Nonrhabdomyosarcoma Soft-Tissue Sarcoma
As a group, nonrhabdomyosarcoma soft-tissue sarcomas comprise almost 50% of pediatric soft-tissue sarcomas. These tumors can occur anywhere in the body but are most commonly seen in the extremities. These uncommon malignancies include malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors, extraosseous Ewing’s sarcoma, alveolar soft-part sarcoma, clear-cell sarcoma or melanoma of the soft parts, synovial sarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, angiosarcoma, epithelioid sarcoma, and hemangiopericytoma.
Tumor Biology
Each of the nonrhabdomyosarcoma soft-tissue sarcomas arises from mesenchymal cells. The tumors are distinguished from one another on the basis of light microscopy, immunohistology, and electron microscopy. The most common types in the pediatric population are synovial sarcoma, malignant peripheral nerve sheath tumor, and fibrosarcoma. These tumors may also be associated with the Li-Fraumeni syndrome, implicating a p53 mutation.[4] Nonrhabdomyosarcomas have also been reported to occur with other syndromes, including neurofibromatosis, Down syndrome, and spina bifida.[20] Histologic tumor grade remains the foremost factor in determining patient prognosis, and for this reason, a formal grading system has been developed as shown in Table 3.[20-22]
According to this system, grade 1 tumors are limited to myxoid, well-differentiated liposarcomas, dermatofibrosarcoma protuberans, extraskeletal chondrosarcoma, well-differentiated leiomyosarcoma, malignant hemangiopericytoma, peripheral nerve sheath tumors, and infantile fibrosarcoma. Grade 2 tumors are less than 15% necrotic at histologic examination, have a mitotic index of 5 to 10 per high-power field, and show no marked nuclear atypia or cellularity.
Grade 3 tumors have marked nuclear atypia or cellularity, greater than 15% necrosis, and/or more than 10 mitoses per high-power field. They include pleomorphic liposarcomas, mesenchymal chondrosarcomas, extraskeletal osteosarcoma, triton tumors, alveolar soft-part sarcomas, extraosseous Ewing’s sarcoma, and epithelioid sarcomas. Fibrosarcoma and malignant hemangiopericytomas in children less than 4 years old are excluded from the grade 3 classification.
Evaluation and Staging
As with rhabdomyosarcomas, the clinical presentation of nonrhabdomyosarcomas varies based on the region of the body. Most will manifest as painless masses. The differential diagnosis is also the same as that described for rhabdmyosarcoma. Radiographic examination should be performed to determine the extent of tumor, whether there has been invasion into adjacent structures, and whether distant metastases are present. MRI is the preferred imaging modality for tumors of the extremity and head and neck. CT scans are useful for abdominal tumors and for evaluation of lung parenchyma for metastatic disease (Figure 9).
Following radiographic evaluation, a tissue diagnosis is obtained via either needle biopsy, incisional or excisional biopsy, or wide local excision based on tumor resectability. If there is clinical evidence of nodal involvement, lymphatic staging may be performed, although nodal involvement is less frequently seen with nonrhabdomyosarcoma than with rhabdomyosarcoma.
Treatment
Multimodal therapy has also been shown to be the most effective approach to treatment for nonrhabdomyosarcoma.
• Surgery—Surgical evaluation begins at the time of tissue diagnosis and surgical staging. Complete resection with negative margins remains the most important prognostic indicator, and surgical intervention must be planned with this goal in mind.[4] Because many children present with locally advanced disease, the most common initial surgery performed is incisional or excisional biopsy in order to obtain a tissue diagnosis. Wide local excision is undertaken as an initial surgery only if complete excision is feasible.
Following any indicated adjuvant therapy, children who have undergone initial biopsy return to the operating room for second-look surgery and complete excision of the remaining tumor (Figure 10 and Figure 11). Positive or unclear margins should be treated with further resection; however, if this is not possible due to adjacent structures, or the prospect of adverse cosmetic or functional outcome, brachytherapy catheters may be implanted to allow aggressive localized radiotherapy. This method may also improve local control in limb-sparing surgery.
Malignant fibrous histiocytoma is an uncommon subtype of nonrhabdomyosarcoma; 44 pediatric patients have been diagnosed and treated for this tumor at the M. D. Anderson Cancer Center over a 15-year period. A review by Corpron et al revealed an excellent prognosis for children with resectable tumors of this type.[23] Treatment for malignant fibrous histiocytoma, as for other nonrhabdomyosarcomas, consists primarily of surgery with the goal of complete resection; chemotherapy and radiation are reserved for patients with residual, metastatic, or recurrent disease. Of note, in 24 patients with microscopic residual disease, survival was not affected, but the rate of recurrence increased.[24]
Surgical resection should also be considered for metastatic disease. According to the findings of several small studies, aggressive metastasectomy for pulmonary disease appears to increase survival.[25] However, this technique needs to be evaluated further and should be reserved for metastatic disease that is localized (Figure 12).
• Radiotherapy—Nonrhabdomyosarcoma was once believed to be radioresistant. However, radiation is now widely used in the adult population with good success.[22] Radiation therapy should be administered to patients with advanced local, residual, or recurrent disease. It may be delivered either by external beam (as is often the case for locally advanced or recurrent disease) or by brachytherapy (which should be considered for patients in whom residual disease is either confirmed or strongly suspected at the time of surgical resection). Brachytherapy treats the tumor bed aggressively, while sparing the surrounding normal tissue and bone.
• Chemotherapy—Chemotherapy has not been well studied in pediatric patients with nonrhabdomyosarcoma, because of the multiplicity of histologic types, differences in biological behavior, and relative rarity of the disease in this patient population. Therefore, based on experience in adults, most children are treated with doxorubicin and ifosfamide (Ifex). Recent studies have shown that children with grade 1 and 2 tumors do not benefit from chemotherapy and that chemotherapy should be reserved for those with either grade 3 tumors, incompletely resected local disease, or metastases at diagnosis.[24]
Summary
Pediatric nonrhabdomyosarcoma soft-tissue sarcomas are a relatively rare group of malignancies. Children with these tumors are beginning to benefit from multimodal therapy. However, the roles of radiation therapy and chemotherapy are not as clearly defined as in rhabdomyosarcoma. Ongoing research will continue to optimize therapy in these patients.
