvant chemotherapy with or without irradiation. The chemotherapeutic regimen for all patients was doxorubicin with ifosfamide.[50]  The prognostic ability of the risk classification system used for COG-ARST0332 was validated using data from the Surveillance, Epidemiology, and End Results (SEER) database.[56]  The current COG trial ARST1321 is a phase 2/3 study evaluating the efficacy of radiation therapy with or without chemotherapy or pazopanib in surgically resectable NRSTSs (clinical trial identifier NCT02180867).[57]

See the pdf below outlining the experimental design schema and table outlining the risk-stratified therapy approach taken in COG-ARST0332.  

COG-ARST0332 experimental design schema.

Table, Risk Based Treatment Stratification used in COG-ARST0332 study. Adapted from Spunt et al., 2014 and Sangkhathat, 2015 ^{[50, 58]} (Open Table in a new window)

 

For certain subtypes of NRSTSs, molecular targeted therapies have shown promising activity. 

The following drugs have been approved by the US Food and Drug Administration (FDA) for NRSTS subtypes:

Atezolizumab, a PD-1/PD-L1 inhibitor, was approved in December 2022 as a single agent for unresectable or metastatic alveolar soft part sarcoma in adults and pediatric patients aged 2 years and older.[59]  

Pazopanib, a tyrosine kinase inhibitor with activity against multiple tyrosine kinases including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and c-kit, is FDA approved for soft tissue sarcomas. Specifically, it has been found to have activity in patients with leiomyosarcomas and synovial sarcomas.[60]  The COG trial ARST1321 is a phase 2/3 study that is evaluating pazopanib in NRSTSs (clinical trial identifier NCT02180867).[57]  

Phase 1 and 2 trials of tazemetostat, an enhancer of zeste homolog 2 (EZH2) inhibitor involved in the INI1 pathway, have shown promising anti-tumor activity in epithelioid sarcoma and malignant rhabdoid tumors (clinical trial identifiers NCT02601937 and NCT02601950).[35, 36, 37, 38, 39]   Tazemetostat received accelerated approval in January 2020 for patients aged 16 years or older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. Approval was based on a phase 2 trial (n=62). The overall response rate was 15%; 1.6% of patients had a complete response, and 13% had a partial response. Of the 9 patients who had a response, 6 patients (67%) had a response that lasted 6 months or longer.[61]

Olaratumab, a monoclonal antibody that targets platelet-derived growth factor receptor α (PDGFR-α), gained accelerated approval in 2016 for adults with soft tissue sarcomas. The drug was withdrawn from the US market in April 2019. In a press release, Eli Lilly and Company reported that the results of ANNOUNCE, a phase 3 trial of olaratumab in combination with doxorubicin in patients with advanced or metastatic soft tissue sarcoma, did not confirm the clinical benefit of olaratumab in combination with doxorubicin compared with doxorubicin.[62]

The following drugs continue to be evaluated in clinical trials:

Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor, has been found to have marked and durable antitumor activity in children and adults with TRK fusion–positive cancers, including infantile fibrosarcoma. Given these promising results, the standard treatment approach to TRK fusion–positive tumors may change.[4, 3]  Nirogacestat (previously called PF-03084014), an inhibitor of γ-secretase which is involved in the NOTCH pathway, has had encouraging results in phase 1 and 2 trials of adults with desmoid tumors and a phase 3 trial is planned.[20, 19]

Sunitinib is a receptor tyrosine kinase inhibitor that also has anti-angiogenic properties. It targets the PDGF receptor as well as the VEGF receptors and has been shown to have effectiveness against alveolar soft part sarcoma (ASPS).[63]

Wide local excision is the primary therapy for most NRSTS. Every attempt is made to obtain negative tumor margins, which can be accomplished in 50-80% of patients. If the initial surgery does not achieve pathologically negative margins, a re-excision should be performed in order to obtain clear margins. The mainstay of local control for sarcomas of the head and neck is aggressive surgical resection. These tumors may be difficult to remove with wide surgical margins. However, modern reconstruction techniques with vascularized flaps, free composite grafts, and rotation flaps assist in complete resection. Lesions in the extremities are usually totally resectable.

Limb-salvage procedures or amputation are the surgical options in patients with limb tumors. Limb or ray amputation may be needed to manage tumors of the hands or feet. In rapidly growing, young children, limb salvage is not always the best option in terms of function because frequent limb-lengthening procedures may be needed. New orthopedic limb-lengthening procedures and prostheses may make limb salvage more feasible than it once was in select patients. For some children with relapsed extremity tumors who were treated with previous radiation therapy, amputation may be the only option.

Dissection of the lymph nodes is not always warranted because of the infrequency of lymph node involvement in association with most NRSTSs. The rate of involvement is 6-9% in pediatric cases, usually high-grade NRSTSs although it is higher in certain subtypes of NRSTSs, most notably epithelioid sarcoma. Lymph node resection is warranted if the lymph nodes are enlarged on examination or scanning or if the tumor arises in an area near lymph nodes.

Surgical staging is important in making treatment decisions. Appropriate staging also allows for prognostication. The tumor, node, and metastases (TNM) staging system is useful and takes into account the size of the tumor (>5 cm or < 5 cm), the involvement of lymph nodes, and the presence or absence of metastatic disease. Another staging system, one used by the IRS researchers, is based on the extent of disease after initial surgical resection. See Staging above for definitions of the TNM stages and IRS groups.

In children with metastatic disease involving isolated pulmonary metastases, an exploratory thoracotomy should be performed in an attempt to resect all gross disease, if feasible.[64] In addition, re-resection of relapsed primary tumors is considered standard treatment.

Patients with sarcomas, particularly children, should be treated at comprehensive cancer centers with devoted multidisciplinary sarcoma programs that involve a pediatric sarcoma oncologist, oncologic surgeons, radiation oncologists, radiologists, and soft tissue pathologists.

For limb salvage procedures or amputation, consultation with a physical therapist and occupational therapist is essential to maximize functional outcome and recovery. The use of these services in certain other patients may be necessary, depending on the site and surgical procedure.

The chemotherapeutic agents described below are used in select cases of nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). Dosages and schedules of treatment for individual agents vary with the clinical environment with the particular patient. For each agent, general facts, representative pediatric dosages, and toxicities are noted.

Class Summary

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).

The cell division rate varies for different tumors. Most common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy, and it is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) also is a potential mechanism of many antineoplastic agents. Refer to specific protocol for duration of therapy with each drug and timing of administration within each treatment cycle.

Doxorubicin (Adriamycin)

Anthracycline antibiotic. Vesicant administered in free-flowing peripheral vein or central venous catheter. Several mechanisms of action: DNA intercalation, topoisomerase-mediated breaks in DNA strands, and oxidative damage due to production of free radicals.

Cyclophosphamide (Cytoxan, Neosar)

Alkylating agent; mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Usually administered IV. Available PO. Use with high doses in combination with aggressive fluid hydration and monitoring of renal output. Chemically related to nitrogen mustards.

Ifosfamide (Ifex)

Alkylating agent. Inhibits DNA and protein synthesis and, thus, cell-proliferation by causing DNA cross-linking and denaturation of double helix.

Cisplatin (Platinol)

Alkylating agent. Forced diuresis with IV fluids, mannitol, and furosemide necessary to minimize renal effects.

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-linking and denaturation of double helix.

Etoposide (Toposar, VePesid)

VP-16 is plant alkaloid. Usually administered IV as slow or continuous infusion. Use PO in certain diagnoses. Rapid infusion causes hypotension and allergic reactions.

Inhibits topoisomerase II and causes breakage of DNA strands, arresting cellular proliferation in late S or early G2 portion of cell cycle.

Vincristine (Oncovin, Vincasar PFS)

Plant alkaloid. Inhibits cellular mitosis by inhibiting function of intracellular tubulin, binding to microtubule and spindle proteins in S phase. Administer IV only in free-flowing vein or central venous catheter. Pain due to peripheral neuropathy usually treated with acetaminophen or codeine.

Dactinomycin (Actinomycin D)

Antibiotic derived from Streptomyces bacterium. Apparently inhibits DNA synthesis.

Vesicant administered in free-flowing vein or central catheter.

Dacarbazine (DTIC Dome)

Alkylating agent. 

Vinblastine (Velban)

Vinca alkaloid. Mechanism of action: binding of tubling thereby inhibiting microtubule assembly and leading to M phase specific cell cycle arrest. 

Methotrexate (Otrexup, Rasuvo, Trexall)

Antimetabolite. Competitively inhibitis dihydrofolate reductase (DHFR) which is an enzyme involved in tetrahydrofolate synthesis and leads to inhibition of DNA synthesis.

Class Summary

Tyrosine kinase inhibitors reduce tumor cell proliferation in vitro. May act at least partially by inhibiting tumor angiogenesis.

Pazopanib (Votrient)

Indicated for advanced soft tissue sarcoma in patients who have received prior chemotherapy. Efficacy not demonstrated in adipocytic soft tissue sarcoma or gastrointestinal stromal tumor (GIST).

Sunitinib (Sutent)

Indicated for gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib.

Imatinib (Gleevec)

Indicated for Kit (CD117)-positive unresectable and/or metastatic gastrointestinal stromal tumor (GIST).

Class Summary

Misregulation of the enhancer of zeste homolog 2 (EZH2) enzyme can result in poorly regulated genes that control cell proliferation. Blocking the misregulated EZH2 enzyme may slow cancer cell growth.

Tazemetostat (Tazverik)

EZH2 inhibitor. It is indicated for metastatic or locally advanced epithelioid sarcoma not eligible for complete resection in adults and adolescents aged 16 years or older.

Class Summary

Monoclonal antibodies to programmed cell death ligand-1 protein (PDL1). Binding PDL1 blocks the interaction between PDL-1 and its ligands (including B7.1 receptors). 

Atezolizumab (Tecentriq)

Indicated as a single agent, for unresectable or metastatic alveolar soft part sarcoma (ASPS) in adults and pediatric patients aged 2 years and older. 

Class Summary

Combination of NSAIDs (sulindac or celecoxib) plus hormonal agents with chemotherapy and tyrosine kinase inhibitors (TKIs) may be options for advanced or unresectable desmoid tumors.

Tamoxifen (Soltamox)

May consider use for pelvic desmoid tumors.

Class Summary

Antineoplastic-induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters (dopamine in the CTZ or acetylcholine in the VC) appears to be a major mediator for inducing vomiting. After antineoplastic agents are administered, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With this release of serotonin and with its subsequent binding to 5-HT3 receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents before and after cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

Effective antiemetics include ondansetron, granisetron, metoclopramide, diphenhydramine, lorazepam, perphenazine, prochlorperazine, and trimethobenzamide.

Ondansetron (Zofran)

Selective 5-HT3 receptor antagonist that peripherally and centrally blocks 5-HT. Prevents nausea and vomiting associated with emetogenic chemotherapy for cancer. Sometimes combined with dexamethasone to potentiate antiemetic effect.

Granisetron (Kytril)

Potent serotonin 5-HT3 receptor antagonist to prevent and treat chemotherapy- and irradiation-induced nausea and vomiting.

Class Summary

Colony-stimulating factors are used for supportive care. They act as hematopoietic growth factors that stimulate the development of granulocytes. They are used to treat or prevent neutropenia when patients are receiving myelosuppressive chemotherapy for cancer and to reduce the period of neutropenia associated with bone marrow transplantation. Colony-stimulating factors are also used to mobilize autologous progenitor cells in peripheral blood in bone marrow transplantation and in the management of chronic neutropenia.

Filgrastim (Neupogen)

G-CSF that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils. Enhances dosage intensification with chemotherapy and speeds recovery from neutropenia.

Class Summary

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide or cyclophosphamide.

In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

Mesna (Mesnex)

Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.

Frequent outpatient visits are required to monitor the effects and adverse effects of therapy. CBC counts should be assessed once or twice a week while patients are receiving granulocyte-colony stimulating factor (G-CSF) therapy. Periodically monitoring the toxic effects of chemotherapy on liver and renal function is required with serum chemistry levels. Supportive treatment with blood products, including packed RBCs and platelets, may be necessary if patients are given chemotherapy

Long-term follow-up is required after therapy is completed to monitor the following:

• Disease recurrence

• Development of a secondary malignancy, particularly if the patient received radiation therapy and/or chemotherapy with etoposide

• Growth and development

• Cardiac function in children who received anthracycline chemotherapy (Perform annual ECG and echocardiography.)

Inpatient care of patients with nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) involves admissions for chemotherapy and for supportive care related to therapy.

Patients must be hospitalized to manage episodes of fever and neutropenia and to start broad-spectrum antibiotic coverage while culture results or recovery from illness are awaited.

The long-term effects of NRSTS treatment in children are many.

Surgical treatments may cause marked permanent functional deficits, depending on the location and extent of surgery.

The use of chemotherapy has been associated with numerous late effects. Doxorubicin can cause life-threatening cardiomyopathy. Ifosfamide can cause permanent renal impairment, hemorrhagic cystitis, infertility, gonadal failure, and an increased risk of secondary malignancies. Radiation therapy can also have lifelong debilitating effects. The effects of radiation depend on the location irradiated and the amount of radiation given to the site. Common effects can include growth plate arrest, pulmonary fibrosis, development of muscle fibrosis and contractures, and development of a secondary cancer in the radiation field.

Prognostic factors for children with NRSTS include the presence of metastatic disease, ability to achieve local control, tumor size and invasiveness, and tumor histologic grade.

According to IRS groups, survival rates are as follows:

• Group I - 82%

• Group II - 67%

• Group III - 12%

• Group IV - 5

Tumor, node, and metastases (TNM) stage 4 ( the presence of metastasis) correlates with an extremely poor prognosis of (< 20%).

Many factors contribute to survival, but the degree of resectability at the time of diagnosis is the most important factor identified to date.