Pediatric Soft Tissue Sarcomas

Pediatric Soft Tissue Sarcomas Rebecca Stein-Wexler, MD After a brief discussion of the rarity of soft tissue sarcomas in children and of the limited ability of magnetic resonance imaging to provide a tissue diagnosis, this article discusses the incidence, presentation, treatment, prognosis, and imaging characteristics of the more common and unusual pediatric soft tissue sarcomas. It begins with extensive discussion of rhabdomyosarcoma, synovial sarcoma, and congenital/infantile fibrosarcoma. It then presents a more abbreviated discussion of uncommon tumors such as alveolar soft part sarcoma, epithelioid sarcoma, extraosseous Ewing’s sarcoma, granulocytic sarcoma, hemangiopericytoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, and undifferentiated sarcoma. Semin Ultrasound CT MRI 32:470-488 © 2011 Elsevier Inc. All rights reserved.

S

oft tissue sarcomas constitute 4%-8% of childhood cancers,1 and as a group they are considered the fifth most common pediatric soft tissue neoplasm, preceded in frequency by leukemia/lymphoma, central nervous system tumors, neuroblastoma, and Wilms’ tumor.2 Approximately 50% are classified as rhabdomyosarcoma (RMS).2,3 In some series, the most common nonrhabdomyosarcomatous tumors are synovial sarcoma, fibrosarcoma, malignant fibrous histiocytoma (MFH), epithelioid sarcoma, and clear cell sarcoma.4 However, the vast majority of soft tissue masses in children are benign, and hemangiomas, lymphangiomas, synovial/ganglion cysts, inflammatory masses, and post-traumatic lesions are far more common than any soft tissue sarcoma.1 As in older children, most soft tissue masses in infants are benign. The most common soft tissue malignancies in this age group are fibrosarcoma and RMS, with hemangiopericytoma, malignant peripheral nerve sheath tumor, and others occurring much less often.5,6 Imaging can suggest the diagnosis but, with some exceptions, is rarely definitive in determining pathology. The success of magnetic resonance imaging (MRI) at determining whether a soft tissue mass is benign or malignant varies between 30% and 90%, depending on the study population.7-10 Some have determined that rapid enhancement and washout correlate with malignancy.11 MRI can correctly identify such benign masses as hemangiomas, lymphatic malformations, venous malformations, lipomas, myositis ossificans, neurofibromas, and periarticular cysts.12,13 However, if a lesion lacks Department of Radiology, University of California at Davis, Sacramento, CA. Address reprint requests to Rebecca Stein-Wexler, MD, Department of Radiology, University of California at Davis, 4860 “Y” Street, Suite 3100, Sacramento, CA 95817. E-mail: [email protected]

470

0887-2171/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.sult.2011.03.006

characteristics specific to these diagnoses, imaging plays a less critical role in defining tissue diagnosis. Malignant masses are more likely to exceed 5 cm in diameter, whereas only 5% of benign masses exceed this size; furthermore, because of their autonomous growth they are likely to outgrow their blood supply and become necrotic and heterogeneous. Malignant tumors are also more often deep.8 Most soft tissue sarcomas exhibit similar features: hypointensity on T1-weighted MRI, hyperintensity on T2weighted MRI, and the presence of a pseudocapsule. The presence of tumor enhancement and perilesional soft tissue edema is not particularly helpful in differentiating benign from malignant processes.8 A few features help differentiate between some malignant lesions. MFH might contain calcifications and tends to occur in older patients. Synovial sarcoma might also demonstrate calcifications, and it is often hypervascular. Liposarcoma might contain foci of fat. Alveolar soft part sarcoma typically demonstrates distinctive flow voids and is hyperintense at both T1- and T2-weighted imaging. Although it rarely provides tissue diagnosis, MRI is essential for determining extent of lesions, which helps in assessing resectability. The invasion of nearby bones and neurovascular bundles, or proximity to other essential structures, decreases the probability of complete resection, and for most tumors complete resection is intricately tied to prognosis. MRI allows excellent definition of adjacent lymph nodes, and it provides better contrast between normal tissue and tumor than does computed tomography (CT). Multiplanar capabilities allow better delineation of the 3-dimensional appearance and the relationship of a soft tissue mass to adjacent structures. CT is predominantly complementary to MRI and most useful for identifying subtle soft tissue mineralization,

Pediatric soft tissue sarcomas which can direct the diagnosis. It can also identify the presence of fat, and adjacent osseous findings can provide insight into the aggressiveness of a soft tissue mass.14 Ultrasound both defines cystic lesions and characterizes vascularity. However, accurate diagnosis of sarcomatous soft tissue tumors depends on a combination of light microscopy, immunohistochemical analysis, and molecular genetics15 and has important therapeutic implications. In general, the mainstay of therapy is complete surgical excision with wide margins, with radiation therapy considered only if margins are poor. The role of chemotherapy varies, but chemotherapy is generally more likely to be used with high-grade tumors.2,16 Many soft tissue tumors, such as RMS, fibrosarcoma, liposarcoma, synovial sarcoma, and epithelioid sarcoma, do better in younger patients. This might be due to the presence of increased host immunity, improved DNA repair ability, less oncogene amplification, and/or a more intact tumor-suppressor gene in the young.17 However, except for infantile fibrosarcoma and hemangiopericytoma, children ⬍1 year of age fare worse, perhaps because of reluctance to use radiotherapy in this exquisitely sensitive age group.18

Rhabdomyosarcoma The most common soft tissue sarcoma in children, RMS accounts for 7% of all pediatric malignancies and 40% of soft tissue sarcomas.19 Almost all pediatric cases are of the alveolar or embryonal subtypes, with pleomorphic RMS encountered almost exclusively in adults. Despite the superficial similarity of these tumor subtypes, they appear to represent unique tumors, typically arising in specific locations and manifesting different biological behavior and pathologic characteristics. Although the histology resembles that of striated muscle, this tumor arises from undifferentiated mesenchyme that has differentiated to simulate muscle cells. Embryonal RMS accounts for 60%-70% of cases and is usually found in the head and neck, retroperitoneum, and genitourinary tract, generally in a younger age group (before age 10). It is characterized by loss of an allele on chromosome 11.19 It can be further divided into botryoid and spindle-cell forms. The botryoid type occurs in a submucosal location as an exophytic, polypoid, grape-like mass. With an exophytic growth pattern, its prognosis is relatively good.20 The spindle-cell form, whose parallel spindle cells are arranged in broad fascicles,20 also has a relatively good prognosis. It is usually found in a paratesticular location or in the head and neck. Alveolar RMS accounts for about 20% of cases, with incidence evenly distributed throughout childhood and adolescence. It consists of ill-defined aggregates of poorly differentiated round or oval tumor cells that are often noncohesive. Eighty percent have 1 of 2 specific chromosomal translocations.19,20 It presents in older patients (average age, 15 years),21 with a predilection for the extremities and trunk.

Etiology Etiology is unknown, but both environmental and genetic factors increase risk of RMS. This tumor is more common in

471 patients with neurofibromatosis I, as well as in those with Beckwith-Wiedemann syndrome, Costello syndrome, and Li-Fraumeni syndrome. Paternal cigarette smoking, advanced maternal age, in utero radiograph exposure, antibiotic use (by mother or child), and maternal recreational pharmaceutical use are associated with an increased incidence.19 Along with osteosarcoma and meningioma, RMS might occur as a second primary in children with retinoblastoma that has been treated with radiation therapy.22 About 32% of children with RMS have congenital malformations, and there is an increased incidence of cancer in their family members.19 Incidence of embryonal RMS is slightly higher in males.19

Presentation RMS occurs most often in young children, especially in the 2to 5-year-old age group, with 65% presenting before 6 years of age,23 and the average age at presentation is 7-8 years.3 It has been diagnosed in infants ⬍1 month of age.6 Presentation depends on location but is usually indolent and nonspecific. Most cases (about 40%) occur in the head and neck, where proptosis or recurrent sinusitis is the typical presentation. Chronic headache might denote intracranial tumor extension.24 A genitourinary location is next most common (25%). Girls with vaginal RMS present with a prolapsing, botryoid mass or with urinary symptoms, whereas boys with bladderprostate RMS typically have bladder outlet obstruction, hematuria, constipation, or a mass.20 Paratesticular RMS presents with a mass that might or might not be painful. An extremity mass is the next most common location, occurring in 15%20 and typically presenting with a nontender soft tissue mass, perhaps with accompanying lymphadenopathy. Intraabdominal and intrathoracic tumor presentation depends on specific location and accounts for the remainder of cases. Systemic symptoms of fatigue, weight loss, and low blood counts might be present with metastatic disease.20 Synchronous nonmetastatic RMS has been reported.25 Metastases are present in 10%-20% of patients at the time of diagnosis26 but are unusually common in infants.5 Regional lymph nodes, lungs, bones, and bone marrow are most often involved, but unusual sites have also been documented, such as breast, testes, and subcutaneous soft tissue.27 Initial work-up includes chest CT to evaluate for lung metastases.20,26 Some form of imaging for bony metastases is also performed: nuclear medicine scintigraphy, fluorodeoxyglucose positron emission tomography (FDG-PET), and/or total body MRI.20,28 Osseous metastases are usually ill-defined and lytic.26,29 Screening of other locations might be motivated by patient symptoms. Pancreatic metastases have been observed at autopsy, and a recent article reported CT evidence of alveolar RMS with pancreatic metastases developing as much as 6 years after initial diagnosis.28 Metastatic foci appeared as multiple or solitary irregular, hypodense lesions at contrast-enhanced CT and demonstrated significant FDG uptake at PET-CT28 (Fig. 1). Omental disease (both primary and metastatic) has also been reported, manifesting as mild to moderate ascites, intraperitoneal nodules and masses, and mesenteric nodules demonstrating various en-

R. Stein-Wexler

472

plete surgical resection is possible as well as the original size of the tumor.

Prognosis Prognosis is complex, depending on the histologic subtype, location, extent, resectability, and presence of metastases. In general, the prognosis for embryonal RMS is better than that for alveolar, although large tumor size, incomplete resection, and metastatic disease confer a worse prognosis.31 Nonmetastatic embryonal tumors arising in the genitourinary system or orbit have the best prognosis. Occasionally older children develop orbital alveolar RMS, however, and this carries a worse prognosis.3 Head and neck tumors outside of the orbit do not fare as well, in part because they lack the bony confines of the orbit and have more associated lymphoid tissue. The prognosis for parameningeal tumors is poor because of abundant lymphatics and the tendency for intracranial spread, which results in nonresectable intracranial disease. Tumors that arise in the extremities also have a worse prognosis, probably because they are usually of the alveolar subtype. Thoracic tumors have an even worse outcome, with only 45% 5-year survival.32 This is probably because they tend to be alveolar, commonly have metastases at presentation, and arise in locations where both resection and radiotherapy are often problematic.32 Overall survival for localized disease is now 75%, but those with metastases have a dismal 5-year overall survival of only 24%.20 Prognosis in infants is generally worse.18

Imaging

Figure 1 CT and FDG-PET of RMS metastatic to pancreas and peritoneum in a 7-year-old boy with primary disease in the right lower extremity. (A) Axial contrast-enhanced abdominal CT demonstrates heterogeneous pancreatic head and hypodense peritoneal mass. (B) FDG-PET demonstrates increased metabolic activity in both areas. (Courtesy of Leslie Grissom, MD, Wilmington, DE.) (Color version of figure is available online.)

hancement patterns. Omental caking, which is otherwise limited to lymphoma and Wilms’ tumor in children, has also been described for both the alveolar and the embryonal subtypes.23,30

Treatment Treatment consists of a 3-pronged approach of chemotherapy, surgery, and radiation. This disease is considered to be metastatic at presentation, and therefore, chemotherapy is offered to essentially all patients.21 After chemotherapy, complete wide excision of the primary, including a clean margin of uninvolved tissue, can be performed more easily. The need for radiotherapy is determined by the extent to which com-

In general, at radiography a soft tissue mass might be present, sometimes with localized bony erosion. Ultrasonography is nonspecific but demonstrates a slightly hypoechoic or hyperechoic, often inhomogeneous soft tissue mass, sometimes with markedly increased flow.20,26 When it occurs at the bladder base, it often protrudes into the bladder lumen, resembling a bunch of grapes. CT demonstrates a nonspecific, vigorously enhancing soft tissue mass and is useful for identifying lymphadenopathy. MRI characteristics of RMS are nonspecific. Intermediate signal intensity is apparent on T1weighted sequences, and the mass is intermediate to high signal on T2-weighted. Enhancement is vigorous, and prominent high-flow vessels might be observed in the alveolar subtype.26 It might be lobulated and is rarely predominantly cystic.20 Vascular structures are considered encased if there is no normal tissue plane between the tumor and adjacent vessels, or if there is more than 180 degrees of circumferential involvement of vascular structures.20 Differential diagnosis generally depends on the site of the primary lesion and is further addressed in the discussion of RMS at specific locations. However, in general, hemangiomas/vascular malformations might be considered, as well as adult-type sarcomas, peripheral neuroectodermal tumor (PNET), lymphoma, infantile fibrosarcoma, aggressive fibromatosis, desmoplastic small round-cell tumor, rhabdoid tumor, and extraosseous Ewing’s sarcoma.

Pediatric soft tissue sarcomas

473

Orbital RMS The most common primary pediatric orbital malignancy, orbital RMS is essentially always unilateral and usually presents in young children, in whom the embryonal subtype is by far most common. This tumor is usually located in the superior orbit and presents with proptosis. If diagnosed promptly, bony structures are usually intact, but if it has been allowed to grow, there can be extensive bony destruction. At CT, the mass is homogeneous and isodense to muscle, although previous hemorrhage results in a heterogeneous appearance. MRI demonstrates a mass that is isointense or slightly hypointense compared with brain at T1-weighted and of increased signal intensity at T2-weighted. Hemorrhage results in focal areas of altered signal intensity. Enhancement is moderate to marked. The tumor might extend from or invade the paranasal sinuses or might extend intracranially.3 Differential diagnosis includes metastatic neuroblastoma, Langerhans cell histiocytosis, plexiform neurofibroma, aggressive fibromatosis, granulocytic sarcoma, and Ewing’s sarcoma.

Extraorbital Head and Neck The embryonal, and specifically the botryoid, subtype is most common in these locations.33 When RMS is encountered in the extraorbital head and neck, it is important to determine whether the tumor is parameningeal, because this affects resection options (Fig. 2). Parameningeal disease occurs in direct or near contact with the skull base and can arise from the nasopharynx, parapharyngeal space, masticator space, nasal cavity, paranasal sinuses, mastoids, or middle ear.24,33 Either skull base involvement or intracranial extension confers a worse prognosis.24 Perineural extension, most often involving branches of the trigeminal nerve or facial nerve, is best appreciated with enhanced T1-weighted, fatsuppressed imaging. Meningeal invasion occurs in 35%-55% of these cases, resulting in death in as many as 90%.33 Signal intensity resembles that of RMS occurring elsewhere. Bone erosion occurs in about one fifth of parameningeal RMS and is especially common in those arising in the middle ear.33 In the absence of calcification (which excludes RMS, weighting the differential toward chordoma, chondrosarcoma, chondroma, or osteosarcoma),33 the differential diagnosis is principally lymphoma or nasopharyngeal carcinoma for extraorbital head and neck RMS.

Figure 2 11-year-old girl with parapharyngeal RMS. (A) Axial contrast-enhanced CT and (B) coronal T1-weighted, gadolinium-enhanced MRI show encasement of the left common carotid and internal jugular vein, as well as extension into the middle cranial fossa.

Genitourinary RMS These tumors are divided into the bladder/prostate group and the non-bladder/prostate group. Taken together, they constitute about 25% of all cases. Tumors arising in the bladder/prostate occur in males and, despite their alveolar histology, have a worse prognosis (prostate is more likely to metastasize than bladder26) (Figs. 3 and 4). In contrast, paratesticular, vaginal, and uterine tumors have a favorable prognosis.20 Bladder/prostate RMS manifests as an intraluminal, often botryoid mass, with associated bladder wall thickening. T2weighted MRI can be especially helpful to evaluate for bladder wall thickening, because intraluminal iodinated contrast

can make enhanced CT images difficult to interpret.20 Alternatively, the patient can be positioned so that suspicious areas are not in a dependent position. Paratesticular RMS has a bimodal distribution, with peaks at 5 and 16 years of age. Presenting as a painless scrotal mass, at ultrasound paratesticular RMS appears homogeneous. It resembles testis at both T1- and T2-weighted imaging, but the presence of low signal tunica albuginea allows differentiation from the adjacent testis.34 In early childhood, female genital RMS occurs in the vagina (Fig. 5), but in older children it is found in the cervix.26 It manifests as a multilobulated, intraluminal, botryoid mass.

R. Stein-Wexler

474

Figure 3 2-year-old boy with bladder/prostate RMS, presenting with urinary tract infection. Oblique image from voiding cystourethrogram (A) and sagittal reformatted CT (B) demonstrate a soft tissue mass invading and displacing the urinary bladder.

Extremities Occurring most often, but definitely not exclusively, in older children and adults, this tumor is usually composed of the alveolar subtype (Fig. 6). Imaging demonstrates regional lymph node involvement in 12% at diagnosis, but with nodal dissection this increases to almost 50%.20 More distant metastases are also common. The tumor appears as a soft tissue mass with imaging characteristics as described previously.

Other Locations The most common pediatric tumor of the biliary tree, RMS usually manifests as a cystic or solid mass at the hepatic hilum, and there is generally associated intrahepatic biliary ductal dilatation.20 RMS might occur in pulmonary congenital cystic anomalies.

Synovial Sarcoma The most common nonrhabdomyosarcomatous soft tissue sarcoma in children,32 synovial sarcoma is a malignant, highgrade tumor that typically manifests as a deep-seated, slowgrowing mass.35 Occasionally tender, it can also present with sensory or motor disturbance and, rarely, with weight loss.36 It accounts for between 5% and 10% of soft tissue sarcomas.35 Despite its high grade, it is not unusual for symptoms to have been present for several years.35,37 Between 30% and 50% of cases occur in patients younger than 20 years old,32,38 and it is slightly more common in males.

characterized by a translocation between chromosomes X and 18.15 It arises within a joint or bursa in only 5% of cases.35 However, it frequently arises within 7 cm of a joint,39 near joint capsules, tendon sheaths, or bursae.35,36 Ninety percent of cases occur in the extremities,35,40 most often in the thigh or near the knee,35,41 but it is also found in the trunk, abdomen, and head and neck region, in decreasing order of frequency.32,36 It is rarely superficial and is usually larger than 5 cm at presentation.39 Although there is a bimodal appearance at pathology, with monophasic tumors having spindle cells only and biphasic tumors being composed of both spindle and epithelial cells, the 2 types do not appear to have prognostic significance42 or to differ in appearance.39

Prognosis Prognosis is best in the presence of a low mitotic index,35 if the initial tumor size is ⬍5 cm,32,35,41,42 if the tumor is more distal,41 and if surgical resection is complete.32,35 Children fare better than adults.43 Presence of SYT-SSX1 fusion, which is a variant result of translocation that involves chromosomes X and 18, is associated with earlier development of metastases.15 The calcifying variant has a better long-term prognosis, but hemorrhage is associated with a worse prognosis.35,40,41 Both gross and microscopic tumor often extends beyond what appears to be a pseudocapsule, often mandating reexcision.32

Treatment Presentation Synovial sarcoma arises from primitive mesenchymal cells that differentiate to resemble synovial cells, and cells are

Local radiation therapy is helpful when surgical margins are narrow, or if there is adjacent nodal involvement,32,35 but the role of chemotherapy is controversial. Metastatic disease,

Pediatric soft tissue sarcomas

475

Figure 4 11-month-old boy with prostate RMS. Axial enhanced CT (A) demonstrates a lobulated soft tissue mass that is of intermediate signal intensity on sagittal T1-weighted fat-suppressed image (B). It enhances heterogeneously (C; sagittal T1-weighted fat-suppressed image) and is heterogeneous on T2-weighted imaging (D), displacing the bladder.

usually involving the lungs but occasionally bone, is found in 25% at presentation40 and is associated with dismal prognosis.32,37 Fluorine-18 FDG-PET is helpful for detecting occult metastatic disease, because synovial sarcoma is typically FDG-avid.37 Local recurrence is common, occurring within the first 2 years of resection in up to 50% of patients, but it can also be delayed as much as 20 years.35 In the absence of metastatic disease, the prognosis is good.

Imaging At CT, the mass might appear well-defined (Fig. 7), and calcifications might be seen in the periphery.44 MRI appearance is variable (Fig. 8). The most common appearance is heterogeneous, multilocular, and cystic, with internal septations.39,44-46 Fluid-fluid levels, often because of layering blood products, are common.39,45-47 Although margins are generally sharp,38,39,44 some margins, especially in larger tumors, might be poorly defined and infiltrative.46,48 The lesion is usually isointense to muscle on T1-weighted sequences and similar to or more intense than subcutaneous fat on T2-weighted.45,46,48 It is usually heterogeneous at T2weighted imaging, especially if large.39 Enhancement is het-

erogeneous.26 Occasionally, the mass is isointense to muscle on both T1- and T2-weighted sequences, and it can appear deceptively benign—small, homogeneous, with well-defined margins (Fig. 9).7,37,40,46,48 In a review of 15 patients with synovial sarcoma, one-third appeared benign at MRI, although larger lesions tend to appear more aggressive.48 Lung nodules might calcify.40 Although not specific, several imaging characteristics of synovial sarcoma are unusual in other tumors and, if present together, might help steer the diagnosis. These are principally the presence of soft tissue calcifications, fluid-fluid levels, hemorrhage, and relative lack of T2-weighted hyperintensity. Radiologically detectable scattered, peripheral-punctate calcifications occur in about 30%36,40,41 and are of diagnostic value, because they are rare in other soft tissue sarcomas.35,46 However, more extensive calcifications resembling osteoid matrix, or central punctuate calcifications, are rare.40 MRI demonstrates calcifications less reliably than do radiographs or CT, but they might be identified as areas of decreased signal on T1- and T2-weighted sequences.37 Unlike many soft tissue sarcomas, hemorrhage is common, occurring in as many as 73%.45 High signal on both T1 and T2 suggests the

476

Figure 5 10-month-old girl with vaginal RMS. Longitudinal pelvic ultrasound (A) demonstrates a lobulated mass protruding into the fluid-filled, obstructed vagina. Sagittal (B) and coronal (C) contrastenhanced CT also demonstrate a moderately enhancing lobulated mass. The uterus can be seen just above the fluid-filled vagina on the sagittal image.

R. Stein-Wexler

Figure 6 Axial MRI in a 7-year-old boy with alveolar RMS of the right lower extremity. (A) Axial T1-weighted image demonstrates a solidappearing mass that is isointense to muscle. There is central and peripheral enhancement (B; T1 fat-suppressed gadolinium-enhanced image). Central serpiginous hypointensity on T2 fat-suppressed image (C) might be caused by large vascular channels. (Courtesy of Leslie Grissom, MD, Wilmington, DE.)

Pediatric soft tissue sarcomas

477 sheath tumor, and inflammatory arthritis.7,37 Sometimes appearing cystic at MRI (Fig. 10), it can be misdiagnosed as Baker’s cyst, hematoma, or ganglion cyst.38 Small lesions can have smooth margins and be homogeneous on both T1- and T2-weighted sequences, appearing deceptively benign. Enhancement is usually inhomogeneous, however, and this can help suggest malignancy.37 Early diagnosis is essential, given the dismal prognosis of 10% 5-year survival when metastatic disease is present.37

Congenital/ Infantile Fibrosarcoma There are 2 forms of fibrosarcoma in children, the congenital or infantile form, which occurs in patients up to 2 years of age, and the childhood form, which peaks in the 10- to 15year-old group and is similar to adult fibrosarcoma. Their histology is similar, uniform spindle-shaped cells packed in a herringbone appearance, but the infantile form is characterized by a specific chromosomal translocation.15 The prognosis for congenital/infantile fibrosarcoma is much better than for the older childhood/adult form, with local recurrence common but metastatic disease rare. The 5-year survival rate for infantile fibrosarcoma is 84%.49,50 The remainder of this discussion refers to congenital/infantile fibrosarcoma.

Presentation The median age at diagnosis is 3 months, but 40% are present at birth.50 The tumor is more common in males than females. Most are located in the distal extremities, although it also occurs in the abdomen, pelvis, and head and neck region.6,51,52 Metastatic disease is more common when lesions are located on the trunk.53 Violaceous skin discoloration is common, resulting in misdiagnosis as hemangioma or lymphangioma.5 Acute, lifethreatening hemorrhage occurs as a result of superficial ulcerations that communicate with large veins.5

Treatment

Figure 7 Synovial sarcoma. Sagittal reformatted CT with contrast in an 18-year-old boy demonstrates a uniformly enhancing, well-defined soft tissue mass several cm from the elbow joint.

presence of hemorrhage, and susceptibility-weighted sequences might be helpful as well. Fluid-fluid levels can be found in almost 20%, and triple-signal intensity, consisting of areas that are hyperintense, isointense, and hypointense compared with fat, occurs in 35%.39 These result from the presence of hemorrhage, fibrous tissue, and cystic as well as solid portions. Synovial sarcoma is a notorious mimic of benign processes such as popliteal cysts, vascular malformations, benign nerve

Complete surgical resection is curative,51,54 although neoadjuvant chemotherapy might be necessary if resection is impossible or would cause severe disability.49,50 Local recurrence mandates additional surgery but does not alter prognosis.49 The role of postoperative chemotherapy is controversial.54,55

Imaging The tumor tends to be quite large and poorly circumscribed, with a tendency to infiltrate surrounding tissues and encase neurovascular structures.51 Radiographs demonstrate bowing deformity and cortical thickening of adjacent bone, and osseous destruction has been reported (Fig. 11).51,56 At MRI, the mass appears solid and inhomogeneous.50 Well-demarcated, like many soft tissue sarcomas it is isointense to muscle at T1-weighted imaging with heterogeneous high signal intensity because of necrosis, hemorrhage, and myxoid material as well as cystic areas at T2-weighted.5,49,57 Intense en-

R. Stein-Wexler

478

Figure 8 Synovial sarcoma in a 16-year-old girl. This mass is intensely heterogeneous, with nodular peripheral enhancement as well as hypointense clumpy peripheral calcification (A; sagittal fast spoiled gradient echo gadoliniumenhanced) and marked heterogeneity on inversion recovery as well (B). A sagittal radiograph (C) demonstrates calcifications corresponding to the hypointense areas on the MRI.

hancement might cause it to mimic the appearance of hemangioma,58 and large draining veins might be identified.5 Differential considerations include other sarcomas, malignant peripheral nerve sheath tumors, RMS, myofibromatosis, and hemangiopericytoma. Early manifestation and rapid growth resemble hemangioma, but the latter has a distinctive appearance at MRI.

Alveolar Soft Part Sarcoma Alveolar soft part sarcoma is a rare tumor of uncertain cell origin, characterized by a specific chromosomal translocation.15 It is organized in a “pseudoalveolar” pattern and typically presents as a painless, soft, slow-growing soft tissue mass. More common in females, it usually arises in the head

Figure 9 Synovial sarcoma in 16-year-old girl demonstrates a deceptively small and well-circumscribed mass of intermediate intensity on coronal proton-density image (A), appearing of uniform high-signal intensity on protondensity fat-saturated sequence (B).

Pediatric soft tissue sarcomas

479 volving the lungs but sometimes the bones, central nervous system, or liver.60,65,66 Osseous metastases are usually lytic.29 Brain involvement is unusual, and brain MRI is recommended only in the presence of pulmonary metastases or neurological symptoms.67 The tumor does not clearly have a good response to chemotherapy,62 but children do fare somewhat better than adults.60

Imaging

Figure 10 Synovial sarcoma in a 15-year-old. Axial contrast-enhanced CT of the lower pelvis demonstrates a homogeneous, welldefined, superficial, predominantly cystic, benign-appearing mass.

and neck, trunk, and extremities in children and adolescents, although in adults it typically occurs in the extremities, especially the thigh.59-62 Intratumoral vascular shunting might result in a bruit.63,64

Prognosis Although some have found that smaller tumor size is associated with a better outcome,60,64 this is controversial.65 Indolent progression is the rule.65 Local recurrence is distinctly unusual, even when local tumor control appears inadequate.66 However, this tumor’s propensity to metastasize results in a poor prognosis unless resection includes a 2-cm margin.62 Metastatic disease is common both at the time of diagnosis (found in up to one third64) and later, usually in-

At unenhanced CT, alveolar soft part sarcoma is of lower attenuation than muscle63,68 and demonstrates significant peripheral enhancement, with central low-density necrosis63 or uniform isodensity or hyperdensity68 (Fig. 12). It appears well-circumscribed at MRI and, unlike many soft tissue sarcomas, is of moderate- to high-signal intensity at T1weighted imaging, perhaps because of abundant but slow blood flow through tumor vessels.63 Enhancement is vigorous.68,69 It is heterogeneously hyperintense at T2-weighted imaging.65,68,69 Dilated vessels in and around the lesion account for serpiginous areas of signal void.63,64,69 This mass might be confused with an arteriovenous malformation because of its hypervascularity.63

Epithelioid Sarcoma A tumor of adolescence, epithelioid sarcoma is most common in the upper extremity, and it is the most common soft tissue sarcoma of the wrist and hand.4 However, it also occurs in more proximal locations, including the chest, genitalia, and perineum; more central tumors can be quite large. Some studies have found the prognosis for distal epithelioid sarcoma is better than for the proximal subtype, but this is not

Figure 11 Sagittal radiograph (A) of congenital/infantile fibrosarcoma in a 2-month-old demonstrates an enormous soft tissue mass along with bowing deformity and cortical thickening of the tibia and fibula. Marked hypervascularity is apparent on angiogram (B).

R. Stein-Wexler

480

Figure 12 Alveolar soft part sarcoma in 14-year-old boy. Nonenhanced axial CT (A) demonstrates a nonspecific soft tissue mass that is slightly less dense than muscle. With contrast (B), there is vigorous enhancement and the suggestion of central enhancing vessels. (Courtesy of Leslie Grissom, MD, Wilmington, DE.)

consistent.70-72 Metastases are relatively common; both subtypes metastasize to lymph nodes more than the typical soft tissue sarcoma,71-74 and pulmonary metastases are also common and found in close to 50% at the time of diagnosis.71 Epithelioid sarcoma consists of a multinodular proliferation of spindle-shaped and epithelioid cells, and central necrosis is common.75 It is characterized by a deletion on chromosome 22.70 Mean age of presentation is 15 years, but no age group is exempt. Peripheral epithelioid sarcoma manifests as a painless, slow-growing mass that might have been present for a long time, simulating a benign, inflammatory process2,70,76; its relatively benign appearance might result in its propensity to manifest metastatic disease. It can appear as either a small, nodular, superficial dermal lesion or as a deep lesion that is often adherent to a tendon sheath or aponeurosis.70,71 Local and plaque-like recurrences are common,70 but if it is completely excised with wide margins, it does not recur locally. Initial tumor size is an important prognostic indicator, but there is some disagreement about whether prognosis deteriorates when tumors exceed 3 or 5 cm.70,71,74,76 When treated with various combinations of lymphadenectomy, radiation, and chemotherapy, the prognosis can be excellent.2 Little has been written about the imaging appearance of the conventional distal epithelioid sarcoma. The more proximal lesions, which are usually quite large (up to 20 cm), typically appear as a multilobulated mass (Fig. 13). Although smaller lesions might be well-circumscribed, margins are usually ill-defined. Hemorrhagic necrosis results in increased signal intensity at T1-weighted imaging and a heterogeneous appearance at T2-weighted imaging. Enhancement is inhomogeneous, depending on the tumor’s cellularity and the extent of degeneration.72

Extraosseous Ewing’s Sarcoma Extraosseous Ewing’s sarcoma is an unusual form of Ewing’s sarcoma, arising in soft tissues instead of bone, usually in older patients than its osseous counterpart. Ewing’s sarcoma and the PNETs are a group of small, round blue-cell tumors that arise from what is probably a mesenchymal cell exhibiting varying amounts of differentiation along the neuroectodermal spectrum.77-79 In the case of Ewing’s sarcoma, there is no evidence of neuroectodermal differentiation, whereas PNETs have neuroectodermal features.78 Almost all tumors in the Ewing’s sarcoma/PNET family manifest a genetic translocation involving chromosome 22.79

Presentation Extraosseous Ewing’s sarcoma is usually painless when it arises in the extremities, but when found elsewhere it can be

Figure 13 Axial CT contrast-enhanced image demonstrates a lobulated, heterogeneously enhancing mass filling the left chest and destroying a rib in a 24-year-old man with epithelioid sarcoma.

Pediatric soft tissue sarcomas

481

Figure 14 Extraosseous Ewing’s sarcoma in a 9-year-old boy. Sagittal T1-weighted image (A) demonstrates a fairly well-circumscribed, moderately heterogeneous soft tissue mass that on FSPGR gadolinium-enhanced image (B) shows moderate heterogeneous enhancement. More marked heterogeneity is apparent on the IR sequence (C). The urinary bladder is displaced posteriorly.

painful. Lesions in the chest wall might cause pleuritic chest pain.80 Most common in children and young adults, the median age at diagnosis is 20 years, older than for osseous Ewing’s sarcoma.80 Extraosseous Ewing’s sarcoma arises most often in the soft tissues of the chest wall, lower extremities, paraspinal region, and retroperitoneum, but it also occurs in the abdomen, pelvis, skin, visceral organs, head and neck, and female genital tract.78,81,82 It is termed Askin’s tumor when it develops in the chest wall.83

Prognosis Like osseous Ewing’s sarcoma, extraosseous Ewing’s sarcoma is an aggressive tumor. It is usually considered disseminated at presentation,79 with metastases involving lung and bone.81 Treatment is typically initial surgery, followed by radiation therapy for positive margins as well as systemic chemotherapy.79 Local recurrence is common; younger age at diagnosis and adequacy of resection are important variables in outcome.83 With modern treatment regimens, 5-year survival is about 70%.84

Imaging Like many other soft tissue tumors, extraosseous Ewing’s sarcoma appears as a nonspecific, homogeneous, solid, hypovascular mass at ultrasound, lacking calcifications, with a pseudocapsule. Heterogeneous at contrast-enhanced CT, it is hypodense on unenhanced examination and might demonstrate rim enhancement.85 Central necrosis might be present. Density of adjacent bone marrow is normal, despite the presence of bony erosion or reactive periosteal new bone.80,81,86,87 Calcifications and bone formation are absent. MRI demonstrates a well-circumscribed mass that is hypointense to muscle at T1-weighted imaging and hyperintense at T2-weighted sequences, with moderate heterogeneous enhancement (Fig. 14).80,88 There might be spontaneous hemorrhage.

Extraosseous Ewing’s sarcoma must be differentiated from periosteal Ewing’s sarcoma. Although both can involve cortex and periosteum, periosteal Ewing’s sarcoma, like other periosteal tumors, manifests a subperiosteal mass with periosteal thickening and a Codman’s triangle.89 In contrast, there might be cortical erosion as well as periosteal and cortical thickening in extraosseous Ewing’s sarcoma, but there is no subperiosteal mass or Codman’s triangle.80,85,86 The prognosis for periosteal Ewing’s sarcoma is better than that for the medullary or extraskeletal forms.89 Histologic evaluation of adjacent bone might be necessary to exclude osseous Ewing’s sarcoma.80,87 Osteosarcoma can also develop in an extraosseous location, occasionally in areas that have been irradiated.90 Extraskeletal osteosarcoma occurs more often in children than in adults, accounting for 1% of soft-tissue sarcomas and 4% of all osteosarcomas. Composed of extraosseous malignant osteoblasts, it is most common to the deep fascia of the lower extremities and pelvis.91 Metastatic disease is very common, involving bone, lungs, and local lymph nodes. Radiographs typically demonstrate a fluffy, heterogeneous mineralized tumor mass, and the margins are indistinct at MRI. Low-grade lesions might be confused with myositis ossificans, but high-grade lesions demonstrate central enhancement, which is not usually encountered in myositis ossificans.92 Principal differential considerations are calcified hematoma, ossifying lipoma, myositis ossificans, parosteal osteosarcoma, synovial sarcoma, liposarcoma, and malignant peripheral nerve sheath tumor.91

Granulocytic Sarcoma This tumor is encountered in approximately 5% of cases of acute myelogenous leukemia and can occur up to 8 years before leukemia actually develops.93 Less commonly, it arises with chronic myelogenous leukemia.93 It consists of primi-

R. Stein-Wexler

482

Figure 15 Orbital granulocytic sarcoma in a 5-year-old boy. Coronal T1 (A), T1 fat-suppressed gadolinium-enhanced (B), and T2 (C) MRI demonstrate a homogeneous, intensely enhancing soft tissue mass centered on the lateral wall of the orbit. Axial CT (D) shows that the bone is predominantly intact.

tive precursors of granulocytic white blood cells that arise in the marrow and then penetrate the periosteum, traversing the cortex via haversian canals. Usually encountered in bone, perineural, and epidural tissues, it occasionally arises in the extremities but is most common in the head and neck, especially in the orbits and subcutaneous soft tissues (Fig. 15).93 However, only 2.5% of pediatric orbital tumors are granulocytic sarcoma.94 This tumor is responsive to chemotherapy, radiation therapy, or both, but about 25% recur.93 It is isointense to muscle on both T1-weighted and T2-weighted imaging, and it typically demonstrates uniform enhancement.95

Hemangiopericytoma Another rare pediatric soft tissue tumor, hemangiopericytoma is unusual because it consists of 2 distinct clinical entities, an infantile and a childhood form. Much more common in adults, only 5%-20% of cases occur in children.96 Of mesenchymal origin, it is derived from vascular pericytes of Zimmerman.96 Malignancy is determined clinically rather than histologically.

The infantile form occurs in children ⬍1 year old and usually in those younger than 2 months. Considered congenital, it is most common in the lower extremities and has an excellent prognosis.97 Location is frequently subcutaneous.98 It was originally considered to be benign, but malignant disease has been reported.96 Neoadjuvant chemotherapy is highly successful at converting nonresectable disease to resectable, but rapid growth and life-threatening hemorrhage might prove fatal.5,97 Maturation to capillary hemangioma might occur after incomplete resection.97 There might be calcific stippling on radiographs, and osseous invasion might be identified.5 CT and MRI appearance is nonspecific. Hemangiopericytoma in older children is, by contrast, a more aggressive disease, requiring a combined approach of surgery, chemotherapy, and (controversially) radiation therapy, although complete surgical resection is the most important predictor of survival.96,97 Typical locations are in or on the head as well as in the lower extremities97 (Fig. 16). As in adults, lymph node and lung involvement might be present at initial diagnosis, and subsequent pulmonary and osseous metastases are common. Overall, the outcome is much worse

Pediatric soft tissue sarcomas

483

Presentation Pediatric liposarcoma is most common in females, and it usually occurs during the late childhood and teen years, although it has been reported in infancy.101 It typically presents as a soft, deep mass, but 10%-15% complain of pain, tenderness, or functional disturbance.103 Myxoid liposarcoma is usually located in the extremities or retroperitoneum in adults, whereas in children it is found most often in the extremities.17,101,104 Metastatic disease is extremely unusual in children, and when present, it involves atypical locations such as the abdomen, retroperitoneum, and extrapleural chest, as in adults.17,105

Treatment

Figure 16 Hemangiopericytoma. Coronal contrast-enhanced CT demonstrates a well-circumscribed, intensely enhancing extraconal mass displacing the right globe in a 15-year-old girl.

than in infants, and recurrence as late as 15 years after excision mandates lengthy follow-up.96 However, complete excision of small, superficial tumors can be curative.96 Imaging characteristics are nonspecific.5

Liposarcoma One of the more common mesenchymal neoplasms in adults, liposarcoma is rare in children, with only 0.7% of cases occurring in those ⬍16 years old.99 Almost all fatty tumors in children older than 3 years of age are benign lipomas.100 Before that, most fatty tumors are lipoblastomas (this tumor is also rarely encountered in older children).100 Early articles reported a peak of liposarcoma in infancy, but these cases probably represented lipoblastoma, which can be difficult to differentiate at imaging and histologically.100,101

Pathology Multiple subtypes of liposarcoma occur in adults: well-differentiated, myxoid, round cell, and pleomorphic, representing a spectrum of biological aggressiveness. However, almost all cases of liposarcoma in children are of the myxoid subtype, and in general they carry a favorable prognosis.102 Myxoid liposarcoma has a prominent plexiform and arborizing vascular pattern within a myxoid matrix. There is slight to moderate cellularity, and cells appear small and round to focally spindled.17 Lipoblastoma can easily be confused with liposarcoma, but the former has more distinct lobulation and a more uniform growth pattern,101 and myxoid liposarcoma carries a specific chromosomal translocation.15

Complete surgical resection is the therapy of choice, with radiation therapy in children considered controversial and generally reserved for residual local disease.102,103 In the setting of incomplete resection without radiation therapy, about one-third of cases recur locally.106 However, prognosis is excellent with complete resection, and even microscopic residual, when treated with radiation therapy, fares well. Reported fatalities in children tend to be associated with gross residual disease.102 Prognosis is better in younger patients, in part because they are more likely to have myxoid tumors, which do better than round-cell or less differentiated subtypes.17

Imaging Well-differentiated liposarcomas appear fatty at MRI, but this subtype rarely occurs in children. The myxoid subtype has little mature fat and therefore predominantly demonstrates low-signal intensity at T1-weighted imaging and high-signal intensity at T2-weighted imaging. There might be scattered foci of high T1, intermediate T2 signal, however, representing islands of fat that are distributed in an amorphous lacy or linear pattern.107 In the absence of gadolinium administration, liposarcomas might mimic a cystic lesion.107 In contradistinction, lipomas are purely fatty.103 Tumors that appear uniformly dark on T1 and bright on T2 typically enhance intensely, allowing ready differentiation from cystic lesions. Myxoid liposarcomas often demonstrate heterogeneous enhancement, but some do not enhance at all. Enhancement is most vigorous in vascular areas with increased cellularity and no necrosis.107

Malignant Fibrous Histiocytoma MFH is usually found in older adults, but 5% of cases occur in children, and it has even been diagnosed in infants.108 However, the pediatric form differs from that encountered in adults in several important ways. Although adult MFH is by far most common in the extremities, in children it is often encountered in the head and neck108 and usually in the dermis or subcutaneous soft tissues.109 The prognosis in childhood MFH is better than for adult, but it is still poor, with metastases occurring in 30% and tumor-related death in 44%.108 However, the prognosis is better when the tumor presents in a superficial location, metastasizing only in

R. Stein-Wexler

484 10%.108 In general, only the storiform-pleomorphic and angiomatoid subtypes occur in children.108,109 Prior radiation therapy, xeroderma pigmentosum, burn scars, dermatoses, and chronic ulcers are all associated with increased risk for pediatric MFH.108 Metastatic disease almost always involves the lungs, with lymph nodes, bone, and liver affected infrequently.

Imaging The appearance is nonspecific, and the various subtypes also do not distinguish themselves. Resembling many soft tissue tumors, MFH is isointense or slightly hyperintense compared with muscle at T1-weighted imaging and typically heterogeneously hyperintense at T2-weighted imaging. There might be low-signal internal septations at T1- and T2-weighted imaging because of fibrous bands or acellular streaks.109

Malignant Peripheral Nerve Sheath Tumor Approximately 50% of malignant peripheral nerve sheath tumors (MPNSTs), or neurosarcomas, occur in patients with neurofibromatosis,110 and these tumors account for most of the mortality in these patients.111 Of neuroectodermal origin, they often arise in benign plexiform neurofibromas, although they occasionally arise in preexisting isolated neurofibromas. Most patients with neurofibromatosis type I (NF1) have an 8%-13% risk of developing MPNSTs, but in those with an unusual mutation of the tumor suppressor gene, as many as 26% develop MPNSTs.112 Previous irradiation is also a risk factor.110 The lifetime risk of MPNST in the general population is 0.001%.113 MPNSTs usually occur in the 20- to 50year age range,114 but they can occur as early as infancy.5 MPNSTs are most common in the extremities, where peripheral nerves are most numerous, followed by the trunk, head and neck, and retroperitoneum.110

Prognosis The presence of NF1 alone might or might not affect prognosis, but tumors tend to be larger in patients with NF1, and large tumor size does clearly correlate with a worse outcome.112,115 Furthermore, NF1 patients tend to be younger (average age of 26 years, compared with 62 years in the general population),113,115 and younger age confers a worse prognosis as well. The 5-year survival in patients with NF1 is 21%, whereas it is 42% in the general population.113 Incomplete resection is also associated with a worse prognosis.110,112 When these tumors occur in the extremities, as they frequently do, some have found the prognosis to be somewhat better, presumably because of improved local control.112 Metastases are more common in patients with NF1 and usually involve the lung, with bone, liver, and lymph nodes also commonly involved. Involvement of brain and soft tissues is unusual.112

Presentation Most MPNSTs arise in plexiform neurofibromas, which have a characteristic appearance of ropelike undulating masses insinuating along peripheral nerves, isointense to muscle on T1- and hyperintense on T2-weighted imaging. Because they have a typical appearance and usually occur in patients with known NF1, the diagnosis of nerve sheath tumor is often readily established, and the question becomes whether malignant degeneration has occurred. Clinical assessment of malignancy is correct 72% of the time.113 Factors that are associated with malignancy include increasing size of a known peripheral nerve sheath tumor, large size, constant pain, neurologic deficits, and location deep to the deep fascia and/or within an extremity.113,116 It is usually the case that lesions that lack clinical signs of malignancy demonstrate imaging findings that are suspicious.113,116

Imaging As with most soft tissue tumors, imaging can suggest but does not definitively establish malignancy. In a recent extensive evaluation of 41 patients with MPNSTs and 20 with neurofibromas, 4 factors were associated with malignancy. These include recent tumor growth (with average size at diagnosis being 10 cm110,117), central cystic changes often caused by necrosis or hemorrhage, peripheral enhancement, and a feathery perilesional edema-like appearance.118 Patchy enhancement also suggests MPNST.114,116 Signal intensity alone does not characterize these lesions.117 However, a target-like appearance on T2-weighted imaging, with central hypercellular hypointensity and peripheral myxoid hyperintensity, has some correlation with benignity,117,119 but this might occur too infrequently to be of value.118 Benign lesions might have a fascicular appearance because of perineurium surrounding bundles of nerve fibers.117 In cases of MPNST, tumor margins might be, like their benign counterparts, welldefined118 or (unlike benign lesions) partially ill-defined.117 Intralesional heterogeneity on T1-weighted imaging correlates with malignancy,116 although this finding might be meaningful only in patients with NF1.118 The high metabolic rate in MPNST results in high sensitivity of FDG-PET, but unfortunately, benign peripheral nerve sheath tumors also exhibit increased uptake, resulting in a specificity of only about 72%. However, the addition of 11-C methionine PET increases the specificity to 91%, and thus PET CT can be helpful both in equivocal cases and for detection of metastatic and/or synchronous disease.111 Angiosarcoma is a very rare but extremely aggressive tumor that has been identified in patients with neurofibromatosis, usually within a peripheral neurofibroma but occasionally within an MPNST. Cases reported in the literature have occurred only in males, and half have been in males younger than the age of 21.120 Imaging appearance is nonspecific, resembling MPNST.

Undifferentiated Sarcoma Although undifferentiated sarcoma is a diagnosis of exclusion, advances in molecular genetic analysis allow precise

Pediatric soft tissue sarcomas

485

Figure 17 Undifferentiated sarcoma in a 15-year-old boy. Chest radiograph (A) demonstrates a nonspecific but very large mass involving the right shoulder and axilla, which at contrast-enhanced CT (B) appears isodense to muscle. Central gas results from recent biopsy. Well-circumscribed except where it abuts the rib cage, it is slightly lobulated and heterogeneous on T1-weighted imaging (C). There is heterogeneous enhancement on the coronal T1-weighted fat suppressed gadolinium-enhanced image (D). It is also heterogeneous on the T2-weighted sequence (E).

classification of many more tumors than in the past, and as a result, the characteristics of undifferentiated sarcoma have been refined.121 There appear to be 2 main histologic subtypes. The more typical pathologic appearance is solid sheets of spindle cells121,122; prognosis for this subtype is relatively

good, similar to that of fibrosarcoma.122 This subtype might be more common in the distal extremities,122 although others have found it tends to present in the trunk and in the head and neck.121 The more primitive type, composed of immature mesenchymal cells, is usually found in the trunk and

486 proximal extremities, and its prognosis is poor. Age at presentation is 1 week-17 years, with median age around 8 years.121,122 Undifferentiated sarcoma is more common in males. If metastases are present at the time of diagnosis, the prognosis is dismal. However, in the absence of metastatic disease, chemotherapy and surgery confer 5-year survival of 89%.121

Imaging The tumor is usually solid; hemorrhage, calcification, and invasion of adjacent structures are rare.121 In our experience, it appears well-circumscribed, slightly lobulated, heterogeneous, and isointense to slightly hyperintense on T1weighted sequences (Fig. 17). It is heterogeneously hyperintense at T2-weighted, and enhancement is confined to the periphery, less intense than in many soft tissue sarcomas. It appears similar to muscle at nonenhanced CT and demonstrates little enhancement.

References 1. Bissett GS 3rd: MR imaging of soft-tissue masses in children. Magn Reson Imaging Clin N Am 4:697-719, 1996 2. McGrory JE, Pritchard DJ, Arndt CA, et al: Nonrhabdomyosarcoma soft tissue sarcomas in children: The Mayo Clinic experience. Clin Orthop Relat Res 374:247-258, 2000 3. Mafee MF, Pai E, Philip B: Rhabdomyosarcoma of the orbit: Evaluation with MR imaging and CT. Radiol Clin North Am 36:1215-1227, xii, 1998 4. Kransdorf MJ: Malignant soft-tissue tumors in a large referral population: Distribution of diagnoses by age, sex, and location. AJR Am J Roentgenol 164:129-134, 1995 5. McCarville MB, Kaste SC, Pappo AS: Soft-tissue malignancies in infancy. AJR Am J Roentgenol 173:973-977, 1999 6. Palumbo JS, Zwerdling T: Soft tissue sarcomas of infancy. Semin Perinatol 23:299-309, 1999 7. Berquist TH, Ehman RL, King BF, et al: Value of MR imaging in differentiating benign from malignant soft-tissue masses: Study of 95 lesions. AJR Am J Roentgenol 155:1251-1255, 1990 8. Kransdorf MJ, Murphey MD: Radiologic evaluation of soft-tissue masses: A current perspective. AJR Am J Roentgenol 175:575-587, 2000 9. Ma LD, McCarthy EF, Bluemke DA, et al: Differentiation of benign from malignant musculoskeletal lesions using MR imaging: Pitfalls in MR evaluation of lesions with a cystic appearance. AJR Am J Roentgenol 170:1251-1258, 1998 10. Soler R, Castro JM, Rodriguez E: Value of MR findings in predicting the nature of the soft tissue lesions: Benign, malignant or undetermined lesion? Comput Med Imaging Graph 20:163-169, 1996 11. Mutlu H, Silit E, Pekkafali Z, et al: Soft-tissue masses: Use of a scoring system in differentiation of benign and malignant lesions. Clin Imaging 30:37-42, 2006 12. Kransdorf MJ, Jelinek JS, Moser RP Jr, et al: Soft-tissue masses: Diagnosis using MR imaging. AJR Am J Roentgenol 153:541-547, 1989 13. Moulton JS, Blebea JS, Dunco DM, et al: MR imaging of soft-tissue masses: Diagnostic efficacy and value of distinguishing between benign and malignant lesions. AJR Am J Roentgenol 164:1191-1199, 1995 14. Subhawong TK, Fishman EK, Swart JE, et al: Soft-tissue masses and masslike conditions: What does CT add to diagnosis and management? AJR Am J Roentgenol 194:1559-1567, 2010 15. Skapek SX, Chui CH: Cytogenetics and the biologic basis of sarcomas. Curr Opin Oncol 12:315-322, 2000 16. Cecchetto G, Alaggio R, Dall’Igna P, et al: Localized unresectable non-rhabdo soft tissue sarcomas of the extremities in pediatric age: Results from the Italian studies. Cancer 104:2006-2012, 2005

R. Stein-Wexler 17. Kilpatrick SE, Doyon J, Choong PF, et al: The clinicopathologic spectrum of myxoid and round cell liposarcoma: A study of 95 cases. Cancer 77:1450-1458, 1996 18. Sultan I, Casanova M, Al-Jumaily U, et al: Soft tissue sarcomas in the first year of life. Eur J Cancer 46:2449-2456, 2010 19. Ognjanovic S, Linabery AM, Charbonneau B, et al: Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975-2005. Cancer 115:4218-4226, 2009 20. Van Rijn RR, Wilde JC, Bras J, et al: Imaging findings in noncraniofacial childhood rhabdomyosarcoma. Pediatr Radiol 38:617-634, 2008 21. Tabrizi P, Letts M: Childhood rhabdomyosarcoma of the trunk and extremities. Am J Orthop (Belle Mead NJ) 28:440-446, 1999 22. Tateishi U, Hasegawa T, Miyakawa K, et al: CT and MRI features of recurrent tumors and second primary neoplasms in pediatric patients with retinoblastoma. AJR Am J Roentgenol 181:879-884, 2003 23. Leung RS, Calder A, Roebuck D: Embryonal rhabdomyosarcoma of the omentum: Two cases occurring in children. Pediatr Radiol 39: 865-868, 2009 24. Freling NJ, Merks JH, Saeed P, et al: Imaging findings in craniofacial childhood rhabdomyosarcoma. Pediatr Radiol 40:1723-1738, 2010, quiz 1855 25. Siegel HJ, Connor GS, Lee D, et al: Synchronous bifocal alveolar rhabdomyosarcoma: A case report. J Bone Joint Surg Br 88:955-958, 2006 26. Kim EE, Valenzuela RF, Kumar AJ, et al: Imaging and clinical spectrum of rhabdomyosarcoma in children. Clin Imaging 24:257-262, 2000 27. Enzinger FM, Shiraki M: Alveolar rhabdomyosarcoma: An analysis of 110 cases. Cancer 24:18-31, 1969 28. Jha P, Frolich AM, McCarville B, et al: Unusual association of alveolar rhabdomyosarcoma with pancreatic metastasis: Emerging role of PET-CT in tumor staging. Pediatr Radiol 40:1380-1386, 2010 29. Yoshikawa H, Ueda T, Mori S, et al: Skeletal metastases from softtissue sarcomas: Incidence, patterns, and radiological features. J Bone Joint Surg Br 79:548-552, 1997 30. Chung CJ, Fordham L, Little S, et al: Intraperitoneal rhabdomyosarcoma in children: Incidence and imaging characteristics on CT. AJR Am J Roentgenol 170:1385-1387, 1998 31. McCarville MB, Spunt SL, Pappo AS: Rhabdomyosarcoma in pediatric patients: The good, the bad, and the unusual. AJR Am J Roentgenol 176:1563-1569, 2001 32. Andrassy RJ, Wiener ES, Raney RB, et al: Thoracic sarcomas in children. Ann Surg 227:170-173, 1998 33. Yousem DM, Lexa FJ, Bilaniuk LT, et al: Rhabdomyosarcomas in the head and neck: MR imaging evaluation. Radiology 177:683-686, 1990 34. Mason BJ, Kier R: Sonographic and MR imaging appearances of paratesticular rhabdomyosarcoma. AJR Am J Roentgenol 171:523-524, 1998 35. Fisher C: Synovial sarcoma. Ann Diagn Pathol 2:401-421, 1998 36. Cadman NL, Soule EH, Kelly PJ: Synovial sarcoma: An analysis of 34 tumors. Cancer 18:613-627, 1965 37. Bixby SD, Hettmer S, Taylor GA, et al: Synovial sarcoma in children: Imaging features and common benign mimics. AJR Am J Roentgenol 195:1026-1032, 2010 38. McCarville MB, Spunt SL, Skapek SX, et al: Synovial sarcoma in pediatric patients. AJR Am J Roentgenol 179:797-801, 2002 39. Jones BC, Sundaram M, Kransdorf MJ: Synovial sarcoma: MR imaging findings in 34 patients. AJR Am J Roentgenol 161:827-830, 1993 40. O’Sullivan PJ, Harris AC, Munk PL: Radiological features of synovial cell sarcoma. Br J Radiol 81:346-356, 2008 41. Tateishi U, Hasegawa T, Beppu Y, et al: Synovial sarcoma of the soft tissues: Prognostic significance of imaging features. J Comput Assist Tomogr 28:140-148, 2004 42. Schmidt D, Thum P, Harms D, et al: Synovial sarcoma in children and adolescents: A report from the Kiel Pediatric Tumor Registry. Cancer 67:1667-1672, 1991

Pediatric soft tissue sarcomas 43. Palmerini E, Staals EL, Alberghini M, et al: Synovial sarcoma: Retrospective analysis of 250 patients treated at a single institution. Cancer 115:2988-2998, 2009 44. Nakanishi H, Araki N, Sawai Y, et al: Cystic synovial sarcomas: Imaging features with clinical and histopathologic correlation. Skeletal Radiol 32:701-707, 2003 45. Valenzuela RF, Kim EE, Seo JG, et al: A revisit of MRI analysis for synovial sarcoma. Clin Imaging 24:231-235, 2000 46. Morton MJ, Berquist TH, McLeod RA, et al: MR imaging of synovial sarcoma. AJR Am J Roentgenol 156:337-340, 1991 47. Tsai JC, Dalinka MK, Fallon MD, et al: Fluid-fluid level: A nonspecific finding in tumors of bone and soft tissue. Radiology 175:779-782, 1990 48. Blacksin MF, Siegel JR, Benevenia J, et al: Synovial sarcoma: Frequency of nonaggressive MR characteristics. J Comput Assist Tomogr 21:785-789, 1997 49. Erturk C, Yarmpapuc R, Altay MA, et al: A giant congenital fibrosarcoma of the leg. J Pediatr Orthop B 19:348-352, 2010 50. Yalcin B, Leblebicioglu G, Guler E, et al: Congenital infantile fibrosarcoma of the thigh in a newborn. Tumori 87:436-438, 2001 51. Chung EB, Enzinger FM: Infantile fibrosarcoma. Cancer 38:729-739, 1976 52. Soule EH, Pritchard DJ: Fibrosarcoma in infants and children: A review of 110 cases. Cancer 40:1711-1721, 1977 53. Laor T: MR imaging of soft tissue tumors and tumor-like lesions. Pediatr Radiol 34:24-37, 2004 54. Cecchetto G, Carli M, Alaggio R, et al: Fibrosarcoma in pediatric patients: Results of the Italian Cooperative Group studies (19791995). J Surg Oncol 78:225-231, 2001 55. Loh ML, Ahn P, Perez-Atayde AR, et alTreatment of infantile fibrosarcoma with chemotherapy and surgery: Results from the Dana-Farber Cancer Institute and Children’s Hospital, Boston. J Pediatr Hematol Oncol 24:722-726, 2002 56. Eich GF, Hoeffel JC, Tschappeler H, et al: Fibrous tumours in children: Imaging features of a heterogeneous group of disorders. Pediatr Radiol 28:500-509, 1998 57. Lee MJ, Cairns RA, Munk PL, Poon PY: Congenital-infantile fibrosarcoma: Magnetic resonance imaging findings. Can Assoc Radiol J 47: 121-125, 1996 58. Teo HE, Peh WC: A 7-week-old female infant with a left thigh swelling. Am J Orthop (Belle Mead NJ) 32:513-515, 2003 59. Bu X, Bernstein L: A proposed explanation for female predominance in alveolar soft part sarcoma: Noninactivation of X—autosome translocation fusion gene? Cancer 103:1245-1253, 2005 60. Zarrin-Khameh N, Kaye KS: Alveolar soft part sarcoma. Arch Pathol Lab Med 131:488-491, 2007 61. Devitt J, England DM, Gilbert-Barness E: Pathological case of the month: Alveolar soft-part sarcoma. Am J Dis Child 146:837-838, 1992 62. Pappo AS, Parham DM, Cain A, et al: Alveolar soft part sarcoma in children and adolescents: Clinical features and outcome of 11 patients. Med Pediatr Oncol 26:81-84, 1996 63. Iwamoto Y, Morimoto N, Chuman H, et al: The role of MR imaging in the diagnosis of alveolar soft part sarcoma: A report of 10 cases. Skeletal Radiol 24:267-270, 1995 64. Stacy GS, Nair L: Magnetic resonance imaging features of extremity sarcomas of uncertain differentiation. Clin Radiol 62:950-958, 2007 65. Anderson ME, Hornicek FJ, Gebhardt MC, et al: Alveolar soft part sarcoma: A rare and enigmatic entity. Clin Orthop Relat Res 438:144148, 2005 66. Nakashima Y, Kotoura Y, Kasakura K, et al: Alveolar soft-part sarcoma: A report of ten cases. Clin Orthop Relat Res 294:259-266, 1993 67. Portera CA Jr, Ho V, Patel SR, et al: Alveolar soft part sarcoma: Clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer 91:585-591, 2001 68. Lorigan JG, O’Keeffe FN, Evans HL, et al: The radiologic manifestations of alveolar soft-part sarcoma. AJR Am J Roentgenol 153:335339, 1989

487 69. Zhu FP, Lu GM, Zhang LJ, et al: Primary alveolar soft part sarcoma of vertebra: A case report and literature review. Skeletal Radiol 38:825829, 2009 70. Casanova M, Ferrari A, Collini P, et al: Epithelioid sarcoma in children and adolescents: A report from the Italian Soft Tissue Sarcoma Committee. Cancer 106:708-717, 2006 71. de Visscher SA, van Ginkel RJ, Wobbes T, et al: Epithelioid sarcoma: Still an only surgically curable disease. Cancer 107:606-612, 2006 72. Tateishi U, Hasegawa T, Kusumoto M, et al: Radiologic manifestations of proximal-type epithelioid sarcoma of the soft tissues. AJR Am J Roentgenol 179:973-977, 2002 73. Baratti D, Pennacchioli E, Casali PG, et al: Epithelioid sarcoma: Prognostic factors and survival in a series of patients treated at a single institution. Ann Surg Oncol 14:3542-3551, 2007 74. Spillane AJ, Thomas JM, Fisher C: Epithelioid sarcoma: The clinicopathological complexities of this rare soft tissue sarcoma. Ann Surg Oncol 7:218-225, 2000 75. Enzinger FM: Epitheloid sarcoma: A sarcoma simulating a granuloma or a carcinoma. Cancer 26:1029-1041, 1970 76. Theunis A, Andre J, Larsimont D, et al: Epithelioid sarcoma: A puzzling soft tissue neoplasm in a child. Dermatology 200:179-180, 2000 77. Shimada H, Newton WA Jr, Soule EH, et al: Pathologic features of extraosseous Ewing’s sarcoma: A report from the Intergroup Rhabdomyosarcoma Study. Hum Pathol 19:442-453, 1988 78. Yip CM, Hsu SS, Chang NJ, et al: Primary vaginal extraosseous Ewing sarcoma/primitive neuroectodermal tumor with cranial metastasis. J Chin Med Assoc 72:332-335, 2009 79. Zagar TM, Triche TJ, Kinsella TJ: Extraosseous Ewing’s sarcoma: 25 years later. J Clin Oncol 26:4230-4232, 2008 80. O’Keeffe F, Lorigan JG, Wallace S: Radiological features of extraskeletal Ewing sarcoma. Br J Radiol 63:456-460, 1990 81. Rud NP, Reiman HM, Pritchard DJ, et al: Extraosseous Ewing’s sarcoma: A study of 42 cases. Cancer 64:1548-1553, 1989 82. Adapa P, Chung TW, Popek EJ, et al: Extraosseous Ewing sarcoma of the thyroid gland. Pediatr Radiol 39:1365-1368, 2009 83. Ahmad R, Mayol BR, Davis M, et al: Extraskeletal Ewing’s sarcoma. Cancer 85:725-731, 1999 84. Raney RB, Asmar L, Newton WA Jr, et al: Ewing’s sarcoma of soft tissues in childhood: A report from the Intergroup Rhabdomyosarcoma Study, 1972 to 1991. J Clin Oncol 15:574-582, 1997 85. Shirkhoda A, Peuchot M: Extraosseous Ewing’s sarcoma: Computed tomography evaluation before and after chemotherapy. Clin Imaging 13:142-146, 1989 86. Angervall L, Enzinger FM: Extraskeletal neoplasm resembling Ewing’s sarcoma. Cancer 36:240-251, 1975 87. Rose JS, Hermann G, Mendelson DS, et al: Extraskeletal Ewing sarcoma with computed tomography correlation. Skeletal Radiol 9:234237, 1983 88. Ulusan S, Koc Z, Canpolat ET, et al: Radiological findings of primary retroperitoneal Ewing sarcoma. Acta Radiol 48:814-818, 2007 89. Shapeero LG, Vanel D, Sundaram M, et al: Periosteal Ewing sarcoma. Radiology 191:825-831, 1994 90. Chung EB, Enzinger FM: Extraskeletal osteosarcoma. Cancer 60: 1132-1142, 1987 91. van Rijswijk CS, Lieng JG, Kroon HM, et al: Retroperitoneal extraskeletal osteosarcoma. J Clin Pathol 54:77-78, 2001 92. Beall DP, Ly J, Bell JP, et al: Pediatric extraskeletal osteosarcoma. Pediatr Radiol 38:579-582, 2008 93. Pui MH, Fletcher BD, Langston JW: Granulocytic sarcoma in childhood leukemia: Imaging features. Radiology 190:698-702, 1994 94. Jakobiec FA: Granulocytic sarcoma. AJNR Am J Neuroradiol 12:263264, 1991 95. Stein-Wexler R, Wootton-Gorges SL, West DC: Orbital granulocytic sarcoma: An unusual presentation of acute myelocytic leukemia. Pediatr Radiol 33:136-139, 2003 96. Sabini P, Josephson GD, Yung RT, et al: Hemangiopericytoma presenting as a congenital midline nasal mass. Arch Otolaryngol Head Neck Surg 124:202-204, 1998

488 97. Rodriguez-Galindo C, Ramsey K, Jenkins JJ, et al: Hemangiopericytoma in children and infants. Cancer 88:198-204, 2000 98. Simonton SC, Swanson PE, Watterson J, et al: Primary mediastinal hemangiopericytoma with fatal outcome in a child. Arch Pathol Lab Med 119:839-841, 1995 99. Mikkilineni RS, Bhat S, Cheng AW, et al: Liposarcoma of the posterior mediastinum in a child. Chest 106:1288-1289, 1994 100. Miller GG, Yanchar NL, Magee JF, et al: Lipoblastoma and liposarcoma in children: An analysis of 9 cases and a review of the literature. Can J Surg 41:455-458, 1998 101. Shmookler BM, Enzinger FM: Liposarcoma occurring in children: An analysis of 17 cases and review of the literature. Cancer 52:567-574, 1983 102. La Quaglia MP, Spiro SA, Ghavimi F, et al: Liposarcoma in patients younger than or equal to 22 years of age. Cancer 72:3114-3119, 1993 103. Brookenthal KR, Meyer JS, Pill SG, et al: Calf mass in an 11-year-old girl. Clin Orthop Relat Res 407:268-277, 2003 104. Orson GG, Sim FH, Reiman HM, et al: Liposarcoma of the musculoskeletal system. Cancer 60:1362-1370, 1987 105. Pearlstone DB, Pisters PW, Bold RJ, et al: Patterns of recurrence in extremity liposarcoma: Implications for staging and follow-up. Cancer 85:85-92, 1999 106. Castleberry RP, Kelly DR, Wilson ER, et al: Childhood liposarcoma: Report of a case and review of the literature. Cancer 54:579-584, 1984 107. Sung MS, Kang HS, Suh JS, et al: Myxoid liposarcoma: Appearance at MR imaging with histologic correlation. Radiographics 20:10071019, 2000 108. Rothman AE, Lowitt MH, Pfau RG: Pediatric cutaneous malignant fibrous histiocytoma. J Am Acad Dermatol 42:371-373, 2000 109. Miller TT, Hermann G, Abdelwahab IF, et al: MRI of malignant fibrous histiocytoma of soft tissue: Analysis of 13 cases with pathologic correlation. Skeletal Radiol 23:271-275, 1994 110. Neville H, Corpron C, Blakely ML, et al: Pediatric neurofibrosarcoma. J Pediatr Surg 38:343-346, 2003, discussion 343-346 111. Bredella MA, Torriani M, Hornicek F, et al: Value of PET in the assessment of patients with neurofibromatosis type 1. AJR Am J Roentgenol 189:928-935, 2007

R. Stein-Wexler 112. Anghileri M, Miceli R, Fiore M, et al: Malignant peripheral nerve sheath tumors: Prognostic factors and survival in a series of patients treated at a single institution. Cancer 107:1065-1074, 2006 113. Furniss D, Swan MC, Morritt DG, et al: A 10-year review of benign and malignant peripheral nerve sheath tumors in a single center: Clinical and radiographic features can help to differentiate benign from malignant lesions. Plast Reconstr Surg 121:529-533, 2008 114. Van Herendael BH, Heyman SR, Vanhoenacker FM, et al: The value of magnetic resonance imaging in the differentiation between malignant peripheral nerve-sheath tumors and non-neurogenic malignant softtissue tumors. Skeletal Radiol 35:745-753, 2006 115. Ferrari A, Bisogno G, Macaluso A, et al: Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer 109: 1406-1412, 2007 116. Mautner VF, Friedrich RE, von Deimling A, et al: Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma. Neuroradiology 45: 618-625, 2003 117. Li CS, Huang GS, Wu HD, et al: Differentiation of soft tissue benign and malignant peripheral nerve sheath tumors with magnetic resonance imaging. Clin Imaging 32:121-127, 2008 118. Wasa J, Nishida Y, Tsukushi S, et al: MRI features in the differentiation of malignant peripheral nerve sheath tumors and neurofibromas. AJR Am J Roentgenol 194:1568-1574, 2010 119. Bhargava R, Parham DM, Lasater OE, et al: MR imaging differentiation of benign and malignant peripheral nerve sheath tumors: Use of the target sign. Pediatr Radiol 27:124-129, 1997 120. Brown RW, Tornos C, Evans HL: Angiosarcoma arising from malignant schwannoma in a patient with neurofibromatosis. Cancer 70: 1141-1144, 1992 121. Somers GR, Gupta AA, Doria AS, et al: Pediatric undifferentiated sarcoma of the soft tissues: A clinicopathologic study. Pediatr Dev Pathol 9:132-142, 2006 122. Alaggio R, Bisogno G, Rosato A, et al: Undifferentiated sarcoma: Does it exist? A clinicopathologic study of 7 pediatric cases and review of literature. Hum Pathol 40:1600-1610, 2009