Background
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]
Pathophysiology
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]
Epidemiology
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.
Prognosis
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.
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COG-ARST0332 experimental design schema.
Tables
|
Primary Tumor |
Regional Lymph Nodes |
Distant Metastasis |
Histologic Grade |
Stage I |
Any tumor size, superficial or deep |
N0 |
M0 |
G1 or G2 |
Stage II |
T1a (tumor < 5 cm, superficial) |
N0 |
M0 |
G3 |
T1b (tumor < 5 cm, deep) |
N0 |
M0 |
G3 |
|
T2a (tumor >5 cm, superficial) |
N0 |
M0 |
G3 |
|
Stage III |
T2b (tumor >5 cm, deep) |
N0 |
M0 |
G3 |
Stage IV |
Any tumor size, superficial or deep |
N1 |
M0 or M1 |
G1, G2, or G3 |
Any tumor size, superficial or deep |
N0 or N1 |
M1 |
G1, G2, or G3 |
Risk group |
Tumor characteristics |
Treatment |
|||
Tumor Grade |
Tumor Size |
Tumor Stage |
Upfront Surgical Resectability |
||
Low |
Low |
Any |
Localized |
Gross resection (with negative or positive microscopic margins) |
Surgery + observation |
| Low | High |
< 5 cm |
Localized |
Gross resection with negative microscopic margins |
Surgery + observation |
| Low | High |
< 5 cm |
Localized |
Gross resection with positive microscopic margins |
Surgery + adjuvant radiation therapy |
Intermediate |
High |
>5 cm |
Localized |
Gross resection |
Surgery + adjuvant radiation therapy + adjuvant chemotherapy |
| Intermediate | High |
Any |
Localized |
Unresectable or Planned delayed surgical resection due to high grade, size >5 cm, and anticipate gross resection only possible with positive microscopic margins |
Neoadjuvant chemotherapy + surgery + adjuvant chemotherapy with or without radiation therapy |
High |
Low |
Any |
Metastatic |
Gross resection |
Surgery + observation |
| High | High |
Any |
Metastatic |
Gross resection |
Surgery + adjuvant radiation therapy + chemotherapy |
| High | High |
Any |
Metastatic |
Unresected |
Neoadjuvant chemotherapy + surgery + adjuvant chemotherapy with or without radiation therapy |
