Prostate Rhabdomyosarcoma: Past, Present and Future

Review Articles Bladder/Prostate Rhabdomyosarcoma: Past, Present and Future Fernando A. Ferrer,* Michael Isakoff and Martin A. Koyle From the Departments of Pediatric Urology (FAF) and Oncology (FAF, MI), Connecticut Children’s Medical Center, University of Connecticut, Hartford, Connecticut, and Division of Pediatric Urology, Denver Children’s Hospital, University of Colorado (MAK), Denver, Colorado

Purpose: The last few decades have witnessed substantial improvement in outcomes in children with bladder/prostate rhabdomyosarcoma. We reviewed relevant historical aspects of treatment, current treatment strategies and new developments. Most importantly we identified areas of existing controversy, which will provide direction for future studies and continued improvements in therapy. Materials and Methods: A database (PubMed, MEDLINE, etc) search was performed from 1966 through January 2005. Approximately 500 citations were identified. Relevant citations were reviewed in detail. Results: While the reported cure rate has improved to approximately 70% to 80% and bladder preservation rates as high as 60% are reported, substantial controversy continues in certain areas. Specifically the long-term function of preserved bladders, the contribution of radiotherapy to bladder dysfunction, the timing of reconstruction and molecular markers of disease progression are among the areas that require further investigation. Conclusions: Substantial progress has been made as a result of multi-institutional collaborative trials. Future combined studies are required to further the treatment of this childhood malignancy. Key Words: bladder, prostate, rhabdomyosarcoma, pediatrics, outcome assessment (health care)

utcomes in children with B/P RMS have improved significantly in the last few decades. Progress has largely been due to collaborative trials done by the IRS. Readers are referred to the COG website (www. childrensoncologygroup.org), where the complete IRS protocols as well as rapid reviews for surgeons are available for members. Nonmembers should consult their institutional COG primary investigator for information on protocols. We reviewed the history of IRS studies, pathological and molecular advances in RMS, current evaluation and treatment guidelines, areas of controversy and future directions.

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PRIOR IRS TRIALS RMS was first described in 1850 by Wiener.1 However, little was published on the treatment of RMS until the 1950s. At that time others described a histological classification system that remains the basis of the system in use today.2,3 Initially surgery was the preferred treatment but subsequently the effectiveness of combined multimodal therapy led to the formation of large multicenter trials performed by the IRS.1,4,5 During the first IRS study (IRS I) (1972 to 1978) up-front anterior exenteration was the primary therapy in patients with B/P tumors.6,7 Surgery followed by chemotherapy with or without radiotherapy had a relatively favorable outcome with 78% overall survival. However, the bladder preserva-

Submitted for publication August 1, 2005. * Correspondence: Department of Urology, Suite 2G, Connecticut Children’s Medical Center, Hartford, Connecticut 06106 (telephone: 860-545-9658; FAX: 860-545-9545; e-mail: [email protected]).

See Editorial on page 1278.

0022-5347/06/1764-1283/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION

tion rate at 3 years was only 23% in IRS I.8 At that time the price for survival was radical exenterative surgery with its associated complications.9,10 During the final years some patients began receiving a trial of primary chemotherapy directed toward bladder preservation. IRS I demonstrated that lymph node dissection and adjuvant therapy benefited patients with nodal disease.11,12 IRS II (1979 to 1984) established the routine use of chemotherapy and/or radiotherapy before surgery. It was hoped that by administering primary chemotherapy the number of patients requiring exenterative surgery or radiotherapy would decrease.13 Ten percent of patients achieved relapsefree survival with chemotherapy alone. Overall survival remained approximately 80%. Disappointingly the rate of survival with an intact functional bladder was only 25%.13,14 IRS III was performed from 1985 to 1992.14 This was the first study to achieve significant improvements in bladder preservation. Chemotherapy was standardized to include doxorubicin, cisplatin and etoposide in patients with B/P tumors. The timing of radiotherapy was fixed at 6 weeks after the induction of treatment. Surgically primary and secondary partial cystectomy was emphasized. Overall survival was approximately 83%. The proportion of patients who retained bladder function at 4 years after diagnosis increased to approximately 60%, although by today’s standards bladder function was evaluated only superficially.15,16 Outcomes in patients with B/P RMS treated in IRS IV (1993 to 1997) were reported by Ardnt et al in this journal.17 Data analysis identified 88 patients with B/P RMS. Of these tumors 70% arose from the bladder. Overall 6-year survival was 82%, although event-free survival was 77% at a mean 6.1-year followup. Of the patients 55 retained the bladder

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without relapse but only 36 (40%) had normal bladder function. It is important to note that functional evaluation was limited, suggesting that the true extent of dysfunction may have been greater.18 IRS IV was the first study to evaluate the use of a TNM pretreatment staging system. IRS IV also concluded that hyperfractionated radiation did not provide an advantage in terms of outcome over that of standard conformal RT.19

PATHOLOGICAL AND MOLECULAR ADVANCES The original histological classification of Horne and Enterline has been modified into an international system, which includes embryonal (encompassing the less common botryoid and spindle cell variants) along with ARMS, pleomorphic and undifferentiated subtypes.3,20 Embryonal sarcomas represented 73% of B/P RMSs documented in IRS studies from 1998 to 2004.21,22 In previous years they represented more than 90% of tumors. Histologically ERMS resembles fetal striated muscle, correlating with a gestational age of 7 to 10 weeks.23 The composition is mainly that of spindle-shaped cells with a central nucleus in an eosinophilic cytoplasm. Of specimens 30% show cross-striation. The diagnosis of ERMS rests on morphological identification of the tumor and spotty nuclear staining for myogenin or MyoD1. Diffuse nuclear staining of myogenin or MyoD1 is seen with ARMS.24 Sarcoma botryoides represents a subtype of embryonal tumor and it typically has a favorable prognosis. The spindle cell variant of ERMS is most common in the paratesticular region and it typically carries an excellent prognosis.20 ARMS is the next most common subtype, representing approximately 15% to 20% of all RMSs. It is usually seen in older children and histologically it resembles striated muscle at gestational ages 10 to 21 weeks. Histological features include clusters of small round cells adhering to fibrosepta, giving the appearance of well-defined alveolar spaces. Unlike ERMS cross-striations are uncommon and the alveolar subtype is more common in the extremities and trunk. Additionally, ARMS typically has distinct molecular alterations, including a t(2;13) or t(1;13) translocation.25 The more common t(2;13) translocation corresponds to a PAX3FKHR gene fusion and the t(1;13) translocation corresponds to a PAX7-FKHR gene fusion. Recently Sorenson et al documented the importance of these gene fusions in patients with ARMS and noted that in those with metastatic disease PAX3-FKHR fusion resulted in a significantly higher rate of relapse and death.25 Patients with PAX3-FKHR fusion also seemed to have a greater predisposition toward bone marrow metastasis. Pleomorphic RMS is not typically found in the bladder or prostate of children. However, it may occasionally present in the bladder of adults.26,27 The undifferentiated subtype is often difficult to identify due to a lack of antigenic markers and nonspecific large round cells with scant cytoplasm. This tumor can be confused with Ewing’s sarcoma and in difficult cases the identification of t(2;13), t(1;13) translocations specific for RMS or t(11;22) specific for Ewing’s sarcoma can be helpful.28,29 Occasionally these tumors can be differentiated by immunohistochemical identification of specific muscle proteins, such as actin, myosin, desmin and myoD.30,31 Rarely electron microscopy can be used to identify Z bands associated with actin-myosin bundles specific to RMS.32

Histological classification related to outcome Histology

Prognosis

% 5-Yr Survival

Sarcoma botryoides spindle cell Embryonal pleomorphic Alveolar undifferentiated

Favorable Intermediate Unfavorable

90 65–75 40–55

Histological classification continues to be one of the strongest predictors of outcome in RMS (see table). RMS can spread by local infiltration, and by lymphatic and hematogenous routes. Spread to local or regional lymph nodes is present in approximately 20% of patients at diagnosis.33 B/P tumors metastasize most commonly to the lung, bone marrow and bone. Omentum is sometimes involved, while metastases to other organs, such as the liver or brain, are rare.34 –36 Genetic analysis of embryonal and alveolar subtypes of RMS has identified a number of common abnormalities, including the described PAX-FKHR gene fusions, aberrant expression of regulatory factors such as MYOD1 and myogenin, and retinoblastoma and p53 pathway mutations.37 Until recently which individual or combined alterations could cause cell transformation was unknown. Sharp et al reported that mice with inactivated INK4a/ARF (cyclin-dependent kinase inhibitor/alternate reading frame) that over express hepatocyte growth factor/scatter factor were found to almost uniformly have RMS with high penetrance and short latency.38 Although the similarity of this model to human RMS remains unclear, the investigators described a unique animal model for further study. Deletions of INK4a/ ARF have an effect on the retinoblastoma and p53 pathways, which are suspected to be important in RMS. EVALUATION AND STAGING B/P RMS typically presents as urinary retention, urgency, frequency or incontinence.35 Gross hematuria and infection may also be present. Occasionally patients present with systemic signs of malignancy. The first study to identify a B/P mass is often ultrasound. Definitive CT or magnetic resonance imaging must be performed in an accurate, reproducible manner, so that serial imaging can be used to help assess the efficacy of primary chemotherapy. Radiography typically involves fine cut crosssectional imaging with tumor measurements along 3 axes. In up to 20% of cases it is impossible to determine whether the site of origin was the bladder or prostate. One should note that even with a good histological tumor response to chemotherapy the residual mass may contain a large amount of stomal tissue. Therefore, the size of the residual mass may not indicate the degree of cancer burden. Regional lymph nodes should be assessed by retroperitoneal thin cut CT (fig. 1). Chest CT is used to evaluate lung metastasis. Brain imaging is not required for tumors limited to the genitourinary system. More recently the use of positron emission tomography has been reported, although in patients with RMS its true usefulness remains to be proved (fig. 2).39 Endoscopic biopsy of the primary lesion may be attempted using a pediatric resectoscope or cold cup biopsy forceps. Because the loop size of the pediatric resectoscope is small, multiple samples may be needed to make an accurate

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may be cut from the tumor endoscopically and then retrieved separately with grasping forceps. If endoscopy reveals no mucosal abnormality but an intra-abdominal/pelvic mass is present or endoscopic biopsy is inconclusive, needle or open biopsy may be indicated. If laparotomy is performed for biopsy, preliminary evaluation of the pelvic and retroperitoneal nodes at or below the level of the renal arteries should be performed. Followup studies to monitor therapy progress are usually done by CT or magnetic resonance imaging. Serial cystoscopy and biopsy allow the evaluation of the tumor response to therapy.41 Previously a clinical group staging system had been used to assign a particular patient to treatment but more recently a tumor, grade, nodes and metastasis system has been used. Based on this system patients are then placed into low, intermediate or high risk groups. Readers are referred to the complete COG protocols for the tumor, grade, nodes and metastasis system, and risk group stratifications.

FIG. 1. CT shows retroperitoneal lymph node metastasis in patient with B/P RMS. Note typical nodal drainage pattern for B/P RMS, that is pelvic to retroperitoneal nodes at or below renal vessel level.

diagnosis. Cautery artifact can mimic a spindle cell appearance to the inexperienced examiner or destroy the sample entirely. Therefore, low cutting current should be used when performing loop biopsy.40 Alternatively a wedge of tissue

TREATMENT Surgical Management Initial treatment may involve the management of urethral or ureteral obstruction. Bladder outlet obstruction is best managed by urethral catheterization. Suprapubic drainage is associated with the potential for tract seeding and it is not our preference. If ureteral obstruction is present, internal stent placement is the preferred choice. However, tumor mass or distortion of the trigone may necessitate percutane-

FIG. 2. Positron emission tomography reveals active retroperitoneal disease (A) and disease response after chemotherapy (B) in same patient as in figure 1.

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ous nephrostomy. It is important to relieve obstruction promptly to protect renal function. Attempting to preserve the bladder without adversely impacting survival is a principal goal of therapy. Consequently radical resection procedures should be delayed as long as there is evidence of a response to therapy. Initial operation usually consists of biopsy. However, if the tumor can be completely resected with preservation of the bladder and urethral function, it should be removed. Definitive surgery is typically performed after chemotherapy and/or radiotherapy has caused the shrinkage of larger, initially unresectable tumors. The tumors are infiltrative and consequently, unlike encapsulated tumors, they are difficult to resect with a clear margin. Ureteral reimplantation or bladder augmentation may be required in conjunction with partial bladder resection. The response of prostatic tumors to chemotherapy may allow prostatectomy to be performed with preservation of the urethra and bladder. What is Pretreatment Re-excision? This concept applies when an initial biopsy was done before considering a malignant diagnosis and 1) gross resectable residual tumor remains, 2) microscopic positive margins exist and 3) margin status is unclear. In these situations a wide envelope of tissue is removed that includes normal margins. They are then examined pathologically and clinical group assignment is made based on pretreatment re-excision. SLO or Delayed Primary Resection Patients undergoing chemotherapy should be assessed for the feasibility of complete resection of the primary tumor at week 12. Patients who achieve clinical complete or partial response status and select nonresponders/patients with stable disease are candidates for SLO. SLO is performed to confirm the clinical response, evaluate the pathological response to therapy and remove residual tumor. It is important to remember that not all residual masses contain viable tumor. In patients with a complete response biopsy should be performed at the site of the original mass to confirm radiographic findings. In patients with B/P RMS with proven residual tumor after the completion of all therapy or in those with early failure and progressive disease after therapy has been initiated anterior exenteration with preservation of the rectum should be considered. It is important to note that the prior IRS protocols used a staging system (groups I to IV) based on disease extent and on the extent of initial surgical resection.14,18 However, current treatment protocols are based on risk stratification. We provide a brief overview of risk based therapy. At the time of manuscript preparation the intermediate and high risk protocols were concepts awaiting final approval. Readers are referred to the COG protocols for a detailed description. Low Risk Group This group includes patients with localized ERMS occurring at favorable sites (stage I), including botryoid RMS (groups I to III), and patients with ERMS occurring at unfavorable sites with completely resected or microscopic residual disease. In addition, it is important to note that after central review, if pathological study confirms an alveolar or undifferentiated RMS subtype rather than the initial preliminary

ERMS, the patient is then changed to an intermediate risk group. Therapy in patients in the low risk group is divided into subsets 1 and 2 based on stage, location and clinical group. Patients treated in the 2 subsets receive VAC for 4 cycles with decreased doses of cyclophosphamide relative to those used in prior IRS protocols. Patients in subset 1 go on to 4 cycles of actinomycin D and vincristine, while patients in subset 2 are continued on actinomycin D and vincristine for another 12 weeks. In addition, in patients who require local control radiation therapy is given at week 13. Intermediate Risk Group This group includes patients with ERMS occurring at unfavorable sites (ie B/P) and those with gross residual disease (group III), patients with metastatic ERMS who are younger than 10 years and patients with nonmetastatic ARMS or undifferentiated sarcoma at any site. In the intermediate risk group the likelihood of bladder preservation decreases to 25% to 45% based on IRS II and III data.42 Typically complete resection at the initial procedure is impossible. An increased number of SLOs and exenterative procedures are anticipated. In the next COG trial it is proposed that irinotecan will be combined with vincristine in 1 randomization arm. Irinotecan belongs to a newer class of chemotherapeutic agents, the topoisomerase I inhibitors, and it has shown initial promise in phase I studies.43,44 In addition, this agent showed efficacy in a recently completed COG phase II trial. Patients in the intermediate risk group will be randomized to receive VAC alone or VAC alternating with vincristine/irinotecan for 43 weeks of therapy. Local radiotherapy will be initiated in each treatment arms at week 4 due to data from prior IRS protocols, which indicate improved local control with earlier radiotherapy. In addition, at week 13 additional local control can be performed in patients who can safely undergo delayed primary excision. High Risk Group This group consists primarily of patients with alveolar and undifferentiated RMS along with patients older than 10 years with ERMS that is associated with metastatic disease. In these patients up-front complete resection of the primary tumor is rarely indicated. The initial procedure typically consists of biopsy only. Surgical resection of the primary lesion may be performed if metastatic disease is controlled, preferably for 3 to 6 months, if biopsy proven residual tumor exists 6 months after external beam radiation, or if early local failure occurs after the initiation of treatment with chemotherapy and external beam radiation. Partial cystectomy performed 6 months after chemotherapy or radiotherapy has caused shrinkage of larger, previously unresectable tumors. Radical exenteration should be considered only if there is no metastatic disease after treatment but local disease remains. Chemotherapy in patients at high risk has had little effect on prognosis.42 Therefore, in the next COG protocol patients will receive standard VAC cycles along with interval compressed multi-agent chemotherapy that has previously shown activity against RMS. Specifically patients will receive interval compressed cycles of vincristine, doxorubicin and cyclophosphamide, alternating with ifosfamide and

BLADDER-PROSTATE RHABDOMYOSARCOMA etoposide. Patients will also receive an up-front window of vincristine/irinotecan to further assess the response of this combination in those at high risk who have been previously untreated. Finally, irinotecan is believed to potentiate the effects of radiation therapy and, thus, it has been used together with vincristine concurrently with radiation therapy in adults. However, the feasibility and toxicity of this combination has not been studied previously in children and, therefore, it will be assessed in this study at weeks 19 to 23. QUESTIONS, CONTROVERSIES AND FUTURE DIRECTIONS Specific Mechanisms of Bladder Injury and Their Prevention Unfortunately surgery, chemotherapy and radiation therapy have the potential to cause bladder dysfunction. The impact of partial cystectomy in terms of decreased storage capacity is easy to understand. Other effects of partial cystectomy are more subtle. For example, the phenomenon of bladder dysfunction after extravesical reimplantation is well known and, therefore, it stands to reason that partial cystectomy can adversely effect innervation and function.45,46 Chemotherapeutic agents may damage the bladder. Specifically oxazaphosphorine alkylating agents, ie cyclophosphamide, have been associated with gross hematuria, fibrosis and bladder contracture. The incidence is dose dependent and it may approach 40%.47 Toxicity is due to acrolein excretion.48 Adequate hydration and catheter drainage have decreased the incidence of side effects.49 Mercaptoethane sulfonate (mesna), which binds to acrolein and forms a nontoxic stable thioester in urine, is routinely used.50,51 Despite these interventions chemotherapy related bladder toxicity is currently still a consideration. The development of newer agents with improved toxicity profiles may help patient outcomes. Several reports have implicated radiotherapy in posttreatment bladder dysfunction. In the series of Yeung et al only the 4 children who did not receive radiation had normal bladder function.52 Similarly Raney et al noted that 13 of 43 patients receiving radiation had bladder dysfunction compared to 1 of 9 without irradiation.6 Hays et al reported that 9 of 19 irradiated patients had long-term bladder sequelae vs 1 of 11 treated without radiation.16 A dose effect was suggested in this study since only 1 of 6 patients receiving less than 40 Gy had dysfunction vs 8 of 13 receiving more than 40 Gy. Radiation sequelae can be divided into acute and longterm effects. Early changes are caused by an inflammatory response in the bladder wall that decreases bladder storage capacity and is typically reversible.53–55 The severity of these acute effects depends on the total dose and the fractionation schedule of the radiation applied.56 – 60 Late effects include urgency, frequency, hematuria and decreased bladder compliance. Severity is related to radiation dose.61 Fibrosis is a consequence of collagen deposition in the muscle and subepithelial layers of the bladder wall. Increased TGF-␤ expression resulting in altered collagen deposition has been implicated.62 Radiation induced interluken-1 or tumor necrosis factor-␣ may trigger increased TGF-␤ production in the bladder.63– 65 Modulation of TGF-␤ levels or its precursors could limit bladder dysfunction but to

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our knowledge agents for this purpose are not yet available. Other potential solutions are better radiation targeting and perhaps brachytherapy. These options are being studied but to date only limited data are available.66 Do Bladder Preservation Strategies Really Work? It is expected that with primary chemotherapy and conservative surgery bladder retention is possible in approximately 60% of patients.10,16,67 However, a review of IRS IV data called into question the true function of these preserved bladders.68 Little objective data are available regarding bladder function in children treated for RMS. To date only 1 small published study has used the gold standard (urodynamics) to investigate bladder function in these children.52 Yeung et al evaluated bladder function in 11 children with tumors involving the bladder base and/or prostate in 6, the pelvic wall in 2, the vagina in 2 and the bladder dome in 1.52 At a mean followup of 6.6 years only 4 of the 11 children had a normal voiding pattern. All children who were irradiated had nocturnal enuresis, continuous dribbling, abnormal bladder capacity and/or abnormal voiding. In addition, 4 children had evidence of upper tract dilatation and 2 went on to require surgery. Four children had urodynamic studies completed. All 4 cases showed decreased functional bladder capacity. Only 1 child had decreased bladder compliance. Soler et al presented data on 8 children undergoing treatment.69 Three patients (37.5%) were asymptomatic with normal urodynamic studies and another had dysuria. The latter boy underwent continent urinary diversion with transverse colon. The other 4 patients had urological complaints. Urodynamic findings revealed decreased bladder capacity in all 4 with overactivity in 2, urgency in 3 and suprapubic pain during filling. A final article is awaiting publication. The remaining published literature on bladder function consists primarily of subjective reports. While others reported reasonable bladder function after therapy for B/P RMS, objective analysis with urodynamics, standardized questionnaires or imaging was not performed.70 –72 IRS IV suggests that significant impairment in bladder function may exist after treatment but the only study that used the gold standard of urodynamic evaluation had a sample size that was too small to be conclusive.52 An association of dysfunction with total radiation dose has been suggested but to our knowledge this remains unproven. Clearly objective data on bladder function and upper tract status in a contemporary cohort are needed to determine the success of our bladder preservation strategies. This could be most readily accomplished by incorporating prospective evaluation into the next generation of studies. Should We Administer Radiation and When? Radiation therapy is a standard component of current IRS protocols in all patients except those at low risk. In the preceding sections we reviewed the potential impact of radiotherapy on bladder function. The question that is often asked is whether radiotherapy must be given before surgery. Does it need to be given at all? Many surgeons believe that, in addition to its known morbidity, radiotherapy makes extirpative surgery and reconstruction more difficult. Merguerian et al advocated delayed radiotherapy based on experience with a group of 13 patients.73 Ten cases were in

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clinical risk group III and the remainder were in group IV. Radiotherapy was reserved for patients with residual or metastatic disease. A survival rate of 80% was reported in group 3 patients, 6 of the 10 did not receive radiation and 1 had positive postoperative margins. Despite the apparently favorable outcome the limited number of patients in this single center experience mandates cautious interpretation of these conclusions. In contrast to this report is the recently reported experience of the International Society of Pediatric Oncology and the Italian Cooperative Group.74 These groups compared outcomes in patients who did and did not receive RT. Of 105 patients 54 did not receive RT as part of initial therapy. It was observed that patients who did not receive RT had poorer 5-year event-free survival than those who received RT (64% vs 79%, p ⫽ 0.02). This finding is supported by the limited data from IRS IV, in which 14 of 62 patients (22%) who received RT went on to tumor recurrence compared to 3 of 9 (33%) who did not receive RT.17 It is important to note that the numbers available are small and the difference between the groups was not statistically significant. Finally, the German cooperative studies (CWS81) showed that hyperfractionated radiotherapy begun earlier resulted in a lower relapse rate than chemotherapy alone.75 Interestingly some younger children who did not receive radiation did not have relapse. At this time insufficient data are available to recommend the routine omission of RT in patients with B/P RMS. Final analysis of International Society of Pediatric Oncology/Italian Cooperative Group data and further randomized clinical trials are required to adequately address this question. Significance of Rhabdomyoblasts on Posttreatment Biopsy? In the past the identification of rhabdomyoblasts in posttreatment specimens caused considerable confusion. Rhabdomyoblast maturation after chemotherapy has since been observed by various investigators and their clinical significance has been called into question.76 Atra et al reported a group of patients with residual rhabdomyoblast who did not go on to relapse during observation.68 Subsequently Heyn et al reported on 2 of 14 patients who had maturing cells on posttreatment biopsy that remained in remission.41 Analysis of post-cystectomy specimens has also demonstrated rhabdomyoblasts along with decreased cellularity in patients treated with chemotherapy, suggesting that this pattern may be indicative of a response to therapy. More recently Chertin et al reported long-term followup in a patient with residual atypical cells after treatment with bladder RMS that had not recurred after 5 years.77 Finally, Ortega et al followed 6 patients with posttreatment biopsy showing mature rhabdomyoblasts (fig. 3).78 All 6 patients remained free of disease at a followup of 37 to 237 months. The investigators emphasized the importance of correctly identifying mature cells as those with a large smooth solitary nucleus, no significant pleiomorphism, no mitotic activity and the absence of cell clusters suggestive of growth from a common precursor. It is important to note that, while the available literature supports observation, particularly when resection would result in organ dysfunction, failure after apparent tumor cell maturation on biopsy has been reported.79 While we await clarification of this question with longer followup, careful serial radiological imaging, cystoscopy/vaginoscopy and biopsy, if indicated, would appear prudent.

FIG. 3. Urothelial mucosa with maturing rhabdomyoblasts. H&E, reduced from ⫻400.

Early vs Delayed Reconstruction Despite advances in therapy certain patients require total or almost total cystectomy as a component of treatment. A principal question in these patients is when they should undergo reconstruction. Duel et al reported their experience with initial urinary diversion followed by delayed continent reconstruction in patients achieving long-term cure.80 Delaying complex reconstruction until cure is proved and deferring the use of recently irradiated bowl segments are advantages cited by the proponents of this approach. In addition, the use of nonirradiated bowl segments such as transverse colon was recommended by the investigators. Others have advocated combining continent reconstruction at extirpative surgery. Lander et al described the use of Le Bag continent reconstruction in 3 children, of whom 1 was 26 months old.81 Unfortunately despite initially negative frozen section analysis permanent sections revealed residual viable tumor, requiring local radiation and chemotherapy. Similarly Merguerian et al performed reconstruction at cystectomy in their patients but they simultaneously cautioned that frozen section is an unreliable predictor of residual disease and several of their patients had residual disease requiring adjuvant therapy or reoperation.73 In addition, early reconstruction of irradiated tissues may lead to impaired healing and an increase in postoperative complications. In light of these considerations one must question the wisdom of proceeding with continent reconstruction before confirming the adequacy of local control. Hensle and Chang also reported success with early reconstruction but suggested that the timing of reconstruction should be considered on an individual basis and early reconstruction should only be performed if it is certain that no further local therapy is required.82 While early reconstruction is feasible and particularly attractive in older children who are less tolerant of incontinent diversion, it must be judiciously applied.82 MOLECULAR STAGING As with many other types of cancer, treatment for RMS will be profoundly impacted by the advent of molecular staging. An example of this is the documented importance of PAX3FKHR and PAX7-FKHR gene fusions in patients with

BLADDER-PROSTATE RHABDOMYOSARCOMA ARMS. Analysis of markers such as these would likely enable us to better stratify patients into risk groups, allowing those at higher risk to receive intensified therapy while sparing those at less risk.25 Furthermore, if PAX3-FKHR oncoprotein confers a survival advantage to tumor cells, such as resistance to chemotherapy, it will become a new therapeutic target in this disease.

3.

4.

5. 6.

OTHER THERAPEUTIC APPROACHES Other, more broadly applied anti-cancer strategies are also being evaluated for RMS. For example, anti-vascular endothelial growth factor antibodies have been shown to have a dramatic effect on RMS growth in animal models.83 The role of vascular endothelial growth factor and other pro-angiogenic molecules, such as basic fibroblast growth factor and interleukin-8, are currently being explored.84 In conjunction with chemotherapy in patients with tumor recurrence a protocol targeting the anti-apoptotic protein Bcl-2 (Bcl-2 antisense) is currently being evaluated by the IRS. Others investigators are pursuing immunotherapy and gene therapeutic strategies for RMS.85 OUTCOMES

7. 8.

9.

10.

On the clinical front future studies must generate objective data on bladder function. This information will allow us to not only assess our results, but also guide us in modifying current therapy. For example, if an association is confirmed between radiation and bladder dysfunction, we must focus on issues such as the dose, timing and technique of radiation delivery. Similarly we may identify patients with a low likelihood of successful bladder preservation who may become candidates for early exenteration.

11.

12.

13.

ACKNOWLEDGMENTS Dr. Fabiola S. Balarezo provided figure 3.

14.

15.

Abbreviations and Acronyms ARMS B/P COG CT ERMS IRS

⫽ ⫽ ⫽ ⫽ ⫽ ⫽

RMS RT SLO TGF-␤ VAC

⫽ ⫽ ⫽ ⫽ ⫽

alveolar rhabdomyosarcoma bladder/prostate Children’s Oncology Group computerized tomography embryonal rhabdomyosarcoma Intergroup Rhabdomyosarcoma Study Group rhabdomyosarcoma radiotherapy second look operation tumor necrosis factor-␤ vincristine, actinomycin D and cyclophosphamide

16.

17.

18.

REFERENCES 1.

2.

Wiener, E.: Rhabdomyosarcoma. In: Pediatric Surgery, 5th ed. Edited by J. A. O’Neil, M. I. Rowe, J. L. Grosfeld et al. St. Louis: C. V. Mosby, pp. 431-445, 1998 Pack, G. and Eberhart, W.: Rhabdomyosarcoma of the skeletal muscle: report of 100 cases. Surgery, 32: 1032, 1952

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