Wilms’ Tumor

Background and Incidence

Wilms’ tumor is a cancer of childhood that arises in the kidney. It is made up of cells that originate from immature tissue. Approximately 500 new cases are seen in the United States each year, representing slightly more than 10% of all cases of childhood cancer.

Most cases are diagnosed between the ages of 1 and 4 years. Wilms’ tumor can occur in older children, however, and occasionally can be detected in adolescents or young adults.

Although most Wilms’ tumors occur spontaneously, certain genes may also be related to its occurrence. The first gene (WT1, also called Wilms’ tumor suppressor gene) has been found to make a protein that is found mostly in the fetal kidney and in tissues that give rise to the genitourinary system. This protein is essential for normal kidney and gonad (ovary, testicle) development. Inactivation of the gene may be responsible for the occurrence of Wilms’ tumor.

WT1 was found when the link between a set of developmental abnormalities (aniridia [lack of an iris in the eye], genitourinary malformations, and mental retardation known as the WAGR syndrome) and an increased risk for the development of Wilms’ tumor was made (See Table 1). In addition to the lack of WT1 and its association with Wilms’ tumor in the WAGR syndrome, an abnormal form of this gene has been identified in children with the Denys-Drash syndrome. This syndrome comprises abnormalities of the ovaries/testicles, kidney failure, and Wilms’ tumor.

A second site for a gene associated with Wilms’ tumor (WT2) has also been identified. This site was identified in association with Beckwith-Wiedemann syndrome (an overgrowth syndrome including enlarged abdominal organs, enlarged tongue, and low blood sugar), a second syndrome associated with Wilms’ tumor (See Table 1)

TABLE 1: Wilms’ Tumor: Associated Findings

Beckwith-Wiedemann syndrome
(enlarged abdominal organs, enlarged tongue, low blood sugar)

Denys-Drash Syndrome
(ovary/testicle anomalies, kidney failure, Wilms’ Tumor)

WAGR Syndrome
(lack of an iris, genitourinary abnormalities, mental retardation)

Hemihypertrophy (enlarged body parts on one side)

Genitourinary abnormalities

Positive family history

11p13 deletion

Clinical Presentation

The average age at presentation for Wilms’ tumor is 3 years. Wilms’ tumor is relatively uncommon in the first 3 months of life; however, one third of all cases are seen between 6 and 12 months of age. Although Wilms’ tumor is rare after 8 years of age, it may still occur in older children, adolescents, and occasionally young adults.

Wilms’ tumor usually presents with a large, round, smooth, and firm abdominal mass that often is detected by a parent while bathing the infant or child or on a routine well-baby examination in the pediatrician’s office. The mass is usually nontender.

The tumor can grow rapidly, which may result from bleeding into the tumor or from actual tumor growth. Blood in the urine may be seen in 10% to 15% of cases, often after relatively minor trauma related to injury of an enlarged kidney involved by tumor. Evaluation leads to the unsuspected finding of a Wilms’ tumor.

Occasionally, masses can be felt on both sides of the abdomen if Wilms’ tumor involves both kidneys. Small amounts of blood in the urine may be noted in almost 20% of cases. Loss of appetite, fever, and weight loss may be observed in 10% to 15% of patients. Increased blood pressure may be present in 20% of cases.

The tumor also rarely may be a site of erythropoietin production which is the hormone responsible for increasing the number of red blood cells in the blood stream. Laboratory tests are usually otherwise normal except in rare instances in which the bleeding and clotting tests are normal.

Figure 1: Computed tomography scan of an infant with a large kidney mass (arrows). The normal kidney tissue is shown to the right of the Wilms’ tumor arising within the kidney (arrow head, white-colored structure).

Diagnostic Evaluation

Evaluation of the site and extent of tumor involvement can be accomplished quickly with a few carefully chosen tests. A plain abdominal radiograph often shows displacement of abdominal organs and occasionally the presence of calcification (<10%). The calcification usually is located on the edge of the tumor whereas with a neuroblastoma the calcification is speckled throughout.

Abdominal ultrasound is sometimes performed and can confirm that the kidney is the site of the tumor; determines whether the mass is a cystic (fluid-filled) or solid tumor (Wilms’ tumor appears primarily as a solid mass); and indicates if the tumor extends into the veins exiting the kidney and going back to the heart: the renal vein, inferior vena cava, or right atrium.

The next diagnostic test obtained is a computed tomography (CT) scan of the abdomen. (See Figure 1).

CT scan shows the tumor within the kidney, often with a rim of normal kidney tissue around the edge and distortion of the urine collecting system of the kidney and displacement of the kidney toward the center of the body.

In contrast, a neuroblastoma (another childhood tumor that may sometimes be confused with Wilms’ tumor on CT scan) rarely affects the urine collecting system and generally indents or pushes on the kidney tissue rather than being surrounded by it. Neuroblastoma pushes the kidney downward (if it arises from the adrenal gland) or to the side (if it arises from the area next to the spine).

CT scan also defines the Wilms’ tumor as being within the kidney; identifies the presence of enlarged and suspicious lymph nodes; evaluates the possible presence of a second Wilms’ tumor in the opposite kidney; assesses involvement of the tumor into the veins leaving the kidney and going back to the heart (renal vein, inferior vena cava, right atrium), and determines if the patient has spread of tumor to the liver.

A chest CT is obtained to evaluate for the presence of tumor spread to the lungs. These studies detect the most common sites of tumor spread: lymph nodes, lung, and liver. A CT scan cannot determine whether the tumor can be removed, however, because this can be assessed accurately only at the time of surgery.

If, after surgery, the “clear cell” variant of Wilms’ tumor is present on pathology, a bone scan is obtained to look for spread to bone. Spread to the bone is unusual for other types of Wilms’ tumors. If the “rhabdoid variant” is present, a CT scan of the head should be done to look for evidence of spread to the brain.

Arteriograms (injection of dye into the arteries so that they can be seen on x-rays) are rarely helpful in the preoperative evaluation of Wilms’ tumor, and for most patients this test is rarely necessary. Magnetic resonance imaging (MRI) may be of help in patients with suspected inferior vena cava or right atrial tumor or in patients with Wilms’ tumor on both sides.

The role of ultrasound to evaluate infants and children with a risk for Wilms’ tumor (Beckwith-Wiedemann syndrome, hemihypertrophy (enlarged legs or arms on one side), aniridia (lack of an iris in the eye), WAGR syndrome, Denys-Drash syndrome, and prior Wilms’ tumor is unclear. In the 1980s and 1990s, studies showed a shift toward identification of lower stage tumors in these patients, suggesting that screening is successful in identifying these children at earlier stages of disease. What has not been proved is that this identification increases overall survival rates.

Screening does increase the proportion of children in whom the tumor can be removed while keeping part of the kidney. Current recommendations are for ultrasound every 3 months until 6 to 8 years of age. For children with Beckwith-Wiedemann syndrome and hemihypertrophy, the adrenal glands and liver should be evaluated in addition to the kidney because this group is also at risk for liver tumors (hepatoblastoma) and neuroblastoma.

Pathologic Variants

Within the group of tumors called Wilms’ tumors, there are different types that have an important impact on the prognosis. These different types have differing levels of aggressiveness of the tumor, patterns of spread and recurrence, and response to therapy. Therapy is now based on the type of tumor and the stage of the tumor. Wilms’ tumors are divided into favorable types and unfavorable types. Fortunately, favorable types form 89% of the cases, whereas unfavorable types occur in 11% of cases. Tumors with favorable types respond to standard therapy and have a favorable prognosis. A cystic variant of Wilms’ tumor has an extremely favorable prognosis.

Unfavorable type tumors are sub-grouped further into anaplastic (4.4%), clear cell (4%), and rhabdoid (2.3%) histology (appearance under the microscope) (See Table 2).

TABLE 2: Wilms’ Tumor: Unfavorable Histology (11%)
Histology (%)	Relapse (%)	Mortality (%)
Anaplastic (4.4)	55	45
Clear cell (4.0)	23	77
Rhabdoid (2.3)	90	86

Anaplastic tumors are rare in children younger than age 2 years. Clear cell tumors (clear cell sarcoma of the kidney [CCSK]) are seen mostly in males and tend to spread early to multiple bones, particularly the skull. The rhabdoid tumor is seen commonly in children younger than age 2 years and may occur in both kidneys as well as in areas outside of the kidney. This tumor has the worst prognosis of all.

Staging

The treatment of patients in North America with Wilms’ tumor is primarily based on results of a series of studies from the National Wilms Tumor Study Group (NWTSG). This study group is about 40 years old and now is part of the Children’s Oncology Group (COG-more recently named CureSearch). Through the results of studies performed by NWTSG, treatment for Wilms’ Tumor has been improved and is based on surgical staging and radiology evaluation for spread of disease.

The surgical stage is determined by whether the tumor was removed completely with a margin of surrounding normal tissue, preoperative or operative rupture of the tumor, and whether tumors are present in both kidneys (Table 3 and Figure 2). In the NWTSG studies, review of the tumor has been performed by a central pathology center. The classification of the type of Wilms’ tumor is more crucial in defining the prognosis and treatment of the tumor than is the stage of the disease.

Figure 2: Incidence of various stages and types of tumor in 1439 patients enrolled in the third NWTSG study. Stage V cases are omitted from the graph and account for 6% of cases. FH = favorable type; UH = unfavorable type

TABLE 3: Wilms’ Tumor Staging

I Tumor on one side without growth through the capsule (outer lining) of the kidney or lymph node involvement. The tumor is completely removed without tumor spill

II Tumor on one side with growth through the kidney capsule, or the tumor is stuck to local surrounding structures, without lymph node involvement. The tumor is completely removed without tumor spill

III Tumor on one side with nearby lymph node involvement, preoperative tumor rupture, significant intraoperative tumor spill, incomplete removal, or tumor biopsy only

IV Spread to lung, bone, brain, liver or distant lymph node involvement

V Tumors in both kidneys

Operative Management

Operative management of Wilms’ tumor includes a carefully planned, well-monitored removal of the kidney under general anesthesia. The procedure is typically performed through an incision across the upper abdomen two fingerbreadths above the belly button. The incision must be large enough to examine both kidneys and to remove the tumor without tumor rupture. A back incision is not adequate to achieve these goals. It is important to avoid tumor spill because this carries an increased risk of intra-abdominal tumor recurrence. (Figure 3) Rarely if the tumor is large and involves the upper part of the kidney and elevates the diaphragm, a combined chest and abdomen incision may be needed.

Figure 3: A Wilms’ tumor before removal (arrows).

If the tumor is too large, extends too far into the vena cava or right atrium, or involves too many other organs to be removed safely, a biopsy should be done, and chemotherapy can than be performed for a number of weeks to reduce the size of the tumor. Removal of the tumor is almost always successful at a second operation after this.

The management of Wilms’ tumor in both kidneys must be individualized according to the extent of tumor present in both kidneys with a goal to preserving adequate kidney tissue to avoid kidney failure. The initial procedure should be biopsies of both kidneys to establish the types in both kidneys. Approximately 4% of cases have different types between the two kidneys.

The patient is treated with chemotherapy and restudied by abdominal CT to evaluate tumor response and determine whether a surgical procedure would be beneficial. If considerable tumor persists in both kidneys, additional chemotherapy is administered, and further surgery is delayed. Radiation therapy is withheld if possible in these cases to reduce the risk of radiation injury to the remaining kidney tissue.

In some patients, the tumor persists in both kidneys, and resection of the tumor with preservation of functioning kidney tissue is not possible. The only remaining option for these rare patients ultimately is removal of both kidneys. Their subsequent care includes peritoneal dialysis or hemodialysis and chemotherapy for approximately 1 year before attempting a renal transplant, but this rarely happens.

Treatment and Prognosis

After surgical removal, treatment depends on tumor stage and type and may involve chemotherapy or a combination of chemotherapy and radiation therapy. Response of favorable types of tumors to therapy has been good, with recent results showing 2-year survival without return of the tumor at the following rates: stage I/favorable type, 94.9%; stage I/anaplastic, 87.5%; stage II/favorable type 85.9%; stage III/favorable type 91.1%; stage IV/favorable type 80.6%; and stages I through IV/CCSK, 84.1% (See Figure 4).

Figure 4: Two-year survival without the Wilms’ tumor returning in patients with Wilms tumor based on stage and tumor type (NWTS-4). FH = favorable type; CCSK = clear cell sarcoma of the kidney.

Therapy for the unfavorable type tumors is more intense in terms of the chemotherapy used because of the poor response to standard therapies. If an anaplastic tumor is completely resected and considered stage I, the outcome is similar to stage I infants with a favorable type of tumor. In more advanced stages, however, anaplastic tumors have a poor outcome. Recent results showed that children with anoplastic tumors had 4-year survival by stage as follows: stage II, 55%; stage III, 45%; and stage IV, 47%. CCSK has shown an improved response to more intense therapy.

Infants and children with rhabdoid tumors have aggressive disease, typically with much tumor spread, and frequently die early (within 1 to 2 years—90% tumor return rate and 86% mortality) despite intense multi-drug chemotherapy. Recurrence in all Wilms’ tumors is associated with significant mortality. In favorable type cases in which the cancer comes back, therapy achieves overall survival in approximating 50% of cases, and in unfavorable cases, survival is much less. The current overall survival for all patients with Wilms’ tumor is 80%. If only patients with favorable type tumors are considered, the survival rate is 90%.

An alternative treatment program in patients with stage III and IV tumors uses preoperative chemotherapy and is used routinely in Europe according to protocols developed by the International Society of Pediatric Oncology. The concept is to shrink the tumor, making the removal easier and safer to perform, thereby reducing the rate of rupture and tumor spill at the time of the operation.

A major problem in evaluating the true benefit of preoperative chemotherapy is that the staging is less clear since it is done by CT scan studies rather than by surgery. Thus, it is possible that some of the chemotherapy given pre-operatively could have been avoided after determining a lower stage at surgery. Also, there may be more instances of tumor return in the area where the kidney had been with this approach than with removal followed by chemotherapy.

The role of radiation therapy in patients with Wilms’ tumor has changed over the years. Because of the frequency of late side effects (i.e., heart failure, lung scarring, and second cancers), radiation therapy currently is only used for certain stages and types of Wilms’ tumor.

Another special circumstance is when tumor extends into the large veins (renal, inferior vena cava, right atrium), which occurs in 4% of cases. Removal of both the kidney and the tumor in the vein is performed when feasible. The level of tumor in the vein is an important preoperative consideration. Of those tumors that do involve the large veins, the distribution is as follows: cava below the liver [61%], cava behind the liver [14%], inferior vena cava above the liver [21%] or right atrium [4%] (See Table 4).

TABLE 4: Wilms’ Tumor: Vena Caval Involvement
Caval Site	%
Below the liver	14
Above the liver	21
Right atrium	4

Although heart-lung bypass has been used successfully by surgeons to remove the tumor in the vein safely from the right atrium and pulmonary artery, more recent studies (as mentioned earlier) have suggested that preoperative chemotherapy can shrink the tumor in the vein and decrease the complications of the surgery. This approach has been recommended by the NWTSG for patients with extensive caval or right atrial involvement. The level of tumor involvement in the veins does not affect survival. The overall survival for infants and children with tumor vein involvement was 88%, 89%, and 62% for stages II, III, and IV. The key indicators for survival in these cases are stage and tumor type.

The management of Wilms’ tumor in both kidneys must be based on two goals: first, to obtain complete removal of the tumor and, second, to preserve kidney tissue to avoid renal failure. As mentioned earlier, current recommendations include initial biopsy on both kidneys, preliminary chemotherapy, avoidance of radiation, and delayed removal of the tumors to achieve maximal decrease in their size allowing preservation of kidney tissue. In many cases, extensive involvement of at least one kidney prevents successful preservation of any kidney on that side.

In a relatively large group of stage V (Wilms’ tumor in both kidneys) patients, the 3-year survival was 76%. Most patients have favorable type tumors (90%) that respond well to therapy. Of tumors in both kidneys, 10% are unfavorable types, and 4% have favorable types on one side and unfavorable types on the other. This latter observation supports the recommendation that biopsy specimens of both kidneys must be obtained.

The best prognosis in stage V disease is in patients younger than 3 years old, with favorable types, no lymph node involvement, and a low stage for the most advanced of the two kidneys. The frequency of chronic renal failure has decreased in Stage V Wilms’ tumors as therapies have improved. In recent studies, only 3.8% of the children developed chronic renal failure. It is believed that the overall decline is related to delay in removal of the tumor and attempts at kidney tissue preservation. The value of chemotherapy in preserving kidney tissue has been confirmed by the United Kingdom Children’s Cancer Study Group.

Based on the successful outcome in selected stage V patients after partial kidney removal, partial kidney removal has been suggested as an alternative to total kidney removal in patients with stage I tumors in only one kidney.

The criteria for partial kidney removal includes a tumor involving only the top or bottom of the kidney and which occupies less than one third of the kidney; no evidence of invasion of the urine collecting system or renal vein; and clear margins between the tumor, kidney, and surrounding structures. In an evaluation of 43 potential cases, only met these criteria. This suggests that a small proportion of patients would be candidates for this type of therapy, and it would be difficult to determine any benefit for the procedure in view of the excellent survival rate achieved for stage I cases after standard removal of the kidney (95%).

Some studies have reported the use of preoperative chemotherapy to decrease the size of the tumor and increase the number of patients in whom such kidney-sparing procedures can be performed. The risks and benefits of this approach in the patient without disease in both kidneys have not been established, and the incidence of chronic renal failure in the NWTSG patients who had one kidney removed was extremely low (0.25%).

A review concerning late effects of cancer treatment seen in earlier survivors at 5- to 10-year follow-up indicated that 1% of patients developed a second cancer, 7% developed a non-cancerous tumor, scoliosis (curvature of the spine) was increased in survivors that received radiation, there was no increased risk of psychological disorders in children receiving vincristine, and there was no major increase in heart disorders after treatment with doxorubicin. The incidence of kidney failure has declined as treatment has improved.

New studies hope to identify genetic factors that would predict tumor behavior.

MESOBLASTIC NEPHROMA

Mesoblastic nephroma (renal embryoma) is a kidney tumor that usually presents in infants younger than 3 to 4 months of age. The tumor is from embryonal (developing embryo) tissue of the kidney and may sometimes be detected on prenatal ultrasound. The mass is solid (made of tissue rather than fluid). An abdominal CT scan shows a solid tumor that occasionally contains calcium with a deformed urine collecting system. The treatment of choice is kidney removal with some of the lymph nodes. A rare case may behave in a malignant fashion. More than 95% of mesoblastic nephromas are benign (non-cancerous) and require no additional therapy.
NEPHROBLASTOMATOSIS
Nephroblastomatosis (nodular renal blastema) is a precancerous (but benign) condition with nests of primitive “nephrogenic” tissue or “nests” around the rim of the kidney. This condition may involve both kidneys. The nephrogenic rests may go away spontaneously or, alternatively, may progress to Wilms’ tumor. 94-99% of bilateral Wilms’ tumors contain areas of nephrogenic rests. The risk of a nephrogenic rest becoming malignant (cancerous) is estimated to be 1% to 3%.

RENAL CELL CARCINOMA

Renal cell carcinoma is a relatively rare condition in children. The disease usually presents in older children and adolescents. The most common finding is an abdominal mass. Blood in the urine is a frequent finding. Diagnosis is achieved by ultrasound, which shows a solid kidney mass. Abdominal CT confirms the presence of a kidney mass often with distortion of the urine collecting system.

The most common sites of tumor spread are the lymph nodes in the area of the tumor, lung, liver, and bone. The therapy of choice is removal of the kidney and sampling of the lymph nodes. Chemotherapy is not effective for this tumor. Trials of immunotherapy and bone marrow transplantation are in progress for patients with tumor spread. Although renal cell carcinoma is less responsive to radiation than Wilms’ tumor, radiation may provide some help in patients with remaining disease or inoperable tumors. The overall survival is 50%.

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