OVERVIEW: What every practitioner needs to know

Wilms tumor (WT) is the most common childhood renal tumor, accounting for about 6% of all childhood malignant disease. Approximately 500 new cases are diagnosed in North America each year. The majority of cases (> 80%) are diagnosed in children less than 5 years of age, with nearly equal distribution between males and females.

The survival of WT patients has improved dramatically over the past few decades, making WT an excellent example of successful cooperative management of a malignant tumor using multi-modal therapy.

Are you sure your patient has Wilms tumor? What are the typical findings for this disease?

The most common clinical presentation of WT is that of abdominal distension or an abdominal mass, often discovered by the parents.

Abdominal pain is the presenting feature in approximately 20%-30% of patients, usually resulting from local distension or spontaneous intralesional hemorrhage. Rarely, there can be tumor rupture with signs and symptoms of an acute abdomen.

About 20%-30% of patients have hematuria, and about 25% of patients have associated hypertension. Some patients will present with fever.

What other disease/condition shares some of these symptoms?

The differential diagnosis for WT includes:

1) other abdominal neoplasms such as neuroblastoma or hepatoblastoma

2) other renal tumors such as renal cell carcinoma, clear cell sarcoma of the kidney, and malignant rhabdoid tumor

3) benign processes involving the kidney such as muti-cystic dysplastic kidneys or hematomas

In neonates and very young infants the majority of renal tumors are congenital mesoblastic nephroma (CMN) rather than WT, although WT may occur.

What caused this disease to develop at this time?

WT arises from clusters of embryonal kidney cells, called nephrogenic rests, that persist into childhood. In this sense, WT is a disorder of disrupted kidney development. Certain genetic conditions, such as WAGR syndrome and Beckwith-Wiedemann syndrome, are associated with persistence of nephrogenic rests. Because nephrogenic rests generally regress as individuals age, WT is most common in young children and is very uncommon during adolescence and adulthood.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A complete blood count, urinalysis and blood chemistry (including BUN, creatinine, liver transaminases and alkaline phosphatase levels) should be done in all cases. Acquired von Willebrand disease can occur in 1%-2% of patients, so some clinicians recommend pre-operative measurement of coagulation parameters (PT, PTT, von Willebrand factor antigen, ristocetin cofactor, and factor VIII levels).

Would imaging studies be helpful? If so, which ones?

Patterns of dissemination of WT can either be via local spread or hematogenous metastases.

Locally there can be invasion of the renal hilum, or penetration of the renal capsule into the perirenal tissues. Tumor thrombus can be seen in the small kidney blood vessels, the renal vein, and can extend up the vena cava into the right atrium. Local lymph nodes may also be positive for disease involvement.

The most common site of metastasis is the lungs, but metastases can also occur to the liver. Brain and bones can be involved but typically these are associated with clear cell sarcoma or rhabdoid tumor, and metastatic spread to these sites with favorable histology WT would be very unusual.

The presurgical evaluation of WT therefore includes an abdominal ultrasound (for assessment of blood vessels for flow and tumor thrombus), an abdominal/pelvis CT or MRI scan, and a CT scan of the lungs. The utility of a CT scan of the chest compared to a plain chest x-ray in the staging of WT patients has long been a source of debate. However, current treatment protocols of the Children’s Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP) require a CT scan of the lungs for decision-making regarding treatment staging.

For patients with clear cell sarcoma and rhabdoid tumor of the kidney, an MRI of the brain and a bone scan are required.

Confirming the diagnosis

The diagnosis of WT needs to be confirmed histologically. Approximately 80% of children with renal tumors have favorable histology Wilms tumor (FHWT). About 5%-10% have anaplastic histology WT (AHWT), and a further 5%-10% have other renal tumors. These include congenital mesoblastic nephroma, clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, and renal cell carcinoma which, although they occur more commonly in adults, can be seen in children of any age.

There are two main approaches to the diagnosis of WT. In North America, it is standard to perform immediate nephrectomy if feasible without excessive morbidity. In Europe and other parts of the world, it is standard to start chemotherapy for presumptive WT without biopsy (in patients > 6 months old) and resect the tumor after 4 weeks.

The advantage of the immediate nephrectomy approach is that it allows for histologic confirmation, biology studies on the tumor tissue, and accurate staging and lymph node assessment. The advantage of the delayed nephrectomy approach is that it decreases surgical complications such as spillage and enables pathologists to assess the histologic response to chemotherapy, which has prognostic value.

There are two staging systems for Wilms tumor that correspond to the timing of nephrectomy. The staging system established by the National Wilms Tumor Study Group (NWTSG) and now used by the COG reflects the stage before chemotherapy is given. The staging system established by SIOP reflects the stage after pre-operative chemotherapy.

The COG staging system is as follows:

Stage I – tumor confined to the kidney, the renal capsule is not penetrated by tumor, there is no tumor invasion of veins or lymphatics of the renal sinus and the tumor is resected completely.

Stage II – tumor penetrates the renal capsule or extends into local blood vessels, but is completely resected with negative surgical margins.

Stage III – tumor is not resected completely. This can occur by several means including the presence of gross residual disease before chemotherapy is given, local lymph node positivity, tumor rupture either pre-operatively or during surgery, peritoneal implants, positive surgical margins or piecemeal resection in which the tumor is transected during surgery. Tumors that are biopsied before nephrectomy are considered to be stage III.

Stage IV – tumors that are disseminated, i.e., have hematogenous metastases or lymph node involvement outside the abdomen. The most common sites of distant metastases are the lungs and the liver.

Stage V – bilateral disease affecting both kidneys.

If you are able to confirm that the patient has Wilms tumor, what treatment should be initiated?

The treatment of WT is one of the major success stories of pediatric oncology. The current treatment of WT includes three major modalities: surgery, chemotherapy and radiation therapy. The three main chemotherapy agents that are used are vincristine, dactinomycin and doxorubicin. Radiotherapy is given for patients with distant metastatic disease, or patients with local Stage III disease that was incompletely resected.

The standard of care in North America for pediatric renal tumors is based on successive studies conducted by the NWTSG between 1969 and 2002. Since then, the NWTSG merged with other pediatric cooperative groups to form the COG, which now oversees the conduct of large pediatric kidney tumor trials in the United States, Canada and several other countries.

The results of the NWTS-5 study showed that patients with Stage I through IV FHWT had excellent results. Results are summarized in Table I.

Patients with loss of heterozygosity (LOH) at chromosomes 1p and 16q (both loci together) had inferior outcomes compared to patients without LOH. Results for anaplastic WT and clear cell sarcoma of the kidney were less favorable, although improved compared to historical controls. The outcomes for malignant rhabdoid tumor were poor, although older age at diagnosis was associated with improved prognosis.

The recent COG trials have attempted to build on the success of NWTS-5. Treatment strategies were designed to continue to improve event -free (EFS) and overall survival (OS) while decreasing long-term toxicity for these patients. The over-arching intent of these studies was to achieve further risk stratification, with tailoring of intensity of therapy according to risk of recurrence.

Recently released results from these COG trials have demonstrated the following key findings:

Patients with stage I FHWT <550 grams had outstanding outcomes when treated with nephrectomy alone and no adjuvant therapy.
Patients with Stage IV FHWT with complete lung nodule response after 6 weeks of chemotherapy treated without lung irradiation (XRT) had event-free survival that was not statistically different compared to historical patients treated with XRT and the overall survival was 95%. This suggests that omission of lung XRT is an acceptable treatment approach for this patient subgroup.
Patients with Stage IV FHWT with an incomplete response lung response after 6 weeks of chemotherapy showed superior event-free and overall survival when treated with vincristine/dactinomycin/doxorubicin with alternating cycles of cyclophosphamide/etoposide (Regimen M) compared to the historical standard of vincristine/dactinomycin/doxorubicin (Regimen DD4A). Patients with stage III/IV FHWT with LOH at 1p/16q had improved event-free survival when treated with Regimen M compared to the historical standard Regimen DD4A.
The combination of vincristine/irinotecan is active against AHWT. Event-free survival for patients with stage II-IV diffuse AHWT was improved with vincristine/doxorubicin/cyclophosphamide/etoposide/carboplatin (and vincristine/irinotecan for stage IV) compared to historical patients treated without carboplatin and irinotecan. The toxicity of the newer regimen was higher, however.

Current treatment regimens used by the COG based on preliminary analysis of the most recent clinical trials are as follows:

-Stage I FHWT, age < 2 years old, tumor weight <550 grams: nephrectomy only

-Stage I/II FHWT: vincristine/dactinomycin x 19 weeks

-Stage III FHWT (without combined LOH at 1p and 16q): vincristine/dactinomycin/doxorubicin x 25 weeks, flank or abdominal radiation therapy

-Stage III FHWT (with combined LOH at 1p and 16q): vincristine/dactinomycin/doxorubicin/cyclophosphamide/etoposide x 31 weeks, flank or abdominal radiation therapy

-Stage IV FHWT (with complete chemotherapy-induced lung nodule response after 6 weeks): vincristine/dactinomycin/doxorubicin x 25 weeks, NO lung radiation therapy

-Stage IV FHWT (with incomplete lung nodule response after 6 weeks OR combined LOH at 1p and 16q): vincristine/dactinomycin/doxorubicin/cyclophosphamide/etoposide x 31 weeks, lung radiation therapy

-Stage I Focal or Diffuse Anaplastic Wilms Tumor: vincristine/dactinomycin/doxorubicin x 25 weeks, radiation therapy

-Stage II-IV Diffuse Anaplastic Wilms Tumor: vincristine/doxorubicin/cyclophosphamide/carboplatin/etoposide x 30 weeks, radiation therapy; consider adding irinotecan for stage IV

-Stage II-IV Focal Anaplastic Wilms Tumor: vincristine/dactinomycin/doxorubicin x 25 weeks, radiation therapy

-Stage I-IV Clear Cell Sarcoma: vincristine/doxorubicin/cyclophosphamide/etoposide, radiation therapy for stage II-IV

-Stage I-IV Malignant Rhabdoid tumor: no standard of care; many physicians use ifosfamide/carboplatin/etoposide alternating with vincristine/doxorubicin/cyclophosphamide, radiation therapy

Importantly, pediatric oncology patients should only be treated in tertiary care pediatric centers with established pediatric oncology programs. SIOP has outlined the minimum requirements for a pediatric oncology center, and these requirements include a full time pediatric oncologist and availability of specialists including surgeons, pathologists, infectious disease experts and nurses.

In addition, whenever possible, patients should be on a research study. Research studies are devised by multidisciplinary teams of experts in the field, and not only provide the opportunity to advance the field, but also have shown that outcomes are superior for pediatric oncology patients enrolled in research studies.

What are the adverse effects associated with each treatment option?

The treatment of WT is associated with toxic effects, some of which occur early, while others occur months or years later. Long-term deleterious effects include:

1) Cardiac: Survivors of advanced stage WT are recognized to be at increased risk for congestive heart failure (CHF), due to toxicity from anthracycline chemotherapy (doxorubicin) as well as radiation to the chest. The cumulative risk for CHF in this group of patients is estimated to be 4.4% at 20 years.

2) Pulmonary: Patients with lung metastases who have received pulmonary radiation are at risk for the development of lung fibrosis. Previous studies have shown that, on average, patients who have received 12 to 14 Gy to their lungs have less than 70% of their predicted FVC. The risk for lung damage is additionally increased in patients who have undergone thoracotomies.

3) Second Malignancies: In the NWTS studies, the cumulative risk of second malignant neoplasm (SMN) at 15 years was 0.6%-1.5%. The risk is associated with doxorubicin, alkylating agents, and radiation therapy. Types of SMNs include bone and soft tissue sarcomas, leukemias and lymphomas. A recent study showed a cumulative risk of breast cancer at age 40 years of 15% in female WT survivors who received lung radiation therapy.

4) Renal: Renal insufficiency is uncommon in unilateral WT treated on standard protocols.

5) Fertility/Pregnancy: Female Wilms tumor survivors who received flank radiation had an increased risk of hypertension complicating pregnancy, fetal malposition, threatened labor, preterm delivery, and having infants with low birth weight. Very few pregnancies have been reported in individuals who received whole abdomen radiation.

Long-term follow-up of all patients with WT is therefore mandatory.

What are the possible outcomes of Wilms tumor?

N/A

What causes this disease and how frequent is it?

The vast majority of WT occur sporadically, although about 10% of patients have congenital anomalies that suggest a genetic predisposition to cancer. Approximately 1% of patients have another family member (immediate or distant) with WT.

Rare WT predisposition syndromes have assisted in the identification of genes involved in tumorigenesis, including the WT1 gene on chromosome 11p13 (associated with WAGR, Denys-Drash and Frasier syndromes) and the IGF2/H19 locus on chromosome 11p15 (associated with Beckwith-Wiedemann syndrome). Other genes that have been associated with genetic predisposition to Wilms tumor include DICER1 (DICER1 predisposition syndrome), PALB2 and BRCA2 (Fanconi Anemia Type D1), BUB1B (mosaic variegated aneuploidy), REST, CTR9, GPC3/4 (Simpson-Golabi-Behmel syndrome), NSD1 (Sotos syndrome), NF1 (Neurofibromatosis 1), TP53 (Li-Fraumeni Syndrome), DIS3L2 (Perlman syndrome), CDC73 (Hyperthyroid-jaw tumor syndrome) and BLM (Bloom syndrome). In addition, two familial Wilms tumor loci have been identified and designated as FWT1 (chromosome 17q) and FWT2 (chromosome 19q), but the relevant genes have not been identified.

Other genes appear to be involved in the progression to more aggressive WT, including the combined loss of heterozygosity (LOH) at chromosomes 1p and 16q, gain of chromosome 1q, and mutation of TP53. High telomerase RNA expression has been noted to be associated with recurrence in WT with favorable histology.

Several case-control studies have identified environmental exposures that may contribute to WT development, but these studies were small and require validation.

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

Although most patients with WT do well, approximately 10%-15% experience relapse. Most recurrences occur within two years of diagnosis, and favorable prognostic features after relapse include relapse within 12 months after diagnosis, favorable histology, relapse as a solitary pulmonary nodule, primary treatment with only two drug therapy (vincristine, dactinomycin), and relapse outside of the primary radiation field.

The approach to treatment of recurrent WT includes using chemotherapy agents that were not given as part of the initial chemotherapy protocol.

For patients who received vincristine/dactinomycin as original therapy, treatment of recurrent disease with vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide resulted in a 4-year overall survival rate of 81%.

For patients who received vincristine/doxorubicin/dactinomycin plus radiation as initial therapy, treatment of recurrent disease with cyclophosphamide/etoposide alternating with carboplatin/etoposide resulted in a 4-year survival rate of 48%.

Another commonly used combination for recurrent disease is ICE (ifosfamide, carboplatin, etoposide).

Recent studies have shown that topotecan and irinotecan are active agents.

Some physicians treat high-risk recurrent Wilms tumor with high-dose therapy and autologous stem cell rescue, but it is not clear whether this provides a benefit compared to other modern treatment regimens. A randomized study to answer this question has not been done.

What complications might you expect from the disease or treatment of the disease?

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

How can Wilms tumor be prevented?

N/A

What is the evidence?

Dome, JS, Graf, N, Geller, JI. “Advances in Wilms Tumor Treatment and Biology: Progress Through International Collaboration”. J Clin Oncol.. vol. 33. 2015 Sep 20. pp. 2999-3007.

Dome, Jeffrey S., Perlman, Elizabeth J., Graf, Norbert. “Risk Stratification for Wilms Tumor: Current Approach and Future Directions ASCO 2014 Educational Book”.

Kalapurakal, JA, Dome, JS, Perlman, EJ. “Management of Wilms' tumour: current practices and future goals”. Lancet Oncol. vol. 5. 2004. pp. 37-46.

Grundy, P, Breslow, N, Li, S. “Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable- histology Wilms tumor: a report from the National Wilms Tumor Study Group”. J Clin Oncol. vol. 23. 2005. pp. 7312-21.

Dix, David B., Gratias, Eric J., Seibel, Nita. “Omission of lung radiation in patients with stage IV favorable histology Wilms Tumor (FHWT) showing complete lung nodule response after chemotherapy: A report from Children’s Oncology Group study AREN0533”. J Clin Oncol. vol. 33. 2015.

Dix, David B., Fernandez, Conrad Vincent, Chi, Yueh-Yun. “Augmentation of therapy for favorable-histology Wilms Tumor with combined loss of heterozygosity of chromosomes 1p and 16q: A report from the Children’s Oncology Group studies AREN0532 and AREN0533”. J Clin Oncol. vol. 33. 2015.

Fernandez, CV, Perlman, EJ, Mullen, EA, Chi, YY, Hamilton, TE, Gow, KW, Ferrer, FA, Barnhart, D, Ehrlich, PF, Khanna, G, Kalapurakal, J, Bocking, T, Huff, V, An, Q, Geller, JI, Grundy, PE, Anderson, JR, Dome, JS. “Clinical outcome and biological predictors of relapse following nephrectomy only for Very Low Risk Wilms tumor (VLR WT). A report from Children’s Oncology Group AREN0532”. Annals of Surgery. 2016.

Ongoing controversies regarding etiology, diagnosis, treatment

Although the treatment of WT is one of the greatest success stories in pediatric oncology, there still remains progress to be made. In order to improve outcomes for patients with favorable histology disease, novel molecular and biologic markers are needed to help stratify patients into risk appropriate treatment groups. For patients with AHWT and certain non-Wilms renal tumor (notably renal cell carcinoma and malignant rhabdoid tumor), novel treatment strategies are needed because survival is suboptimal with current treatment regimens. One of the most important aims of the COG and SIOP is to discover and develop new molecular and biologic markers.

Even with the success of Wilms tumor treatment, there remain controversies and unanswered questions. Some of the common questions that arise are as follows:

1. Are CT scans necessary for the initial tumor staging, or do chest x-rays suffice? If CT scans are performed, should there be size or number cut-offs for lung nodules to define metastatic disease?

2. Are CT scans necessary for surveillance after completion of therapy, or do chest x-rays and abdominal ultrasounds suffice?

3. Is it ideal to remove the tumor up-front, or is it better to give chemotherapy first?

4. Is abdominal radiation therapy needed for all patients who receive pre-operative chemotherapy when treated with COG treatment regimens?

5. Is high-dose chemotherapy with stem cell rescue superior to conventional-dose chemotherapy in the treatment of recurrent WT?

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