This review summarizes recent key publications dealing with pediatric genitourinary tumors. It will highlight diagnosis and treatment, molecular genetics, and late effects of therapy.
Wilms tumor represents approximately 95% of pediatric renal tumors with a peak incidence at the age of 2–3 years [1••]. It may, however, be congenital or occur in older children and rarely in adults. It most commonly presents as a painless abdominal mass, although pain, hematuria (gross or microscopic), fever, and hypertension are well known associations.
Diagnosis and treatment
The primary imaging modality remains computed tomography (CT) of the chest, abdomen, and pelvis. If tumor extension into the inferior vena cava is suspected, ultrasound or echocardiogram is recommended prior to surgery [1••]. Fluorodeoxyglucose-PET is not currently recommended in the initial evaluation of Wilms tumor, although it may be helpful for detecting residual disease at the end of therapy and in evaluating for disease extent at relapse .
Two different treatment approaches exist for Wilms tumor. In the United States, a succession of trials by the National Wilms Tumor Study (now the Children's Oncology Group or COG), of which the most recently completed is fifth National Wilms’ Tumor Study (NWTS-5), advocate up front surgery for accurate staging and histologic diagnosis. This differs from the approach of the International Society for Pediatric Oncology, which believes that preoperative chemotherapy reduces the surgical risk . Both groups have an overall survival (OS) rate of approximately 90%, and current trials are trying to minimize the late effects of treatment while maintaining or improving an excellent OS.
Data from NWTS-5 have shown that loss of heterozygosity (LOH) on chromosomes 1p and 16q are associated with a relatively poorer prognosis. This has been incorporated into the current COG studies, which include a tumor collection and biology classification protocol (AREN03B2), and four treatment protocols which use age, tumor weight, histology, stage, and LOH to risk stratify patients. Gene expression analysis is also being studied to further refine stratification of therapy [4•].
Patients enrolled on AREN0532 (treatment for very low and standard risk favorable histology Wilms tumor) who are stage I, less than 2 years old, and with a tumor weight of less than 550 g have surgery alone as definitive treatment. This is similar to the arm in NWTS-5, which was closed early due to stopping rules when tumor recurrences led to a 2-year disease-free survival (DFS) of 86.5%. However, the rate of salvage was much greater than anticipated, which allowed the arm to open in the current study. Recent data suggest that among these very low-risk patients, histologic and molecular differences may identify two groups with different risks of relapse [4•]. Favorable histology stages I and II patients with no LOH who do not qualify for surgery alone are treated with vincristine and dactinomycin for seven cycles (regimen EE-4A). If LOH of 1p and 16q is found, doxorubicin is added to the vincristine and dactinomycin for nine cycles (regimen DD4-A). Stage III patients with no LOH are also treated with DD4-A with radiation therapy added.
More intensive chemotherapy is indicated for higher risk patients. These include stage III disease with LOH of 1p and 16q, and stage IV disease. Chemotherapy includes vincristine, dactinomycin, and doxorubicin with cyclophosphamide and etoposide added in addition to radiation therapy. Patients with stage IV disease with pulmonary lesions and no LOH who completely respond to chemotherapy at week 6 are treated with DD4-A with no pulmonary radiation. Patients with anaplastic histology are eligible for treatment on AREN0321 (high-risk renal tumors). Patients with stage IV focal anaplasia and stages II–IV diffuse anaplasia are treated with 30 weeks of vincristine, doxorubicin, cyclophosphamide and carboplatin, etoposide, cyclophosphamide with radiation therapy (regimen UH-1). Enrolled patients with stage IV diffuse anaplasia and measurable disease will also get one to two cycles of vincristine/irinotecan up front to evaluate tumor response and possible future addition to therapy. This is followed by regimen UH-1.
Approximately 5–7% of patients with Wilms tumor will have bilateral disease. Nephron-sparing approaches facilitated by preoperative chemotherapy should be used for those with bilateral disease, and in those with syndromes that predispose to late renal failure. Feasibility of nephron sparing is not always predictable from preoperative imaging and requires surgical expertise to minimize postoperative urine leak and to utilize techniques to ensure complete resection of all macroscopic disease .
Approximately 25–50% of patients who relapse after initial treatment for unilateral Wilms tumor can be salvaged. Ifosfamide/carboplatin/etoposide (ICE), cyclophosphamide/etoposide, and carboplatin/etoposide are commonly used salvage regimens [6,7]. Limited data on using hematopoetic stem cell transplantation (HSCT) as consolidation for salvage therapy are available. Several groups are investigating the use of HSCT after ICE or ICE along with topotecan .
The molecular genetics of Wilms tumor is complex, with multiple genes involved (Table 1). Despite a favorable outcome for most patients with favorable histology Wilms tumor, LOH for chromosomes 1p, 16q, or both (seen in about 5% of favorable histology Wilms tumor) and high telomerase expression are adverse prognostic factors. Mutations of the Wilms tumor genes WT1 (on chromosome 11p13), WTX (on chromosome Xq11.1), and CTNNB1 (the gene encoding β-catenin on chromosome 3p22.1) are cumulatively detected in approximately one-third of Wilms tumors . These and other genes play a role in WNT signaling, which determines lineage specificity and may be a common denominator in many Wilms tumors [10,11].
WT1 encodes a transcription factor that may act as a tumor suppressor or, when over expressed, as an oncogenic protein. Mutations of WT1 may be germline (constitutional) in addition to tumor-specific, and these patients have an increased risk of bilateral disease and recurrent disease . Another relatively high-risk group of patients are those with constitutional 11p15 abnormalities (WT2), which may result in a variety of clinical phenotypes, including Beckwith–Wiedemann syndrome and other syndromes associated with abnormal growth and an increased risk of developing Wilms tumor. Constitutional 11p15 abnormalities have been found in 3% of patients with sporadic (nonsyndromic) Wilms tumor . Specifically, epimutations in the IGF2-H19 imprinting center were identified. Like those with WT1 mutations, individuals with constitutional 11p15 (WT2) mutations have a higher rate of tumor recurrence compared with those without 11p15 mutations .
The WTX gene on the X chromosome, first reported in 2007, is mutated in 7–29% of Wilms tumors . This discovery contributes to a paradigm of X-linked tumor suppressor genes, thus challenging the traditional ‘two hit’ model. WTX has been shown to act as a tumor suppressor gene by negatively regulating WNT/β-catenin signal transduction. More recently, the WTX protein has been shown to go between the cytoplasm and nucleus and enhance WT1-mediated transcription, suggesting a role in transcriptional regulation [15••]. Germline mutations of WTX cause osteopathia striata congenital with hyperostosis and craniofacial malformations. Interestingly, these individuals do not appear to be predisposed to developing Wilms tumors or other malignancies, despite loss-of-function mutations of this tumor suppressor gene [16••]. Further analysis of WTX mutations in Wilms tumor samples suggests that the mutations are probably a relatively late event of unclear clinical significance rather than an early, causative mutation . Dallosso et al.  recently reported that protocadherin gene clusters on chromosome 5q31 are frequently hypermethylated and thus silenced during malignant transformation. Protocadherin proteins may, therefore, act as tumor suppressors.
Nephrogenic rests are foci of embryonal cells rarely (<1%) found in normal infant kidneys and commonly (25–40%) found in Wilms tumor-bearing kidneys. They may be perilobar, intralobar, or both, and they are widely considered to be precursors to Wilms tumor, although malignant transformation is believed to be rare. In addition, they determine the histologic phenotype to a greater degree than epigenetic changes . Finally, gene expression profiling is helping to better classify Wilms tumors compared with traditional parameters such as age, stage, and tumor size [4•].
Other pediatric renal tumors
Although they are collectively less common than Wilms tumor, many other pediatric renal tumors occur, including congenital mesoblastic nephroma, renal cell carcinoma (RCC), renal medullary carcinoma, clear cell sarcoma, anaplastic sarcoma, rhabdoid tumor, primitive neuroectodermal tumor, desmoplastic small round cell tumor, and intrarenal neuroblastoma [19••]. These non-Wilms tumors occur more frequently in children less than 6 months or more than 12 years of age. Imaging modalities are limited in distinguishing these entities, and it is crucial to make a tissue diagnosis . Surgery is the mainstay of therapy for these non-Wilms tumors, although some may benefit from adjuvant chemotherapy [19••]. Pediatric RCC has biological and clinical differences compared with adult RCC. In general, children with RCC have a better prognosis than adults with RCC [21•]. The small-molecule tyrosine kinase inhibitors, sorafenib, sunitinib, and temsirolimus, and the mAb bevacizumab hold promise as adjuvant therapies for RCC, but they have not yet been studied in children [21•]. COG is prospectively studying high-risk renal tumors with a risk-adopted treatment approach, utilizing six different treatment approaches based on diagnosis and stage (protocol AREN0321). This protocol is also in conjunction with the COG Renal Tumor Biology and Classification Study (AREN03B2), which provides central pathology review.
Rhabdomyosarcoma (RMS) originates from immature mesenchymal cells, and can commonly affect bladder, prostate, and paratesticular sites in children. The perineum, vulva, vagina, and uterus are less common sites [22•].
Diagnosis and treatment
Genitourinary RMS can present with a painless scrotal/inguinal swelling, pelvic mass, vaginal mass or bleeding, or hematuria/urinary obstruction. Biopsy with adequate tissue sampling for diagnosis and classification is important in diagnosis. There are two main histologic subtypes, embryonal and alveolar. Embryonal RMS (ERMS) is more common than alveolar histology in primary genitourinary sites . Primary surgical resection is reserved for cases when resection can be made without significant morbidity. This is difficult in some genitourinary RMS, particularly pelvic tumors. For patients with paratesticular primary sites and enlarged nodes on CT and those at least 10 years of age (even with a normal CT), staging ipsilateral retroperitoneal lymph node dissection (SIRLND) is important because of the high rate of regional metastasis .
Both pretreatment staging and clinical grouping are important in treatment planning, as they have been shown to correlate with clinical outcome. Pretreatment staging is based on the TNM Classification of Malignant Tumours system and includes primary tumor site, tumor size (≤5 cm or >5 cm), regional lymph node status, and metastatic disease. In combination with stage and histology, the COG also assigns treatment according to postsurgical grouping classification based on residual disease following surgery. Current COG protocols use the stage and clinical grouping to stratify patients into low, intermediate, and high-risk categories.
Standard treatment for RMS includes systemic chemotherapy for all patients, and local control involving surgery with or without radiation therapy for most. Vincristine, dactinomycin, and cyclophosphamide (VAC) therapy currently remains the ‘gold standard’ adjuvant therapy for RMS, although some low-risk patients may not require cyclophosphamide. Numerous studies have tried additions and substitutions to VAC in an attempt to improve outcomes, but nothing to date shows superiority to VAC. In COG study D9803, intermediate-risk patients were randomized to VAC versus VAC alternating with vincristine, topotecan, and cyclophosphamide (VTC). At a median follow-up of 4.3 years, 4-year failure-free survival was not significantly different between the two groups (VAC 73%, VAC/VTC 68%, P = 0.3) [24•]. COG protocol ARST0431 for patients with high-risk RMS used intensive multiagent chemotherapy; it closed to accrual in 2008 and the results are pending. The current COG intermediate-risk protocol (ARST0531) is investigating the addition of irinotecan to a VAC backbone. Some patients, particularly patients with pelvic primaries, may have residual tumor at the end of treatment. Aggressive resection of residual pelvic disease can cause significant morbidity. A recent study [25•] assessing group III patients treated on Intergroup RMS Study-IV protocol with chemotherapy and radiation with or without surgery for local control compared the 5-year failure-free survival of patients with a complete response (CR) to patients who had a partial response (PR) or no response in residual tumor size. There was no increased risk of failure or death in the PR/no response group compared with the CR group. The authors concluded that ‘aggressive alternative therapy may not be warranted for RMS patients with a residual mass at the end of planned therapy’ [25•].
Patients with high-risk and relapsed disease continue to have a poor prognosis. High-risk patients have a 3-year DFS of less than 30%, and DFS is even lower for patients with relapsed disease. New strategies are needed to improve survival in these patients. Currently, therapies such as high-dose chemotherapy with stem cell rescue [26,27] and novel agents such as the proteosome inhibitor bortezomib  are under investigation.
Molecular biology of rhabdomyosarcoma
The more aggressive alveolar RMS (ARMS) is associated with two reciprocal translocations: t(2;13)(q35;q14) and t(1;13)(p36;q14), which generate fusions of paired box gene 3 or 7 (PAX3 or PAX7), and forkhead box O1 (FOXO1) (also known as FKHR), respectively (Table 1). The PAX3–FOXO1 fusion is present in approximately 70% of cases of ARMS; the PAX7–FOXO1 fusion is present in approximately 10–20% of cases of ARMS and has a more favorable prognosis compared with those with the PAX3–FOXO1 fusion. ERMS is associated with an 11p15.1 LOH and has a more favorable prognosis compared with ARMS. Molecular classification of RMS utilizing gene expression profiling and LOH analysis combined with immunohistochemistry is highly reproducible and more accurate than histopathology alone . The integrin-linked kinase (ILK) gene has been shown to act as an oncogene in ARMS and, paradoxically, as a tumor suppressor gene in ERMS. These opposing functions are determined by the ILK interactions with a c-Jun N-terminal kinase/c-Jun signaling pathway, and these interactions are altered by the PAX3–FOXO1 fusion . Thus, ILK inhibition is a potential therapeutic target. Other promising therapies are muscle-specific microRNAs, which can promote differentiation of rhabdomyoblasts . The platelet-derived growth factor receptor-A has also been shown to be a potential therapeutic target in ARMS . Multiple other genetic changes have been identified in ARMS, including aberrations in the function or expression of human telomerase reverse transcriptase, H-Ras, MYCN, p53, Rb, and p16INK4A/p14ARF.
Primary testicular tumors are rare in children. A bimodal age distribution correlates with the observation that prepubertal tumors are generally distinct from those seen in adolescents, who have more adult-like tumors [34•]. The differential diagnosis for a painless scrotal mass in a child/adolescent includes leukemia, RMS, and a primary testicular tumor [germ cell tumor (GCT) or non-GCT]. Scrotal ultrasound remains the imaging modality of choice [35•]. Yolk sac tumors (endodermal sinus tumors) and teratomas are the most common primary prepubertal testicular tumors. Embryonal carcinomas, choriocarcinoma, and mixed malignant GCTs may occur in older children (typically teenagers). Gonadoblastoma, Leydig cell, and Seroli cell tumors are rare in children. Prior to radical inguinal orchiectomy, a serum alpha-fetoprotein (AFP) and beta-human choriogonadotropin should be obtained. Age-adjusted AFP values should be used. Because of low rates of nodal involvement in children, SIRLND is reserved for patients with persistently elevated tumor markers or persistent retroperitoneal lymphadenopathy following chemotherapy. SALL4 is a new diagnostic marker that will aid pathologists in classifying testicular GCTs . For GCTs requiring chemotherapy, platinum-based regimens result in excellent long-term survival [34•].
Despite the overall favorable prognosis for patients with Wilms tumor, it is now clear that survivors are at increased risk of death for many years. Even after 5 years, deaths due to the original disease are relatively common. Over time, however, late effects from therapy become a more common cause of mortality. These include second malignant neoplasms (SMNs), heart failure, end-stage renal disease, and pulmonary disease [37•]. Most SMNs occur in the radiation fields . Preliminary evidence suggests that less frequent use of radiation therapy combined with lower doses of radiation therapy and chemotherapy will decrease this risk [37•]. Knowledge of these late effects is not only driving current treatment approaches but also highlights the importance of careful long-term follow-up . The general health of Wilms tumor survivors is worse compared with siblings, but their psychological health is relatively good . Other late effects suffered by survivors of pediatric genitourinary tumors include bladder dysfunction, hypertension, musculoskeletal deformities, and reproductive problems .
The molecular genetics of pediatric genitourinary tumors continues to shed light into the pathogenesis of these tumors. Wilms tumor and RMS share complex genetic characteristics. Patients are being risk stratified by adding molecular findings to clinical criteria, and contemporary clinical trials are increasingly incorporating these new risk criteria into treatment algorithms. The elucidation of these molecular abnormalities will likely lead to targeted therapies that should improve survival and minimize long-term complications.
There are no conflicts of interest.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 298–299).
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. Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children's oncology group study D9803. J Clin Oncol 2009; 27:5182–5188. This study from COG investigators reports the results of a large randomized clinical trial for patients with intermediate-risk RMS. It enrolled a total of 617 eligible patients, and shows that the addition of topotecan with cyclophosphamide to VAC does not significantly improve survival compared with VAC alone in this subgroup of patients.
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. Prognostic significance of tumor response at the end of therapy in group III rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 2009; 27:3705–3711. This is another report from COG investigators, which studied the outcomes for 419 patients with clinical group III RMS. Interestingly, response status (complete, partial, or none – as defined in the protocol by radiographic measurement) at the end of therapy was not predictive of outcome (recurrence and death), suggesting that aggressive alternative therapy (such as radical surgery, radiation therapy, or additional chemotherapy) may not be necessary for RMS patients with a residual mass at the end of planned therapy.
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