|Neha Vapiwala, MD and Eric Shinohara, M.D., MSC I|
| Last Modified: February 25, 2008
What is a Wilms' Tumor?
Wilms' tumor (WT) is also known as nephroblastoma, a medical word that basically means an embryonic ("blast") tumor ("oma") of the kidney ("nephro"). It is named after Max Wilms, the physician who first described this disease. Wilms' tumor represents about 6% of all childhood cancers. Overall, it is the fourth most common tumor of childhood, and is the most common pediatric tumor of the abdomen. The tumor usually only affects one kidney (unilateral WT), but can involve both kidneys (bilateral WT) in up to 4-8% of cases.
How common is Wilms' Tumor?
There are just under 500 new cases of WT yearly in the United States .The rate of new cases is 8.1 for every million Caucasian children less than 15 years of age.
Who gets Wilms' Tumor?
As mentioned above, WT is a cancer of children, ie: a pediatric cancer. Both boys and girls can be affected, with girls having a slightly higher risk. Girls have an approximately 10% higher risk of developing WT. Girls are also 70% more likely to have both kidneys involved compared with boys. The median age at time of diagnosis is 37 months in boys -- about 3.1 years old -- and 43 months in girls -- almost 4 years old. This is for unilateral WT. In cases of bilateral WT, the median ages are younger, about 24 months for boys and 31 months for girls. More than 75% of all WT is diagnosed before the age of 5 years and 95% prior to the age of 10 years.
Interestingly, WT is about 3 times more common among African-American children compared to East Asian children. The rates for Caucasian kids, both in the United States and in Europe, fall somewhere in between.
What causes Wilms' Tumor?
In normal human development, each person has an entire set of paired chromosomes; one half of the pair is from the mother and the other half is from the father. Each chromosome is further divided into smaller sections called genes, which contain a person's unique DNA, or "genetic code". This code is used to build very important proteins in the body. WT is thought to result from accidental loss of certain genes known as tumor suppressor genes. As their name implies, these genes code for a very special set of proteins which are vital in regulating growth and in preventing uncontrolled, excessive multiplication of human cells. The loss or deletion of tumor suppressor genes can result in a cell being unable to control its growth. The unregulated cell growth results in a tumor, or cancer. There have been several tumor suppressor genes which have been linked with WT, including WT1, WT2, and P53, among others. As long as one copy of these tumor suppressor genes is normal, enough tumor suppressor protein can be made to prevent uncontrolled growth. However, if both copies of the gene are defective, the person may develop WT.
The loss or deletion of genetic information that leads to WT happens early during development, typically before birth. A majority of the cases are "sporadic", meaning that WT does not "run in the family", but occurs because both copies of a tumor suppressor gene (mother's and father's) are somehow deleted. It is not clear what exactly triggers and leads to the gene deletions in the first place.
Remember, both copies of a tumor suppressor gene have to be missing to develop WT. If only one copy of the gene is missing, a person is a carrier of the mutation, but does not necessarily have the disease.
In contrast to the sporadic cases, about 10-13% of WT cases are associated with a congenital syndrome, (a group of developmental abnormalities that are present at birth). Among these are the WAGR syndrome, which includes WT, Aniridia, (eyes without the irises, or colored parts), Genitourinary malformations (such as genital or kidney deformities) and mental Retardation, and the Beckwith-Wiedemann syndrome, which is marked by abnormally large body size and overgrown abdominal organs. There is about a 30% chance of developing WT in people with WAGR syndrome, and a 6% chance of developing WT in people with Beckwith-Wiedemann syndrome. Another syndrome which has been associated with WT is Denys-Drash syndrome. People with Denys-Drash syndrome have progressively advancing renal disease, ambiguous genitalia, and WT. There are even rarer genetic disorders such as Perlman syndrome and Soto’s syndrome that are associated with WT. From studying patients with these congenital syndromes, researchers have discovered two different genes whose loss can lead to WT (WT1 and WT2 as mentioned above). Furthermore, there are likely to be other WT genes that haven't even been identified yet, and so not every WT patient has the same exact missing gene. Finally, a small percentage of Wilms' tumor cases are familial (about 1 to 2%), meaning they "run in the family". In these patients, either the mother or the father carries a gene deletion, and then passes this on to the child. The child is thus born with only one copy of the gene, and if that is somehow deleted, he or she will develop WT.
Are all Wilms' Tumors the same?
No. The two main types of WT are favorable histology (FH), which makes up more than 80% of cases, and the less common unfavorable or anaplastic histology (UH). As one might expect from the names, the favorable WTs have a better prognosis than the unfavorable type. The amount of anaplastic histology that is present in the tumor is also important in determining treatment in WT. The classification is based on unique microscopic appearances that have been associated with degree of clinical aggressiveness. Younger children (less than two years old) tend to have a better prognosis. Recent research has suggested that there are certain mutations which predict a worse prognosis. One mutation causes a loss of heterozygosity (LOH) at 16q and 1p. This means that a portion of a chromosome has been lost, although the exact mechanism as to why this causes a worse outcome is still being studied. High expression of telomerase, a protein commonly elevated in cancers, has also been shown to be associated with a worse outcome.
What symptoms does a Wilms' Tumor cause?
The overwhelming majority of kids present with an abdominal mass, which may or may not be associated with abdominal pain from pressure, bleeding, or bowel rupture secondary to the growing mass. Other possible symptoms include fever (23%) and hematuria, or blood in the urine (21%). Less likely are things like high blood pressure, hernias, or heart failure. If WT is diagnosed at an advanced stage, it can present with disease that has spread (metastasized) to the lungs, which in some cases could cause respiratory symptoms. Additionally, any child with WT should be evaluated for abnormalities of the genitalia or urinary tract. They should also be carefully examined for any of the traits related to the genetic diseases mention above as WT may be part of a broader syndrome. Routine screening in people with genetic defects known to be associated with WT may be of benefit, however this is controversial.
How is Wilms' Tumor evaluated?
The medical workup of these tumors starts with a thorough history, including family history and a physical examination. Diagnostic imaging typically includes the following studies:
Abdominal ultrasound is usually the first test ordered to evaluate the kidneys. Doppler ultrasound can also be used to evaluate blood flow to the kidneys. Doppler is also used to evaluate whether the tumor has spread into the blood vessels of the kidney. Abdominal CT is also recommended to determine if there has been any spread to other organs as well and if there is any disease in the other kidney. CXR or CT scan of chest is used to determine if the disease has spread to the lungs..
How are Wilms' Tumors staged?
There are currently two widely used staging systems for WT, the National Wilms' Tumor Study (NWTS) and the International Society of Pediatric Oncology (SIOP). The NWTS system is used in United States and will be discussed here.
Stage I (~40% of patients)
Stage I WT is defined as tumor limited to the kidney and completely removed by surgery. The tumor is not ruptured at any time during the surgery. The blood vessels around the kidney are not involved with tumor. There is no remaining cancer visible beyond the area where the surgeon operates.
Stage II (~25% of patients)
Stage II WT is when tumor extends beyond the kidney but is completely removed by surgery. The extension beyond the kidney can be due to blood vessel involvement, local tumor "spillage" during surgical removal, or other nearby tumor extension. If there was a biopsy of the tumor, it is considered stage II. There is no remaining cancer visible at or beyond the area where the surgeon operated.
Stage III (~25% of patients)
Stage III WT is when all of the visible tumor can not be completely removed with surgery, and there is tumor left behind but only in the abdomen.
Stage IV (~10% of patients)
Stage IV WT is defined as disease that has spread outside of the abdomen via the blood, aka hematogenous metastases. The areas in the body where WT can spread include the lung, liver, bone, brain, or to a combination of these sites.
Stage V (5% of patients)
Stage V WT is the presence of bilateral renal involvement at initial diagnosis.
As mentioned above, the amount of anaplasia present in the tumor also affects how these tumors are treated, though this is not directly factored into the staging system.
How are Wilms' Tumors treated?
In general, pediatric cancers are rare compared to adult cancers and compared to other, non-cancer pediatric diseases. Given this fact, all children with WT should be considered for entry into a clinical trial. Treatment should involve a multidisciplinary team of cancer specialists, including a pediatric surgeon or urologist, a pediatric radiation oncologist, and a pediatric oncologist, all of whom have some experience in treating WT patients.
Extensive research in the treatment of WT has been done by the Wilms' Tumor Study Group, (WTSG), which is now part of the Children's Oncology Group (COG). Additionally, there have been several studies in Europe conducted by the International Society of Pediatric Oncology. The difference between the American and the European strategies for treating WT is that in American, upfront surgery is preferred whereas the Europeans favor chemotherapy prior to surgery. The findings of the four National Wilms' Tumor Studies (NWTS) conducted by the WTSG have helped establish the current treatment guidelines in the United States. These guidelines typically incorporate a combination of surgery, chemotherapy and, in some patients, radiation therapy.
General Treatment Modalities
The most important role of surgery is to entirely remove the tumor without rupturing it, and visually assessing the surrounding area for possible local disease spread. Total removal of the involved kidney, known as a radical nephrectomy, together with sampling, or "biopsy" of specific abdominal lymph nodes, is the surgical procedure of choice. Partial removal of the kidney is not currently recommended, although it may be an option for very small tumors that are incidentally found by an ultrasound performed for another reason. The contralateral kidney should be felt and visually inspected.
As in all cancer surgeries, any suspicious-looking area should be sampled. Special titanium surgical clips should be placed at the borders of where the surgeon removes the tumor (margins of resection). In most patients, surgical removal up front is possible, and should be pursued.
Patients with very large or extensive tumors that can not be feasibly and safely removed by surgery can be considered for preoperative chemotherapy. Prior to starting chemotherapy, a biopsy through the abdominal skin (percutaneously) should be performed to officially establish the diagnosis. Preoperative chemotherapy makes tumor removal easier and may reduce the frequency of surgical complications.
The chemotherapy drugs commonly used in WT patients are dactinomycin, vincristine, and doxorubicin. Less commonly used are etoposide and cyclophosphamide, which are usually used with vincristine and doxorubicin in children with a large amount of anaplastic tumor. In some early stage WT vincristine and actinomycin can be used alone after surgery. Mesna is not itself a chemotherapy drug, but is a medication used to protect the bladder wall from the harmful effects of the chemotherapy.
Newborns and all infants less than 12 months old need a 50% reduction in chemotherapy doses compared to doses given to older children. This is an effort to decrease the chemotherapy toxicity seen in children of this age group studied in the NWTS studies while not compromising the overall efficacy of the treatment.
There is a very limited role of radiation therapy in the treatment of WT (about 25 to 30% of patients will require radiation), and is restricted largely to treating symptoms caused by widespread, Stage IV disease, (ie: palliation of metastatic disease).The use of radiation as part of the definitive treatment of non-Stage IV patients is discussed below in the stage-specific subsections. Of note radiation should generally begin within 9 days of the surgery to minimize the risk of disease spread. Radiation may be delivered either to the flank where the tumor was or it may be used to treat the entire abdomen. Reasons to treat the entire abdomen include rupture of the tumor either before or during surgery, if the tumor was very large or if there was diffuse involvement of the abdominal cavity with metastatic disease.
The chemotherapy drug dactinomycin should not be administered during radiation therapy, as this can worsen the side effects of the radiation, aka "radiation recall".
Children treated for WT are at increased risk for developing second cancers. This risk depends on the intensity of their therapy, including both chemotherapy (doxorubicin) and radiation therapy. Certain genetic factors also likely play a role, as these predisposed the child to get WT in the first place.
Stage-specific Treatment Guidelines
Stage I Wilms' Tumor
Favorable and Unfavorable Histologies: Nephrectomy with lymph node sampling and 18 weeks of chemotherapy with vincristine and single-dose (pulse-intensive) dactinomycin.
* It may be possible to treat a subset of stage I WT patients with just surgery, without chemotherapy. The COG is planning a large study to address this question.
Stage II Wilms' Tumor
Favorable Histology: Nephrectomy with lymph node sampling and 18 weeks of chemotherapy with vincristine and pulse-intensive dactinomycin.
Unfavorable Histology, focal anaplasia: Nephrectomy with lymph node sampling, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.
Unfavorable Histology, diffuse anaplasia: Nephrectomy with lymph node sampling, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.
Stage III Wilms' Tumor
Favorable Histology: Nephrectomy with lymph node sampling, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.
Unfavorable Histology, focal: Nephrectomy with lymph node sampling, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.
Unfavorable Histology, diffuse: Nephrectomy with lymph node sampling, abdominal irradiation, and 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.
Stage IV Wilms' Tumor
Favorable Histology : Nephrectomy with lymph node sampling, abdominal irradiation based on the local stage of the tumor, bilateral pulmonary irradiation for patients with chest x-ray evidence of pulmonary disease, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.
Unfavorable Histology, focal: Nephrectomy with lymph node sampling, abdominal irradiation based on the local stage of the tumor, bilateral pulmonary irradiation for patients with chest x-ray evidence of pulmonary metastases, and 24 weeks of chemotherapy with vincristine, doxorubicin, and pulse-intensive dactinomycin.
Unfavorable Histology, diffuse: Nephrectomy with lymph node sampling, abdominal irradiation, whole-lung irradiation for patients with chest x-ray evidence of pulmonary metastases, and 24 weeks of chemotherapy with vincristine, doxorubicin, etoposide, cyclophosphamide, and mesna.
Stage V Wilms' Tumor
In the past, the surgical approach to bilateral WT was removal of the kidney with the larger lesion. However, removing one kidney may lead patients with bilateral WT to kidney failure down the road. Besides, studies do not show any survival difference in children who undergo initial bilateral biopsy followed by chemotherapy and surgery later, as compared with patients who have the surgery upfront and chemotherapy later. Thus, the surgical goal should be to preserve as much of the kidneys as possible in order to minimize the risk of late kidney failure.
Bilateral biopsies and lymph node sampling should be performed first.
Next, 6 weeks of chemotherapy should be given, after which the patient is reassessed. If imaging studies show no further reduction in tumor size, a second-look surgery (partial nephrectomy) should be performed if negative margins can be obtained. Further chemotherapy should follow based on the surgical stage found on the second operation. Alternatively, if it is not possible to resect the disease at the time of the second surgery or if the tumor is incompletely resected, additional chemotherapy is considered.
The use of chemotherapy and/or radiation therapy after the second-look operation will depend on the patient's response to the initial chemotherapy. More aggressive therapy is needed for patients with little response to initial therapy, as documented by the second surgical procedure.
There are several side effects associated with both radiation and chemotherapy. These include the risks of damage to the heart, liver and lungs as well as decreased height due to decreased growth of the bones of the spine. There remaining kidney can also be damaged with treatment. There is also an increased risk of developing secondary cancers later in life.
Stage I Wilms' Tumor
Regardless of whether the histology is favorable or unfavorable, all stage I WT patients have an excellent prognosis.
For favorable histology (FH) patients, the 2-year relapse-free survival (RFS) is about 95%.This means that 95 out of every 100 Stage I WT patients have their disease goes away completely after treatment, and 2 years later are alive without any episodes of the disease returning.
For the unfavorable histology (UH) group, the 2-year RFS is about 87.5%, a little less than the favorable group, as expected, but still very high.
Stage II Wilms' Tumor
FH patients have 2-year RFS of 86% and a 2-year overall survival of 97%.1
UH patients have a 70% 4-year overall survival.
Stage III Wilms' Tumor
FH patients have a 2-year RFS of 91% and a 2-year overall survival of 98%.
UH patients have a 56% 4-year overall survival.
Stage IV Wilms' Tumor
FH patients have a 2-year RFS of 80.6% and a 2-year overall survival of 89.5%.
UH patients have a 17% 4-year overall survival.