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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 139ESoft Tissue Sarcomas of Childhood

, MD and , MD.

Soft tissue sarcomas (STS) in children and adolescents comprise a heterogeneous group of mesenchymally derived connective tissue neoplasms that may arise in nearly any location in the body. STS are traditionally divided into two broad classifications: rhabdomyosarcomas (RMS), which are uniformly high-grade tumors, and the nonrhabdomyosarcoma soft tissue sarcomas (NRSTS), which exhibit greater biologic and clinical diversity. In the United States, approximately 850 to 900 cases of STS are diagnosed each year in children and adolescents, with RMS representing the single most common entity (approximately 350 cases, or nearly 40% of the total). 1 In children under the age of 15 years, RMS represents nearly 50% of the total cases of STS, with an incidence of 4.6 cases per million. A series of therapeutic clinical trials conducted over the past three decades under the aegis of the Intergroup Rhabdomyosarcoma Study Group (IRSG) has led to the development of increasingly effective multi-modality treatment approaches for RMS; 2– 5 because of the greater heterogeneity of the NRSTS, the optimal management of these tumors has been less clear.


Rhabdomyosarcoma falls into the broader category of the “small, round, blue cell tumors” of childhood. It is the third most common extracranial solid tumor in children, following neuroblastoma and Wilms’ tumor. More than half the RMS cases develop in children under the age of 10 years, and it is slightly more common in males than in females. The most common sites of origin are the structures of the head and neck, including the orbit and parameningeal sites (approximately 35%), the genitourinary tract (slightly more than 20%), and the extremities (just under 20%). Presenting signs and symptoms may be myriad, depending on the site of origin of the primary tumor, but are produced by the local effects of a firm, painless mass. For example, tumors arising in the orbit or from head and neck structures may cause proptosis or symptoms suggestive of sinusitis, whereas tumors of the genitourinary tract may present in ways ranging from asymptomatic scrotal enlargement from a paratesticular primary to urinary outflow or intestinal obstruction from tumor arising in the bladder/prostate region. Extremity tumors, which tend to behave more aggressively, not infrequently present with an initially nontender mass that rapidly enlarges over days to weeks.

Fewer than half of all cases of RMS are surgically resectable at the time of diagnosis. Regional lymph node involvement tends to vary by site, being less common in tumors arising in head and neck structures (and virtually never seen in patients with orbital tumors), and relatively more common in patients with paratesticular and extremity (particularly alveolar) tumors. Only 1 in 5 cases has radiographically detectable distant metastases at the time of diagnosis; however, all patients are considered to have micrometastatic disease and, consequently, multi-modality treatment utilizing chemotherapy, in addition to surgery and/or radiation therapy, is critical for optimal outcome. When overt metastatic disease is found, the most common sites of dissemination are the lungs, bone marrow, and bones. The overall survival rate for children with RMS diagnosed between 1985 and 1994 was approximately 64%. 1

The overwhelming majority of cases of RMS appear to be sporadic, with no clear predisposing risk factors. An increased risk of developing RMS has been found in children with major congenital anomalies, particularly of the genitourinary system (including Beckwith-Wiedemann syndrome, a fetal overgrowth syndrome associated with abnormalities on chromosome 11p15, the location of the gene for insulin-like growth factor-2 [IGF-2]); genetic conditions, such as Li-Fraumeni syndrome (associated with mutations of p53); and, with parental use of illicit drugs. 6– 11

The hallmark pathologic finding in these tumors is the demonstration of markers of skeletal muscle differentiation. The light microscopic identification of cross-striations characteristic of skeletal muscle must be supplemented by the demonstration of the presence of (relatively) muscle-specific genes or proteins on immunohistochemical staining (e.g., myogenin, MyoD, muscle-specific actin and myosin, myoglobin, Z-band protein, and desmin). Two major histologic subtypes of RMS exist, embryonal (ERMS), accounting for more than two-thirds of the total, and alveolar (ARMS). 12, 13 ERMS and ARMS are characterized by unique cytogenetic and molecular genetic abnormalities, by relatively unique clinical features and, possibly, by differences in response to therapy. 14– 16 Pleomorphic RMS is rarely diagnosed in children, and many cases of undifferentiated sarcoma are likely to be more accurately classified utilizing molecular diagnostic markers. 17, 18

ERMS and its less common (and possibly more favorable) botryoidal and leiomyomatous variants tend to occur in younger children and most typically arise in the orbit and other head and neck sites, the genitourinary system (particularly in the paratesticular region, and the structures of the female genital tract, where the finding of a grape-like mass protruding from the vagina is virtually pathognomonic of botryoidal RMS). Histologically, ERMS has a more spindled appearance, and tends to be less densely cellular and relatively more stroma rich. These tumors are characterized by the loss of heterozygosity (LOH) on the short arm of chromosome 11 (LOH 11p15) (Fig. 139E.1) This is of particular interest, in that this is the region of the IGF-2 gene that is uniformly overexpressed in rhabdomyosarcomas. IGF-2 is normally imprinted, that is transcriptionally silent, from the maternal allele. 19, 20 In RMS, however, the normal silent maternal allele becomes transcriptionally active, a feature termed loss of imprinting (LOI). 21, 22 Since LOH at 11p15 is associated with loss of the transcriptionally silent maternal allele and duplication of the normally active paternal allele, 23 LOH may in this case lead to activation of the IGF-2 locus similar to LOI.

Figure 139E.1. Upper left panel shows the typical spindle cell histologic appearance of embryonal rhabdomyosarcoma.

Figure 139E.1

Upper left panel shows the typical spindle cell histologic appearance of embryonal rhabdomyosarcoma. The lower left panel is a schematic depiction of the normal 11p15 locus around IGF-2 and the LOH at the 11p15 locus typically seen in ERMS. In the normal locus, (more...)

ARMS and its less common solid alveolar variant are relatively more common in older children and adolescents, have a predilection for the extremities (nearly 40% of all cases of ARMS arise in the extremities), and frequently exhibit a more aggressive course (spread to regional lymph nodes and/or distant metastases). ARMS is typically composed of small, round cells with a dense appearance that may seem to “line up” along spaces reminiscent of pulmonary alveoli. Most cases of ARMS are characterized by the presence of a translocation involving the long arms of chromosome 13 and either chromosome 2 (most common) or 1. (see Fig. 139E.1) This translocation creates a transforming, chimeric oncogene, PAX3-FKHR [t(2;13)] or PAX7-FKHR [t(1;13)], that fuses the DNA-binding domain of the PAX gene to the transactivation domain of FKHR. This novel transcription factor appears to be a more potent transactivator, compared with wild type PAX3, suggesting the possibility that the fusion transcription factor functions, at least in part, by potently activating genes not normally activated by wild-type PAX3. 24, 25 The identification of such activated genes is an area of ongoing research. Potentially important genes that appear to be activated by the PAX3-FKHR fusion protein include c-met, a tyrosine kinase receptor for hepatocyte growth factor, and IGF-2 and its binding protein IGF-BP5. 26– 28

The staging of RMS incorporates a combination of a site-modified TNM system, based primarily on pretreatment clinical and radiographic findings, and a Clinical Group system based on the extent of primary surgical resection. (Tables 139E.1 and 139E.2). Favorable sites—which in the absence of distant metastases are always stage I—include the orbit, nonparameningeal head and neck structures, and nonbladder/nonprostate genitourinary tract sites. 29 The staging of other sites is dependent on the size of the primary tumor (≤ 5 cm versus > 5 cm) and the presence or absence of clinically defined regional lymph node involvement. With some exceptions, the presence of distant metastases at diagnosis is predictive of poor outcome. 30 Utilizing these systems in combination defines distinct groups of patients with excellent (event-free survival [EFS] ≥ 85%), very good (EFS 70–85%), intermediate (EFS 50–70%), and poor (EFS ≤ 30%) prognoses for whom risk-based therapies can be administered, as is currently being done in the fifth-generation Intergroup Rhabdomyosarcoma Study (IRS-V). (Table 139E.3)

Table 139E.1. Site-modified, Pre-modified, Presurgical TNM Staging System for Rhabdomyosarcoma.

Table 139E.1

Site-modified, Pre-modified, Presurgical TNM Staging System for Rhabdomyosarcoma.

Table 139E.2. Clinical Group System for Rhabdomyosarcoma.

Table 139E.2

Clinical Group System for Rhabdomyosarcoma.

Table 139E.3. Prognostic Stratification for Rhabdomyosarcoma.

Table 139E.3

Prognostic Stratification for Rhabdomyosarcoma.

The evaluation of a child with a tumor suspected to be RMS should consist of an MRI or CT scan of the primary site, a CT scan of the chest, a bone scan, and bilateral bone marrow aspirates and biopsies. A lumbar puncture should be performed on patients with parameningeal tumors to rule out seeding of the meninges. Accurate preoperative imaging of the primary site is critical, not only for accurate staging but, more importantly, for delineation of the anatomic boundaries of the tumor for subsequent radiation therapy in the majority of patients whose tumors cannot be widely excised.

The guiding principle of surgery for RMS is to perform maximum function- and cosmetic-sparing surgical resection. 31, 32 Amputation is virtually never indicated as the initial surgical procedure. Pretreatment re-excision, to convert patients with microscopic residual disease to a more complete resection, has been found to be beneficial, particularly for extremity tumors. 33 Delayed surgical resection of initially unresectable tumors, following a course of neoadjuvant chemotherapy, may permit a reduction in the subsequent dose of local radiotherapy or even the elimination of the need for local radiotherapy in selected cases. 34– 36 The impact on survival of delayed surgical resection of residual radiographic abnormalities following completion of local radiation therapy is unclear, but there was a suggestion of some benefit to this approach in IRS-III. 4 The role of lymph node exploration and/or dissection remains controversial, though given the relatively high incidence of regional lymph node involvement in extremity and paratesticular RMS, it is probably appropriate in at least a proportion of these patients, if radiographic imaging does not strongly suggest the presence of involved lymph nodes. 37– 39 In cases of RMS where regional lymph nodes are clinically or radiographically suspicious, surgical resection should be attempted.

Following the establishment of the histologic diagnosis, and the completion of appropriate staging studies, initiation of multi-drug chemotherapy will produce prompt and dramatic regressions of tumor in ≥ 90% of patients. A fairly large number of cytotoxic agents, singly and in combination, are active against RMS, including vincristine, actinomycin-D, cyclophosphamide, doxorubicin, melphalan, and ifosfamide and etoposide. 40 More recently, topotecan and CPT-11 (irinotecan), which inhibit the DNA repair enzyme topoisomerase I, have been found to have striking activity in both newly diagnosed and recurrent RMS. 41– 44 Since first opening in 1972, the sequential IRSG studies have helped define a chemotherapy “backbone” for most cases of RMS, consisting of vincristine and actinomycin-D, generally given in combination with an alkylating agent (primarily cyclophosphamide). 2– 5 Reduction of therapy, via elimination of the alkylating agent (e.g., treatment with just vincristine and actinomycin-D), appears to be a reasonably safe strategy for those patients with an extremely favorable prognosis (such as patients with orbital ERMS or young boys with paratesticular ERMS that has not spread to regional nodes). 45 A preliminary analysis of data from IRS-IV suggests that there is no improvement in outcome when ifosfamide replaces cyclophosphamide or when etoposide replaces actinomycin-D. 5 Thus, the three-drug regimen of vincristine, actinomycin-D, and cyclophosphamide (VAC) is now the IRSG “gold standard” of therapy for most patients with RMS. It should be noted, however, that IRS-IV asked what was, in effect, a “substitution” question. The study did not address the question of whether the incorporation of additional active agents, such as doxorubicin, ifosfamide, and etoposide, might improve outcome for patients with intermediate-risk tumors, as has been suggested by at least one pilot study of RMS patients and as has been demonstrated for patients with Ewing’s sarcoma family of tumors. 46, 47 Currently, the major chemotherapy question being addressed for intermediate- and poor-prognosis patients on IRS-V is whether the addition of a topoisomerase I inhibitor (topotecan, given in combination with cyclophosphamide, for patients with intermediate-risk tumors, or CPT-11 [irinotecan] given as a phase II window to high-risk patients) can improve outcome. Intensification of therapy via myeloablation with high-dose chemotherapy or chemoradiotherapy has not proven to be a useful strategy in patients with high-risk (metastatic) tumors. 48– 51

For patients with microscopic or gross residual disease following initial surgery, radiation therapy plays a critical role in achieving local control. 52– 53 Radiation to the primary site may be of benefit for all patients with ARMS, even those whose tumors have been completely resected with negative margins (Clinical Group I), although the data in support of this latter approach are less firm. 54 Doses of radiation therapy of between 36 and 50.4 Gy, given in daily fractions of 150 to 180 cGy or twice-daily fraction of 110 to 120 cGy are generally considered sufficient to achieve local disease control, with the lower dose being adequate for most cases of microscopic residual disease, and the higher dose reserved for patients with gross residual disease. 55 Initiation of local radiotherapy can generally be safely delayed until after 4 to 5 courses of chemotherapy have been administered (i.e., until approximately 9 to 12 weeks into treatment). Immediate or early commencement of local radiotherapy is generally limited to the patient with base of skull erosion and/or intracranial extension of a parameningeal tumor. 56 Although there is relatively less experience with it, brachytherapy may be useful for select tumors in anatomically “critical” areas (such as the vagina), particularly in young children. 57 Newer techniques, such as three-dimensional conformal radiation therapy and intensity-modulated radiation therapy (IMRT), hold great promise as a means of delivering higher doses of radiation therapy directly to the tumor, while minimizing the damage to normal surrounding tissues and organs.

Given the generally favorable outcome of patients with RMS, strategies to prevent or reduce late effects of treatment are particularly warranted. Elimination of alkylating agents for patients with extremely favorable prognosis may reduce the incidence of infertility and second malignant neoplasms; reductions in the dose of radiation therapy may reduce the risk of radiation-related toxicities, including cataracts, neuroendocrine dysfunction, and growth and skeletal disturbances. 58– 64

The greatest remaining challenges in the treatment of RMS are the improvement of outcome for patients who present with overt metastases at diagnosis and the development of more effective “salvage” therapies for the 30% of patients with localized tumors who experience a relapse. Two recent studies of post-relapse survival identified a small fraction of “favorable-risk” patients (approximately 20% of the total) who are still potentially curable, but long-term survival for the vast majority of patients who relapse is dismal (approximately 10%). 65, 66 Given the relatively large number of conventional cytotoxics with significant activity against RMS, it is unlikely that the identification of additional active conventional cytotoxics, even those with “novel” mechanisms of action, will significantly improve outcome for these groups of patients. Agents with nontraditional mechanisms of action, such as the farnesyltransferase inhibitors, hold great interest, particularly because of the relative frequency of ras mutations in RMS, and the critical role of protein farnesylation in normal skeletal muscle function. 67

Finally, investigators have recently begun to explore the feasibility of using the PAX3-FKHR fusion protein expressed in ARMS as a target for cytotoxic T cells (CTLs). This is based on the fact that CTLs recognize small peptide fragments that are the product of normal proteolytic cleavage. Such peptides (9-10mers) are actively transported to the endoplasmic reticulum, where they bind to major histocompatibility (MHC) class I molecules. These complexes are then transported through the Golgi apparatus to the cell surface, where they can be recognized as a peptide-MHC complex by T-cell receptors. 68 Thus, even nuclear transcription factors can be recognized as peptide fragments by CTLs. Since the expression of the PAX3-FKHR fusion peptide is restricted to ARMS tumor cells, it has the potential to be recognized as a tumor-specific antigen. To test this hypothesis, small peptides spanning the translocation break-point regions were generated and used to immunize mice, using peptide-pulsed, antigen-presenting cell-vaccination strategies (Helman L, unpublished observations). Mice so vaccinated were found to specifically recognize tumor cells carrying the full-length PAX-3-FKHR cDNA, demonstrating fundamental proof of principle. On the basis of these preclinical models, clinical studies are currently underway to determine whether patients with PAX3-FKHR–expressing ARMS can be induced to generate an antitumor CTL response to the fusion peptide.

Nonrhabdomyosarcoma Soft Tissue Sarcomas

The NRSTS of childhood comprise a diverse group of relatively uncommon histologies. 69 Given the relative rarity of these tumors, consensus treatment approaches have not been developed except for the least complicated clinical presentations. 70– 75 Pediatric NRSTS are broadly divided along the lines of histologic grading, into low (grade 1), intermediate (grade 2), and high (grade 3) lesions, with modifications of the cytohistologic features used to classify adult sarcomas that take into account the unique behavior of the childhood lesions. 69 Histologic grade is highly predictive of both local aggressiveness and of the risk of developing distant metastases. Low-grade lesions are less likely to be large or invasive and more likely to be surgically resectable at the time of presentation. High-grade lesions tend to be larger and more locally infiltrative, are less likely to be completely resectable, and are more likely to present with (or develop) distant metastases.

The most frequent sites of origin of pediatric NRSTS are the extremities, trunk, and abdomen and pelvis. The most common histologic subtypes of pediatric NRSTS are malignant peripheral nerve sheath tumors, synovial cell sarcoma, undifferentiated sarcoma, malignant fibrous histiocytoma, and fibrosarcoma. Increasingly, NRSTS are being found to contain tumor-specific molecular abnormalities that may be useful as an adjunct in establishing the diagnosis, as well as offering a tool for the detection of minimal residual disease and/or immunotherapy. 69 One recent study of synovial sarcoma suggested that the specific type of translocation found in the tumor was predictive of subsequent clinical behavior. 76

As with RMS, adequate preoperative imaging of the primary tumor with MRI and/or CT scan is of critical importance. Metastatic disease surveillance should consist of a CT scan of the chest and bone scan. The single most important prognostic variable is the presence or absence of distant metastases. The outcome for patients with metastatic pediatric NRSTS is uniformly poor, with fewer than 1 patient in 4 surviving 3 years. 77, 78 Among patients with localized pediatric NRSTS, surgical resectability defines patients who are potentially curable. 73 Appropriate placement of the initial diagnostic biopsy incision is critical, particularly in situations where an attempt will not be made to resect the tumor per primum. Definitive therapy for patients with low- and intermediate-grade tumors consists of wide local excision, if possible, followed by radiation therapy (with doses between 45 and 60 Gy) for “close” margins. The definition of the “adequacy” of the margins of resection (traditionally considered to be ≥ 2 cm) may not be an absolute and may well be less for low-grade compared with high-grade lesions. 79, 80 There is no role for adjuvant chemotherapy in the treatment of such patients. The optimal management of patients with completely resected high-grade (grade 3) lesions is far more problematic. Postoperative radiation therapy with doses of 45 to 60 Gy is generally indicated unless radical margins of resection have been achieved. Although these tumors are not infrequently chemoresponsive, randomized clinical trials have not demonstrated a benefit of adjuvant chemotherapy. 81 Consequently, outside of prospective, randomized clinical trials, the role of chemotherapy for pediatric NRSTS patients, other than those with unresectable or metastatic lesions, remains unproven. Patients with initially unresectable or metastatic lesions should receive aggressive preoperative chemotherapy (with the active drug combinations of vincristine, doxorubicin, and cyclophosphamide [VAdriaC] and/or ifosfamide and etoposide [IE]) in an attempt to render their tumors surgically resectable. 82 Preoperative radiation therapy may also be of benefit in converting an initially unresectable lesion into a surgically resectable one. The inability to rid patients of gross disease predicts ultimate treatment failure. 73


Pediatric STS are a heterogeneous group of neoplasms with behavior that may range from fully benign to floridly malignant. While consensus multi-modality treatment approaches utilizing neoadjuvant and adjuvant chemotherapy, in addition to surgery and/or radiation therapy for local control, have been delineated for RMS, the optimal management of patients with NRSTS, particularly for those with completely resected, high-grade lesions, remains uncertain. For patients with favorable-prognosis lesions, strategies to reduce late toxicities that impair function and quality of life are appropriate. For patients with metastatic disease at diagnosis, or those who relapse after achieving an initial remission, newer therapies are desperately needed. It is hoped that the tumor-specific molecular abnormalities being identified in a growing number of pediatric STS will lead to important insights into the pathogenesis of these disorders, as well as suggesting avenues for novel therapeutic approaches.


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Bookshelf ID: NBK20961


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