Figure 105-7. Microscopic examination of Wilms tumor showing highly cellular areas composed of undifferentiated blastemal cells

with loose surrounding stroma with undifferentiated mesenchymal cells and immature tubules. (From Rubin E, Farber JL.

Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999, permission granted with previous edition.)

Several biologic factors have been identified in Wilms tumors that associate with risk. Tumor-specific

LOH at chromosomes 1p and 16q are independent prognostic indicators and are associated with greater

risk of relapse and mortality. The fifth National Wilms Tumor Study Group trial (NWTS-5) found that

tumors with LOH at 16q had an adverse effect on prognosis with relapse rates three times higher and

mortality rate 12 times higher than those without LOH at chromosome 16q.89 Patients with LOH for

chromosome 1p also had relapse and mortality rates higher than those without LOH at 1p.90 LOH for

both chromosomes 1p and 16q are found in up to 5% of Wilms tumors.

Presentation, Diagnosis, and Staging

Children may present with a palpable asymptomatic abdominal mass identified by parents or

pediatrician during well-visit examination. If present, symptoms may include intermittent abdominal

pain, gross or microscopic hematuria (25% of patients), and hypertension (25% of patients).

Hypertension occasionally results from either an increase in renin secretion by the tumor or by

compression of the renal artery by tumor mass effect. Intraparenchymal bleeding and preoperative

rupture may occur causing systemic symptoms of fever and anemia. The mass is typically nontender and

nonmobile on physical examination. The child should be examined for aniridia, macroglossia,

hemihypertrophy, and genitourinary abnormalities. Signs of intravascular spread may present as ascites,

hepatosplenomegaly, and cardiac murmur. Standard complete blood count and serum chemistries should

be assessed though renal function is usually unaffected. Red blood cells may be present on urinalysis.

The diagnostic imaging workup is initiated with abdominal ultrasound and CT scan with oral and

intravenous contrast. CT scan is the standard imaging modality that will provide information about

mass location, size, extent of tumor invasion, and involvement of the contralateral kidney (Fig. 105-8).

Critical examination of renal vasculature and intracaval extension is evaluated by Doppler

ultrasonography. A good posteroanterior and lateral chest radiograph is obtained to determine the

presence of lung metastases. It is critical to determine whether a patient with Wilms tumor has lung

metastases because these patients are assigned to higher disease stage and receive radiation to the lungs

and more intensive chemotherapy. There is considerable controversy regarding the utilization of chest

CT scan versus plain chest radiograph to detect lung metastases in patients with Wilms tumor because of

interobserver variability in interpretation.91 If utilized for staging workup, chest CT should be

performed with standardized techniques and interpretation through a central review process considered.

Pulmonary metastases identified on chest CT but not on plain chest radiograph may identify a subgroup

of patients at increased risk of pulmonary relapse.92 It may be beneficial to obtain histopathologic

confirmation of pulmonary metastases by surgical biopsy given the potential for upstaging and

radiotherapy.93

In the United States, nephrectomy follows the initial diagnostic workup, allowing the combination of

surgical and histologic parameters to be included in staging at diagnosis. During the procedure, the

surgeon must determine tumor extent, tumor rupture, and the status of regional, paraaortic, and

paracaval lymph nodes. Distant metastatic disease should also be determined by inspecting the

peritoneal surfaces, diaphragm, and liver. The COG no longer recommends direct visualization and

manual palpation of the contralateral kidney as long as the contralateral kidney is clear of tumor on

cross-sectional imaging.

The staging of Wilms tumor is based on the anatomy of the tumor and lymph nodes as detailed by the

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NWTSG staging system. The staging system incorporates clinical, surgical, and pathologic information

and allows stage-based approach to treatment to minimize exposure to cytotoxic agents (Table 105-4).

Stage 1 tumors are limited to the kidney and completely resected with an intact renal capsule without

involvement of the renal sinus vessels. Stage 2 tumors extend beyond the kidney by either penetration

of the renal capsule or invasion of sinus vessels. Biopsy before removal or local tumor spillage is

classified as stage 3. Tumors that are unresectable or incompletely resected with positive margins are

also stage 3 tumors. Tumors with regional lymph node metastases are stage 3 criteria as well. Stage 4

tumors have distant spread (liver, lung, bone, brain) or lymph node spread outside of the abdomen.

Bilateral Wilms tumors are classified as stage 5 though precise staging for patients with bilateral Wilms

tumor is based on local stage for each kidney. Advanced tumor stage at diagnosis predicts an increased

risk of recurrence and tumor rupture at surgery predisposes to relapse.94 Older age is also an adverse

prognostic factor and predicts disease recurrence.95 Tumor stage and histology are the most significant

prognostic factors for children with Wilms tumor.

Treatment

Most children diagnosed with Wilms tumor are cured by multimodal therapy. Much of the success in

therapy is the result of collaboration and research trials conducted by three cooperative groups, the

NWTSG, now a part of the COG, the United Kingdom Children’s Cancer Study Group (UKCCSG), and the

SIOP. In the United States and Canada, nearly all children are treated according to protocols established

by the NWTSG. The primary goals of therapy are to treat on the basis of well-defined risk groups and to

achieve the highest cure rates with minimal toxicity.

Figure 105-8. A: Abdominal CT scan with left Wilms tumor displacing midline organs and vessels, rim of kidney enhancing at

lateral border. B: Intraoperative view of right Wilms tumor arising from retroperitoneum, displacing colon and midline structures,

approached via a generous right supraumbilical transverse abdominal incision.

6 Surgery is a critical component of local primary tumor control and treatment outcomes. In the

United States, the standard of care starts with radical nephrectomy at the time of diagnosis of resectable

primary tumors, followed by chemotherapy and radiation to sites of residual and metastatic disease.

Preoperative chemotherapy is given to patients with inoperable tumors, bilateral disease, solitary

kidney, and for tumors with intravascular extension above the hepatic veins. A significant number of

patients are downstaged after preoperative chemotherapy without altering recognizable anaplasia.96 In

contrast to this treatment approach, SIOP therapy begins with chemotherapy administration for several

weeks prior to nephrectomy in all patients presenting with Wilms tumors.97 The standard

chemotherapeutic drugs with activity against Wilms tumors are vincristine and actinomycin-D.

Doxorubicin is added to patients with stage 3 tumors and to those with unfavorable histology or adverse

biologic prognostics markers such as LOH at chromosome 1p or 16q. Combinations of

cyclophosphamide, ifosfamide, carboplatin, and etoposide are utilized for select stage 3 and 4 cases with

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unfavorable biology and for resistant or relapsed cases. In the United States, the optimal combination,

duration, and mode of administration of chemotherapy are optimized through clinical trials and studies

of the NWTSG and COG.

The first two NWTS, NWTS-I and NWTS-II, found that routine postoperative radiation was

unnecessary in patients with tumors confined to the kidney and completely resected. Combination

therapy of vincristine and actinomycin-D was more effective than single-agent therapy, and the addition

of doxorubicin improved survival in higher-stage patients. In addition, the duration of combination

chemotherapy was successfully reduced in low-stage patients from 15 months to 6 months without

compromising survival outcomes.98,99 These studies established criteria that identify unfavorable

(anaplasia) and favorable histologic features that stratify patients into high-risk and low-risk treatment

groups. High-risk patients are at a higher risk of recurrence and also include those with unresectable

tumors, lymph node metastases, and diffuse tumor spill. This patient group benefits from intensified

chemotherapy and abdominal radiation. These findings paved the way for NWTS-III that demonstrated

successful treatment of stage 1 favorable histology Wilms tumors with lower dosing and further reduced

duration of vincristine and actinomycin D. The 4-year relapse-free and survival rates with this regimen

were 89% and 95%.100 This study found that stage 2 patients with favorable histology were treated

successfully with vincristine and actinomycin D without postoperative radiotherapy or doxorubicin, and

stage 3 patients had no differences in abdominal recurrence with reduction of abdominal radiotherapy

compared to patients with high-dose radiotherapy when doxorubicin was administered (10.8 Gy

compared to 20 Gy). The NWTS-III also found that patients with stage 4 favorable histology tumors

were successfully treated with vincristine, actinomycin D, doxorubicin and local radiotherapy based on

local tumor stage. The addition of cyclophosphamide was without benefit. This group received lung

radiation to both lungs (12 Gy), with 4-year relapse-free and overall survival of 79% and 80.9%. The

NWTS-IV trial was largely based on improving treatment results through modifying drug administration

utilizing shorter and “pulse-intensive” chemotherapy regimens compared to standard divided dose

regimens.101 The results of this study revealed that shorter pulse-intensive regimens were equivalent to

standard treatment regimens in terms of overall survival with total chemotherapy duration of 6 months.

Since the NWTS-IV trial, survival rates for children with Wilms tumor have steadily improved with

shorter chemotherapy schedules and lower treatment costs.102 Based on results of NWTS-IV, the current

overall survival rate for children with favorable histology Wilms tumor approaches 90%. Current 10-

year relapse and overall survival for stage 1 favorable histology Wilms tumors are 91% and 96%, and

for stage 2 tumors, 85% and 93%, respectively.103 NWTS-V completed enrollment in 2003 and was

designed as a nonrandomized single arm therapeutic trial to treat patients with stage- and histologyspecific treatment plans. In this study, patients were not randomized to therapy, rather biologic

properties of tumors were assessed. The aims included determining whether tumor LOH for

chromosomes 1p and 16q was associated with poorer prognosis in patients with favorable histology

Wilms tumors and to determine whether increased DNA content in tumor cells was associated with

adverse outcomes.104 LOH for 1p and 16q identified a subgroup of favorable histology patients who

have a significantly increased risk of relapse and death.90 LOH for these chromosomes is now used as an

independent prognostic factor as patients with LOH for chromosome 1p and 16q have 75% relapse-free

survival.

STAGINGa

Table 105-4 Wilms Tumor Staging System

The NWTS-V also attempted to verify that surgery alone may have acceptable overall survival rates in

a subgroup of children younger than 2 years at diagnosis with very low-risk favorable histology of

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Wilms tumors that weigh less than 550 g.105 The incidence of relapse was higher in this subgroup of

patients receiving surgery only, but the salvage rate was surprisingly high with long-term survival being

the same as patients receiving conventional postoperative chemotherapy. Given this, cooperative group

trials will further study optimal management of surgery alone in this subgroup to determine whether

very low-risk patients may be spared adjuvant therapy.

Since 2006, the COG has opened four clinical trials for the treatment of children with Wilms tumors.

For these therapeutic studies, patients are stratified into very low-risk, low-risk, standard-risk, and highrisk groups on the basis of tumor histology, stage, biologic assessment, tumor weight, and age. To

facilitate accurate risk assessment, it is currently recommended that all patients diagnosed with Wilms

tumor be enrolled and follow protocol recommendations of AREN03B2, a biology classification-based

trial. The current treatment recommendations are summarized in Table 105-5 and are based on the most

recent COG trials developed to build upon and refine results of previous NWTS (Table 105-5).106 The

protocol guidelines recommend that stage 1 and 2 favorable histology patients undergo initial

nephrectomy and lymph node sampling, followed by vincristine and actinomycin-D chemotherapy

(regimen EE-4A). Doxorubicin (regimen DD-4A) is added to the treatment plan in patients with stage 1

and 2 tumors with favorable histology and LOH at chromosome 1p and 16, as this subgroup has been

shown to have an increased risk of relapse and death. Stage 1 tumors with unfavorable histology (focal

or diffuse anaplasia) have lower 10-year relapse-free and overall survival of 69% and 82% and are

treated with vincristine, actinomycin-D, doxorubicin (regimen DD-4A), and abdominal radiotherapy.

Stage 3 patients with favorable histology are treated with nephrectomy, lymph node sampling,

vincristine, actinomycin-D, and doxorubicin (regimen DD-4A) and abdominal radiotherapy, with 10-year

relapse-free and overall survival of 84% and 89%. Cyclophosphamide and etoposide (regimen M) are

added to the treatment regimen for stage 3 tumors with favorable histology and LOH at chromosomes 1

and 16q. The presence of diffuse anaplasia also intensifies therapy in stage 2 and 3 tumors with the

addition of cyclophosphamide, carboplatin, and etoposide for 30 weeks (regimen UH-1) and abdominal

radiotherapy, with 10-year and overall survival rates of 43% and 49%. Stage 4 patients with favorable

histology and pulmonary metastases are treated with nephrectomy, lymph node sampling, and

vincristine, actinomycin-D, and doxorubicin for 24 weeks. In patients with stage 4 disease, the primary

tumor is staged separately to determine the requirement for abdominal radiation. Lung radiotherapy is

currently utilized if metastases remain detectable after 6 weeks of chemotherapy. For these reasons, it

remains advantageous to resect the primary tumor prior to the initiation of chemotherapy even in

patients with stage 4 disease. Based on results of NWTS-4, the 10-year relapse-free and overall survival

for patients with stage 4 favorable histology Wilms tumor is 75% and 81%. Stage 4 favorable histology

tumors with LOH at chromosomes 1p and 16q are treated with the addition of cyclophosphamide and

etoposide (regimen M) and abdominal radiation. Stage 4 tumors with focal or diffuse anaplasia (without

measurable disease) are treated with the addition of cyclophosphamide, carboplatin, and etoposide for

30 weeks (regimen UH-1) and radiotherapy. This subgroup of patients has the worst 10-year relapsefree and overall survival of 18%. Stage 5 Wilms tumors (bilateral tumors) with favorable histology have

10-year relapse-free survival and overall survival of 65% and 78%. Patients with bilateral Wilms tumors

are treated with preoperative chemotherapy (vincristine, actinomycin-D, doxorubicin) and renal-sparing

surgery.

Table 105-5 Recommended Therapy According to COG Protocols

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Surgical Considerations

Preoperative biopsies are contraindicated unless a tumor is judged unresectable. For most patients,

unilateral radical ureteronephrectomy with abdominal exploration is accomplished through a wide

transverse abdominal incision that will allow safe resection and regional lymph node sampling without

rupture. A thoracoabdominal incision may be utilized as necessary for tumors reaching the diaphragm.

Complete abdominal and pelvic exploration is performed. The contralateral kidney does not require

exploration if preoperative imaging does not suggest involvement. The lateral peritoneal reflection is

incised and the colon is reflected medially. Although a formal retroperitoneal lymph node dissection is

not recommended, lack of adequate lymph node sampling along with the primary tumor resection

automatically upstages treatment to stage 3 disease because of the risk of local relapse.106 Gentle

handling of the tumor is critical to avoid tumor rupture and spillage as there is a sixfold increase in local

relapse and also automatic tumor upstaging to stage 3.107 Both local and diffuse tumor rupture will

increase relapse risk. It is often unsafe to attempt to ligate the renal vein prior to tumor manipulation

given the size of most Wilms tumors as traditionally recommended by most authors. Later ligation of

the renal vein after tumor mobilization has not been shown to adversely affect survival outcomes, and

early ligation should not be attempted if technically difficult. The dissection is carried out along the

tumor capsule and outside of Gerota fascia identifying the renal hilum and isolating the renal artery,

vein, and the ureter (Fig. 105-9). The renal vein and inferior vena cava are palpated for intravascular

tumor extension. The ureter is divided as distal as possible to the renal hilum though it is not necessary

to remove the entire ureter. The tumor and the kidney are then removed en bloc. The adrenal gland

may be left in place if it does not abut the tumor or if the tumor arises from the lower pole of the

kidney.108 Titanium clips should be utilized to identify any gross residual tumor. The tumor and the

nephrectomy specimen should not be placed into fixative but delivered fresh and sterile to the

pathologist to optimize histologic and cytogenetic analysis based on pediatric tumor protocols.

There have been reports of laparoscopic resection of Wilms tumor.109 These are more likely feasible

after preoperative chemotherapy with lower risk of tumor rupture, though safety has not been

confirmed. Success of laparoscopy for Wilms tumor is hindered by tumor spill and by inaccurate staging.

Patient selection for preoperative chemotherapy is a critical step in surgical and treatment planning.

The overall incidence of surgical complications in patients undergoing nephrectomy for Wilms tumor is

12.7%.110 The most common surgical complications are small bowel obstruction (5.1%) and excessive

hemorrhage (1.9%), followed by wound infection (1.9%) and vascular injury (1.5%) as reported by the

NWTS-IV trial. Higher-stage tumors, intravascular extension, and resection of contiguous organs are risk

factors associated with surgical complications. The risk of renal insufficiency after unilateral

nephrectomy for Wilms tumor is low (0.25%), and patients with Denys-Drash syndrome are most at risk

for progressive tumor in the remaining kidney.111 For these reasons, nephron-sparing procedures are

currently reserved for children with bilateral Wilms tumor and for those at risk for developing renal

failure and not indicated for patients with standard unilateral tumors with a normal contralateral

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kidney.

Figure 105-9. Anatomy and operative approach to resection of a Wilms tumor.

Renal Vein/Inferior Vena Cava

Four percent to 10% of patients with Wilms tumor have intravascular extension into the renal vein,

inferior vena cava, and rare cases extending into the atrium. Patients may have symptoms of vascular

involvement depending on the degree of venous obstruction that may include hypertension,

hepatosplenomegaly, ascites, and heart failure. The preoperative ultrasonography and CT scan are

accurate in detecting intravascular tumor extension, but the vessels should still be palpated prior to

ligation of the renal vein during tumor excision. Studies of Wilms tumors with intravascular extension

have found that preoperative chemotherapy facilitates resection by decreasing the extent of tumor

thrombus. Overall frequency of complications and the 3-year relapse-free survival rates were similar

between the preoperative therapy group and the upfront resection group.112 Control of the renal vessel

and vena cava below and above the tumor thrombus is essential to obtain vascular control and to

minimize bleeding after venotomy. Effort should be made to avoid transecting tumor thrombus. If the

patient has intracardiac tumor extension after preoperative chemotherapy, a combined

thoracoabdominal incision with cardiopulmonary bypass is the safest surgical approach for tumor

thrombus excision. The overall survival of children with intravascular extension is the same as children

with disease limited to the kidney of similar stage and histology.113

Bilateral Wilms Tumor

Five to eight percent of patients with Wilms tumors present with bilateral disease. Bilateral Wilms

tumor is found more frequently in patients with hemihypertrophy and genitourinary anomalies. Primary

tumor excision at diagnosis is discouraged and patients may be enrolled on NWTS trials without an

initial biopsy. If obtained because of uncertainty in diagnosis, core needle biopsies through a posterior

approach are preferable to minimize contamination of the abdominal cavity and three-drug

chemotherapy is initiated. All children with bilateral Wilms tumors should receive preoperative

chemotherapy with the goal of renal preservation. The current COG protocol recommends reevaluation

by abdominal CT scan after 6 weeks of chemotherapy to determine the feasibility of a renal-sparing

procedure. If the tumor response is less than 50% shrinkage, the COG recommends bilateral open renal

biopsies to assess tumor histology prior to additional chemotherapy. After 12 weeks of therapy, all

patients should undergo surgical resection as continuing therapy beyond 12 weeks has not been shown

to improve outcomes. The primary surgical goal is to spare as much renal parenchyma as possible while

obtaining complete tumor resection. Children with synchronous bilateral Wilms tumor or tumor with

contralateral nephrogenic rests that have complete radiographic response may not require surgical

excision and have low risk for local relapse.114 These children are monitored for recurrence by serial

imaging. If partial nephrectomy is not safe after 12 weeks of chemotherapy, then nephrectomy is

recommended. In NWTS-IV, children with bilateral Wilms tumor who had partial resection with

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complete resection of all gross disease had local relapse rate of 8% and 4-year overall survival of

81.7%.115

Partial Nephrectomy

Nephron-sparing surgery is utilized in patients with bilateral Wilms tumor and in select patients at high

risk for bilateral disease or renal failure. Partial nephrectomy is not indicated in patients with standard

unilateral Wilms tumor given the low risk of renal failure with unilateral nephrectomy. Children with

Wilms tumor predisposing syndromes such as WAGR, Beckwith–Wiedemann syndrome, and Denys–

Drash syndrome are predisposed to the development of tumors in the contralateral kidney and are,

therefore, managed with a nephron-sparing partial nephrectomy approach for unilateral tumors.

Screening imaging studies in such patients at risk of developing Wilms tumors may detect lesions that

are appropriate for nephron-sparing procedures. These patients may still benefit from preoperative

chemotherapy to minimize the extent of renal resection. A radionucleotide dimercaptosuccinic acid renal

scan (DMSA scan) is useful to assess preoperative and postoperative renal function.

Partial nephrectomy is typically feasible only if tumor involves one pole and less than one-third of the

kidney and if the collecting system and renal vein are uninvolved. For bilateral tumors, the kidney with

the lowest tumor burden is addressed first to determine whether partial nephrectomy is feasible. A

transverse abdominal incision is utilized for abdominal exploration and partial nephrectomy utilizing the

same principles of radical nephrectomy with respect to tumor spillage. Manual compression of the

kidney may control blood loss and avoid vascular ischemia. Tumor resection is accomplished by opening

Gerota fascia and mass excision via wedge resection with 0.5-to 1.0-cm margin of normal renal

parenchyma. Enucleation may be considered for large centrally located lesions. The specimen should be

examined closely for rhabdomyomatous changes and anaplasia and nephrectomy considered in patients

with positive margins or high-risk histology.116 Renal functional outcomes after nephron-sparing

surgery are assessed by serum creatinine level, glomerular filtration rate, hypertension, and

proteinuria.108 Improved surgical techniques and intraoperative ultrasound have vastly improved the

safety and feasibility of nephron-sparing surgery in children at risk of postoperative renal failure.

Future Directions

Future studies will continue to focus on personalized treatment plans based on tumor biology and

patient risk stratification. New COG protocols are currently in place with efforts to further improve

curative outcomes while minimizing toxicity with refined stratification based on tumor-specific biologic

properties. Next-generation exome sequencing has enhanced the capacity to identify disrupted molecular

pathways in Wilms tumors, and there is extensive research on identifying their role in Wilms tumor

development and pathogenesis.117 There are very few known genetic alterations in Wilms tumors that

have been shown to drive tumorigenesis or progression. Examples of this are the discovery of new

mutations in Wilms tumor genes involved in miRNA processing including SIX1 and SIX2.118 Mutations in

this pathway may underlie high-risk Wilms tumors and serve as biomarkers and new therapeutic

targets. Several researchers have found significant epigenetic alterations such as changes in DNA

methylation or chromatin structure in Wilms tumors. Epigenetic changes at the imprinted region at

chr11p15.5 that show an allele-specific pattern of methylation resulting in abnormal expression of IGF2.

Targeting IGF2 is an active area of investigation in preclinical drug development.119 Circulating

epigenetically modified DNA and miRNAs have been detected in the blood of patients with cancer,

leading researches to investigate the utilization of tracking genetic mutations in the circulation as a

mechanism of diagnosis, risk stratification, and tracking tumor burden in Wilms tumor.117,120 Other

areas of intense research continue in the role of myeloablative chemotherapy and the role of autologous

bone marrow transplantation in patients with relapsed Wilms tumors.

NON-WILMS RENAL TUMORS

Congenital Mesoblastic Nephroma

Congenital mesoblastic nephroma (fetal renal hamartoma) is the most common renal neoplasm in

neonates and infants younger than 3 months and is considered a separate clinical entity from Wilms

tumor. In contrast to Wilms tumor, classic congenital mesoblastic nephroma is considered a benign solid

tumor of infancy, occurring in a younger age group with an excellent overall prognosis. Almost all cases

are diagnosed within the first 6 months of life, representing 5% of renal neoplasms in children.121 There

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