Nonrhabdomyosarcoma Soft Tissue Sarcomas

Updated: Mar 27, 2015
  • Author: Justine K Walker, MD; Chief Editor: Robert J Arceci, MD, PhD  more...
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Overview

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 share some biologic characteristics but differ in histology. The most common types in the pediatric population include fibrosarcomas, 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. 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]

See Soft-Tissue Sarcomas: What You Need to Know, a Critical Images slideshow, to help identify and treat some of these malignant tumors of mesenchymal origin.

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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.

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.

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.

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.

Patients with IFS have an excellent prognosis, with survival rates of more than 90% in some series. They are usually treated with surgery alone; however, preoperative chemotherapy has made more conservative approaches possible. [2] 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; [3] 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%).

Surgical resection followed by radiation of residual disease is the best therapy. [4] Chemotherapy may have a role in unresectable and metastatic disease, as well as in adjuvant therapy after resection. [5] 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. [6]

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. [7]

Surgical resection with clear margins is the treatment of choice, although this can be difficult due to the infiltrative nature of these tumors. When complete surgical excision is not feasible and the tumor may cause significant morbidity or mortality, one should consider neoadjuvant interventions such as radiation therapy or chemotherapy; vinblastine and methotrexate are active agents. [8] Systemic chemotherapy may also be of use in the treatment of progressive disease. However, partially excised or recurrent tumors that do not pose a risk to vital organs may simply be closely monitored if re-resection is not an option.

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. [9]

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.

Malignant fibrous histiocytoma

Malignant fibrous histiocytomas (MFH) were once the most commonly diagnosed soft tissue sarcoma in the adult population. These pleomorphic tumors were given this name because they were presumably derived from histiocytes capable of fibroblastic transformation. However, whether MFH should be a true diagnosis has become controversial. 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. Therefore, the World Health Organization (WHO) now no longer recognizes MFH as a distinct diagnostic category. These neoplasms are now a subtype of undifferentiated pleomorphic sarcomas. [10, 11]

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Epidemiology

Frequency

United States

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.

Mortality/Morbidity

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 malignant fibrous histiocytoma and 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. See Prognosis.

Race

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

Sex

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

Age

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.

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