Continuing Education Activity

Wilms tumor, or nephroblastoma, is the most common pediatric renal cancer, the most common pediatric abdominal cancer, and the fourth most common pediatric cancer overall. Wilms tumor is typically found in children younger than five years old. This activity describes the evaluation and management of children with Wilms tumor and describes the role of the interprofessional team in improving care for affected patients.

Objectives:

• Summarize the typical clinical presentation of a patient with Wilms tumor.
• Outline the differential diagnosis of abdominal masses in children.
• Identify treatment considerations for patients with Wilms tumor.
• Describe how the coordination of the interprofessional team can lead to rapid diagnosis of Wilms tumor and subsequently decrease associated morbidity and mortality in affected patients.

Introduction

Wilms tumor, or nephroblastoma, is the most common renal cancer in the pediatric age group.[1][2] It is also the most common pediatric abdominal cancer and the fourth most common pediatric cancer overall.  Wilms tumor is typically found in children younger than five years old. The tumor is named after the German physician, Dr. Max Wilms, who first described it in 1899.

Etiology

The cause of Wilms tumor is not precisely known, but it is believed to be due to genetic alterations that deal with the normal embryological development of the genitourinary tract. Some of the genetic markers that have been associated with Wilms tumor include WT1, CTNNB1, and WTX gene alterations that have been found in about 1/3 of all Wilms tumors.  Other genes associated with Wilms tumor include TP53 and MYNC.  A poorer prognosis has been linked to TP53 and with the loss of heterozygosity at chromosomes 1p, 1q, 11p15, and 16q.[3][1]

Only about 1% of Wilms patients have a relative with the disease who is typically not a parent.

Wilms is thought to develop from persistent metanephric tissue or nephrogenic rests. These may occur in 1% of infantile kidneys but typically regress during childhood. These abnormal metanephric cells are found in up to 100% of cases of bilateral Wilms but only 35% of unilateral tumors.[1]

Hemihypertrophy and aniridia as well as a variety of urological disorders like cryptorchidism, horseshoe kidney, and hypospadias, are associated with the malignancy although it is unlikely they play any role in actual carcinogenesis.

The bilateral disease represents only about 5% of all patients with Wilms tumor and is more commonly found in girls.

Epidemiology

Wilms tumor is the most common abdominal cancer in childhood and typically presents between ages 3 to 5 years. There are approximately 650 new cases in the United States every year.  Girls are slightly more likely to have Wilms than boys.[4]

Wilms is more common in Africans and African Americans while it is least common in East Asians.  Asian patients also had fewer unfavorable histology tumors, tend to have lower-stage disease, and enjoy better survival outcomes.

European and North American rates are about the same. 

Ninety percent of Wilms tumors are diagnosed before six years of age with the median age of diagnosis being 3.5 years.

With marked improvements in chemotherapy, the overwhelming majority of affected children now survive.

Overall 5-year survival in the US is 92% but in poor parts of the world with fewer resources, the survival rate is only 78%.

Wilms tumor is associated with a number of specific syndromes including WAGR syndrome. WAGR syndrome refers to the presence of Wilms tumor, aniridia, genitourinary anomalies, and mental retardation. Children with WAGR syndrome have a 50/50 chance of developing Wilms tumor. Children with this syndrome have a specific chromosomal abnormality in the WT1 gene which is involved in both renal and gonadal development.

Another syndrome associated with Wilms is the Denys-Drash syndrome or just Drash syndrome. This includes male pseudo-hermaphroditism and progressive renal failure starting in infancy.  The renal disease begins with simple proteinuria in newborns and infants which eventually progresses to nephrotic syndrome and eventually full-blown renal failure. Ninety percent of affected individuals will eventually develop Wilms tumor.

Beckwith-Wiedemann syndrome is clinically diagnosed by hemihypertrophy, pancreatic enlargement, hypertrophic kidneys, omphalocele, ear creases, macrosomia, and macroglossia. Affected patients have a 5% to 10% chance of developing Wilms.[5]

Other syndromes sometimes associated with Wilms include Sotos syndrome, Perlman syndrome, Trisomy 18 (Edward's syndrome), Frasier syndrome, Bloom syndrome, Li-Fraumeni syndrome, and Simpson-Golabi-Behmel syndrome.

Wilms tumor in boys may also present with cryptorchidism, varicocele, or hypospadias, and about 10% of affected girls will have congenital uterine anomalies. Various other renal congenital abnormalities, such as duplication and renal ectopia, are not uncommon.

A finding of perilobar nephrogenic rests in children younger than one year of age is associated with a marked increase in their risk of developing a contralateral Wilms tumor.

Histopathology

Grossly, Wilms tumors are usually well-circumscribed and have a pseudo-capsule. 

Histologically, Wilms is divided into "favorable" and "unfavorable" histologies.

"Favorable" Histology: Ninety percent of Wilms tumors will demonstrate "favorable" histology, which generally has a better prognosis. Classical histological features of a "favorable" Wilms tumor include a triphasic pattern of blastema, epithelial, and stromal tissues.  The blastema is the most undifferentiated and possibly the most malignant component.  It consists of collections of small, round blue cells with very active mitotic activity and overlapping nuclei.

The epithelial component can demonstrate wide variations in differentiation from an early tubular formation with primitive epithelial rosette-like structures to differentiating tubules or glomeruli-like structures, representing nephrogenesis at different developmental stages.

The stromal component may include densely packed undifferentiated mesenchymal cells or loose cellular myxoid areas. The latter areas may be difficult to distinguish from non-tumorous stroma associated with chemotherapy-induced change. Heterologous differentiation of neoplastic stroma in the form of well-differentiated smooth or skeletal muscle cells, fat tissue, cartilage, bone, and even glial tissue is present in some cases, especially in tumors that have undergone preoperative chemotherapy.

Even with "Favorable" histology, the loss of heterozygosity at 1p and 16q loci tend to have a worse prognosis. For this reason, when Wilms tumor tissue is available, it should be checked cytogenetically for 1p and 16q deletions.

"Unfavorable" Histology: Wilms tumors with "unfavorable" histology will demonstrate much higher degrees of anaplasia and are associated with a relatively poorer prognosis and survival.

Anaplasia is histologically defined as hyperchromatic, pleomorphic nuclei that are three times larger than adjacent cells and have abnormal mitotic figures. Anaplasia is associated with a poor response to treatment.

History and Physical

Wilms tumor usually presents as an asymptomatic abdominal mass in the majority of children. The mother may have discovered the mass during bathing the infant. Other features include:

• Abdominal pain
• Gross hematuria
• Urinary tract infections
• Varicocele
• Hypertension or hypotension (Up to 1/3 of Wilms patients will demonstrate hypertension which normalizes after nephrectomy)
• Fever
• Anemia
• If the patient has lung metastases, dyspnea or tachypnea may occur.

Abdominal pain is the most common initial presenting symptom (30% to 40%), followed by hypertension (25%) and hematuria (12% to 25%).

Evaluation

The usual labs are not specific for Wilms tumor but need to be ordered to look for other pathologies. Routine blood work includes:[6][7][8][9]

• Complete blood count to look for anemia
• Chemistry profile
• Renal function
• Urinalysis
• Coagulation studies
• Cytogenetics studies to look for 1p and 16q deletion.

Imaging studies utilized include the following:

• Renal ultrasonography (often the initial study) but is operator dependent
• Chest x-ray to look for lung metastases
• Abdominal and chest CT with sedation
• Abdominal MRI is an optional study.

Imaging is particularly important in surgical planning. Surgical risk factors include larger tumor size, contralateral tumor extension, and displacement of the great vessels, which typically result in longer surgical times, increased blood loss, and higher complications rates. 

The most common site of metastases is the lungs, so chest imaging is recommended. Abdominal CT and MRI appear to be about equal in diagnosing Wilms, so either can be used. Metastases to bones are uncommon but ominous and typically develop later as a relapse or recurrence. 

Recently, MRI diffusion studies have possibly made it easier to differentiate Wilms tumor from neuroblastoma, the other common abdominal malignancy in children. It was found that the apparent diffusion coefficient (ADC) was substantially higher for Wilms. This differentiation is critical as the treatments for these two tumors are different. It was suggested that a cutoff ADC value of greater than or equal to 0.645 × 10 - 3 mm2 per second be used with higher values suggesting Wilms and lower values indicating neuroblastoma. While useful, this will need to be confirmed with additional studies before it can be considered a reliable indicator.

Treatment / Management

Treatment of Wilms tumor is usually nephrectomy followed by systemic chemotherapy, but some protocols initiate chemotherapy first and do the nephrectomy later. The opposite kidney may be explored to ensure that cancer has not spread, although this is unnecessary for low-stage tumors with favorable histology if imaging is negative. Lymph nodes around the aorta are sampled for staging and to improve survival.[10][11][12][13]

There is no apparent significant difference in short-term morbidity, mortality out to three years, hospital readmission rate, or surgical margin status between traditional open surgery or minimally invasive techniques.  Open surgery, however, typically provides more lymph nodes in the surgical specimen.

Routine biopsies are not recommended except in unusual circumstances as a biopsy automatically increases tumor staging to Stage III.  This stage requires radiation and chemotherapy.

Postoperative radiation may or may not be administered depending on tumor histology and extent of spread. For patients without metastases who will be receiving radiation, initiation of therapy within 14 days of surgery appears to improve overall survival.  

Combination chemotherapy is usually administered for more aggressive disease. Initial chemotherapy most typically includes vincristine and dactinomycin. Doxorubicin, cyclophosphamide, etoposide, and carboplatin are also used.[14]

In children with bilateral disease, immediate nephrectomy is not performed. Some experts attempt high-dose chemotherapy to kill the tumor cells and hopefully salvage the kidney. Bilateral nephrectomy immediately mandates dialysis, and so all efforts are made to salvage the kidneys. Repeat biopsies are required to determine if the tumor is responding to therapy.  Nephron sparing surgery can be performed in select cases.[15]

Patients who relapse after initial combined therapy tend to have a worse prognosis than newly discovered Wilms patients. 

The hepatic veno-occlusive disease can occur in patients receiving therapy for Wilms.  It is characterized by right upper quadrant pain associated with jaundice, ascites, weight gain, and/or hepatomegaly. Treatment for hepatic veno-occlusive disease is mainly supportive.[16]

Differential Diagnosis

Differential diagnosis of Wilms tumor can be tricky. While Wilms is the most common childhood renal tumor, the second most common is clear cell renal sarcoma. The prognosis is not as good as Wilms as it has higher mortality and relapse rates. It often metastasizes to bone. Histological appearance can sometimes be similar to Wilms which can lead to a misdiagnosis.[17]

Rhabdoid renal tumors are highly malignant and are most often seen before age two and almost never in children older than five years. It is often widely metastatic at the time of initial presentation and has a very poor prognosis with an 80% mortality rate within one year of diagnosis.

Congenital mesoblastic nephroma is typically found in the first year of life, most often by ultrasound. Hypertension and elevated renin levels usually accompany it.

Renal cell carcinoma is rare in the pediatric age group. However, when present, it is often at a more advanced stage than in adults. Neuroblastoma patients who are post-radiation and post-chemotherapy are at increased risk.

Renal medullary carcinoma is a very aggressive and dangerous cancer that is found almost exclusively in individuals with sickle cell disease, usually trait. It tends to be highly locally invasive and metastasizes early.

Staging

Stage I indicates the tumor was completely contained within the kidney without any breaks or spillage outside the renal capsule and no vascular invasion.  This stage accounts for 40% to 45% of all Wilms tumors.

Stage II would be a tumor that has grown outside the kidney to some degree, such as into surrounding fatty tissue.  Usually, the tumor would be completely removable by surgery, and regional lymph nodes are negative. About 20% of all Wilms tumors are at this stage.

Stage III comprises about 20% to 25% of all Wilms tumors and indicates a tumor which could not be completely removed surgically such as the following:

• Cancer has spread to the regional lymph nodes but not to more distant nodes, such as in the chest
• Cancer has grown into nearby vital structures so it could not be surgically removed completely
• Deposits of the tumor (tumor implants) are found in the peritoneum, or there are positive surgical margins
• Cancer cells were accidentally “spilled” into the abdominal cavity during surgery
• The tumor was removed in separate pieces surgically; such as one piece from the kidney and another from the adrenal gland
• A renal biopsy of the tumor was done before it was surgically removed

Stage IV tumors are those that have spread through the vascular system to distant organs such as the lungs, liver, brain, or bones, or to distant lymph nodes.  These account for about 10% of all Wilms tumors.

Stage V are those cases where both kidneys are involved with tumor at the time of initial diagnosis.  About 5% of all Wilms tumors are at this stage.  Individual staging of each renal unit is needed as well.

Prognosis

The prognosis varies by tumor stage and histology. Favorable histology has survival rates of 99% to 86%, while unfavorable histology survival ranges from 84% to 38%, depending on the stage.[18][19][20][21]

End-stage renal failure occurs in about 1% of patients, usually due to metachronous bilateral tumors.

Females with Wilms tumor-aniridia (WAGR) syndrome may develop streaked ovaries and are at an increased risk for developing gonadoblastoma.

A poorer prognosis is associated with the following characteristics:

• Anaplastic histology in stage II to IV tumors
• Diffuse anaplasia is worse than focal
• Loss of heterozygosity at chromosomes 1p, 1q, 11p15, and 16q or presence of TP53 
• Higher stage (most epithelial predominant tumors are stage I; most blastema predominant tumors are stage III and IV)
• Age older than two years
• Higher positive lymph node density
• Large tumor size
• Even small tumor foci can be associated with a poorer prognosis due to resistance to chemotherapy.

Complications

Radiation and chemotherapy are effective in improving survival in higher-stage Wilms tumor patients, but they may also be responsible for an increased risk of secondary malignancies years later.[22]

It is well established that radiation therapy will increase the risk for bone, breast, colon, and thyroid cancers later on in life.  It will also increase the risk of osteoporosis.

Chemotherapy with dactinomycin, doxorubicin, and vincristine contributes to a higher risk of secondary malignancies as well as specific toxicities such as hearing (carboplatin), cardiac function (adriamycin), and peripheral neuropathy (vincristine).[14]

About 5% to 10% of Wilms patients will present with Von Willebrand's disease, which can complicate treatment.  Initial therapy for this should be DDAVP. If not successful, cryoprecipitate (concentrated Von Willebrand Factor) can be used.[23]

Postoperative and Rehabilitation Care

Immediately postoperatively patients must have the following monitored:

• Blood pressure
• Electrolytes, temperature, and blood glucose
• Urine output

Follow-up visits for Wilms tumor are usually scheduled:[24]

• every 3 months for 2 years after diagnosis
• then every 6 months for another 2 years
• then once every 2 years

 Follow-up visits for Wilms tumor may include:

• feeling the abdomen for signs of any local recurrence or a liver tumor
• listening to the lungs for any signs of metastasis
• feeling the thyroid for any growths (if the child had radiation therapy to the chest)
• breast examination in female patients who received radiation therapy to the chest
• check for peripheral neuropathy (a complication of Vincristine therapy)
• check for liver/veno-occlusive disease in patients with right-sided tumors who received radiation therapy

 Tests are part of follow-up care. These will include:

• Abdominal ultrasound (yearly is recommended)
• CT scan
• MRI
• Chest x-ray
• Liver function testing
• Renal function blood tests
• Early screening for infertility
• Hearing tests for patients who received carboplatin
• Cardiac function tests, such as an echocardiogram or electrocardiogram at least every 3 years for patients who received doxorubicin (Adriamycin)
• Early screening for colon cancer in patients who received abdominal radiation (should start 10 years after radiotherapy treatment or by age 35, whichever is later)

After lung or chest radiation, the following is added:

• Thyroid-stimulating hormone (TSH) and free thyroxine (T4) to monitor thyroid function
• Thyroid US is recommended every 3 years to screen for thyroid nodules and masses
• Bone density testing should be started 10 years before it would normally be done due to early osteoporosis
• Early screening for breast cancer in women

Pearls and Other Issues

Present-day survival of patients after undergoing treatment is about 80% to 90%. The addition of radiation has made a significant difference in survival compared to the use of surgery alone. The primary research issue today in Wilms is to develop ways to prevent the drug toxicity associated with combination chemotherapy. Most children can live a normal life with one kidney.

Of note, recent studies indicate that in females who survive, there is an increased risk of developing invasive breast cancer at an early age (younger than 40). This risk was highest in females who had been previously treated with chest radiation.

Patients with anaplastic histology face a recurrent risk of about 50%. Even patients with low-risk histological features can expect a 15% recurrence rate. There is some controversy about the potential for a renal biopsy to spread the disease or increase the risk of local recurrence, but this has not yet been conclusively determined. When a recurrence is found, it most often affects the lungs and is usually early, most often within two years of the initial tumor discovery.

There is also a risk of delayed development of Wilms in the contralateral kidney, which is found in about 1% of patients, usually within two years of the initial discovery of the Wilms tumor in the original kidney. This is thought to be due to persistent focal nephrogenic rests in the contralateral kidney.

About 15% of patients with Wilms are at risk for a recurrence.  The majority of these will be found within the first 2 years after surgery.  

Circulating tumor DNA may prove to be a useful diagnostic tool in diagnosing pediatric tumors like Wilms but is still investigational. 

New chemotherapy drugs appear promising, such as topotecan and irinotecan, while stem cell transplants and targeted therapies represent promising new approaches to Wilms tumor treatment.

Enhancing Healthcare Team Outcomes

Wilms tumors are still relatively rare, but survival for most patients is quite good, especially for those with "favorable" histology who are diagnosed early and receive proper treatment. The majority of patients first present to the pediatrician, nurse practitioner, or primary care provider. These clinicians need to be vigilant about infants with abdominal pain as the cause may be Wilms tumor. The key to improved survival is a prompt referral to the oncologist. Because the diagnosis is often devastating to the families, a mental health nurse should provide counseling in concert with the clinician. The pharmacist should educate the family about the chemotherapeutic medications and their adverse effects. The oncology nurse should educate the family on the surgery, the post-operative care, and follow up as well as assist the clinician in monitoring the patient and providing regular follow-up. 

Social workers should be involved early in the care so that the patient has adequate support and does not miss out on treatment.

An interprofessional team approach is necessary for patients deemed candidates for surgery, as the recovery is prolonged and can be associated with complications. The message to the family should be consistent and realistic. Only through such an approach can client-patient relationships can be improved and hopefully translate into positive outcomes.

New approaches are being developed for those who do not initially respond well to treatment. Bilateral Wilms tumor can be particularly challenging and require close coordination between oncologists, pediatricians, nurse practitioners, primary care providers, radiologists, and surgeons in the timing and implementation of neoadjuvant chemotherapy with bilateral nephron-sparing surgery or nephrectomies.[25]