State of the Art Oncology in EuropeFont: aaa

Wilms tumour – 2015

UPDATED OCTOBER 2015

1. General information

1.1 What is the disease and how is it treated?

What is Wilms tumour?
Wilms tumour (WT), also called nephroblastoma, is a rare childhood cancer of the kidney.

What are the causes of the disease?
Wilms tumour is caused by gene mutations, most of which are unknown. Some mutations can be favoured by exposure to agents such as pesticides before birth (during pregnancy) or right after, or even by parental exposure to these agents before conception.

Is it a frequent disease?
No, it is rare, but nonetheless it is the most frequent kidney cancer in children and teens, accounting for approximately 90% of renal tumours below 15 years of age.

How is it treated?
Wilms tumour is treated with surgery, to remove the entire affected kidney or just the tumour, and chemotherapy. In selected cases radiotherapy is added.

2. What is it, how does it occur, how is it diagnosed?

2.1 What is Wilms tumour?

Wilms tumour, also called nephroblastoma, is a rare childhood cancer of the kidney. Despite being rare, it represents the most frequent renal tumour in children and teens, accounting for approximately 90% of the cases below 15 years of age.
It generally occurs as a large, well-delimited mass in the kidney. Most often it affects only one kidney (unilateral disease) but in about 5% of children it affects both kidneys (bilateral disease). In 7% of children there are two or more tumour masses in the same kidney (multicentric disease).

2.1.1 Microscopic features and nomenclature

When WT is discovered, it can be described with various terms according to its microscopic appearance: it is called of monophasic, biphasic, or triphasic type depending on the presence or absence of three different kinds of tumour tissue, called blastema, epithelium, and stroma. However, this is only a descriptive classification that does not change treatment choices or prognosis, at least when it is recognized in untreated tumours.
On the contrary, an important feature that can be present in cancer tissue is anaplasia: a transformation of malignant cells that lose their normal features as kidney cells and revert to a more primitive form, usually dividing rapidly and acquiring an abnormal appearance. Seven per cent of WTs show anaplasia (anaplastic WT). Anaplasia can be restricted to a limited area (focal anaplasia) or be extensive within the tumour (diffuse anaplasia) and usually occurs in children older than 3 years. Anaplastic WTs tend to be more resistant to conventional therapies, require stronger treatments, and have a worse prognosis. Wilms tumours without anaplasia are therefore usually termed “favourable-histology” WTs, while those with anaplasia are described as having “unfavourable-histology”.
It must be noted that if the tumour is treated with chemotherapy before being removed, its microscopic appearance can change, and the way it reacts to therapy is important to distinguish low-risk, intermediate-risk, and high-risk tumours, and predict the possible outcomes (the nomenclature and risk categories for these pre-treated tumours have been established by the International Society of Paediatric Oncology (SIOP), see Table 1 in the Professional area).
Another feature that can be present is known as “nephrogenic rests”: remnants of the embryonic kidney cells that persist after the 36th week of pregnancy instead of becoming mature kidney cells. Nephrogenic rests are found in 30%-45% of kidneys with WT and signal a higher risk that the opposite kidney may also be affected by WT or could develop one later on.

2.1.2 Disease stats

Wilms tumour is rare. According to the RARECAREnet project, a network that follows rare cancers in Europe (http://www.rarecarenet.eu/rarecarenet), there are on average 600 new cases of WT a year in Europe. The peak incidence occurs between 2 and 3 years of age, with 95% of children being diagnosed before the age of 10. Girls are more affected than boys.
For the period 2000-2007, the incidence rate of WT in the overall European population was 1.3 cases per million persons per year, but among children the incidence rate was 7 cases per million children per year. The incidence increased slightly in the period 1978-1997, but in a later period (1995-2007) it did not change significantly.
In Europe (EU27), at the beginning of 2008, about 18,150 living people had received a diagnosis of WT in their lifetime. Slightly less than 10,000 of them (54%) had survived more than 15 years after diagnosis; they are usually considered cured of their cancer.
In 2012, 132 deaths for kidney cancer were estimated in European children.

2.2 Risk factors

As WT often appears at an early age, it is likely favoured by environmental factors such as exposure to particular substances before birth (during pregnancy) or just after birth (in the postnatal period), and even by parental exposure to those environmental agents before conception.
The most relevant factors known to increase the risk are maternal or paternal exposure to pesticides during pregnancy or before conception, maternal hypertension during pregnancy, and high birth weight (over 4,000 grams).
Other factors seem to increase the risk according to some studies, but their role is less clear. Among them are paternal exposure to hydrocarbons and metals during various periods, fathers exposed to chemicals while working as welders or mechanics, prenatal ionising radiation from diagnostic x-rays during pregnancy, and childhood exposure to pesticides.
Other potential risk factors have been considered, but there is no clear indication that they might have a role (e.g., maternal consumption of coffee and tea or use of hair dye or certain drugs during pregnancy).
A small proportion of WT cases appear to be heritable, presumably due to mutated genes transmitted from parents to children, and some genes involved in the disease are being identified. Approximately 1.5% of patients in a large series had one or more family members (siblings or cousins) with WT.
Though most WTs appear in otherwise healthy children, a few cases develop in children with congenital disorders and genetic conditions that increase the risk of WT (these are rare disorders that cause several congenital malformations and other symptoms, such as Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome, Perlman syndrome, Denys-Drash syndrome, and WAGR syndrome).

2.3 What are the symptoms?

Most children with WT are brought to medical attention because of abdominal swelling or the presence of an abdominal mass. Renal masses may also be discovered unexpectedly during routine clinical examination or during medical procedures (see abdominal ultrasound) performed for other causes.
Abdominal pain, gross haematuria, or fever are other possible signs at diagnosis (but in the vast majority of cases these symptoms are not due to cancer). High blood pressure is present in about 25% of patients.

2.4 Diagnosis

When a renal mass is detected, the doctor will perform further examinations to establish if it is due to a benign or malignant condition. The doctor will thoroughly review the patient’s clinical history and perform a physical examination, which may reveal additional signs or symptoms to aid in the diagnosis.
A non-renal cancer called neuroblastoma, or benign processes such as polycystic kidney disease, renal abscess, or hydronephrosis, may produce clinical and radiographic findings similar to the ones produced by renal tumours.
Renal tumours are rare in children and include a spectrum of pathologies that require different managements and treatments. Besides WT, the most common malignant paediatric renal tumours are clear cell sarcoma of the kidney, rhabdoid tumour of the kidney, mesoblastic nephroma, and renal cell carcinoma.
To distinguish between these different diseases, the doctor will usually obtain a histological diagnosis, through nephrectomy, or with a biopsy in those cases in which chemotherapy is planned before nephrectomy. However, there are cases in which the radiological exams are sufficient to reveal WT and the biopsy might be omitted.
If a renal tumour is suspected, diagnostic imaging studies will be performed to evaluate the extent of disease and plan surgery or monitor the response to therapy.
The initial radiographic study is an abdominal ultrasound examination. Either contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen is often performed to further evaluate the nature and extent of the mass. This examination helps in adequate planning of surgery and may reveal if small tumours are present in the other kidney.
Despite thorough clinical and radiographic evaluation, some renal masses will remain indeterminate, and their management is subject to individual clinical opinions. A multidisciplinary approach, including the paediatrician, paediatric radiologist, paediatric surgeon, paediatric oncologist, and pathologist, is essential to the evaluation of these patients.
WT most commonly metastasizes to the lungs, followed by lymph nodes and liver, and the presence or absence of metastases, too, should be evaluated with imaging studies.

3. How is Wilms tumour treated?

3.1 General information

Wilms tumour is usually treated with surgery, to remove the affected kidney or, in rare cases, just the tumour, and chemotherapy[the use of drugs that destroy or slow the growth of cancer cells]. Sometimes radiotherapy[the use of high-energy rays to destroy cancer cells] is added to further kill malignant cells that have spread (metastases).
Chemotherapy can be performed after the surgery, to kill residual cancer cells, or initiated before the surgery (pre-operative chemotherapy) to shrink the tumour, and continued afterwards. Pre-operative chemotherapy can shrink the tumour, making it easier to remove it with fewer complications, reduce the risk of tumour rupture during surgery, and make the tumour regress to a less advanced stage (see below 4 “Stages of Wilms Tumour”), so that less chemotherapy is required after surgery and the prognosis improves. Also, how the tumour changes in response to preoperative chemotherapy is important to distinguish low-, intermediate-, and high-risk tumours, in order to decide further treatments and predict the possible outcomes (see Table 1 in the Professional area).
During the last three decades, several national and international cooperative groups have conducted many sequential studies on treatment for children with WT. Among these groups are the North American Children’s Oncology Group (which performed the National Wilms Tumor Study, http://www.nwtsg.org); the International Society of Paediatric Oncology (SIOP); the United Kingdom Children’s Cancer and Leukaemia Group; and the Italian Association of Paediatric Haematology and Oncology. These groups conducted several extensive trials to find the best therapies for different kinds of patients, according to the characteristics of the disease and its response to first treatments.
The combinations of drugs, their mode of administration, duration of treatments, and the use of radiotherapy have been refined, intensifying the therapy provided for high-risk patients and decreasing or modifying the therapy for low-risk patients, to get the best balance between efficacy and side effects. So the doctor will choose the best combinations of drugs and other treatments for each patient considering several factors, including favourable or unfavourable histology due to the presence of anaplasia (see above 2.1.1), tumour staging, patient’s age and response to chemotherapy. Recently some gene mutations have also been indentified that might help to better assess the risk in some patients.

3.2 Surgery

Surgery is a crucial part of treatment for renal tumours, to remove the primary tumour in the kidney and analyze the cancerous tissue to establish the tumour stage.
Radical nephrectomy[removal of the entire kidney] is the usual choice for most patients. To ensure optimal outcome, it is important to remove the tumour without rupture or spill (which increases the risk that some cancerous cells may spread and the disease may recur in nearby tissues). It is also important to determine if the tumour spread in the nearby abdominal areas. For this reason, a biopsy of the regional lymph nodes (small glands present all over the body where malignant cells that spread from the original cancer can be found) is usually performed.
After surgery, the one remaining kidney will usually be enough to filter the blood without problems for the whole life. The risk of failure of the remaining kidney has been evaluated in a large group of successfully treated children with unilateral WT without congenital syndromes, and it is 0.7% (only seven children in 1,000 developed renal failure).
In patients with bilateral disease a more limited surgery, which removes only the tumours, sparing a part of the unaffected kidneys (partial nephrectomy), is performed whenever possible.
Partial nephrectomy can also be preferred in some children with unilateral tumour, especially if they have disorders increasing their risk of renal failure or recurrence of WT in the remaining kidney, but it is still not clear in which cases this is the best choice.

3.3 Chemotherapy and radiotherapy

Regardless of the timing of chemotherapy (before or after surgery), three drugs are highly effective for WT: vincristine, actinomycin-D, and doxorubicin.
Two-drug chemotherapy (vincristine plus actinomycin-D) is used for stage I or II tumours. Doxorubicin and radiation therapy are added when the disease is more advanced, in stages III and IV (see below 4 “Stages of Wilms Tumour”).
Only a minority of high-risk tumours (see Table 1) needs adjunctive drugs such as etoposide, carboplatin, and either cyclophosphamide or ifosfamide.
Radiotherapy is used only in selected cases, mainly when there is residual tumour tissue after surgery (e.g., because not all malignant tissue could be removed) or the tumour has spread nearby or to other body parts.
Pulmonary radiotherapy can be performed in patients in which lung metastases are present when WT is discovered, but currently it is usually omitted if lung metastases disappear rapidly and completely after preoperative chemotherapy.

3.4 Bilateral disease

In 5-7% of patients both kidneys are simultaneously affected by WT (bilateral disease). In these patients the treatment presently recommended is initial chemotherapy. Response should ideally be evaluated after at least 6 weeks of double-agent chemotherapy (with vincristine and actinomycin-D) to determine whether the tumours shrank enough to allow a limited surgery to remove the tumours while preserving a substantial amount of normal renal tissue (partial nephrectomy), instead of removing the entire kidney.
If further tumour reduction is required, additional courses of the same chemotherapy regimen can be administered before surgery. It is under discussion whether adding additional drugs might allow a higher rate of kidney-sparing surgical procedures.
After surgery, chemotherapy should be continued in relation to tumour stage and features.

4. Stages of Wilms tumour

Staging is currently one of the most important prognostic indicators for WT. The staging system is summarized in Table 1 (see Table 2 in Professional area for a complete description).

 Table 1. Staging system for Wilms tumour.
STAGE CHARACTERISTICS
I Tumour confined to the kidney and completely removed after surgery
II Tumour extends beyond the kidney but is completely removed after surgery
III Gross or microscopic residual tumour tissue remains in the nearby area after surgery
IV There are metastases (tumour cells that spread) outside the abdomen (e.g., lung, liver, bone, brain)
V Wilms tumour is present in both kidneys (bilateral WT)

5. Prognosis

5.1 General information

Prognosis indicates the likelihood that treatment will be successful. It is a statistical measure obtained from different studies that observe the progress of the disease in a high number of patients. It is important to remember that these statistics merely provide an indication: no doctor is able to predict exactly what the outcome of treatment in an individual patient will be, nor how long the patient will live, as prognosis depends on several factors, in relation with the individual patient.

5.2 Prognosis of Wilms tumour

The prognosis for children with WT has improved dramatically as the result of advances in treatments, careful pre- and post-operative management, anaesthesia, and supportive care. Children who are 0-2 years old at diagnosis have a more favourable prognosis than those diagnosed later. For example, five-year survival from WT for children diagnosed in all Europe in 2005-2007 was 90%, ranging from 94% in Central Europe to 84% in Eastern Europe.

5.3 Prognostic factors

The recognized prognostic factors in children with WT are disease stage and tumour histological features (i.e., the microscopic structure of tumour tissue).
Advanced tumour stage at the time of diagnosis leads to an increased risk of recurrence and mortality (see above section 4, «Stages of Wilms tumour»).
The most important histological predictor of response and survival in untreated WT is the presence of diffuse anaplasia (see above 2.1.1). Children with stage II to IV WT with diffuse anaplasia have a worse prognosis. In stage I, when anaplastic tissue is completely removed by surgery the outcome is more favourable. Recent studies showed that analysis of some gene mutations (in a gene called TP53) might improve risk evaluation in diffuse anaplastic WT, as patients with these mutations seem to have an increased risk of recurrence and death, while those without these mutations should have a more favourable outcome.
Other genetic abnormalities seem to cause more aggressive tumours, with an increased risk of relapse and death, even in patients with a favourable histology, but their relevance is still being evaluated.
A further prognostic factor is response to drugs. According to how the tumour tissue changes in response to preoperative chemotherapy, it is possible to distinguish low-, intermediate-, and high-risk tumours, which require different treatments and have different prognosis (see Table 1 in the Professional area).
Finally, children less than 2 years old at diagnosis have a better outcome.

6. What to do after treatment

6.1 Late sequelae

Generally, late complications of WT are a consequence of treatment and depend on its type and intensity. The use of radiotherapy and drugs belonging to the group of anthracyclines, such as doxorubicin, increases the risk of these complications. Significant late sequelae that may occur in survivors include cardiac toxicity, reproductive problems, musculoskeletal effects, renal dysfunction, and the development of second malignant tumours.
Heart failure is the most common late effect of doxorubicin and can occur many years after treatment. Among participants in an old, extensive series of studies (the National Wilms Tumour Studies), the cumulative incidence of congestive heart failure was 4.4% 20 years after diagnosis for those who received doxorubicin as part of their initial therapy, and 17.4% among patients who received doxorubicin for a relapse. Female sex, cumulative doxorubicin dose, and radiation therapy received on the left flank (where the heart is) were significant risk factors for congestive heart failure. It must be noted that cardiac toxicity largely depends on the drug’s total cumulative dose. Severe heart dysfunction has not been detected in survivors receiving a total dose under a defined threshold (less than 250 mg/m2) and current protocols recommend this dose as the limit. A regular echocardiogram is usually performed to check for heart problems in survivors treated with doxorubicin.
Fertility and pregnancy outcome are both compromised in females receiving abdominal radiotherapy in which both ovaries or the uterus are within the treatment field. Male fertility is generally not at risk.
Renal impairment is rare in patients in which one kidney has been removed, as the remaining kidney is usually sufficient for normal renal function. Life-long evaluation of renal function is recommended only for children with conditions known to predispose to renal dysfunction.
The type and distribution of second cancers following WT suggests that patients treated with radiotherapy are at greater risk than those not given radiation. Among participants in the National Wilms Tumour Studies, the risk of a second malignant cancer was 1.6% 15 years after diagnosis. These patients should be appropriately counselled about their risk and offered, whenever available, surveillance to achieve early diagnosis. A recent analysis from the National Wilms Tumour Studies database showed that female survivors of WT who were treated with chest radiotherapy had a high risk of developing early breast cancer, with nearly 15% developing invasive disease by age 40.

6.2 Follow-up

Although no studies have been carried out to evaluate the most effective schedule to follow-up patients treated for WT, the aim of an organized follow-up programme are:

  • detection of relapse at a stage at which a new treatment has the best chance of efficacy;
  • monitoring and treating therapy-related toxicities;
  • early diagnosis of a new WT in children who may be predisposed to such an event;
  • detection of secondary malignancies.

Most relapses (about 90%) occur in the first 2 years after diagnosis and the remainder in the next 2 years. The first site of relapse is the lung, so chest radiograph must be performed routinely at regular intervals until approximately 5 years post-diagnosis.
Children with WT-predisposing syndromes or with nephrogenic rests (see above) require longer and closer abdominal follow-up, because the remaining kidney(s) continue to be at risk for several years.
A recommendation for follow-up of patients treated for WT has been drafted by the Italian Association of Paediatric Haematology and Oncology, and is as follows:

  • clinical examination and chest x-ray every 2 months during treatment and in the subsequent first year after the end of treatment, every 3 months in the second year, every 4 months in the third year, every 6 months in the fourth year;
  • post-operative abdominal ultrasound every 4 months in the first 2 years, every 6 months in the third year then yearly;
  • in stage III patients, abdominal ultrasound should be performed every 2 months during the first year, every 3 months in the second year, every 4 months in the third year, then yearly;
  • echocardiogram at the baseline, then for several years for patients treated with doxorubicin and/or whole lung radiotherapy;
  • pulmonary function test at the baseline, then for several years for patients treated with whole lung radiotherapy.

 7. What to ask the doctor

Here is a list of questions that you might wish to ask your doctor or any specialists you may consult. To avoid unnecessary concern, it is useful to ask about any doubts you might have, no matter how small they may appear.

General questions

  • What leaflets, books, or websites could I read to learn more about WT?
  • Is there a patient association or online support group I could contact?
  • How will the disease and treatments interfere with school and playing?
  • Should my child pay special attention to activities such as playing or sports?
  • Do you have special advice regarding nutrition?
  • Is there any contraindication regarding vaccinations?
  • Does WT run in families? Are my other children at risk of getting WT?
  • How can I help my child to remain serene?
  • Can you refer me for counselling?

Diagnosis and exams

  • What tests are you going to do?
  • What are you looking for?
  • Is biopsy painful? Is it performed under general or local anaesthesia?
  • How long will the exam take?
  • Will the child be asleep?
  • Are CT or MRI dangerous because of radiation exposure?
  • How long will it take to confirm diagnosis?

Treatment

  • Do I need a highly specialized centre for my child? Which is the centre with the highest expertise in my country to treat this disease? Are there more specialized centres abroad?
  • Is the histology of the tumour favourable or unfavourable?
  • What is the cancer stage, and what does that mean?
  • What type of treatment is needed?
  • Is there any choice of treatments?
  • What is the outlook for cure?
  • What are the options if the first therapy doesn’t work?
  • Are there any clinical trials we might want to consider?
  • What are the risks and benefits of the treatments?
  • How long will treatment last? Where will it be done?
  • Will treatment reduce symptoms and discomfort?
  • What are the possible side effects of therapy? Will my child lose his/her hair, or have nausea and vomiting?
  • How can I help to reduce the side effects?
  • During treatment should I take special precautions or change some habits?
  • Which supportive therapy is suggested during treatment?
  • How will treatment affect my child?
  • What late effects could treatment have?
  • Will treatment affect my child’s growth, future sex life, or ability to have children?
  • What is the risk of further kidney problems?
  • Could WT recur?