Wilms Tumor: A Pediatric Oncology Success Story

Wilms tumor (or nephroblastoma), the most common childhood renal tumor^[1,2], is named after Max Wilms, a German surgeon and an early advocate for radiation therapy.^[3] This neoplasm accounts for approximately 5% of all pediatric malignancies,^[2,4] with an estimated 500 new cases diagnosed each year, the majority (>80%) of which are in children younger than 5 years.^[1,2,4] The incidence of Wilms tumor in males and females is nearly equal when the disease is unilateral (0.92:1.00), but a female preponderance exists in bilateral disease (0.60:1:00).^[1] Most Wilms tumors are unilateral and consist of a single tumor, but 5%-10% of affected children have more than one tumor in the same kidney, and an estimated 5% of children have bilateral disease.^[2] The survival of patients with Wilms tumor (5-year survival: 90%^[4]) has improved dramatically over the past few decades, making this disease an excellent example of how cooperative management of a malignant tumor with multimodal therapy can significantly improve outcomes.^[4,5]

Scanning electron micrograph of a Wilms tumor courtesy of the National Cancer Institute (NCI)/Dr Timothy Triche.

Certain underlying genetic conditions are associated with Wilms tumor, including which of the following?

1. Neurofibromatosis type 1
2. Li-Fraumeni syndrome
3. WAGR syndrome
4. Ataxia-telangiectasia

Image of a postnephrectomy Wilms tumor courtesy of Dr Arnold C. Paulino.

Answer: C. WAGR syndrome.

About 10%-15% of Wilms tumor cases are associated with congenital defects, including WAGR (Wilms tumor, aniridia [shown], genitourinary [GU] malformations, mental retardation), Beckwith-Wiedemann (BWS) (macroglossia, organomegaly, hemihypertrophy), and Denys-Drash syndromes (DDS) (gonadal dysgenesis, nephropathy, Wilms tumor).^[1,2,4,6] Wilms tumor involves WT1 on chromosome (chr) 11p13 and the IGF2/H19 locus on chr 11p15.5 (WT2).^[1,2,6] WT1 is important for normal nephrogenesis; the loss/mutation of one WT1 allele results in GU defects and is the first event required to give rise to Wilms tumor.^[7] In WAGR syndrome, deletions encompass a number of contiguous genes, including the aniridia gene PAX6 and WT1, whereas WT2 gives rise to BWS and WT1 gives rise to DDS.^[1,6] Other genes with adverse prognostic significance in Wilms tumor include the combined loss of heterozygosity (LOH) at chr 1p and 16q, gain of chr 1q, and TP53 mutation. Two familial Wilms tumor loci are known (FWT1 on chr 17q; FWT2 on chr 19q) but not their relevant genes.^[1,6]

Image courtesy of Neethirajan G et al. BMC Med Genet. 2004;5:9. [Open access.] PMID: 15086958; PMCID: PMC419353.

Pathology
Wilms tumor is an abnormal proliferation of the mesanephric blastema with no differentiation into tubules or glomeruli. It usually arises from three tissue elements (shown): epithelium (A), stroma (B), and blastema (C).^[1,6] The blastema consists of microscopically undifferentiated, small round blue cells arranged in a diffuse or organoid pattern. The epithelium consists of epithelial structures (tubules or glomeruli) that develop out of condensations of blastema and may simulate the nephrogenic development of the kidney. However, unlike normal nephrogenesis, large capillary formations and/or heterologous squamous/mucinous elements may be present. The stroma usually manifests as immature spindled cells, but heterologous differentiation may result in the presence of skeletal muscle, osteoid, or fat. Tumors with all three tissue elements are termed triphasic, but some masses are biphasic or monophasic (eg, blastemal Wilms tumor). Those with a majority of heterologous elements are termed "teratoid."

Image courtesy of Thevendran G, Farne HA, Kaisary AV. J Clin Med Res. 2010;2(4):194-7. [Open access] PMID: 21629539; PMCID: PMC3104656.

Tumor histopathology and staging are critically important and affect prognosis.^[1,2,4,6] Wilms tumors are categorized as having either favorable histology (FH) (no anaplasia) or unfavorable histology (UH) (anaplasia is present).^[1,2,4,6] The image shows a Wilms tumor with UH; it features hyperdiploid mitotic figures, nuclear enlargement (3-fold or larger), and hyperchromasia. Although UH tumors account for about 10% of Wilms tumors, affected patients have a much more poor prognosis than those with FH masses.^[1,2,4,6]

How does Wilms tumor most commonly present?

1. Blood in the urine (hematuria)
2. High blood pressure
3. Abdominal distention
4. Bone pain

Image courtesy of Karen Goddard, MBChB, MA, FRCP(C), FRCP(UK).

Answer: C. Abdominal distention.

Often, while bathing a child with Wilms tumor, a relative notices that the child's abdomen is very distended. However, the differential diagnosis of pediatric abdominal swelling includes benign conditions (eg, hydronephrosis) that must be differentiated from neoplasms. The most common pediatric abdominal tumors are Wilms tumor and neuroblastoma.^[8] In neonates and very young infants, the majority of renal tumors are congenital mesoblastic nephroma (CMN) rather than Wilms tumor.^[9]

Image courtesy of Jain V, Mohta A, Sengar M, Khurana N. Indian J Med Paediatr Oncol. 2011;32(4):214-6. [Open access] PMID: 22563156; PMCID: PMC3343249.

The table shows how to clinically differentiate between Wilms tumor and neuroblastoma in infants and young children.

Wilms tumor spreads via local extension as well as lymphatic, and hematogenous routes^[1,2,4,6,10]; neuroblastoma metastasis spreads by lymphatic and hematogenous routes.^[10] Which of the following sites is the most common for hematogenous metastases from Wilms tumor?

1. Brain
2. Liver
3. Bones
4. Lungs

Table courtesy of Karen Goddard, MBChB, MA, FRCP(C), FRCP(UK).

Answer: D. Lungs.

Wilms tumor spreads most commonly to the lungs (shown) and, less commonly, to the liver, bones, and brain.^[1,2,4,6] If a renal tumor spreads to the bones, it is most likely another type of neoplasm rather than Wilms tumor.

To stage Wilms tumor, the following investigations are necessary:

• Detailed medical history, including family history
• Physical examination
• Imaging studies, including plain abdominal radiography, ultrasonography to confirm the presence of an abdominal mass and to assess for tumor thrombi in blood vessels, and computed tomography (CT) scanning to assess the extent of abdominal disease (tumor and regional lymph nodes) and to evaluate for potential pulmonary metastases^[1,2,4,6] (Note: Magnetic resonance imaging [MRI] is the more modern approach to assess the extent of local disease.)

Image courtesy of David Dix, MBChB, FRCPC, FAAP.

Imaging Studies
The plain abdominal film (left) shows a large unilateral Wilms tumor displacing the bowel. No bowel gas is seen on the right side of the abdomen. The coronal CT scan (right) shows the same tumor.

Image courtesy of Karen Goddard, MBChB, MA, FRCP(C), FRCP(UK).

This coronal MRI shows a large left-sided Wilms tumor that has ruptured in its superior aspect. MRI allows abdominal images to be obtained without respiratory artifacts and provides a sharp contrast between pathologic and healthy tissue, even without the administration of contrast medium.^[11]

Image courtesy of Karen Goddard, MBChB, MA, FRCP(C), FRCP(UK).

Diagnostic Approaches
There are two main diagnostic approaches for Wilms tumor.^{[1,2,4,6,9,12]} In North America, an up-front nephrectomy is performed at the initial presentation. In Europe and other parts of the world, chemotherapy is initiated for a presumptive diagnosis of Wilms tumor without biopsy (patients >6 months old), and the tumor is resected after 4 weeks.

The up-front nephrectomy approach allows for histologic confirmation of the tumor, accurate staging, and biologic studies on the tumor tissue that are of increasing prognostic importance.^[6,9] The delayed nephrectomy approach reduces surgical complications (eg, tumor spillage)^[9] and enables pathologists to assess the histologic response to chemotherapy, which has prognostic value.^[6,9,12]

Image courtesy of Wikipedia/The Armed Forces Institute of Pathology.

Staging
Two staging systems exist for Wilms tumor. The staging system established by the National Wilms Tumor Study Group (NWTSG) and used in North America by the Children's Oncology Group (COG) (shown) is based on surgical staging at initial presentation.^{[1,2,4,6,9,12]} The staging established by the International Society of Pediatric Oncology (SIOP) is based on patients' response to treatment following preoperative chemotherapy.

The treatment of Wilms tumor involves multimodal therapy (major modalities: surgery, chemotherapy, radiation therapy [RT]), it is dependent on the tumor stage and pathology, and the management approach differs between North America and Europe.^{[1,2,4,6,9,12]} Regardless of the management approach, surgery is always used to resect the tumor, and it is often used to stage the disease. Chemotherapy is typically necessary, except for patients with very low-risk tumors. RT is used to treat patients with high-risk tumors.

Surgery
The standard approach for resectable tumors is to make a transverse-transperitoneal incision with division of the ipsilateral rectus muscle across the midline (shown). On entering the peritoneal cavity, the surgeon (1) assesses the tumor extent; (2) biopsies suspicious nodules; (3) explores the contralateral kidney; (4) opens Gerota fascia and palpates the anterior/posterior kidney surfaces; (5) inspects hilar and regional lymph nodes, then biopsies, samples, and/or excises lymph nodes as appropriate (eg, hilar, iliac, para-aortic, inferior vena cava, celiac), and places titanium clips at lymph-node biopsy sites to guide subsequent RT (Failure to sample lymph nodes is an adverse prognostic feature.); and (6) removes the kidney for unilateral disease but obtains biopsies for bilateral disease; if radical nephrectomy is not possible, titanium clips are placed in residual tumor areas to guide postoperative RT.^[13]

Image courtesy of Jain V, Mohta A, Sengar M, Khurana N. Indian J Med Paediatr Oncol. 2011;32(4):214-6. [Open access] PMID: 22563156; PMCID: PMC3343249.

Chemotherapy
Combination chemotherapy typically involves vincristine, actinomycin D (dactinomycin), and doxorubicin (for higher-risk tumors). Other agents include cyclophosphamide, etoposide, irinotecan, and/or carboplatin.^[1,2,4,6] These drugs, in combination with surgery and sometimes RT, achieve excellent outcomes in patients with FH Wilms tumor.^[5] Images courtesy of Wikimedia Commons/Armin Kübelbeck (needle) and Sam Shlomo Spaeth (vial).

Current chemotherapy regimens for Wilms tumor with FH in North America are as follows: Stage I/II FH disease consists of vincristine/actinomycin D × 19 weeks; stage III/IV FH disease uses vincristine/actinomycin D/doxorubicin × 25 weeks, followed by RT.

For Wilms tumor with UH, the North America chemoradiotherapy regimens are as follows: Stage I focal or diffuse anaplastic disease consists of vincristine/actinomycin D/doxorubicin × 25 weeks, followed by RT; stage II-IV diffuse anaplastic disease uses vincristine/doxorubicin/cyclophosphamide/etoposide, followed by RT; and stage II-IV focal anaplastic disease consists of vincristine/actinomycin D/doxorubicin × 25 weeks, followed by RT.

Radiation Therapy
Low-dose RT is used under the following circumstances^[1,2,4]:

• If a tumor is upgraded from stage II to stage III disease, low-dose flank RT is given in the North American approach.
• If diffuse rupture of a tumor has occurred and the entire peritoneal cavity is contaminated, low-dose whole abdominal RT is given.
• In the presence of postsurgical gross residual disease in the abdomen or pelvis after flank or whole abdominal RT, extra RT is given.
• Pulmonary metastases are present.

The image shows the extent of a low-dose RT field used to cover both lungs for bilateral pulmonary metastases and an RT flank field used to treat a local stage III FH Wilms tumor. Research is ongoing as to whether pulmonary RT can be omitted in patients who have complete resolution of their pulmonary metastases after 6 weeks of chemotherapy with vincristine, actinomycin D, and doxorubicin.

Image courtesy of Karen Goddard, MBChB, MA, FRCP(C), FRCP(UK).

Relapse
Most patients with Wilms tumor do well with treatment, but 10%-15% experience a relapse.[6] Favorable prognostic features after relapse include (1) relapse occurs within 12 months after the initial diagnosis, (2) FH tumor pathology,^[1,2,4] (3) early disease stage at initial diagnosis (ie, stage I/II),^[1,2,4] (4) relapse in the form of a solitary pulmonary nodule, (5) primary treatment used a two-drug therapy (vincristine, actinomycin D),^[2,4] and (6) relapse occurs outside the primary radiation field^[2], among other factors.

Myeloablative megatherapy (a high-dose chemotherapy strategy^[14]) and autologous stem cell transplantation (SCT) (shown) rescue have been used to treat high-risk recurrent Wilms tumor, but it is unclear whether this strategy provides a benefit compared to other modern treatment regimens.^[15] No randomized studies exist to address this question. Whenever possible, patient participation in clinical trials is crucial, as their involvement is essential to advance knowledge within the field. Outcomes for children with Wilms tumor who are enrolled in research studies are generally superior to those of non-study participants.^[16]

Image courtesy of Wikimedia Commons.

Late Treatment Effects
Although the aim of treatment for Wilms tumor and other childhood cancers is to maximize the probability of cure and reduce the risk of long-term side effects (late effects), late effects may occur many years after therapy and include the following[1,2,4,17]:

• Postoperative hypertension (often after nephrectomy)
• Small risk of anthracycline-induced cardiomyopathy
• Post-RT mild scoliosis and osteoporosis; reproductive/pregnancy issues
• Secondary malignant neoplasms (small risk, many years after therapy)

Fortunately, most of the health problems are quite rare. The image shows undergrowth of half of each vertebral body (red lines) as a consequence of the RT field edge having bisected the middle of these bones. Thus, normal bone in the RT field did not develop fully. For many years, clinicians have avoided using RT for Wilms tumor owing to the very high risk of scoliosis as a side effect.

Image courtesy of Karen Goddard, MBChB, MA, FRCP(C), FRCP(UK).

National Wilms Tumor Study Group
The excellent outcomes for Wilms tumor are mainly due to the work of the NWTSG. Dr. Giulio D'Angio (cofounder) first expressed the concept that the aim of therapy should be not only to cure Wilms tumor but also to reduce the risk of long-term therapy-related toxicities. Five sequential trials (1969-2002) by multiple collaborators formed the standard of care. The results of the NWTS-V trial (shown) revealed superb outcomes in those with stage I-IV FH disease but inferior outcomes in those with LOH at chr 1p and 16q (both loci together) versus patients without LOH.^[18-20] In 2001, the NWTSG merged with other pediatric oncology cooperative groups to form COG (oversees North American pediatric renal tumor clinical trials). COG treatment strategies aim to build on the success of NWTS-V by improving relapse-free periods and overall survival while decreasing long-term toxicity. By improving patient risk stratification, targeting of therapy intensity to recurrence risk may be improved.^[16] Current COG trials stratify patients on the basis of a tumor's genetic signature and its response to initial chemotherapy.

Table courtesy of David Dix, MBChB, FRCPC, FAAP.

Treatment of Wilms tumor is one of the great success stories in pediatric oncology, but there is still progress to make. One of the most important aims of COG and SIOP is to discover and develop new biologic markers to help stratify patients into risk-appropriate treatment groups. For patients with FH Wilms tumor, who have excellent outcomes, therapy must focus on reducing the late effects of treatment. For patients who continue to have poor outcomes, including patients with anaplastic histology tumors (ie, UH) and recurrent Wilms tumor, an important goal of future research will be to identify novel agents for disease control.^[16]

Image courtesy of David Dix, MBChB, FRCPC, FAAP.