Discussion

Wilms tumor usually presents as an asymptomatic abdominal mass in an otherwise healthy child. Up to one third of patients will have associated symptoms of abdominal pain, fever, anemia, hematuria or hypertension.

Current theories of tumor development suggest a genetic mutation that predisposes to the persistence of nephrogenic rests. Nephrogenic rests are also present in the predisposition syndromes of WAGR (Wilms tumor- aniridia - genital anomalies - retardation), Denys-Drash (nephropathy, intersex disorders), Beckwith-Wiedemann (hemihypertrophy, macroglossia, hypoglycemia) and isolated hemihypertrophy. These patients may benefit from screening ultrasound. The frequency of screening is dependent on the syndrome.

Current recommendations suggest surveillance abdominal ultrasound examinations for the above patients, siblings of patients with familial Wilms and offspring of patients with bilateral Wilms.

Patients who have finished therapy for Wilms should have ultrasound examinations every three months until the age of seven years. (DP/JW)

Discussion

The goal of adjuvant therapy in Wilms tumor is to increase event free survival and overall survival while minimizing toxicity and long term late effects. The patient described above can be classified as very low risk Wilms tumor (VLRWT). Criteria necessary for VLRWT include

• Stage I disease (i.e. tumor limited to the kidney and completely resected, an intact renal capsule, tumor is not ruptured or previously biopsied, no tumor involvement of the renal sinus vessels, negative surgical margins and lymph nodes must be sampled and be negative for tumor).
• Favorable histology Wilms tumor
• Tumor weight of less than 550 g
• Age under two years at diagnosis

In a study by Fernandez, 116 patients with VLRWT were treated with nephrectomy and observation. During the median follow up of 80 months, 12 patients relapsed. The estimated four-year event free survival was 89.7% with an overall survival of 100%. Therefore, most patients with VLRWT could avoid the toxicity of chemotherapy and all patients who relapsed were salvaged with chemotherapy. Loss of heterozygosity (LOH) and loss of imprinting (LOI) at 11p15 have been identified as biologic risk factors that can predict Wilms tumor relapse. In patients with 11p15 LOH or LOI the risk of recurrence is 20 and 25%, respectively, as compared to a three percent recurrence risk in those with neither LOH nor LOI of 11p15.

In the patient presented with VLRWT and no biologic risk factors, observation alone is safe, has a high event free and overall survival and avoids the toxicity and late effects of chemotherapy. Adjuvant chemotherapy with vincristine and dactinomycin for 18 weeks (i.e. regimen EE-4A) can be used to treat VLRWT but would have increased toxicity and late effects compared to observation only. Adjuvant therapy with vincristine, dactinomycin and doxorubicin for 24 weeks is known as Regimen DD-4A. DD-4A is utilized in more advanced Wilms tumor and is associated with treatment toxicity and late effects.

Discussion

In a retrospective study of data from NWTS-3 and NWTS-4, surgical tumor spillage was identified in 22% of the patients analyzed. Flank irradiation, but not doxorubicin, reduced abdominal relapse rates. The odds ratio for the risk of recurrence relative to no radiation was 0.35 for 10 Gy of radiation and 0.08 for 20 Gy of radiation. Tumor spillage resulted in a higher relapse rate and significantly lower survival rates. Based upon these results, patients with tumor rupture or “spillage” confined to the flank are included in Stage III. This also includes those who have a biopsy of the tumor as the initial procedure.

In NWTS-1 and NWTS-2, a delay of ten or more days after surgery before receiving radiation therapy was associated with significantly higher abdominal relapse rates. In NWTS-3 and NWTS-4, a delay of ten or more days did not demonstrably influence the abdominal tumor recurrence rate. Nevertheless, current COG protocols recommend that in patients who should receive flank irradiation (patients with contained spill) and whole abdomen radiation (patients with diffuse spill, cytology positive ascites, preoperative tumor rupture or peritoneal seeding), it should be delivered as soon as practical after nephrectomy and not later than fourteen days after surgery. These patients are best treated under the most recent guidelines of a multicenter trial group like COG. (RM/DP)

Discussion

WAGR (Wilms tumor, aniridia, genitourinary malformations, range of abilities) is one of the genetic syndromes that is strongly associated with the development of Wilms tumor. Most commonly, patients will present with aniridia noted in the neonatal period and genetic testing will show a deletion on chromosome 11p13 - the locus of which includes the WT1 gene as well as the PAX 6 gene which is responsible for the aniridia as well as brain malformations. Patients with WAGR undergo renal ultrasounds every three months for six years and then a yearly exam to detect Wilms tumor. Forty-five to 55% of patients will develop Wilms tumor.

Bilateral Wilms tumor (BWT) occurs in four to seven percent of patients with Wilms and has a worse prognosis and survival than unilateral disease. Twenty-two percent of BWT are associated with syndromes such as WAGR, Denys-Drash, Beckwith-Wiedemann and hemihypertrophy. Therefore, it is important to screen patients with these conditions. Nephron sparing surgery is important for BWT and even more critical in patients with WAGR since 50% of those patients will develop renal failure by 20 years of age even when they do not develop Wilms tumor.

COG (AREN 0534) and SIOP protocols for BWT do not recommend biopsy due to the upstaging by tumor spill. As well, data from NWTS 4 and 5 demonstrated that biopsy often misses anaplasia. Therefore, patients with BWT receive initial neoadjuvant three drugs chemotherapy for high risk Wilms. In patients with WAGR, BWT may be indistinguishable from bilateral nephroblastomatosis. However the treatment plan remains the same with six weeks of chemotherapy followed by imaging and, if there is no response, surgery is indicated. If there is substantial response, then consideration is given for an additional six weeks of chemotherapy to allow for further shrinking followed by nephron sparing surgery. (SI/CLS)

Discussion

Current pediatric protocols are designed to individualize treatment using risk factors of known predictive value to maximize survival and minimize late effects such as secondary malignancy or heart disease. Cooperative group trials have guided the understanding of such optimal management. National Wilms Tumor Study 5 (NWTS 5) demonstrated that loss of heterozygosity (LOH) at chromosomes 1 p and 16 q predicts adverse outcome in patients despite favorable histology Wilms tumor. A more aggressive chemotherapy regimen is therefore used in such circumstances.

Diploid cells typically contain two copies of an allele§. Loss of heterozygosity (LOH) occurs when a somatic cell only has one copy of an allele. LOH can occur with deletion of chromosome segments, nondisjunction during mitosis or failure of segregation. LOH becomes significant when the remaining allele contains a mutation that can promote cancer development (e.g. inactivation of tumor suppressor gene).

WT-1 was the first specific gene mutation identified in Wilms tumors. It was recognized in patients with WAGR syndrome (Wilms, aniridia, genitourinary abnormalities and mental retardation), but it has also been found in children with Denys-Drash and Frasier’s syndromes. It does not portend a poorer prognosis except in very low risk Wilms tumors where low WT-1 expression predicts relapse. WT-2 is found in patients with Beckwith-Wiedemann syndrome but has no known impact on prognosis of those who develop Wilms tumors.

N-myc amplification is associated with a worsened prognosis in children with neuroblastoma. RET oncogene is a tyrosine kinase gene which is found in association with thyroid malignancy, multiple endocrine neoplasia and Hirschsprung disease. (CL/JW)

§one of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome.

Discussion

Event free survival is the timespan after treatment of malignancy during which there is no objective sign of recurrence.

In COG protocol AREN0533 for patients with favorable histology Wilms tumor and lung metastases the lung nodules are reassessed after six weeks of chemotherapy. Radiation therapy is omitted if there has been a complete response. The rationale for this is based on the report by Grundy of 186 patients from NWTS-4 and -5 with favorable histology Wilms tumor and nodules seen only on computerized tomography (CT). In this analysis, the five-year event free survival was greater for patients receiving three drugs (vincristine, dactinomycin, doxorubicin), with or without lung irradiation, than those receiving two drugs (vincristine, dactinomycin). However, there was no benefit in five-year overall survival with the addition of doxorubicin or pulmonary radiation.

The lung is the most common metastatic site of Wilms tumor. Chest radiographs have historically been used to assess patients for lung metastases but chest CT scans are clearly more sensitive. On NWTS-5 129 patients had lung lesions detected on CT scan but not by chest radiograph. Lung nodules are considered to have tumor unless proven negative by biopsy. Of note, the 42 patients who underwent lung biopsies in NWTS-5, tumor was confirmed in only 31 (73.8%). (CL/JW)

Discussion

In the surgical treatment of Wilms tumor, the debate between surgical resection at diagnosis versus preoperative neoadjuvant chemotherapy has continued on for almost twenty years. Most European multicenter trials favor neoadjuvant chemotherapy while North American trials favor upfront resection when feasible. Survival results are the same for both strategies with recurrences higher when biopsies have been taken prior to resection. In addition, histologic analysis considered important for staging is also sacrificed with preoperative chemotherapy if no biopsy is taken.

Children’s Oncology Group Stage IV disease, which includes pulmonary metastases, is not an absolute indication for preoperative chemotherapy if the primary tumor is resectable. Thus, the current COG strategy calls for exploration of all patients with the intent of complete resection. The exceptions to this rule are

• intravascular extension above the suprahepatic cava
• large or infiltrative tumors where resection might risk spillage
• bilateral disease.

Extension beyond midline does not influence prognosis or staging for Wilms tumor. Family history, genetic mutations as an etiology, and age do not independently affect treatment strategy. (RM/DP)

Discussion

Lung metastasis is the most common site of stage IV disease in children with Wilms tumor. Lung metastasis, however, does not necessarily imply that the abdominal tumor is unresectable. A common surgical pitfall is not to attempt upfront resection of the abdominal tumor just because lung metastasis are visualized. The abdominal tumor should be removed and staged locally if possible.

It is not generally necessary to biopsy or resect pulmonary nodules at the time of the initial primary tumor resection. There are three situations when a surgeon may be asked to remove a pulmonary nodule. The first is at diagnosis if the diagnosis of metastatic disease is in doubt. In the case of small lesions seen on computerized tomography but not chest radiograph (i.e. CT only nodules) there is a 70% to 80% chance that the nodules are tumors. The second indication, and the topic of this question, is if lung lesions shrink but do not go away completely after chemotherapy. It is therefore important to discern whether the residual lesions contain viable tumor tissue. The third situation is if tumor remains after both chemotherapy and radiotherapy thereby requiring surgical resection for cure. Most Wilms tumor metastasis are peripheral and superficial and many of these lesions can be fully excised by video assisted thoracoscopic surgery. (RM/DP)

Discussion

Lung metastasis with a unilateral Wilms tumor (WT) does not preclude an upfront resection of the abdominal tumor. In WT, staging consists of an abdominal (local) stage and a disease stage. Local stage determines the treatment of the abdomen and disease stage is the overall burden of disease including lung treatment. This child can be stage II locally yet have overall stage IV disease. Although she will need three drug chemotherapy and lung radiation due to metastatic pulmonary disease, if a biopsy was done this would locally upstage the child and mean that she would additionally need abdominal radiation. A five cm tumor is small, poses limited risk of rupture, and is easily removed.

Partial nephrectomy is contraindicated in almost all children with unilateral WT for several reasons. Although technically feasible, the WT develop from clonal expansion of nephrogenic rests which are multifocal within the kidneys of most children with WT. Thus, premalignant lesions could be left behind. Second, the rate of renal failure at forty years in patients with WT is 0.9%. Thus, renal failure is not a long term complication and there is a high risk of positive margins when doing partial nephrectomies which exposes the child to increased chemotherapy, radiotherapy and their late effects.

Partial nephrectomies are only indicated in children with bilateral WT, a single kidney or high risk patients with unilateral disease (such as Beckwith-Wiedemann syndrome). An intraoperative biopsy followed by nephrectomy at the same operation if found to be WT is inappropriate as this would upstage the child to stage III. Biopsies are only needed if the tumor is unresectable.

There are clinical situations where it is agreed that primary nephrectomy is contraindicated. These are

• when there is extension of 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)
• bilateral tumors
• tumor in a solitary kidney
• pulmonary compromise due to extensive pulmonary metastases. (PE,AH/,JW)

Discussion

This child with Beckwith-Wiedemann syndrome is at increased risk of developing cancers. The estimated cancer risk is around 5-10%. Wilms tumor is the most common cancer found in these patients. Ninety-five percent of which are diagnosed by seven years of age. The currently accepted screening protocol for children with Beckwith-Wiedemann for Wilms tumor and hepatoblastoma includes quarterly abdominal ultrasounds until four years of age followed by quarterly renal ultrasounds until seven years of age.

The most recent COG study evaluated children with bilateral renal tumors as well as children with cancer predisposition syndromes with unilateral tumors. In this study, patients were treated without upfront biopsy and underwent definitive surgical resection by 12 weeks. This approach using standardized three drug chemotherapy with eventual nephron-sparing surgery rather than radical nephrectomy (if possible) demonstrated improved event free survival and preservation of renal parenchyma as compared to historical controls. There is no role for upfront radiation therapy in this scenario.

Discussion

Ipsilateral lymph node sampling is a critical part of evaluation and staging for pediatric renal tumors. The nodal status determines the stage and the risk stratification and therefore the appropriate chemotherapy protocol. Unfortunately, according to a 2016 study, lack of lymph node sampling is the single most common surgical protocol violation (SPV). In 3356 patients over a 10 year period there were 564 SPV’s, and 67% were lack of lymph node sampling. The Children’s Oncology Group has a goal of 50% reduction in these SPV’s over the next few years and is educating pediatric surgeons about this issue. While intraoperative vena cava ultrasound may be used, preoperative imaging is adequate. Omentectomy and peritoneal biopsy are not part of the evaluation of a non-ruptured Wilms tumor, while contralateral renal operative evaluation is not required due to currently adequate evaluation with computerized tomography. (SI/CL)

Discussion

For accurate staging and treatment, the extent of peritoneal spillage must be accurately documented. Types of spillage include preoperative tumor rupture, tumor biopsy, tumor spillage, and removal of tumor in more than one piece. Local spills are limited to the renal fossa and anything beyond is considered diffuse spillage. All spillage will be classified as stage III. Flank radiation is needed for local soilage while diffuse spillage is managed with whole abdominal radiation.

Preoperative tumor rupture is difficult to detect. A retrospective review of computerized tomography scans in patients with known tumor rupture demonstrated a sensitivity of 54 to 70% and a specificity of 88%. Another study demonstrated that clinical signs were only seen in 39 of 57 patients with tumor rupture.

Attempted resection when the tumor rupture is confined to the retroperitoneum increases the risk of tumor contamination of the peritoneal space. Any hematoma associated with rupture is assumed to be seeded with tumor. In such cases, the hematoma boundaries should be marked with clips to guide postoperative radiation treatment.

In this case, the tumor has gross spillage with diffuse peritoneal involvement and biopsy of the tumor and peritoneal seeding should be performed to confirm the diagnosis. This patient will be treated with chemotherapy followed by surgery and then abdominal radiation and additional chemotherapy. (EB, SL/CS/CLS)

Discussion

Cystic renal tumors can be a diagnostic and therapeutic challenge [1] with a spectrum ranging from

• cystic nephroma (CN) - benign cystic tumors with only mature elements in the septae and cystic tissue
• cystic partially differentiated nephroblastoma (CPDN) - intermediate risk tumors with immature components in the septae and cystic tissue but no solid components
• cystic Wilms tumor (CWT) - malignant lesions with cystic and solid components

Although CN tends to occur in children under one year of age and a solid component may be an indicator of CWT, radiographically the three types may be indistinguishable.

In the United States, left nephrectomy would be the most appropriate initial therapy. Preoperative chemotherapy would be a consideration by SIOP standards if CWT was suspected based upon solid components. However, a decision could be made to forego this if the imaging did not have solid components and CN or CPDN were suspected. Biopsy is inappropriate and would upstage the patient if the tumor were subsequently determined to be CWT. The decision for postoperative chemotherapy would be based on appropriate staging for WT if that were the pathology. No chemotherapy would be needed for CN.

Although controversial, the literature appears to indicate that chemotherapy may not be needed for CPDN after resection. Blakely published a report from the Wilms Tumor Study Group in 2003 reviewing 21 patients with CPDN. Thirteen patients received chemotherapy despite ten of the tumors being Stage I. Four patients experienced toxicity. Eight patients received no chemotherapy. All survived with no recurrences [2]. In a retrospective review from the SIOP/GPOH Study group in 2007, 14 patients were identified with CN or CPDN. Two patients had received chemotherapy before operation and one after surgery. Two patients underwent partial nephrectomy. Survival was 100% and there was no progression of disease [3]. (RM/CS)