Renal tumors account for 6.3% of the cancers found in children less than fifteen years of age. Wilms tumor (WT) is the most common primary renal tumor in childhood (91%) and the second most common abdominal tumor in children after neuroblastoma. Over the last fifty years survival for children with WT has improved dramatically. In both North American and European trials survival rates now approach 85% overall and 95 to 99% for many of the low stage tumors. The current risk based therapies for WT are based on a series of multidisciplinary cooperative trials by the Children’s Oncology Group (COG, formerly the National Wilms Tumor Study Group) and the Société Internationale d’Oncologie Pédiatrique (SIOP).
see also Nephrectomy for Wilms Tumor
Content in these topics is referenced in SCORE Wilms Tumor, Renal Cell Carcinoma, and Hemihypertrophy overview
Wilms tumor is associated with several congenital syndromes, some of which are also at risk for synchronous and metachronous tumors.
What is the incidence of Wilms tumor in the population?
The incidence of pediatric renal tumors in North America is 7.1 per million with approximately six hundred new cases annually. The risk of Wilms tumor (WT) in the general population is 1 per 10,000 with most children presenting between one and four years of age. The mean age at diagnosis is 2.5 years with WT occuring about six months later in girls than boys. Ninety percent of all WT are unilateral. The male to female ratio in the unilateral cases is 0.92:1.00 and for bilateral cases is 0.60:1.00 .
Which patients are at higher risk for developing Wilms tumor?
WT (especially anaplastic histology) is more common in African Americans and less common in the Asian population. There are several well defined congenital syndromes that have a higher risk of developing WT (see table below) accounting for approximately ten percent of all WT. Many patients with these congenital syndromes have a higher risk of synchronous or metachronous tumors, however most children with bilateral Wilms tumor do not have an underlying congenital anomaly. The risk of developing WT is significantly increased with antenatal maternal exposure to pesticides, high birth weight and preterm birth .
high risk ( greater than 20%)
WT1 deletions (including WAGR, 85% are unilateral)
WT1 mutations (truncating and missense mutations including Denys-Drash)
familial Wilms Tumor
Mosiac Variegated Aneuploidy
Fanconi Anemia D1/ Biallelic BRCA2 mutation
moderate risk (5 to 20%)
WT1 intron 9 splice mutations (Frasier syndrome)
Beckwith-Wiedemann Syndrome (85% unilateral)
Simpson-Golabi-Behmel syndrome caused by GPC3 mutations/deletions
low risk ( less than 5%)
hereditary hyperparathyroidism-jaw tumor syndrome
trisomy 18, trisomy 13, 2q37 deletions
Several genes have been associated with Wilms tumor and the genetic analysis of tumors has begun to guide therapy.
What is the current understanding of Wilms tumor carcinogenesis?
Wilms tumor (WT) is thought to arise from the clonal expansion of a nephrogenic rest (NR) . The mechanism is not completely elucidated but it is based on the Knudsen two hit hypothesis. NRs represent the presence of embryonic renal tissue beyond 37 weeks of gestation . Not all children with NRs will develop WT since a hyperplastic rest can follow two pathways. Most become dormant, regress and disappear. Other clones transform into WT. The risk of a rest developing into a WT decreases markedly after age eight.
While most WTs are a result of sporadic mutations, the well established associations of WT and congenital anomalies such as aniridia, Beckwith-Weidemann syndrome and hemihypertrophy have led investigators to candidate genetic loci . Several genes have been identified as having a role in the development of WT including p53 (a classic tumor suppressor gene), CTNNB1 (encoding β-catenin, a classic oncogene), WTX (a tumor suppressor gene) and Wilms tumor 1 (WT1) . WT1 is critical in the normal differentiation of various organs and loss or overexpression of this gene may lead to different phenotypic consequences depending on the status of cellular differentiation .
Genetic analysis of tumors from NWTSG have identified specific genetic mutations that have been incorporated into a risk based stratagem which directly impacts patient care. Loss of heterozygosity (LOH) at 1p/16q is a specific marker for increased risk of relapse in favorable histology WT. This finding was studied in the prospective, nonrandomized NWTS- 5 trial which established that combined LOH at both chromosomes 1p and 16q was an adverse prognostic indicator for all stages of WT. Although only occurring in five percent of patients, identification of LOH 1p/16q selectively targets these patients for intensification of treatment. (see Staging)
Subsequent analysis of subsets of very low risk tumors from NWTS-5 have demonstrated that WT1 mutation and 11p15 LOH are associated with relapse and this finding may be incorporated in future clinical trials. Recent COG data indicates that 1q gain occurs in approximately thirty percent of tumors and is a marker for tumor recurrence.
Patients with Wilms tumor have a local and disease stage based on histology, age, tumor extension or residual disease. Additional criteria include the response to therapy and molecular markers that determine risk based therapy.
What are the histopathological criteria that impact risk based therapy?
A combination of clinical, pathological, biologic and response to therapy factors impact staging and prognosis. These are constantly evolving based on new biologic discoveries and the results of clinical trials.
Based on histology , Wilms tumor (WT) is classified as either favorable (90%) or unfavorable (10%). Favorable histology tumors (FH) exhibit blastemal, stromal and epithelial elements while unfavorable tumors are anaplastic (AH). Patients with FH have a better overall survival by stage than any other group of WT patients. Anaplasia is a marker of resistance rather than tumor aggressiveness and is classified as diffuse or focal. Focal anaplasia has a better prognosis and different adjuvant therapy. It is also important to note that diffuse anaplasia cannot be diagnosed by a core or needle biopsy .
How are patients with Wilms tumor staged?
The tumor stage is determined by the extend of local and distant disease from the results of imaging, the surgical findings at nephrectomy and pathologic examination.
Two principle WT staging systems are utilized.
COG staging is based on pretreatment findings prior to administration of chemo- or radiotherapy. The local stage defines the extent of abdominal disease while the disease stage considers both the local extent of disease and distant metastasis. Both factors determine the treatment protocol with the use of radiation therapy to the tumor bed based on the local stage and the chemotherapeutic regimen based on the disease stage. Size alone is not a determinant of local stage and complete removal of a resectable WT may preclude the need for abdominal radiation even in the presence of Stage IV disease. A child may have a local stage I tumor and pulmonary metastasis for a disease IV stage. Treatment will be different than for a patient with a local stage III tumor and pulmonary metastasis.
tumor is limited to the kidney and has been completely resected
tumor was not ruptured or biopsied prior to removal
no penetration of the renal capsule or involvement of renal sinus vessels
tumor extends beyond the capsule of the kidney but was completely resected with no evidence of tumor at or beyond the margins of resection
penetration of the renal capsule or invasion of the renal sinus vessels
gross or microscopic residual tumor remains postoperatively including
inoperable tumor, positive surgical margins, tumor spillage, regional lymph node metastases, positive peritoneal cytology or transected tumor thrombus
tumor was ruptured or biopsied prior to removal
hematogenous metastases or lymph node metastases outside the abdomen (e.g. lung, liver, bone, brain).
bilateral renal involvement is present at diagnosis
each side is considered to have a distinct stage.
SIOP protocols recommend chemotherapy followed by nephrectomy with surgicopathologic staging occurring at the time of nephrectomy. Tumors are classified on SIOP protocols as completely necrotic (low risk tumor), blastemal (high risk tumor) or other histology (intermediate risk tumors).
tumor is limited to the kidney or surrounded with a fibrous pseudocapsule if outside the normal contours of the kidney
renal capsule or pseudocapsule may be infiltrated with the tumor but it does not reach the outer surface and it is completely resected
tumor may be protruding (bulging) into the pelvic system and dipping into the ureter, but it is not infiltrating their walls
vessels of the renal sinus are not involved
intrarenal vessels may be involved
tumor extends beyond the kidney or penetrates through the renal capsule and/or fibrous pseudocapsule into the perirenal fat but is completely resected
tumor infiltrates the renal sinus and/or invades blood and lymphatic vessels outside the renal parenchyma but it is completely resected
tumor infiltrates adjacent organs or vena cava but is completely resected
tumor has been surgically biopsied (wedge biopsy) prior to preoperative chemotherapy or surgery
incomplete excision of the tumor which extends beyond resection margins (gross or microscopic tumor remains postoperatively)
any abdominal lymph nodes are involved
tumor rupture before or during surgery (irrespective of other criteria for staging)
tumor has penetrated the peritoneal surface
tumor implants are found on the peritoneal surface
tumor thrombi present at resection margins of vessels or ureter transected or removed piecemeal by surgeon
hematogenous metastases (lung, liver, bone, brain)
lymph node metastases outside the abdominopelvic region
bilateral renal tumors at diagnosis
each side has to be substaged according to above classifications
Age and weight
Children less than two years in age and tumors weighing less than 550 grams have a lower risk than other patients if they are stage I.
Response to therapy
Children with pulmonary metastasis that respond within six weeks to three drug chemotherapy can avoid pulmonary radiation.
Loss of heterozygosity (LOH) refers to the loss of genetic material and allelic uniqueness . LOH has been found in children with WT on chromosomes 11p, 16q and 1p. Prior WT retrospective analysis suggested that these children had poorer outcomes independent of stage or histology than those without LOH. For the NWTS-5 study, LOH at chromosomes 11q, 16q and 1p were prospectively evaluated. The outcomes for patients with LOH at 16q and 1p were at least 10% worse than those without LOH. In the most recent COG studies, augmented therapies for LOH positive patients significantly improved overall and event free survival across all stages.
1 q gain was found in a review of children with WT from NWTS-4 and 5 to be a very strong predictor of relapse. This will be tested prospectively with treatment stratification based on the presence or absence of 1 q gain.
Although stage, histology, age (less or greater 24 months) and the loss of heterozygosity at 1p and 16q can often predict those patients at risk for relapse, these factors account for only one third of the patients who relapse and imply that other factors are involved in treatment failures. WT patients who relapse have a poor prognosis .
The majority of Wilms tumor (WT) patients present with an asymptomatic abdominal mass noticed by either a parent or pediatrician on a well child visit. Renal tumors can be found on routine screening in children with known predisposing clinical syndromes. Rarely a child with a tumor rupture or internal hemorrhage will present with a relatively acute onset of abdominal pain, distension and anemia. Varicocele is an unusual finding in this age group and its presence suggests venous obstruction due to tumor thrombus. Microscopic hematuria is found in up to 24% and gross hematuria in 18% of children with WT at presentation. Gross hematuria can be a warning sign of ureteric extension and the ureter should be carefully palapated at the time of nephrectomy.
In contrast to patients with neuroblastoma, constitutional symptoms such as fever, anorexia and weight loss are infrequent occuring in only ten percent of cases. Hypertension is present in twenty to 25% of cases and has been attributed to activation of the renin-angiotensin system.
What is the differential diagnosis of a pediatric renal mass?
renal cell carcinoma (adenocarcinoma)
cystic nephroma or cystic partially differentiated nephroblastoma
diffuse hyperplastic perilobar nephroblastomatosis
papillary renal cell carcinoma
clear cell sarcoma
cellular, classic, or mixed mesoblastic nephroma
metanephric tumor (adenoma, adenofibroma, atromal tumor)
ossifying renal tumor of infancy
renal medullary carcinoma
rhabdoid tumor of kidney
oncocytic renal neoplasms
renal tumors associated with TFE3 or TFEB translocations
What are the appropriate imaging studies to order in a child with a suspected Wilms tumor?
An ultrasound (US) is the best initial imaging choice for patients with a suspected renal mass. The US will help determine whether the tumor is of renal origin, what side the tumor is on and whether there is extension into the venous system. If a renal tumor is confirmed, a computerized tomography (CT) scan or magnetic resonance image of the abdomen and CT of the chest is obtained to assess the extent and stage of the disease.
A CT will confirm the renal origin of the mass and determine whether there are bilateral tumors. Wilms tumor (WT) typically appears on CTs as pushing normal renal parenchyma away producing a classic "claw sign" and tend to displace blood vessels whereas neuroblastomas usually show encasement.
About four percent of WTs present with inferior vena cava or atrial involvement and 11% with renal vein involvement. Embolization of a caval tumor thrombus to the pulmonary artery is a rare but potentially lethal event. The presence of tumor in the vessels should be identified preoperatively to prevent embolization and guide treatment.
A COG report indicated that contrast CT can accurately identify cavoatrial thrombus and obviate the need for a subsequent US . Early generations of CT scanners missed seven to ten percent of bilateral lesions . A more recent evaluation documented that modern helical CT scans miss only 0.25% of bilateral tumors and these were all small lesions . Although magnetic resonance imaging (MRI) avoids radiation exposure it often requires sedation and has not been shown to be superior to CT in standard assessments. Contrast enhanced MRI is currently being used with increasing frequency and may evolve into the diagnostic study of choice in order to limit radiation exposure . MRI is also being evaluated as a method to help distinguish nephrogenic rests from WT.
In addition to abdominal views, pulmonary CT imaging must be performed since the common sites of metastatic spread of WT are to the lungs and the liver. Between 13 to 15% of patients will present with lung metastasis. CT lesions are not invariably tumor and these may require biopsy to differentiate between benign and malignant disease and direct therapy. This is especially important for lower stage tumors because as many as a third of pulmonary lesions less than one cm are found to not be metastatic WT.
What is the association between Wilms tumor and horseshoe kidney?
Horseshoe kidney is the most common type of fusion abnormality where two distinct functioning kidneys are fused at the lower poles by an isthmus of functional parenchyma or fibrous tissue across the midline. Horseshoe kidneys have a 1.96 times higher incidence of WT than the general population. They present a distinct anatomic challenge that may not be recognized preoperatively because of the large tumor mass .
for surgical anatomy see Nephrectomy for Wilms tumor
It is important to determine whether a Wilms tumor has favorable or unfavorable/anaplastic histology.
Ninety percent of Wilms tumor (WT) have favorable histology (FH) consisting of blastemal, stromal and epithelial tubule elements . Tumors can contain various proportions of each of these elements. Triphasic tumors are the most characteristic lesions but biphasic and monophasic lesions also occur. The proportion of these three elements in WT does not predict outcomes. Abnormal mucinous or squamous epithelium, skeletal muscle, cartilage, osteoid or fat are less frequently found in WT.
Unfavorable histology tumors are those with focal or diffuse anaplasia defined by multipolar polyploid mitotic figures, marked nuclear enlargement (giant nuclei with diameters at least three times those of adjacent cells) and hyperchromasia . Determining whether a tumor has diffuse or focal anaplasia is important for prognosis and therapy. Focal anaplasia is defined as the presence of a few distinct and localized regions of anaplasia within a primary tumor that otherwise demonstrates no nuclear atypia. Diffuse anaplasia must have at least one of the following four criteria: anaplastic cells outside of the kidney, presence of anaplasia in a random kidney biopsy, anaplasia in more than one region of the kidney or anaplasia in one region with extreme nuclear pleomorphism in another site. Anaplasia occurs primarily in children older than two years.
Clear Cell Sarcoma
Clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumors of the kidney (RTK) were grouped in the initial NWTSG studies with the unfavorable histology WT. They are now considered distinct entities from WT based on their pathologic appearance, biologic behavior and response to different therapies . CCSK is a malignant tumor with an unusual tendency for bony metastasis. It generally appears as a large unifocal and unilateral tumor with a homogeneous mucoid, tan or gray/tan cut surface, often with foci of necrosis or prominent cyst formation . Unlike WT, which compresses the margin of surrounding renal parenchyma into a pseudocapsule, CCSK invades the surrounding kidney. The classic histologic appearance is uniform oval nuclei with a delicate chromatin pattern, prominent nuclear membrane, and sparse, poorly stained vacuolated “water-clear” cytoplasm with indistinct cell membranes. Recently, a translocation t(10;17) and deletion 14q have been described in CCSK suggesting that they may play a role in its pathogenesis . The cell of origin of this tumor is not known. In addition to osseous metastases, clear cell sarcomas also have a significant incidence of metastases to the brain. Clinical trials must consider results after an extended interval of follow up since as much as thirty percent of relapses occur more than two years after diagnosis .
Rhabdoid Tumor of the Kidney
Accounting for two percent of renal tumors, malignant rhabdoid tumor of the kidney (RTK) occurs in young infants and is the most aggressive and lethal pediatric renal tumor. Grossly these tumors are unencapsulated and invasive with characteristic involvement of the perihilar renal parenchyma. Histologically, rhabdoid tumors are characterized by monomorphous, discohesive, rounded to polygonal cells with acidophilic cytoplasm and eccentric nuclei containing prominent large “owl eye” nucleoli reminiscent of skeletal muscle but lacking its cytoplasmic striations, ultrastructural features and immunochemical markers . Ultrastructural examination suggests a neuroectodermal origin . These tumors are notable for the occurrence of second primary neuroglial tumors resembling medulloblastoma in the midline of the brain . A deletion of 22q11-12 has been described in both renal and extrarenal rhabdoid tumors . All renal tumors except RTK show nuclear positivity for immunohistochemical staining for the wild type INI-1 protein while in renal and extra renal rhabdoid tumors this is absent .
Although surgery is the primary therapy for patients with Wilms tumor the current treatment paradigm is risk based and constantly evolving to balance cure with toxicity. Chemotherapy is given to most children with Wilms tumor and radiation therapy is used in children with higher stage disease.
What is the role of chemotherapy in Wilms tumor?
Adjuvant chemotherapy dramatically improves outcomes in children with Wilms tumor (WT). Various regimens have been developed and tested based on stage, pathology and now molecular markers. In children with stage I favorable histology, age less than two years and with tumors weighing less than 550 grams surgery alone will cure 89% of patients. If these patients suffer a relapse, chemotherapy will cure 100%.
Other stage I and II tumors can be treated with just two chemotherapy agents. Stage III , IV and V tumors use a combination of between three to five agents. The table below Table Chemotherapy regimens from the most recent COG studies shows the agents for the most recent COG trials. In patients with lung metastasis, three drugs are used in a response based fashion. If all the lung nodules have disappeared by six weeks these children can be spared radiotherapy .
vincristine and dactinomycin
vincristine, dactinomycin, doxorubicin and possibly radiation therapy
vincristine, dactinomycin, doxorubicin, cyclophosphamide (CPM1), and etoposide (ETOP)
vincristine, dactinomycin, doxorubicin, cyclophosphamide and etoposide
vincristine, dactinomycin, doxorubicin, cyclophosphamide, carboplatin, and etoposide
vincristine, dactinomycin, doxorubicin, cyclophosphamide, carboplatin, etoposide, and irinotecan
vincristine/irinotecan window therapy
vincristine and irinotecan in conjunction with revised UH-1 or revised UH-2 depending on response
What is the role of abdominal and pulmonary radiation in the treatment of children with Wilms tumor?
Radiation therapy decreases local recurrence in patients with Stage III abdominal disease. Flank radiation (10 cGy) is used in most cases with whole abdomen radiation (40 cGy) reserved for those with preoperative rupture, large inoperative ruptures and anaplastic histology . Flank radiation is most effective if given within ten to fourteen days following nephrectomy.
The treatment of metastatic pulmonary disease has undergone a considerable evolution in the hopes of decreasing therapy to avoid late effects. Fifteen percent of children with pulmonary radiation will develop breast cancer. In stage IV patients with favorable histology WT three drug chemotherapy is administered. If all the pulmonary disease resolves by six weeks these patients can avoid pulmonary radiotherapy. Patients with persistent pulmonary disease after six weeks of chemotherapy require radiotherapy
Surgical Decision Making
What are the goals of the surgery and how does it impact further therapy?
The goals of surgery are to perform a safe operation, remove the kidney without intraoperative spill, sample lymph nodes and document all findings such as preoperative or intraoperative tumor rupture, extension into other structures and the presence of peritoneal metastasis . Failure to sample lymph nodes is the most common operative error made by surgeons. Without lymph node sampling the child cannot be properly staged . Some children have very favorable tumors and may not need chemotherapy or radiation therapy to achieve a cure, but the lymph node status must be known to accurately determine their disease stage.ExPERT
Preoperative rupture and peritoneal metastasis mandate whole abdomen radiation and increased chemotherapy. Intraoperative spill from the tumor, ureter or vascular system mandates flank radiation and increased chemotherapy. Failure to give radiation or chemotherapy in these situations increases the risk of relapse. Obtaining central venous access where appropriate with a tunnelled catheter or port should also be done at the same time if possible. A discussion with your anesthesia team about postoperative pain management should occur prior to surgery .
When should preoperative chemotherapy be given?
- there is extension of a tumor thrombus above the level of the hepatic veins
- the tumor involves contiguous structures whereby the only means of removing the kidney tumor requires removal of the other structures (e.g. spleen, pancreas, colon but excluding the adrenal gland)
- there are bilateral tumors
- the tumor is in a solitary kidney
- there is pulmonary compromise due to extensive pulmonary metastases
The presence of pulmonary metastasis does not mean that the primary tumor is unresectable. That decision is determined by the local anatomy and the conditions listed above. If the primary tumor can be removed, a nephroureterectomy should be performed even in the presense of pulmonary metastasis.ExPERT
What is the role of nephron sparing surgery for Wilms tumor?
COG protocols reserve renal nephron sparing surgery (NSS) for children with bilateral disease (BWT), children at high risk for metachronous tumors (WAGR, Beckwith-Weidemann syndrome and multifocal tumors) and those with a single kidney .
In all of these cases prenephrectomy chemotherapy is given. In the COG protocols this is usually three drug chemotherapy.
Specific and validated criteria for NSS do not exist. WT will compress the normal parenchyma and procedures to open the collecting system have been reported but require experience to perform.
In BWT it is a balance between saving the “kid" and the "kidney”. In a child with BWT with favorable histology, positive margins are acceptable but must be treated with radiotherapy . Although the kidney is at risk for late renal failure, transplants are often easier to obtain when the child is older. In contrast, anaplasia should never be left behind.
Chemotherapy beyond twelve weeks has not be shown to be effective and in many cases results in long term toxicity that precludes a transplant. It is important to remember that children with BWT die from disease progression and not renal failure. Although difficult, bilateral nephrectomies can be lifesaving. In general, a child must be disease free for at least two years before being considered a transplant candidate.ExPERT
The risk of performing NSS in a child with unilateral Wilms tumor (WT) is controversial since the risk to benefit ratio is unknown. The risk of renal failure in children with nonsyndromic WT is less than the general population at only 0.6%. Renal failure and hypertension in WT is due to disease progression and radiotherapy. SIOP reported their results with unilateral WT treated with NSS in seventy five patients. One third of the cases had positive margins requiring radiotherapy and a similar result was observed in a COG series . Interestingly most patients did not have their lymph nodes sampled. Thus patients who might have been able to be treated by surgery alone were given radiotherapy which placed them at increased risk of renal failure. Presently COG does not support NSS for routine unilateral WT.
How are lung metastasis managed?
Primary resection of lung metastasis is not needed. Lung surgery should only be performed if the diagnosis of a lung nodule is unclear or after chemotherapy and radiotherapy have been unsuccessful .ExPERT
Should any patients receive surgery alone?
Certain children have been identified who can be cured by nephrectomy alone. In a review of all NWTSG studies it was noted that adjuvant therapy did not improve the outcomes of children who were under two years of age with stage I tumors less then 550 g who had a greater than ninety percent survival . Based on this result, a trial of 75 patients who met these criteria were treated solely with nephrectomy . In three infants a metachronous, contralateral WT developed and eight patients experienced relapse 0.3 to 1.05 years after diagnosis. The sites of relapse were pulmonary (five cases) and the operative bed (three cases). The two year disease free survival, including both relapse and metachronous tumors, was 86.5% and the two year survival rate was 100% with a median follow up of 2.84 years. The two year disease-free survival, excluding metachronous contralateral WT, was 89.2%, and the two year cumulative risk of metachronous contralateral WT was 3.1% .
A recent long term follow up study was reported on this surgery only cohort as well as the children entered into the protocol who eventually were treated with vincristine and actinomycin D . Eighty-five percent of the infants avoided any chemotherapy and did well. Fifteen percent suffered a local relapse treated with three agents (vincristine, actinomycin D and doxorubicin) and all survived. Thus the survival of children in the subgroup who didn’t receive chemotherapy until relapse was equivalent to those who received it immediately after nephrectomy.
What are the key laboratory tests to order prior to surgery?
A complete blood count (CBC) and blood typing is needed as children may have anemia at presentation. Coagulation studies are also important due to the possibility of acquired von Willebrand disease (vWD) which has been reported in patients with Wilms tumor (WT) and other malignancies and obviously has important implications for the surgeon . Initially considered to be clinically insignificant, recent reports of profuse intraoperative bleeding that only stopped after ligation of the renal vessels have contradicted this assumption . The mechanism of acquired vWD in WT is unknown and the initial finding may be only a prolonged prothrombin time (PT) and partial thromboplastin time (PTT) . These abnormalities mandate a more detailed history for bleeding and a factor analysis. Although correction of factor levels prior to surgery appears to help in most cases it does not guarantee that significant intraoperative bleeding will not occur. Preoperative embolization should be considered as a management strategy.
Steps of the Procedure
When can chemo- and radiotherapy be given after surgery?
Routine postoperative care should be provided. Depending on the extent of the retroperitoneal dissection, a significant postoperative ileus may result and oral intake should be deferred until the return of bowel function.
What are the surgical complications?
Postoperative complications include intestinal obstruction (five percent), intussusception and wound infection. Children with retroperitoneal dissections are at increased risk of postoperative intussusception. The diagnosis requires a high index of suspicion and may require laparotomy. Most complications tend to occur within three months of the surgical resection .
What is the survival of children with Wilms tumor?
Patients with favorable histology stage I or II disease without loss of heterozygosity (LOH) have an event-free survival (EFS) greater than 85% and overall survival (OS) greater than 99%. Below is a summary of EFS and risk of late effects for children with renal tumors.
risk of late effects
moderate to high
excellent (greater than 85%)
stage I/II FHWT, LOH-
stage I/II CCSK
stage III FHWT, LOH-
good (75 to 84%)
stage IV FHWT, LOH-
stage II AHWT
stage III CCSK
poor (less than 75%)
stage I/II FHWT, LOH+
stage I AHWT
stage I-IV RCC
stage III/IV FHWT, LOH+
stage III/IV AHWT
stage V WT
stage IV CCSK
stage I-IV MRT
FHWT - familial histology Wilms tumor
AHWT - anaplastic histology Wilms tumor
LOH - loss of heterozygosity
CCSK - clear cell sarcoma of the kidney
MRT - malignant rhabdoid tumor
The COG recently released the results of several unilateral Wilms tumor (WT) trials.
- Very low risk patients (those receiving surgery alone) - 116 were enrolled, 12 relapsed with a median relapse at 4.3 months. EFS was 89% and OS 100%.The majority of patients who experienced a relapse had 11p15 LOH or LOI but these factors did not reach significance .
- Patients with LOH at 1p and 16q
- Stage I and II received three drug chemotherapy. The four year EFS was 83.9%, OS was 100% (compared to NWTS-5 with a four year EFS of 75% and OS of 90.5%, p=0.6414).
- Stage III and IV received regimen M (see Medical Treatment). The four year EFS was 91.5%, OS was 97.8% (compared to NWTS-5 with a four year EFS of 66% and OS of 77.5%, p=0.0188).
- Patients with stage IV FH WT
- who were treated with regimen M and whose lung nodules did not respond by six weeks: EFS of 88% and OS of 92% (compared to NWTS-5 EFS of 75%)
- whose lung nodules did respond by six weeks, 105 patients enrolled, 20 relapses with EFS of 78% (equal to NWTS but the patients did not receive pulmonary radiation)
- Patients with unfavorable AH treated on ARENO321. EFS for Stage II 85%, Stage III 74% and Stage IV 46%.
When and where do most relapses occur?
Most relapses happen by eighteen months postoperatively with about half occuring in the primary tumor bed and the rest mostly in the lung. The outcomes of patients who relapse are significantly worse - especially for AH .
What are the late effects of treatment for Wilms tumor?
In a twenty-five year follow up of WT survivors from the Childhood Cancer Survival Study, 65.4% had a chronic health condition and 24.2% had a severe chronic health condition . Chronic health conditions are classified with grade 1 being the least severe and grade 4 the most severe. Compared to a sibling group, WT survivors had twice the rate for any chronic health condition compared to a sibling group (hazard ratios 2.0, [95% CI 1.8 to 2.3]). For severe or grade 4 only, WT survivors had 4.7 (95% CI 3.6 to 6.1) times higher rates of severe chronic health conditions compared to a sibling group. WT survivors reported more adverse general health status than their sibling group with a prevalence ratio of 1.7 (95% CI 1.2 to 2.4) although overall mental health status, socioeconomic status and health care utilization were similar.
Second malignancies are a problem for survivors of childhood malignancies . The cumulative incidence of a second malignant neoplasm (SMN) was 3.0% (95% CI 1.9 to 4.0) and the mortality was 6.1% (95% CI 4.7 to 7.4%). The most common SMNs were breast cancers and sarcomas.
Congestive heart failure and early cardiovascular disease is another late effect of treatment . Doxorubicin with or without radiation are the main factors. In patients who received no doxorubicin the hazard ratio (HR) was 6.6 (95% CI, 1.6 to 28.3), in patients who received less than 250 mg/m2 of doxorubicin the HR was 13.0 (95%CI 1.9 to 89.7) and in those who received greater than 250 mg/m2 of doxorubicin the HR 18.3 (95% CI 3.8 to 88.2). Radiation exposure in combination with doxorubicin increased the risk, especially when the left flank was irradiated.
The risk of end stage renal disease (ESRD) is exceptionally low for the majority of unilateral WT patients . In most cases the loss of the second kidney was due to disease progression. This is also true for bilateral WT. The cumulative risk of ESRD at twenty years after the diagnosis of unilateral WT is determined by associated syndromic findings.
unilateral Wilms tumor (WT)
unilateral WT with no anomaly
unilateral WT with an anomaly
hypospadias or cryptorchism
bilateral Wilms tumor (BWT)
BWT no anomaly
BWT with an anomaly
hypospadias or cryptorchism
DDS - Denys-Drash syndrome
WAGR - Wilms tumor, aniridia, genitourinary anomalies and retardation
Standard follow up for patients with Wilms tumor (WT) includes renal ultrasound and intermittent computerized tomography or magnetic resonance imaging. Each protocol will have an "on study" assessment road map and an end of therapy follow up. Lab work and imaging can be found at the COG website - www.childrensoncologygroup.org. A sample follow up schedule is shown in the table below. These are constantly evolving but the general principles still apply.
history, physical exam
every 3 months x 8, 6 months x 4 , 12 months x 1
CBC, urinalysis, electrolytes
Ca, Mg, PO4, liver enzymes
every 6 months x 4, year x 3
CT of the chest
every 3 months x 8 then switch to CXR
starting 24 months off therapy every 6 months x 4, 12 months x 1
CT/MRI of abdomen
every 3 months x 8, 6 months x 2, 12 months x 1
ECHO/ECG for stage III
either yearly or every other year depending on the regimen
CBC - complete blood count, CT - computerized tomography, CXR - plain chest radiograph, MRI - magnetic resonance imaging, ECHO - echocardiogram, ECG - electrocardiogram
There are other specific imaging studies depending on the pathology. For example patients with clear cell sarcoma will also get scheduled for bone scans and a brain CT scan.
Research and Future Directions
Despite the excellent outcomes for children with Wilms tumor (WT), 25% of patients have event free survival less than ninety percent and 25% have significant life threatening long term health conditions. Future clinical studies and research will focus on high risk tumor patients and ways to reduce the late effects of treatment . High risk tumors include stage II - IV anaplastic WT, BWT, Stage I - IV rhabdoid tumors and Stage II - IV clear cell sarcoma of the kidney. The agents which cause the most serious late effects are abdominal and pulmonary radiation and chemotherapy agents, especially doxorubicin.
Targeted Molecular Studies
WT has always displayed unexplained clinical and pathologic heterogeneity. Recent translation studies may provide a biologic rational for these observations. Molecular studies have identified five novel subsets of patients with different gene expression and clinical outcomes. These subsets also had a different pattern of gene expression than that seen in normal renal development.
1 characterized by epithelial favorable histology WT
no nephrgenic rests
no WT-1 mutations
no CTNNB1 mutations
no WTX mutations
no recurrence disease in this group
low number of WT1 mutations and varying degress of WTX ,CTNNB1 mutations and these subsets have intralobar nephrogenic rests
subsets have different ages at presentation and preidcted rate of relapse
5 (largest group)
biallelic methylation of the imprint control region 1 of 11p15 and both intralobar and perilobar nephrogenic rests.
Characterising these subsets will help with the future development of subset specific therapy.
New Risk Stratification
In the last COG study a biologic marker (LOH at 1p and 16q) was used for the first time with the traditional other risk factors to stratify patients. This stratification method improved outcomes for these high risk patients. However, only five percent of patients have LOH at 1p and 16q. 1q gain has been associated with many different cancers and is present in up to thirty percent of WT patients. There is a strong association of 1q gain and the risk of relapse in WT patients. Thus the high prevalence and high relative relapse risk indicates a potentially strong biomarker for relapse . In the next generation of COG studies, the presence of 1q gain will be used to increase therapy intensity and its absence will be used to reduce therapy such as the potential need for radiation and doxorubicin.
NWTS-5 and COG ARENO532 both showed that 85% children less than two years of age with stage I favorable histology WT and tumors less 550 grams can avoid chemotherapy . There is no good rationale why a child who is two and half years with a tumor weighing 600 g could not also be treated by surgery alone. Biological analysis of this group found that the patients in this group with LOH at 11p15 and WT abnormalities were significantly associated with relapse in very low risk WT (p < 0.0001) as were WT1 abnormalities (p = 0.004) . A study has recently validated this observation and it is anticipated that these factors will be used to design a study whereby more children (e.g. age 4 years, tumors up to 1000 g and stage I) can be included in the surgery only arm and those with LOH at 11p15 or WT-1 abnormalities would be excluded.
Pulmonary radiation has significant short term and long term effects including breast cancer that can occur in up to fifteen percent of WT survivors . The recent ARENO533 study showed that 45% of patients with stage IV favorable histology WT (due to pulmonary disease) will completely respond to three drug chemotherapy and do not need lung radiation therapy. It would be ideal to identify a larger group of patients who could also be spared pulmonary radiation and possibly be treated solely with chemotherapy and perhaps thoracoscopic resections.
Perspectives and Commentary
To submit comments about this topic please contact the editors at NaT@eapsa.org.
Invited commentary from Robert Shamberger (March, 2016)
Wilms tumor is the quintessential example of a tumor best treated by multidisciplinary care as this excellent chapter has so aptly demonstrates. Since Sidney Farber first demonstrated in the early 1960’s the excellent response of Wilms tumor to actinomycin-D, all children with this tumor have been treated with surgery, chemotherapy and often radiotherapy. Wilms tumor was the first tumor treated with adjuvant chemotherapy when there was no evidence of residual disease. Based on the early response of advanced stage tumors to chemotherapy, Dr. Farber first prescribed the use of adjuvant chemotherapy after apparent surgical cures of this tumor. One must remember that in the early 1960’s, radiographic imaging was quite primitive and many metastatic lesions we can identify with modern day computerized tomography and magnetic resonace imaging were not visualized. Hence, the high rate of relapse after surgery alone. He stated that this therapy “was based upon the supposition that in the children with Wilms tumor who died, the tumor must have metastasized already at the time of discovery of the primary tumor” although no evidence of spread was available .
We are able to treat our patients today based on an excellent series of prospective randomized trials performed by the National Wilms Tumor Study Group (NWTSG) with the first study initiated in 1969, comparable studies performed in Europe by the Société Internationale d’Oncologie Pédiatrique (SIOP) with its initial enrollment in a renal tumor study in 1971 and the United Kingdom Children’s Cancer Study Group (UKCCSG) with its first Wilms tumor study begun in 1980. While each group has taken divergent paths in their management of patients with renal tumors, all have achieved excellent long term results. Results by stage are difficult to compare, however, between the two groups because the stage in North America is based on findings before chemotherapy and those in SIOP are after chemotherapy. NWTSG and now its successor, the Children’s Oncology Group (COG), have generally recommended initial surgical resection which provides prechemotherapy staging information upon which subsequent chemotherapy and radiotherapy treatments are based. Patients treated on the SIOP protocols are generally treated with initial chemotherapy followed by surgery with subsequent chemotherapy and radiotherapy based upon posttreatment pathology. This approach has been widely documented as resulting in "down staging" of patients. It has been shown that staging after chemotherapy results in different stages than prechemotherapy. Presumably, evidence of metastatic disease to the lymph nodes is lost with preliminary treatment explaining the “stage shift”. On the other hand, the histologic typing of the tumor remains unchanged and, hence, classification as an anaplastic tumor, clear cell sarcoma or rhabdoid tumor is feasible despite preliminary chemotherapy.
Overall outcomes for children with renal tumors have generally been excellent as outlined in this chapter. The tumors which have been recalcitrant to therapy, however, are metastatic anaplastic, clear cell and rhabdoid tumors. These tumor types comprise generally ten percent of the overall patients presenting with renal masses and yet they account for the majority of deaths. Continued intensification of chemotherapy for these tumors has not resulted in significant improvement in their response. In contrast, patients with favorable histology Wilms tumor are generally quite responsive to chemotherapy and overall survival rates have been excellent. Recent efforts in management of these patients have actually involved decreasing the intensity of chemotherapy or avoidance of radiotherapy entirely in patients with expected favorable outcomes.
Recently the genetic abnormalities identified in Wilms tumor have been studied to assess their prognostic significance. Loss of heterozygosity (LOH) of 1p and 16q were associated with a higher risk of recurrence  as was 1q gain . The now closed COG study utilized more intensive therapy for patients whose tumors had LOH at both 1p and 16q in an effort to improve their event free and overall survival. Results of these studies have been released. While the event free survival of children with stage 1 and 2 tumors were not significantly improved, those of children with stage 3 and 4 tumors were . Thus, the genetic characteristics of the tumor, as with MYCN amplification in neuroblastoma, are now defining the treatment regimen in an effort to decrease intensity of therapy to those patients with overall excellent results and increase the intensity of therapy only for those with a higher risk of mortality.
As the number of patients surviving from Wilms tumor has grown, evidence of the long term morbidity of these patients has become evident as discussed in this chapter. The Childhood Cancer Survivor Study (CCSS) has performed a series of excellent evaluations of these patients and the long term morbidity of therapy has been well documented. In fact, significant morbidity has been demonstrated in 65.4% of patients who have survived over 25 years following treatment for Wilms tumor and 24% have severe morbidity . The cumulative incidence of mortality for the Wilms tumor survivors is 6.1% which is almost five times that of their siblings. These long term results have resulted in attempts to decrease or, in fact, avoid all use of adjuvant chemotherapy. Dan Green and the investigators performing the NWTS-5 study identified a cohort of children who were deemed as having "very low risk Wilms tumors": patients under a year of age with favorable histology tumors which were stage 1 and in which the weight of the tumor and kidney were under 550 grams. Dr. Green had the temerity to question if all patients with Wilms tumor should be treated with adjuvant chemotherapy as had been espoused by Sidney Farber. This cohort of patients had an overall survival rate of 95% regardless of the type of chemotherapy they received on past protocols. Dr. Green postulated that a high percentage of these patients might do quite well without receiving any adjuvant chemotherapy. In NWTS-5 a single arm study of patients who met these criteria were treated with surgery alone and received no adjuvant chemotherapy. In 1998, this study was closed as the frequency of recurrence exceeded the limits set by the protocol . It had been presumed that fifty percent of the patients who relapsed could be salvaged based on experience from prior NWTSG studies. What was found in the long term follow-up of these patients, however, was a very high rate of salvage unpredicted by the results of prior studies . A subsequent follow-up study performed by COG lowered the event free survival allowed based on the very high salvage rate seen in the prior study. That study demonstrated that these patients continue to do quite well without use of adjuvant chemotherapy. If they do relapse, using a chemotherapy regimen based on their stage at relapse as if they are primary patients (i.e. not considering them as relapsed patients), had overall excellent survival . While a small number of patients with recurrence were thus treated with three drug chemotherapy (vincristine, actinomycin-D and doxorubicin), the vast majority required no treatment at all. A recent study from the same CCSS has demonstrated that over the last three to five year intervals of treatment, both the frequency of recurrence of patients treated for all malignancies and that the long term morbidity (not including cancer recurrence deaths) has declined . This is attributed to efforts to decrease the intensity of therapy in generally favorable patients.
In the surgical arena, there have been efforts espoused by investigators to treat patients initially with chemotherapy to allow "nephron sparing surgery" in patients with unilateral tumors. These efforts have been based upon reports of long term morbidity and mortality related to the absence of one kidney. These results are in conflict with prior studies from the NWTSG in which Norman Breslow and colleagues demonstrated an extremely low frequency, approximately 0 .2%, of renal failure occurring long term in patients with unilateral Wilms tumor at twenty years (in a very large cohort of over 5,500 patients) . It does seem counterintuitive, when we are attempting to decrease the amount of chemotherapy and radiation therapy given to some patients, that efforts are being made by to utilize the same modalities to make unilateral tumors more resectable and to save a portion of the involved kidney. This remains as an unresolved issue in Wilms tumor treatment and regrettably no studies from the NWTSG, COG, SIOP or UKCCSG address this issue.
In another effort to address a perplexing renal tumor problem (i.e. bilateral Wilms tumor) the COG has sponsored the first prospective study of bilateral Wilms tumor with a recommended algorithm for care of these complex patients. A marked diversity of treatments had been documented in patients with bilateral Wilms tumor treated on NWTS-4. Surgery was often long delayed in an effort to obtain maximum regression of the tumors . The challenge with these patients is they were often seen to be nonresponsive to increasingly intense chemotherapy. Ultimate resection revealed that these nonresponsive patients tended to fall into two categories: they either had anaplastic Wilms tumor which would have been better treated by more intensive chemotherapy or had quite mature tumors which one would never expect to respond to chemotherapy . In the bilateral study, biopsy of nonresponsive tumors (those decreasing less thanfifty percent in volume after two courses of chemotherapy) was recommended. This intervention would identify the unfavorable tumors so that chemotherapy can be appropriately intensified or the mature tumors in which surgical resection should be performed. Resection was recommended after four courses of chemotherapy as the SIOP trials have clearly shown that additional regression is rarely seen with further therapy . It is hoped that results from this study will further guide our care of patients with bilateral lesions and increase their event free and overall survival which are lower than those of patients with unilateral tumors.
Invited commentary from Peter Ehrlich (January, 2016)
The first descriptions of Wilms tumor (WT) have been attributed to either Rance in 1814 or Wilms in 1899.The first known specimen of this tumor was preserved by the British surgeon John Hunter between 1763 and 1793. This specimen of a bilateral tumor in a young infant remains in the Hunterian Museum of the Royal College of Surgeons in London.
Carl Max Wilhelm Wilms was a German pathologist and surgeon. Wilms name became forever connected to this tumor in children after publication of his monograph in 1899 titled “Die Mischgeschwülste der Niere” which described seven children with nephroblastoma as part of a monograph on “mixed tumors of the kidney.” The first successful nephrectomy was probably performed by Thomas Jessop in Leeds, England on the 7th of June, 1877 on a two year old child with hematuria and a tumor of the kidney. Initially, surgical resection was the main treatment but carried with it significant morbidity and mortality. In 1916 radiation therapy was first attempted. In the 1930’s Ladd and Gross described the principles of operative therapy for WT which reduced the morality from the operation dramatically. Sidney Farber first used adjuvant chemotherapy therapy in WT well before it was used in other solid tumor in adults and children. Combined with renal fossa radiation, the multimodality approach to the treatment of WT was born.
A major event in the 1970’s which helped advance the care of children with WT and other cancer was the recognition that no one center had enough WT cases to run large scale trials. In the 1970’s two multidisciplinary cooperative groups, the National Wilms Tumor Study Group (NWTS) in North America and the Société Internationale d’Oncologie Pédiatrique (SIOP) in Europe, were created to study children with WT. Both groups ran several complimentary large scale clinical trials that have improved the overall survival of a child with WT. Several surgical therapy and quality studies have helped define key surgical factors such as avoiding spill and sampling lymph nodes. These cooperative groups have become the model for gaining knowledge for other disease process. Today both groups still run trials with the NWTS now part of the Children’s Oncology Group. The leaders of these groups recognized the importance of a multidisciplinary input approach to cancer and have passion for children. This culture continues today with the development of novel molecular investigations to “personalize” treatment.
Although tremendous improvement in outcomes for WT has occurred the basic tenets of treatment have not changed. Surgery is still the mainstay of treatment of a child with WT and the conduct of the operation has remained unchanged since first described by Ladd and Gross. A subset of patients can just be treated with surgery alone. Surgery is critical to the care of a child with BWT. Furthermore the backbone of adjuvant chemotherapy using vincristine and dactinomycin is also unchanged. Even today all regimens include the drugs first used by Sydney Farber. Radiation therapy still is essential in treating children with WT - only the dosage and methods have changed.
Although the child has the disease, the whole family is affected. For many years these family factors have often taken a back seat to “traditional” treatment. Family centered care is recognized as a key contributor to successful treatment. Social media can help the surgeon gain insight into what a family and a long term survivor goes through with WT. I would encourage pediatric surgeons and oncologists to visit the “Wilms Tumors Survivors” facebook site to read what our patients and families think about when we are not around.
Despite all this good news, up to 25% of children, such as those with anaplastic WT, have poor outcomes. Outcomes have improved but in small steps and we still have much to do. WT occurs at a young age and we want survivors to live a long time. A great advance of the cooperative groups is that long term outcomes studies exist. We know that as these children get older they are at risk for chronic and sometimes life threatening health issues - far earlier than in the general population. These problems are result of treatment but extend beyond just risk of renal failure or a second malignancy. Many of these survivors have trouble finding adult doctors who understand their risk; it can affect their job opportunities and reproductive capacity - all of which can have a significant impact on their quality of life. As surgeons we often are oblivious to these and other concerns.
Taken together much has been accomplished and much remains to be done from DNA to the family.
Children’s Oncology Group- www.childrensoncologygroup.org
International Society of Pediatric Oncology- www.siope.eu
National Institutes of Health, Surveillance, Epidemiology, and End results (SEER) for Cancer Incidence and Survival among children and adolescents - http://seer.cancer.gov…
Onco Link - This document provides links to online pediatric oncology journals. www.oncolink.upenn.edu
APSA Standardized Toolbox of Education for Pediatric Surgery (STEPS) Abdominal Masses of Childhood
APSA Handbooks for Cancer Surgery Handbook for Children with Renal Tumors
APSA parent and patient education materials on Wilms tumor (aka nephroblastoma)
Stay Current in Pediatric Surgery podcast Wilms Tumor
Discussion Questions and Cases
To submit interesting or controversial cases which display thoughtful patient management please contact the editors at NaT@eapsa.org.
A 28 month old girl is sent to you with a left sided renal mass.
What is your initial approach to the diagnosis?
How would your management change if the tumor extended in the vena cava up to the atrium?
You are referred a three month old child with hemihypertrophy.
Is this child at risk for Wilms tumor and if so what type?
How often would you monitor the kidneys?
What would you do if on one of the screening ultrasounds there was a five cm lesion in one kidney?
You are preparing to operate on a four year old male with a Wilms tumor and her preoperative labs include a hemaglobin of 8 and a prolonged prothrombin time of 18.
What should be done prior to the operation?
During the operation there is extensive bleeding from the tumor and it ruptures with spill throughout the abdomen.
How will this effect postoperative therapy?
Additonal questions are in SCORE Wilms Tumor, Renal Cell Carcinoma, and Hemihypertrophy conference prep
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