Childhood Rhabdomyosarcoma
FRANK J. PENNA
MARTIN A. KOYLE
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, accounting for 5% of all cancers in children and about half of all soft tissue sarcomas. RMS is also the most common extracranial neoplasm, following neuroblastoma and Wilms tumor. This tumor is nonencapsulated, grows rapidly, spreads locally to regional lymph nodes, but can also metastasize hematogenously and is not limited to skeletal muscle. In children and adolescents (<20 years of age), the incidence is 4.3 cases per million, with approximately 350 new cases diagnosed annually in the United States (1). Genitourinary RMS, involving the bladder, prostate, paratestis, vagina, and uterus represents 18% to 20% of all cases (1). There is a bimodal age distribution with a peak incidence in the first 2 years of life and again during early adolescence (2).
RMS was first described in 1850 by Wiener (3). Little was published on RMS, until the 1950s when a histologic classification system for the condition was described. Theriault initially described alveolar RMS in children and Stout described pleomorphic RMS (4,5). In 1958, Horn and Enterline created the classification of RMS that reflected varying degrees of embryonic rhabdomyogenesis (6). In fact, RMS is considered one of the “small round blue cell tumors of childhood,” the others being neuroblastoma, Ewing sarcoma, and lymphoma. Once almost uniformly fatal, RMS has become highly curable with multimodal therapy, with the majority of patients achieving long-term survival. These advances were the result of the Intergroup Rhabdomyosarcoma Study Group in exploration of the optimal therapy for childhood RMS.
The Intergroup Rhabdomyosarcoma Study Group (IRSG) initiated studies in the United States in 1972 to achieve better survival with less morbidity in successive coordinated large, multicenter trials. During the first IRSG study (IRSG I) from 1972 to 1978, radical surgical resection was employed with adjuvant chemotherapy, traditionally using vincristine, dactinomycin, and cyclophosphamide (VAC) at the expense of bladder preservation, with a rate of preservation of only 23% at 3 years (3). The second IRSG study from 1979 to 1984 incorporated neoadjuvant chemotherapy and/or radiation prior to surgical excision. In this study, overall survival remained high at 80% with 10% of patients achieving relapse-free survival with chemotherapy alone (3). Early in these studies, when the bladder was involved with tumor, radical exenterative surgery was employed. With the success of chemotherapy, bladder-sparing surgery was then invoked; however, only 25% being left with an intact, functional bladder (3).
The third IRSG from 1985 to 1992 marked the advent of the organ-sparing era. With bladder-sparing surgery, retained bladder function of 60% was noted at 4 years after diagnosis while preserving an 83% survival rate (3). Also during this time, chemotherapy was standardized to include doxorubicin, cisplatin, and etoposide in patients with bladder and prostate RMS. IRSG IV initiated the use of the tumor-node-metastasis (TNM) pretreatment staging system and also concluded that hyperfractionated radiation was not more beneficial compared to standard conformal radiation therapy.
The IRSG is now the Soft Tissue Sarcoma Committee of the Children’s Oncology Group, which has taken over responsibilities for these trials, and is currently investigating new chemotherapeutic options including sorafenib, pazopanib, crizotinib, TH-302, aurora-kinase inhibitors, and anaplastic lymphoma kinase inhibitors (7). Patient survival, which was only 40% to 73% prior to chemotherapy, has improved to 86% in IRSG IV with VAC (8).
PATHOLOGIC FEATURES AND MOLECULAR MECHANISMS
RMS is derived from immature striated skeletal muscle cells in various stages of embryonic myogenesis. There are three variants of RMS as described by the IRSG: embryonal, alveolar, and pleomorphic RMS. Embryonal RMS, the most common subtype, is typically found in infants and young children and includes sarcoma botryoides, a polypoid variant that is found in the hollow organs such as the bladder or vagina and carries a favorable prognosis as well as the spindle cell variant which is common in the paratesticular region and also carries a favorable prognosis (1). Embryonal RMS resembles fetal striated muscle at 7 to 10 weeks gestational age and is composed mainly of spindle-shaped cells with a central nucleus that stains for nuclear transcription factors such as myogenin or MyoD1, surrounded by eosinophilic cytoplasm (3). Embryonal RMS is associated with an 11p15.1 loss of heterozygosity and, in general, carries a favorable prognosis (9).
Alternatively, alveolar RMS is the second most common form and portends a poorer prognosis; it resembles striated muscle at 10 to 21 weeks gestational age, has a vague resemblance to fetal alveoli, with clusters of small round cells adherent to fibrosepta, and is typically diagnosed in older children (1,6). Alveolar RMS also has distinct genetic mutations, including t(2;13) or t(1;13) translocation, which generate the PAX3-FKHR and the PAX7-FKHR gene fusions, respectively. The presence of these gene fusions have been associated with a high rate of relapse and death in patients with metastatic disease, particularly patients who exhibit the PAX3-FKHR mutation, which is present in approximately 70% of alveolar RMS (3). The downstream effect of these mutations results in decreased gene products that play a role in normal myogenic differentiation. These mutations, and not the histologic features, have been implicated as the source of the poorer outcome in this subtype (6). In fact, fusion-negative alveolar RMS behaves more characteristically of embryonal in terms of presentation and clinical outcome.
Pleomorphic is not classically associated with childhood RMS originating from the prostate or bladder (1). Undifferentiated type RMS is remarkably anaplastic and difficult to identify due to nonspecific large round cells with scant cytoplasm and lack of antigenic markers.
RMS is associated with particular familial conditions that result in a genetic predisposition to developing the condition including Li-Fraumeni, Beckwith-Wiedemann, Gorlin syndrome, and neurofibromatosis type 1, with the latter seen commonly with genitourinary RMS with embryonal histology (1). The most common genetic mutations include PAX-FKHR gene fusions, alterations affecting MyoD1 and myogenin expression, as well as the retinoblastoma and p53 pathways (3). There has been much effort put forth on applying the recent advances in molecular biology and bioinformatics to provide more robust criteria for risk stratification, predicting clinical outcome, and tailoring “rational” therapy based on the identification of critical targets in RMS (10).
DIAGNOSTIC EVALUATION AND STAGING
Signs and symptoms are dictated by the primary organ(s) involved. Hence, imaging will vary accordingly. Evaluation of pelvic organs with diagnostic imaging modalities including conventional radiography, ultrasonography, computerized tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine studies such as bone scan, positron emission tomography (PET). MRI has been shown to improve the detection of residual pelvic RMS with well-delineated tissue planes and more accurate assessment of tumor invasion into adjacent structures compared with CT (11). Suspected paratesticular RMS are evaluated initially with scrotal ultrasound. Metastatic workup is completed with a chest X-ray, liver function tests, bone scan, and bone marrow biopsy. The initial staging algorithm is demonstrated in Figure 91.1.
The mechanism of metastasis for RMS is variable, with local and regional spread via lymphatic channels present in approximately 20% of patients (3). The most common sites of hematogenous metastases include lung, bone marrow, and bone, whereas sites such as the liver or brain are rare. Prognostic factors that are considered unfavorable include primary sites such as bladder or prostate, the presence of distant metastasis at diagnosis, regional lymphadenopathy, primary tumors greater than 5 cm, and age younger than 1 year or older than 10 years (2). A substantial number of patients with low-stage disease are subjected to unavoidable testing so there has been an effort to characterize patients with low-stage, node-negative, and noninvasive RMS disease early to avoid studies such as bone marrow aspirate and bone scan as well as the unnecessary radiation exposure from chest CT (12). The IRSG protocols included both preoperative staging and postoperative grouping (8) (Tables 91.1 and 91.2). The IRSG I to III studies grouped patients based on completeness of resection, introducing biases (shifting patients from group 1 to group 3) that are not seen with the use of the TNM system in IRSG IV and V.
 FIGURE 91.1 RMS initial staging algorithm. CT, computerized tomography. (Adapted from Weiss AR, Lyden ER, Anderson JR, et al. Histologic and clinical characteristics can guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from the Children’s Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol. 2013;31[26]:3226-3232.) |
Bladder and Prostate Rhabdomyosarcoma
Bladder and prostate RMS present initially with obstructive urinary symptoms, including urinary frequency, stranguria, hematuria, incontinence, and acute urinary retention, and tend to be located at the trigone and bladder neck. Bladder RMS typically grows intraluminally and usually occurs in the botryoid form. Most present by 10 years of age, whereas neonatal RMS is very rare but has been reported in the literature and detected via prenatal ultrasonography (13).
Prostatic RMS usually presents as a solid mass and carries a poorer prognosis (2). On physical examination, an abdominal mass may be present. Imaging including ultrasonography, CT, or MRI can delineate disease extent including retroperitoneal lymphadenopathy, and cystoscopy can facilitate diagnosis via transurethral biopsy with a pediatric resectoscope or cold-cup biopsy forceps (Fig. 91.2).
A study from the late 1980s of 36 children with RMS employed a multimodal approach including conservative surgery when indicated, radiation, and chemotherapy with VAC, with an overall and event-free survival rate of 80% and 74%, respectively (14). The study also emphasizes the importance of urethral biopsies when evaluating bladder and prostate RMS because urethral involvement can be subtle due to submucosal extension and may not be apparent with cystoscopy alone.
Serial imaging with CT or MRI can be used to assess response to treatment, including chemotherapy. Chest CT is useful for evaluating lung metastases, and more recently, PET has been implemented, but its use is still under investigation (3). Based on the
tumor site, grade, presence of lymphadenopathy, and metastatic lesions, patients are categorized into low-, intermediate-, or highrisk groups.
tumor site, grade, presence of lymphadenopathy, and metastatic lesions, patients are categorized into low-, intermediate-, or highrisk groups.
TABLE 91.1 INTERGROUP RHABDOMYOSARCOMA STUDY GROUP PRETREATMENT CLINICAL STAGING | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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Paratesticular Rhabdomyosarcoma
Paratesticular RMS presents as a unilateral painless scrotal mass or with scrotal swelling that is appreciably distinct from the testis. Paratesticular RMS represents 7% to 10% of genitourinary RMS with a peak presentation of 1 to 5 years of age (2). The majority of paratesticular tumors are stage 1 and embryonal in histology, which portends a good prognosis. Imaging, including CT, is recommended to assess for retroperitoneal lymphadenopathy, which can occur in up to 20% of patients. Interestingly, although ultrasonography is the imaging modality of choice for intratesticular pathology, paratesticular RMS on ultrasonography and even MRI may be elusive and often confused with other conditions such as epididymitis, adenomatoid tumor, and leiomyoma (15) (Fig. 91.3).
TABLE 91.2 INTERGROUP RHABDOMYOSARCOMA STUDY GROUP CLINICAL GROUPING CLASSIFICATION | |||||||||
|---|---|---|---|---|---|---|---|---|---|
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 FIGURE 91.2 A 2-year-old boy with RMS demonstrated by ultrasound (top left) of the bladder showing mass filling bladder lumen and coronal MRI (top right), T1-weighted. voiding cystourethrogram (bottom left) showing filling defect in the bladder and ball valving of mass in posterior urethra (bottom right). |
Vaginal and Uterine Rhabdomyosarcoma
Vaginal RMS typically presents with a vaginal discharge, bleeding, or a painful, expanding introital, anterior vaginal wall mass in the first few years of life. Uterine RMS typically presents as an abdominal mass originating from the uterine body or with vaginal bleeding from a cervical mass. These lesions carry an excellent prognosis due to their botryoid histology (2). Historically, these patients were treated with aggressive surgical resection with an anterior pelvic exenteration. With the advent of more efficacious chemotherapeutic agents, preservation of the vagina and uterus is paramount, and the patients are surgically resected only if persistence of disease after neoadjuvant chemotherapy, as determined by a postchemotherapy biopsy. Complications of treatment of vaginal and uterine RMS include vaginal stenosis, ureteral obstruction, intestinal stricture or fistula, and ovarian failure (Fig. 91.4).
 FIGURE 91.3 Scrotal ultrasound of a boy with paratesticular RMS showing mass (left) and flow to mass (right). |
TREATMENT
The treatment of RMS involves the coordination of multimodal therapy including surgical resection, chemotherapy, and radiotherapy. A number of factors determine the treatment regimen including the specific pathologic and histologic subtype, primary site, biology, clinical stage of disease, and extent of resection. Many cooperative organizations, including the Soft Tissue Sarcoma Committee of the Children’s Oncology Group (STS COG), Study for Malignant Mesenchymal Tumors of Société Internationale d’Oncologie Pédiatrique (SIOP-MMT), and Cooperative Weichteilsarkom-Studie (CWS), have defined specific risk-adapted treatment regimens (1).
According to the protocols set by STS COG, surgical resection or adequate biopsy is the initial treatment followed by adjuvant chemotherapy. Adequate tissue for a definitive diagnosis should be obtained, and if possible, the tumor should be removed without removing or potentially damaging the affected and adjacent organs (with the exception of paratesticular RMS, where the testis is removed inguinally with the tumor). This allows for characterization via IRSG risk group and will determine the subsequent treatment algorithm. If excision is not possible, primary chemotherapy should be given. In follow-up staging, a biopsy is needed during the “secondlook” operation because the residual mass does not always represent tumor: The cancer can involute more rapidly than the supporting stroma. With pelvic tumors, definitive surgery aims to attain complete disease excision with clear margins but with an organ-sparing goal. If microscopic residual disease is found, it is treated with brachytherapy or external beam radiotherapy. Exenteration is reserved for patients who fail this protocol of chemotherapy, conservative surgery, and radiotherapy. In Europe, the approach is to give primary chemotherapy without initial local control (radiotherapy or surgery) and offer local therapy based on the initial chemotherapy response (16). SIOP treatment regimens advocate for neoadjuvant chemotherapy followed by completion surgical resection depending on the chemotherapeutic response.
 FIGURE 91.4 An 11-month-old in foster care with a 3-month history of enlarging vaginal mass. Resected with total response to chemotherapy. The patient is alive and with no evidence of disease after 17 years. |
Effective local therapy and control is essential for overall survival in patients with RMS (1). The dilemma between radical local treatment and preservation of residual organ function (bladder, vagina, testes/ovaries, and sexual function) is difficult but must be optimally determined to allow for the greatest cancer control and the least disruption of function. Certainly, the potential for bladder dysfunction in bladder-sparing procedures must be considered in the treatment algorithm. Other surgical procedures that have the potential to disrupt innervation and function, including extravesical reimplantation, have been associated with postoperative bladder dysfunction (3).
Radiotherapy, an alternative therapy, has been remarkably successful in decreasing the need for radical surgery to achieve a cure and has allowed for improved local control and relapse prevention (1). Newer therapies such as intensity-modulated radiation therapy, brachytherapy, and proton radiation allow for a minimization of treatment toxicity without compromising efficacy. In fact, multimodal treatment including limited surgical resection in combination with chemoradiation therapy may allow for preservation of function while maintaining cancer control. Radiation therapy has also been associated with bladder dysfunction in a dose-dependent manner, with both acute and chronic effects (3). The early effects include inflammatory changes in the bladder, which result in decreased bladder capacity, but it is typically reversible. The chronic effects are also dose-dependent and include lower urinary tract symptoms such as urgency, frequency, hematuria, and diminished bladder compliance secondary to fibrosis. The fibrosis is due to increased transforming growth factor-β expression resulting in increased collagen deposition in the muscle and subepithelial layers of the bladder. The difficulty with radiotherapy and bladder RMS is that because the tumors tend to be located at the bladder neck, even the lowest dose (41 Gray [Gy]) may significantly affect urinary continence. The longterm risk of radiation vasculitis, which is inevitably progressive, as well as possible bony pelvis deformity in these children is another issue to consider. Therefore, one must sometimes weigh whether preserving a bladder without an outlet is better than removing the bladder entirely (17). The final issue is that postradiation artifact makes subsequent biopsy very difficult to interpret, so it would make sense to delay radiation until the patient is free of gross disease. With radiotherapy, there is also an increased risk of a secondary neoplasm, often another sarcoma, typically in the radiation field. Current attempts at
limiting radiation toxicity to adjacent organs involve both conformal radiotherapy and brachytherapy.
limiting radiation toxicity to adjacent organs involve both conformal radiotherapy and brachytherapy.
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