All About Wilms' Tumor
What is a Wilms' Tumor?
Wilms' tumor (WT) is also known as nephroblastoma, is a cancer that starts in the kidneys. It is named after Max Wilms, the physician who first described this disease. Wilms' tumor is the most common cancer of the kidneys in children. The tumor usually only affects one kidney (unilateral WT), but can involve both kidneys (bilateral WT) in about 5%of cases. In some cases, there is more than one tumor in the same kidney (called multicentric). Each year about 500 new cases are diagnosed in the United States.
Who gets Wilms' Tumor?
Both boys and girls can be affected, with girls having a slightly higher risk. Wilms’s tumor is also more common in African Americans. Average age of diagnosis is 3 -4 years old.
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. Wilms is thought to result from accidental loss of certain parts of DNA, known as tumor suppressor genes. These genes are responsible for regulating cell growth. When these suppressor genes are lost, there is an overgrowth of kidney cells, which results in a cancer (tumor) forming in the kidney. There have been several tumor suppressor genes that have been linked with wilms tumor, including WT1, WT2, and P53, among others.
The accidental loss of this DNA or gene 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". It is not clear exactly what triggers these genes to be deleted and there are no known causes of WT (like anything that a child or mother could have been exposed to). Because each person has 2 copies of each gene, 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.
Only about 1% of WTs are "familial" or 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.
About 10% of WT cases are associated with other medical problems and together these medical problems are called syndrome. Examples are the WAGR syndrome, which includes Wilms Tumor, Aniridia, (eyes without the irises, or colored parts), Genitourinary malformations (such as genital or kidney deformities), 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 that has been associated with WT is Denys-Drash syndrome. People with Denys-Drash syndrome have kidney disease, ambiguous genitalia, and WT.
Are all Wilms' Tumors the same?
Not all Wilms’ tumors are the same. The two main types of WT are favorable histology (FH), 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 (cell changes seen with a microscope) 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 the aggressiveness of the tumor. WT may be metastatic or have spread to other areas of the body, including the lung and the liver, which will be evaluated for if WT is diagnosed.
What symptoms does a Wilms' Tumor cause?
Most kids present with an abdominal mass which is often large enough to be felt. The child may or may not have abdominal pain from pressure, bleeding, or bowel rupture secondary to the growing mass. Other possible symptoms include fever, nausea, lack of appetite, difficulty passing stool, blood in the urine (hematuria), and difficulty breathing. 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 syndromes mentioned 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?
Once a WT is suspected, the medical workup starts with a thorough history, including family history and a physical examination. Imaging tests will be ordered.
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 and whether the tumor has spread into the blood vessels of the kidney. Abdominal CT scan 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 the chest is used to determine if the disease has spread to the lungs. MRI, bone scans and lab tests may also be ordered. At the time of surgery to remove the tumor a biopsy will also be done.
How are Wilms' Tumors staged?
The most commonly used staging system for Wilms’ tumor is the Children’s Oncology Group staging system.
Stage I: 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.
Stage II: 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: The visible tumor can not be completely removed with surgery, and there is tumor left behind. The cancer may have spread to lymph nodes in the abdomen or pelvis.
Stage IV: Disease has spread outside of the abdomen via the blood, also called 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: Tumor in both kidneys at initial diagnosis.
Instead of stage, your doctor may discuss your risk group, which helps to guide treatment (very low, low, standard, higher, or bilateral). These risk groups are based on the stage of the tumor, the age of the patient, the weight of the tumor, the histology of the tumor and some of the genetics of the tumor (Loss of Heterozygosity or LOH). See the chart at the end of this article for more detailed information on the classification of risk groups.
How are Wilms' Tumors treated?
In general, pediatric cancers are rare compared to adult cancers and compared to other, non-cancer pediatric diseases. Because this cancer is rare, many of the current treatment modalities are the result of years of research and clinical trials. Children with Wilms’ Tumor will be cared for by a multidisciplinary team of care providers which may include a surgeon, an oncologist and a radiation oncologist. The three types of treatments include surgery, chemotherapy, and radiation.
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.
Patients with very large or extensive tumors that cannot 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, doxorubicin. etoposide and cyclophosphamide. Not all medicines may be used for everyone. For example in some early stage WT only vincristine and actinomycin may be used after surgery. Mesna may be used, which is not a chemotherapy drug, but is a medication used to protect the bladder wall from the harmful effects of the chemotherapy cyclophosphamide.
There is a very limited role of radiation therapy in the treatment of WT and is restricted largely to treating symptoms caused by widespread, Stage IV 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 drugs dactinomycin or doxorubicin should not be administered during radiation therapy, as this can worsen the side effects of the radiation (also called "radiation recall").
Risk group-specific Treatment Guidelines
Very low and low risk Favorable Histology Wilms' Tumor
Nephrectomy (removal of the kidney) with lymph node sampling and chemotherapy with vincristine and dactinomycin.
Standard risk Favorable Histology Wilms' Tumor
Nephrectomy (removal of the kidney) with lymph node sampling, abdominal irradiation, and chemotherapy with vincristine, doxorubicin, and dactinomycin.
Higher risk favorable histology Wilms' Tumor
Nephrectomy (removal of the kidney) with lymph node sampling, abdominal and lung irradiation, and chemotherapy with vincristine, doxorubicin, and dactinomycin.
Unfavorable Histology Wilms Tumor
Is treated with nephrectomy and different chemotherapy medication schedules, which may include: Cyclophosphamide, carboplatin, and etoposide, vincristine, doxorubicin, and irinotecan.
Bilateral Wilms' Tumor
In general, biopsy does not need to be performed if the diagnosis is certain based on imaging. Chemotherapy is given based on the histology and stage first.
Next, the patient is reassessed with imaging and a surgery is planned between week 6 and 12 of treatment with plan for additional chemotherapy after that.
Follow Up and Long-term Effects
After treatment is finished, your child will have a plan for follow up care, based on the initial stage and histology of the tumor. At first, the visits with their physician will be frequent, but as time passes, there will be more and more time in between visits. These visits may include blood tests and radiology scans. It is important to continue to be seen by a primary care provider who has information about the cancer treatment, and can follow your child for any long term concerns in conjunction with the oncology team.
There are several side effects associated with both radiation and chemotherapy that can occur months to years after treatment, often called "late effects". These include the risks of damage to the heart, liver, lungs, and kidneys, as well as decreased height due to decreased growth of the bones of the spine. Research has found that childhood cancer survivors are at higher risk for chronic health conditions than those who have not had cancer. It is important for survivors to incorporate healthy lifestyle behaviors, such as exercise, healthy diet, not smoking and regular medical and dental care, to reduce their risk of these chronic health concerns.
Having one functioning kidney can raise concerns for damage to or a decrease in the functioning of the kidney and high blood pressure, as the kidney regulates blood pressure. The remaining kidney can also be damaged with treatment. Children treated for WT may be at increased risk for developing second cancers. This risk depends on the intensity of their therapy and certain genetic factors. These patients should be followed life-long by a survivorship clinic in cooperation with a primary care provider.
References & Further Reading
Wilms Tumor – The American Cancer Societty
Wilms Tumor – St Jude Children’s Research Hospital
Al-Hussain, Turki, Afshan Ali, and Mohammed Akhtar. "Wilms tumor: an update." Advances in anatomic pathology 21.3 (2014): 166-173.
American Cancer Society. Wilms Tumor. 2016. Found at: https://www.cancer.org/cancer/wilms-tumor.html
Friedman AD. Wilms tumor. Pediatrics in Review. 34(7):328-30; discussion 330, 2013 Jul.
Lankadeva, Yugeesh R., et al. "Loss of a kidney during fetal life: long-term consequences and lessons learned." American Journal of Physiology-Renal Physiology 306.8 (2014): F791-F800.
National Cancer Institute. Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ). 2016. Found at: https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq#link/_23_toc
Oeffinger, Kevin C., et al. "Chronic health conditions in adult survivors of childhood cancer." New England Journal of Medicine 355.15 (2006): 1572-1582.
Termuhlen, Amanda M., et al. "Twenty?five year follow?up of childhood Wilms tumor: A report from the Childhood Cancer Survivor Study." Pediatric blood & cancer 57.7 (2011): 1210-1216.