Sarcoma, Soft Tissue

Introduction

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 include dermatofibrosarcoma protuberans, synovial cell sarcoma, malignant fibrous histiocytoma, 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.

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 occurs in the extremity in 70% of patients and is rarely metastatic. 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.

IFS is usually treated with surgery alone, with survival rates of more than 90% in some series. 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;1 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%.

Malignant fibrous histiocytoma

Malignant fibrous histiocytomas are rarely observed in young children and usually affect individuals older than 10 years. These tumors primarily occur on an extremity.



Cytogenetic analysis demonstrates chromosome 19p+ and ringed chromosomes. Malignant fibrous histiocytomas have histologic features similar to those of fibrosarcomas except for the loss of the herringbone cellular pattern and except for a more malignant phenotype. Malignant fibrous histiocytomas are commonly observed in radiation-induced sarcomas. The most common metastatic site is the lung.

Surgical excision with irradiation to residual local disease is the therapy of choice. Chemotherapy may be useful in select cases. Chemotherapeutic regimens including vincristine, dactinomycin, and cyclophosphamide with and without irradiation have been somewhat successful in select pediatric and adult patients. Activity has also been observed with combinations of ifosfamide and etoposide. Optimal use of chemotherapy to treat this tumor has yet to be determined.

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. 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. Chemotherapy may have a role in unresectable and metastatic disease. 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. The most common site of metastasis is 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.

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.



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.

Clinical

History

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

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.

Causes

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 ionizing 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.

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