Wilm’s Tumor or Nephroblastoma

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Introduction   

Wilms tumor, or nephroblastoma, is the most common malignant renal tumor in children and the most frequent pediatric abdominal cancer, ranking as the fourth most common pediatric cancer overall [1]. Dr. Max Wilms first described this tumor in 1899, and it most often occurs in children under five years of age [2].  

As a childhood embryonal tumor, Wilms tumor demonstrates the intersection between disrupted organogenesis and tumorigenesis, with many associated genes playing critical, non-redundant roles in early kidney development [3]. Despite curative therapy being achievable in 90% of affected children—including those with disseminated disease—survival disparities persist within and between countries, highlighting the need for a global commitment to change [4]. Recent epidemiological studies have provided new insights into variations in global incidence rates. 

The most important prognostic feature in Wilms tumor is histology, focusing on the distinction between favorable histology and anaplasia [1] [5]. Current prognostic classifications are based on clinical and pathological findings, along with dedicated protocols addressing molecular alterations. Treatment involves conventional cytotoxic chemotherapy and surgery, with radiation therapy used in certain cases. Multimodal therapy is associated with a good prognosis, allowing for a focus on risk-adapted strategies to maximize oncologic outcomes while minimizing therapeutic morbidity [6].  

Future research aims to adopt biology-driven approaches to risk stratification and develop new drugs, including advanced imaging techniques to better understand tumor composition, optimizing irradiation methods to reduce target volumes, and evaluating new surgical procedures. For the effective treatment of a Wilms tumor patient, an interprofessional team approach is crucial, necessitating collaboration among healthcare professionals to address survival disparities and implement advances in treatment. 

Abbreviations 

• WT (Wilms Tumor) 
• ERWT (Extrarenal Wilms tumor) 
• FHWT (Favorable histology Wilms tumor) 
• RT (Radiation Therapy) 
• WLI (Whole Lung Irradiation) 
• WAI (Whole Abdominal Irradiation)  

Case Study: A 3-Year-Old Girl with Abdominal Swelling 

Patient Presentation: 

A 3-year-old African American female arrives at the pediatric clinic by her mother, who noticed a swelling in her daughter’s abdomen while bathing her. The child appears healthy, with no complaints of pain, fever, or changes in appetite. There is no history of trauma or recent illness. 

Medical History: 

• No significant past medical history. 
• Developmental milestones are appropriate for age. 
• No known allergies or prior surgeries. 

Family History: 

• No family history of cancer or renal disease. 
• No known genetic syndromes. 
• No history of congenital anomalies in the family. 

Physical Examination: 

• Vital Signs: Temperature 36.8°C, Heart rate 100 bpm, Respiratory rate 22 breaths per minute, Blood pressure 110/70 mmHg (elevated for age). 
  • General Appearance: Well-nourished and active child. 
• Abdominal Examination: 
  • Palpable, firm mass in the left flank area. 
  • Mass is smooth, non-tender, and does not cross the midline. 
  • No signs of organomegaly. 
• Genitourinary Examination: 
  • Normal external genitalia. 
  • No signs of cryptorchidism or hypospadias. 
• Other Findings: 
  • No aniridia (absence of the iris). 
  • No hemihyperplasia (asymmetric overgrowth). 
  • No macroglossia (enlarged tongue). 
  • No skin abnormalities or ear creases. 

Laboratory Findings: 

• Complete Blood Count (CBC): Within normal limits. 
• Comprehensive Metabolic Panel: 
  • Renal Function Tests: Normal serum creatinine and BUN levels. 
  • Liver Function Tests: Within normal ranges. 
• Urinalysis: 
  • Microscopic hematuria detected. 
  • No proteinuria. 
• Coagulation Profile: 
  • Normal PT, aPTT, and INR. 
• Additional Tests: 
  • Serum alpha-fetoprotein (AFP): Normal. 
  • Beta–human chorionic gonadotropin (β-hCG): Normal. 
  • Urine catecholamines: Normal. 

Imaging Studies: 

• Abdominal Ultrasound: 
  • Reveals a well-defined, heterogeneous mass originating from the left kidney. 
  • The mass measures approximately 8 cm in its largest dimension. 
  • No evidence of calcifications. 
  • The right kidney appears normal. 
• Abdominal CT scan with Contrast: 
  • Confirms a solid renal mass in the left kidney. 
  • No invasion into adjacent organs. 
  • No evidence of tumor thrombus in the renal vein or inferior vena cava. 
  • No enlargement of regional lymph nodes. 
  • No ascites observed. 
• Chest CT Scan: 
  • No pulmonary nodules or metastatic lesions were detected. 

Differential Diagnosis: 

• Wilms Tumor (Nephroblastoma) 
• Clear cell sarcoma of the kidney (CCSK) 
• Congenital mesoblastic nephroma 
• Renal cell carcinoma (Less probable due to the patient’s age) 
• Rhabdoid tumor of the kidney 
• Neuroblastoma (The mass does not cross the midline, and urine catecholamines are normal, reducing the probability) 

Diagnosis: 

Based on the patient’s age, clinical presentation, and imaging findings, the most probable diagnosis is Wilms tumor. 

Treatment Plan: 

1. Multidisciplinary Team Consultation:
   1. Pediatric oncologist 
   2. Pediatric surgeon 
   3. Radiation oncologist (consulted to plan potential postoperative radiation therapy) 
2. Surgical Intervention:
   1. Planned Procedure: Left radical nephroureterectomy with regional lymph node sampling. 
   2. Surgical Goals: 
   3. Complete removal of the tumor without rupture (to prevent tumor spillage). 
   4. Accurate staging through lymph node assessment. 
   5. Preservation of surrounding organs unless directly involved. 
3. Pathological Examination:
   1. Histology: 
   2. Determine if the tumor has favorable histology or anaplasia. 
4. Molecular Studies: 
   1. Assess for loss of heterozygosity (LOH) at chromosomes 1p and 16q. 
   2. Check for gain of chromosome 1q. 
5. Staging: 
   1. Assign a final stage based on surgical and pathological findings (Stage I or II). 
6. Adjuvant Therapy:
7. Chemotherapy: 
8. If Stage I favorable histology Wilms tumor (FHWT): 
   1. Consider observing or administering an EE4A regimen (vincristine and dactinomycin) for 18 weeks [7]. 
9. If Stage II FHWT: 
   1. Recommend EE4A regimen [7]. 
10. Radiation Therapy: 
    1. Not indicated for Stage I FHWT [8]. 
    2. Consider if Stage III or unfavorable histology [1].  
11. Genetic Counseling and Screening:
    1. Although no congenital anomalies are present, discuss the risks of familial WT. 
    2. Educate the family about the importance of monitoring for signs of recurrence or secondary malignancies. 
12. Follow-Up Care:
13. Short-Term: 
    1. Monitor for postoperative complications. 
    2. Begin chemotherapy within 14 days post-surgery if indicated. 
14. Long-Term: 
    1. Regular follow-up visits every 3 months for the first 2 years, then every 6 months until 5 years have passed. 
    2. Surveillance imaging (abdominal ultrasound and chest X-ray or CT) to detect recurrence. 
    3. Monitor renal function due to the remaining solitary kidney. 
    4. Assess for late effects of chemotherapy, such as cardiotoxicity from doxorubicin (if used). 

Discussion: 

The incidental finding of an abdominal mass by a caregiver is a common scenario. The absence of symptoms like weight loss, fever, or malaise, along with normal laboratory tests, supports the likelihood of WT over other malignancies like neuroblastoma [9]. Constitutional symptoms occur in 10% of children with Wilms tumor [9]. 

The management follows standard protocols emphasizing surgical removal of the tumor with careful attention to prevent intraoperative spillage, which could upstage the disease and necessitate more aggressive therapy. Lymph node sampling is crucial for accurate staging and risk stratification [10]. 

Oncologists tailor chemotherapy based on the stage and histology of the tumor. Patients with Stage I (favorable histology Wilms tumor) FHWT can sometimes avoid chemotherapy to reduce toxicity [11]. However, doctors must monitor patients to detect any recurrence early. Consider Wilms tumor in children presenting with an asymptomatic abdominal mass. Early detection and a multidisciplinary approach are key to successful treatment and minimizing long-term adverse effects. The prognosis for this patient is favorable, with a high likelihood of cure and normal development. 

Differential Diagnosis  

When children present with abdominal swelling or a suspicious mass, it is crucial for providers to consider a wide range of potential diagnoses, including Wilms tumor (WT), other renal tumors, extrarenal tumors, and benign renal conditions [12]. According to the “Principles of Abdominal Mass Evaluation” ([WILMS-A] in the algorithm), initial testing should include a thorough history and physical examination [13]. This examination involves measuring blood pressure and assessing for genitourinary malformations such as cryptorchidism and hypospadias, as well as other congenital anomalies associated with WT [1][13].  

Laboratory tests, including blood chemistry tests to evaluate renal and liver function, blood count, and coagulation assessments are meaningful.  

Imaging studies are essential and include abdominal ultrasound and abdominal computed tomography (CT) or magnetic resonance imaging (MRI), as outlined in the “Initial Evaluation” ([WILMS-1] in the algorithm) [13]. Ultrasound can assess without sedation and determine the presence and origin of a mass. If ultrasound detects a mass, providers can use CT or MRI to evaluate its extent and involvement. Additional CT imaging of the pelvis may be necessary if the mass extends into that area, as detailed in the “Principles of Imaging” ([WILMS-B] in the algorithm) [13].  

The primary goals of imaging are to differentiate tumors of primary renal origin from extrarenal tumors and benign renal conditions, determine whether the kidney disease is unilateral or bilateral, and assess for the presence of metastatic disease [12]. It is also important to evaluate for ascites, which may raise concern for tumor rupture. 

When suspecting WT or any malignant renal tumor, assess further for metastatic disease. 

Clinicians can recommend a chest CT scan to evaluate pulmonary nodules, the most common site of metastasis [14]. It is preferable to perform the chest CT without sedation and before any other sedation procedures to avoid the complication of atelectasis, which can interfere with the evaluation. When the origin of the abdominal mass is unclear, consider additional tests such as urine catecholamines, alpha-fetoprotein (AFP), or beta-human chorionic gonadotropin (β-hCG). 

Surgeons perform surgery for children with suspected unilateral Wilms tumor (WT) [15]. Clinicians evaluate the clinical stage before surgery, then confirm the diagnosis and complete staging through tissue analysis for pathology, histology, and molecular markers. This information guides decisions on the most appropriate postoperative treatment regimens. 

The differential diagnosis for renal tumors includes clear cell sarcoma of the kidney, congenital mesoblastic nephroma, renal cell carcinoma (including renal medullary carcinoma), rhabdoid tumor of the kidney, renal sarcoma, primitive neuroectodermal tumors, DICER1 (endoribonuclease Dicer) – associated sarcoma, desmoplastic small round cell tumors, renal neuroblastoma, and perivascular epithelioid cell tumors [16] [52]. Other intra-abdominal malignancies that can present as a flank mass include Burkitt lymphoma, desmoplastic small round cell tumors, Ewing sarcoma, extrarenal WT, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, malignant germ cell tumors, and other rare malignancies [17] [54].  

Patients with nephroblastomatosis are at increased risk for developing WT, and those with cystic nephroma are at risk for transformation into renal sarcoma [12]. 

It is essential to rule out benign renal conditions that may include adrenal hemorrhage, angiomyolipoma, dysplastic kidney, hydronephrosis, metanephric tumors such as adenoma, stromal tumor, and adenofibroma, multicystic kidney disease, polycystic kidney disease, renal hemorrhage, and renal vein thrombosis [18]. Through systemic evaluation, clinicians can diagnose the cause of abdominal masses in children and initiate appropriate treatment regimens. 

Etiology  

Wilms tumor (WT) is a pediatric kidney cancer with an unclear cause, often arising from genetic alterations affecting the embryonic development of the genitourinary tract [1]. Most children with sporadic WT are present with a palpable abdominal mass noticed by a caregiver or primary care physician [1]. These patients often appear otherwise healthy, which helps differentiate WT from conditions like neuroblastoma that may present with systemic symptoms [1]. In 20% to 25% of cases, symptoms include hypertension, hematuria, and flank pain [1] [19]. 

Genetic factors play a significant role in the etiology of WT. Germline mutations in key kidney development genes cause the disease. The most common germline variant is in the WT1 gene located on chromosome 11p13, which codes for a transcription factor crucial for normal kidney and genitourinary function [20] [21]. Mutations in WT1 are associated with syndromes like WAGR (Wilms tumor, Aniridia, Genitourinary anomalies, and Range of developmental delays), Denys-Drash, and Frasier syndromes, all of which carry a higher risk of bilateral WT [22]. 

The WT2 gene on chromosome 11p15 drives insulin-like growth factor 2 (IGF2) overexpression, which promotes cell growth and increases the risk of Wilms tumor in Beckwith-Wiedemann syndrome [23]. Somatic genetic alterations in WT involve mutations in CTNNB1, DROSHA, WTX (AMER1), DGCR8, SIX1, SIX2, BCORL1, MLLT1, MYCN, and TP53. TP53 mutations correlate with anaplastic WT and a worse prognosis [24]. Loss of heterozygosity at chromosomes 1p, 1q, 11p15, and 16q has also been associated with adverse outcomes [24]. 

Nephrogenic rests or metanephric tissue cause Wilms tumor development due to the persistence of embryonic kidney tissue [25]. These remnants occur in about 1% of infant kidneys and regress during childhood [25]. When they persist, they form tumors. Nephrogenic rests appear in most cases of bilateral Wilms tumor and in 35% of unilateral tumors [12]. 

Genetic predisposition syndromes cause 10% to 20% of Wilms tumor cases in children [26]. Congenital anomalies such as aniridia (absence of the iris), hemi hyperplasia (asymmetric overgrowth of one side of the body), macroglossia (enlarged tongue), and genitourinary abnormalities like cryptorchidism, horseshoe kidney, and hypospadias are indicators of increased WT risk [27] [28].  

Syndromes associated with higher WT risk include: 

• Denys-Drash Syndrome: Up to a 90% risk; associated with male pseudohermaphroditism and glomerulopathy [22]. 
• Perlman Syndrome: The risk stands at 75% [29]. 
• WAGR Syndrome: About 50% risk [30]. 
• Beckwith-Wiedemann Syndrome: Around a 10% risk, varying with specific genetic alterations; those with germline hypermethylation of 11p15 have up to a 24% risk [31]. 
• Simpson-Golabi-Behmel Syndrome: A 5%–10% risk [32]. 
• Mosaic Variegated Aneuploidy: Over a 25% risk [33]. 
• Bohring-Opitz Syndrome: 7% risk. 

Familial WT is rare, accounting for about 1%–2% of cases, and does not involve WT1 mutations [34]. Genes associated with familial WT include FWT1 on chromosome 17q and FWT2 on chromosome 19q [34]. Siblings have less than a 1% chance of developing WT [12][34]. 

Given these genetic risks, children with predisposition syndromes should undergo routine screening to detect WT at an early, asymptomatic stage. The goal is early intervention, through partial nephrectomy, to preserve renal function. Screening recommendations from organizations like the American Association for Cancer Research and the National Comprehensive Cancer Network (NCCN) include physical examinations and renal ultrasounds every three months until at least eight years of age [35]. 

It is important to note that having a genetic predisposition does not guarantee the development of WT; it signifies a higher risk, necessitating vigilant monitoring. Early detection through surveillance programs has been effective in identifying tumors when they are smaller and more manageable in children who present at a younger age and are more prone to multifocal or bilateral disease. 

The etiology of Wilms tumor involves a complex interplay of genetic factors affecting embryonic kidney development. Understanding these genetic influences is crucial for early detection, risk assessment, and management of WT in children, aiming to improve outcomes through timely and appropriate interventions. 

Epidemiology 

Wilms tumor (WT), also known as nephroblastoma, is the most common primary renal tumor in children and the most frequent abdominal cancer in childhood [1]. In the United States, healthcare providers diagnose 650 new cases each year, representing over 90% of primary renal tumors in clients under 20 years old and about 5% of all childhood cancers [12]. The majority of children present with WT between the ages of 1 and 5, with the median age of diagnosis around 3 to 3.5 years [1][4]. Girls have a higher likelihood of developing WT compared to boys [1][4]. 

The incidence of WT is highest among African and African American children, followed by Caucasian children, and is least common in East Asian populations [1] [36]. Asian patients have a lower incidence of the disease, tend to present with lower-stage cases, have fewer unfavorable histology tumors, and demonstrate better survival outcomes [1] [36]. European and North American incidence rates are similar [1][36]. 

Significant advancements in chemotherapy have improved survival rates, with the overall five-year survival in the United States exceeding 90% for children with all stages of favorable histology Wilms tumor (FHWT) who receive appropriate treatment [12][37]. However, survival remains poor for children with higher stage diffuse anaplastic WT [1][37]. In resource-limited parts of the world, the survival rate is approaching 78% [36]. Most children have resectable disease in one kidney, and clinicians recommend performing upfront unilateral nephrectomy.  

In boys, WT may also present with cryptorchidism (undescended testes), varicocele, or hypospadias, and about 10% of affected girls may have congenital uterine anomalies [1][12]. Many other renal congenital abnormalities, such as duplication anomalies and renal ectopia, occur [1][12]. Early detection and monitoring are crucial for improving outcomes in these high-risk groups. 

Diagnostic Workup  

Treatment planning for Wilms tumor requires a comprehensive initial assessment to inform therapeutic decisions. This begins with a thorough history and physical examination, emphasizing the identification of any predisposition syndromes, end-stage renal disease (ESRD), and relevant family history. Physical signs such as hemihypertrophy, genital malformations, and eye anomalies are critical findings that can influence treatment strategies. Assessing hematuria is also important, as its presence or absence may affect surgical planning. 

Laboratory evaluations should include a complete blood count and a comprehensive metabolic panel with liver function tests to establish baseline values and detect any abnormalities that could impact treatment choices. With this information, a multidisciplinary team can develop an individualized treatment plan, which involves surgical intervention, chemotherapy, and radiotherapy, tailored to the patient’s specific condition and needs. 

Treatment  

Treatment for Wilms tumor (WT) ranges from surgery alone to intensive chemotherapy, surgery, and radiation therapy (RT) [1]. The choice of treatment depends on several factors, including whether the tumor is unilateral or bilateral, the local stage of the disease, the presence of metastases, the patient’s age, tumor weight, biological risk factors, histology, and clinical response to therapy [1]. A multidisciplinary team of surgeons, pediatric oncologists, and radiation oncologists should evaluate the client before initiating treatment. 

Surgeons recommend surgery at some point for most children with suspected WT, including those with unresectable or those with bilateral or metastatic disease. Risk assessment after surgery determines the need for and type of adjuvant therapy (see Risk Assessment for Favorable Histology Wilms Tumor [FHWT], [WILMS-F] in the algorithm) [11][13]. Most children present with resectable unilateral kidney disease, and upfront unilateral nephrectomy is the standard recommendation for these patients (see “Initial Treatment of Unilateral Renal Tumor” [WILMS-2] in the algorithm) [11][13]. Multifocal unilateral tumors (occurring in about 10% of cases) or primary bilateral renal tumors (found in 5%–13% of patients) are less common [1]. 

The primary goals of WT treatment are to maximize cure rates while minimizing long-term toxicity by risk-stratifying patients and selecting less-intensive treatment whenever possible. Long-term toxicities include the risk of secondary malignancies from chemotherapy and/or RT and the development of end-stage renal disease (ESRD), among other long-term risks associated with surgery and radiation therapy.  

Studies of cancer survivorship cohorts have shown that patients treated with historical regimens have a 65% incidence of chronic health problems 25 years after treatment, with severe conditions occurring in 24% of patients [38]. In most patients with unilateral favorable histology WT, the risk of long-term renal failure after treatment is 0.6% [39]. However, the incidence of ESRD is higher (12%) in children with bilateral WT [39]. Patients treated with radiation therapy also have an increased risk of developing second malignancies [40]. 

In the Children’s Oncology Group (COG), surgeons perform nephrectomy at the time of initial diagnosis [41]. Neoadjuvant chemotherapy may be necessary in certain clinical scenarios, such as: 

1. Extension of tumor thrombus above the level of the hepatic veins. 
2. Direct tumor invasion requires removal of adjacent organs. 
3. Excessive tumor burden makes the patient a poor surgical candidate. 
4. Concerns surgical morbidity, intraoperative tumor spillage, and/or residual tumor following resection. 

Tumor biopsy and intraoperative tumor spillage have been associated with an increased risk of local failure. As a result, when this occurs in patients, the COG studies upstage them to stage III, requiring local radiotherapy, unless histologic confirmation of bilateral WT is present [41]. 

For a subset of patients with very low-risk WT—children younger than two years old with stage I favorable histology WT and kidney and tumor weight less than 550 grams—surgery alone may be sufficient treatment [10]. In the COG study AREN0532, the estimated four-year event-free survival (EFS) rate for these patients was 89.7%, and the overall survival (OS) rate was 100% at a median follow-up of 80 months, supporting the approach of observation alone after nephrectomy [10]. 

Surgical Management  

The primary surgical goals in treating Wilms tumor (WT) are to remove all tumor tissue without causing rupture (avoiding gross tumor spillage), achieve accurate lymph node staging, and obtain a complete pathological evaluation. For most clients with favorable histology Wilms tumor (FHWT), surgeons perform a unilateral radical ureteronephrectomy. Surgery must include regional lymph node sampling to ensure accurate staging and guide subsequent therapy.  

Surgeons perform nephron-sparing surgery (NSS) on clients with bilateral disease, genetic predispositions, or an elevated risk of renal failure. Avoid NSS for unilateral disease without genetic risk factors. 

Surgical tissue specimens undergo testing to confirm the diagnosis, assess for molecular markers such as loss of heterozygosity (LOH), and determine the tumor histology, including factors like blastemal predominance or anaplasia [42]. The results of these assessments are crucial for risk stratification and selecting the appropriate adjuvant therapy. 

Prior to treatment, it is vital to evaluate whether the tumor is resectable, determine the most appropriate type and timing of surgery, and assess the need for neoadjuvant chemotherapy to reduce tumor size before surgery. Before surgery, clinicians assign a clinical stage, but they confirm the definitive diagnosis of WT and complete staging after the operation. Evaluating resectability involves assessing the number and extent of tumors and determining if the patient is at risk for pulmonary compromise, tumor spillage, or long-term renal failure. 

Contraindications to immediate surgery include tumor extension into contiguous structures, the presence of a solitary kidney, extension of a tumor thrombus above the hepatic veins, unacceptable anesthesia risk due to pulmonary metastases or large abdominal tumors, and significant risks of morbidity or mortality, gross tumor spillage, residual tumor, or long-term renal failure [12] [41]. Metastases do not serve as a contraindication to surgery. 

The preferred surgical approaches are transabdominal or thoracoabdominal exposures using a transperitoneal route to minimize the risk of tumor spillage [24]. The surgical procedure should include an assessment of the size and extent of the tumor(s), thorough abdominal exploration, and lymph node sampling. Sample a minimum of five lymph nodes from the renal hilum, paracaval, and para-aortic regions associated with the kidney. Surgeons should assess tumor rupture, ascites, and retroperitoneal adenopathy. Although Wilms tumors do not often invade surrounding organs, they often adhere to them; therefore, resection of adjacent organs is unnecessary [24].  

Despite the use of preoperative imaging modalities like abdominal CT or MRI, surgical exploration remains indispensable, as imaging cannot replace the information gained during surgery. Document any occurrence of tumor spillage, as spillage classifies clients as stage III and necessitates radiation therapy. Avoid using invasive surgical techniques for children with Wilms’ tumor (WT). Depending on the clinical scenario and the tumor’s response to neoadjuvant chemotherapy, the surgeon performs either a partial or total nephrectomy on one or both sides. Regardless of the surgical approach, regional lymph node sampling is mandatory. 

In cases of unilateral WT, surgery plays a critical role in removing the primary tumor, performing complete nodal staging, and providing tissue for comprehensive risk stratification. Since studies have not shown survival benefits from adrenalectomy and en-bloc resection of surrounding organs, performing a radical nephroureterectomy optimizes local control. Patients classified as stage I or II may receive inadequate treatment without complete nodal staging.  

Although there is no specific recommendation for the exact number of lymph nodes required for complete staging, studies have shown a correlation between the number of lymph nodes removed and overall survival (OS) [43].  

Chemotherapy 

Data indicates that combining neoadjuvant and/or adjuvant chemotherapy with surgery—either with or without radiation therapy—improves survival rates for most children with Wilms tumor (WT) [10]. Common chemotherapy regimens used in treatment include EE4A (vincristine and dactinomycin), DD4A (vincristine, dactinomycin, and doxorubicin), VAD (vincristine, dactinomycin, and doxorubicin), regimen M (vincristine, dactinomycin, doxorubicin, cyclophosphamide, and etoposide), and regimen I (vincristine, doxorubicin, cyclophosphamide, and etoposide) [12] [44] [45].  

While these regimens often utilize the same agents, their schedules and combinations vary, and they may be employed as either neoadjuvant or adjuvant chemotherapy depending on the clinical scenario. 

In the National Wilms Tumor Study (NWTS), chemotherapy commenced at week zero, whereas in the Children’s Oncology Group (COG) protocols, it begins at week one; however, the total number of chemotherapy doses remains the same between the two approaches [12].  

The VAD regimen, used in the neoadjuvant setting for patients eligible for nephron-sparing surgery (NSS), administers 6 to 12 doses of vincristine, 2 to 4 doses of dactinomycin, and 2 to 4 doses of doxorubicin (cumulative dose of 70–140 mg/m²) over 6 to 12 weeks, depending on treatment response and the timing of surgery [46]. In this regimen, dactinomycin and doxorubicin work together.  

Regimen M includes 9 doses of vincristine, 5 doses of dactinomycin, 5 doses of doxorubicin (cumulative dose of 150 mg/m²), and four courses each of five daily doses of cyclophosphamide and etoposide over 24 weeks [12] [44] [45]. Administer dactinomycin and doxorubicin together, along with cyclophosphamide and etoposide. Regimen M starts at week seven for tumors requiring augmented therapy based on molecular markers or the response of lung metastases after six weeks of DD4A [12] [44] [45]. 

Regimen I comprises 9 doses of vincristine, 4 doses of doxorubicin (cumulative dose of 180 mg/m²), seven courses of 3 to 5 daily doses of cyclophosphamide, and three courses of five daily doses of etoposide [12] [44] [45]. This regimen combines doxorubicin with three daily doses of cyclophosphamide, while five daily doses of cyclophosphamide pair with etoposide. Depending on the timing of surgery, regimen I begins at week 7, 9, or 12 for tumors requiring augmented therapy based on histological findings [12] [44] [45]. 

The clinical setting determines the specific regimen, which follows the treatment algorithm. At week six of neoadjuvant chemotherapy, clinicians re-image tumors to assess resectability. Pulmonary lesions, if present, assist in evaluating the chemotherapy response; persistent lesions may undergo surgical removal after six weeks if excision can occur without significant morbidity. In some cases, achieving a complete response by week six may eliminate the need for surgery. If there is less than a partial response, an open biopsy assesses for anaplasia or confirms the WT diagnosis.  

Chemotherapy continues for a total of 12 weeks when a partial response occurs at week six, but the patient is not yet a surgical candidate, including for NSS. Surgery takes place by week 12, as clinical trial data show no further tumor shrinkage beyond this point with extended chemotherapy. 

Adjuvant chemotherapy should commence no later than 14 days after surgery. Risk stratification guides the selection of the most appropriate adjuvant chemotherapy regimens, as detailed in the “Initial and Final Risk Assessment for Favorable Histology Wilms Tumor” (WILMS-F) in the treatment algorithm [13]. When radiation therapy becomes necessary, coordinate the timing of adjuvant chemotherapy to avoid giving full doses of dactinomycin or doxorubicin concurrently with radiation, minimizing potential toxicities. 

Radiation Therapy 

When clinicians suspect Wilms tumor (WT), the NCCN Panel recommends consulting a radiation oncologist early to ensure adequate time for radiation planning and coordination with chemotherapy if needed. Patients at higher risk after surgery should receive adjuvant radiation therapy (RT), while those with low-stage, lower-risk disease do not require it [47]. The clinical scenario determines whether adjuvant flank radiation therapy (RT) or whole abdominal irradiation (WAI), with or without whole lung irradiation, is necessary. For instance, adjuvant flank RT suits patients with local stage III favorable histology Wilms tumor (FHWT) or stage IV disease with local stage III involvement. 

Note that a biopsy alone does not upstage a tumor to stage III when determining the need for adjuvant RT. Most boys receiving adjuvant flank RT should use testicular shielding to protect fertility. Patients with cytology-positive ascites, any preoperative tumor rupture, peritoneal seeding, or diffuse surgical spillage should receive (Whole Abdominal Irradiation) WAI [47][48]. Administer supplemental boost irradiation for a gross residual disease that remains after adjuvant flank RT or WAI [47][48].  

Recommend adjuvant whole lung irradiation (WLI) for patients with lung metastases [48]. In select patients with FHWT and metastases confined to the lungs, providers can delay adjuvant whole lung irradiation until week six of chemotherapy [49].  

Studies have shown that initiating RT later than 14 days after surgery is associated with an increased risk of abdominal recurrence in patients without metastases [12]. Consider patient-specific factors, such as age and the need to assess the response of lung metastases to chemotherapy, when deciding the timing of adjuvant RT. Coordinate the scheduling of RT with chemotherapy to avoid giving full doses of dactinomycin or doxorubicin with RT. Administer full doses of dactinomycin or doxorubicin before starting RT. 

Clinical Presentation  

Children receive a diagnosis of Wilms tumor (WT) through two primary methods. 

The most common presentation involves signs suggesting a renal condition, such as abdominal swelling or a suspicious mass [1]. Many of these children remain asymptomatic, and caregivers often discover the mass during routine activities like bathing, or pediatricians find it during a physical examination. To prevent rupturing of the tumor, avoid vigorous or frequent palpation of the abdominal mass [1].  

The second method of detection occurs through planned radiologic screening for children identified as having a genetic predisposition or congenital anomalies. Tumors found during routine imaging are small and asymptomatic. In rare cases, healthcare providers discover WT during surgery for unrelated conditions, such as trauma or appendicitis. 

Most children are present with a solitary tumor in one kidney; however, 5% to 13% have bilateral tumors, and about 10% have multifocal tumors within a single kidney [12]. The majority of patients (83%) exhibit abdominal swelling or an abdominal mass, with or without additional symptoms like abdominal pain (37%), fever (23%), hematuria (21%–25%), and hypertension (20%–25%) [1][12]. Clinicians may mistake left-sided renal tumors for an enlarged spleen (splenomegaly) and right-sided tumors for an enlarged liver (hepatomegaly) during examination [1]. 

Less common symptoms include varicocele, hernia, enlarged testicle, congestive heart failure, hypoglycemia, Cushing syndrome, pleural effusion, acute abdominal symptoms, and sudden rupture leading to bleeding and shock [50]. A healthy-appearing child with an abdominal mass may have WT, while an ill-appearing child may have neuroblastoma [1][50]. Calcification of the tumor occurs in 5% to 10% of WT cases, compared to 60% to 70% in neuroblastoma [1][6][50]. 10% of patients with WT exhibit coagulopathy, such as acquired von Willebrand disease [51]. 

Wilms tumor can extend into perirenal soft tissues, the renal vein, and the vena cava. The most common sites of hematogenous metastasis are the lungs (81%), followed by both the lungs and liver (15%), and other sites (4%) [6]. Spread to regional lymph nodes is also common. Unlike clear cell sarcomas or other kidney cancers, it is rare for WT to metastasize to the bones and brain [1]. Extrarenal Wilms tumors (ERWT), though rare, represent recognized entities, with the diagnosis made through histological examination of a tumor occurring outside the kidney [53]. 

Conclusion

Wilms tumor, also known as nephroblastoma, remains the most common renal malignancy in children and ranks as a leading cause of pediatric abdominal cancer. Despite advances in treatment, which have enabled curative outcomes in approaching 90% of affected children, significant survival disparities exist across different regions.  

Understanding the complex interplay of genetic factors, disrupted organogenesis, and tumorigenesis is essential for developing more effective diagnostic and therapeutic strategies. Recent epidemiological research highlights the need for global efforts to address variations in incidence and improve treatment accessibility worldwide. 

The most critical prognostic indicator in Wilms tumor cases is histology, distinguishing between favorable and unfavorable histological patterns. Current treatment protocols leverage a combination of chemotherapy, surgery, and, in some cases, radiation therapy. Multimodal therapy has proven effective when guided by risk-adapted strategies that aim to optimize oncologic outcomes while minimizing treatment-related morbidity.  

Future research focuses on enhancing risk stratification through biological markers, developing advanced imaging techniques, and refining surgical and irradiation methods to improve precision and reduce side effects. 

The management of Wilms tumor underscores the importance of a multidisciplinary approach, involving pediatric oncologists, surgeons, radiologists, and other healthcare professionals. Collaborative care ensures comprehensive treatment planning, accurate diagnosis, and tailored interventions that address both localized and disseminated disease.  

As research continues to evolve, there is hope for more biology-driven, personalized treatment approaches that can bridge survival gaps and offer improved outcomes for children worldwide, emphasizing the need for coordinated global healthcare efforts. 

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