Renal tumors are responsible for about 6% of all pediatric cancers and are the second most common abdominal tumor seen in infants and children after neuroblastoma. They represent a wide spectrum from benign to extremely malignant tumors ( Box 62.1 ).

Advances in the management of these tumors have been significant since Sidney Farber first administered dactinomycin (actinomycin D) for advanced-stage Wilms tumors (WT) in the 1960s.

WT in particular has been a model for effective cooperative multiinstitutional randomized trials, with startling improvement in outcomes. Current therapies are derived from trials by the Children’s Oncology Group (COG, formerly the National Wilms Tumor Study Group) and the International Society of Pediatric Oncology (SIOP). Key information from previous COG and SIOP studies is given in Table 62.1 .

The goal of this chapter is to provide a thorough understanding of pediatric renal tumors, with a particular focus on WT. The discussion will include tumor formation, molecular genetics, pathologic subtypes and premalignant syndromes, and current treatment algorithms for children with renal tumors.

The history of WT is summarized in Table 62.2 , including the initial description by Max Wilms in the 1890s and the first use of adjuvant chemotherapy by Farber.

WT represents the most prevalent kidney tumor among children, with an occurrence rate of 7.6 per million children under 15 years of age, equivalent to 1 in every 10,000 infants. Annually, this accounts for about 600–650 cases across North America. Most (90%) cases are sporadic.

Comparatively, WT has lower incidence rates in East Asian children than in White children, and higher rates in Black children. ^, The reasons for these racial and geographical differences in incidence remain unclear. On average, children are diagnosed at 36 months, typically between 12 and 48 months. The condition tends to manifest earlier in boys than in girls. While WT incidence diminishes after age 10 and is rarer below 6 months, it still represents 20% of all kidney tumors in infants under 6 months. In patients younger than 6 months old, congenital mesoblastic nephroma (CMN) is the most common pathology. Bilateral Wilms tumors (BWT) are found in 4%–13% of patients. ^{, ,}

Non-Wilms histology makes up about 20% of renal tumors in children. Renal cell carcinoma (RCC) and clear cell sarcoma of the kidney (CCSK) are the two entities most commonly reported. Median age at diagnosis for RCC is 13 years old with a slight male preponderance; at this age, RCC becomes more common than WT as the primary renal tumor most frequently observed. In contrast to what is seen in adults, the most common subtype observed in children and adolescents is translocation RCC involving Xp11.2 ( TFE3 gene locus).

CCSK is also seen in young children with most patients diagnosed around age 2 years. CMN and rhabdoid tumor of the kidney (RTK) are other examples of relatively rare non-Wilms renal tumors that occur in the younger age group.

It is currently estimated that 10%–15% of all WTs are associated with one of several syndromes. These associations have led to significant increases in understanding of molecular genetics of WT and other tumors, and risk categories for the development of WT in the most common WT-related syndromes have been defined.

A variety of genetic alterations/biomarkers have been identified over the years in WT. There are around 40–50 proven or suspected WT drivers. Exome sequencing efforts of the International Society of Pediatric Oncology– Renal Tumor Study Group (SIOP-RTSG) and the COG research groups have added additional genes. The types of genetic alterations associated with Wilms tumorigenesis include kidney development, chromatin biology or epigenetic modifiers, mRNA processing and RNA metabolism, transcriptional machinery, growth factor signaling, and genome maintenance.

A 2017 COG review found that WTs (1) commonly arise through more than one genetic event, (2) show differences in gene expression and methylation patterns based on different genetic aberrations, (3) have a large number of candidate driver genes, most of which are mutated in <5% of WTs, and (4) have recurrently mutated genes with common functions, with the majority involved in either early renal development or epigenetic regulation of transcription (chromatin modifications, transcription elongation, and miRNAs).

CTNNB1 mutations: CTNNB1 regulates the Wnt signaling pathway, is involved in 15% of WTs, and is linked to WTX and WT1 mutations. This is one of the most commonly mutated genes, and it is associated with favorable histology.

WTX mutations: One of the most common gene mutations in WT (29%), this tumor suppressor gene is located on the X chromosome. Complete inactivation occurs with a single mutational event in males, and in females only if the active X chromosome is affected. There do not appear to be any survival differences related to WTX mutations. ^,

WT1 mutations and LOH: WT1 is a gene (located at 11p13) known to be critical for early renal development and involved in cell growth, differentiation, and apoptosis. Loss of imprinting (LOI) or loss of heterozygosity (LOH) of 11p15 is observed in a considerable majority of all WTs and results in overexpression of IGF2. LOH at 11p15 was validated as an adverse prognostic marker in COG AREN0532. In the very-low-risk cohort of this study (defined as age <2 years, tumor weight <550 g, nonsyndromic, stage I tumors treated with nephrectomy only), patients with LOH at 11p15 comprised 37% of the group, yet represented 67% of the relapses. ^,

1q Gain: One of the most common cytogenetic abnormalities in WT, 1q gain is observed in approximately 30% of tumors and is associated with inferior event-free survival (EFS) across all stages of favorable-histology WT. ^,

LOH 1p/16q: Combined LOH for 1p and 16q has been shown to be associated with decreased relapse-free (RFS) and worse overall survival (OS) as demonstrated in Fig. 62.1 . ^,

(A) Relapse-free survival with loss of heterozygosity at chromosomes 1p and 16q for patients with stage I/II Wilms tumor of favorable histology. (B) Relapse-free survival for patients with stages III/IV Wilms tumor with favorable histology and LOH at chromosome 1p and 16q.

Reprinted with permission from Grundy PE, Breslow N, Li S. Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol. 2005;23:7312–7321.

Screening with serial renal sonograms has been recommended in children at risk for developing WT (see conditions above). Review of most studies suggests that 3–4 months is the appropriate screening interval. The frequency of screening does not change as the patient ages; the rate of tumor growth is expected to be the same in older children. Tumors detected by screening will usually be at a lower stage. No studies have demonstrated that early detection has improved patient survival. However, early detection can provide an opportunity for nephron-sparing surgery (NSS), because these children are at an increased risk for bilateral disease. The smaller tumors found on screening studies are more amenable to renal-sparing surgery. A report from the American Association for Cancer Research Childhood Cancer Predisposition Workshop recommended that screening be performed when a condition has a WT incidence of greater than 1%. Others have recommended screening when the WT incidence is greater than 5%. ^, Ultrasound surveillance is recommended until at least 7 years of age, although some recommend continuing up to 10 years of age. For patients with BWS/IHH, trisomy 18, and SGBS, screening for hepatoblastoma is also required. Patients with these conditions need full abdominal ultrasound and simultaneous serum alpha fetoprotein (AFP) screening every 3 months starting at birth (or at the time of diagnosis) and continuing through the child’s fourth birthday. CT or MRI should be performed if ultrasonography demonstrates a suspicious lesion. Nonmalignant renal lesions—for example, renal cysts—do occur at an increased rate in children with BWS, and recognition of these is important to avoid unnecessary nephrectomy when new lesions are identified on screening ultrasonography. ^,

WTs are categorized as favorable (FH, 90% of cases) and unfavorable histology (UH, also known as anaplasia). The former (FH) are comprised of three tissue types: blastemal, stromal, and epithelial ( Fig. 62.4 ). Triphasic (all three elements) is the most common type of FHWT, but tumors can be biphasic or monophasic. The proportion of these three elements in patients with prechemotherapy WT histology have been studied but have not been shown to predict outcomes. Under the current COG treatment protocols, the proportions of these elements in prechemotherapy WT histology are not utilized to determine therapy. This is in contrast to SIOP, which uses a postchemotherapy staging system. In that system, blastemal predominance (after chemotherapy) has been considered a high-risk pathological finding, with more intensive adjuvant chemotherapy administered. This increased risk was also noted in a report from Japan.

The classic “triphasic” histologic pattern (blastemal, epithelial, and mesenchymal derivatives) of a Wilms tumor is seen on this H&E slide. There is a predominance of small undifferentiated blastemal cells in the image that surround a few neoplastic ducts and tubular epithelial structures ( solid arrows ). In the center is an island ( asterisk ) of spindle-shaped fibroblastic mesenchymal cells that surround a few tubules. The neoplastic cells in the image lack the requisite features of an anaplastic variant.

UH is defined by the presence of anaplasia, which can be either focal or diffuse ( Fig. 62.5 ). Anaplastic features include multipolar polyploid mitotic figures, nuclear enlargement (giant nuclei, three-fold greater than normal diameter), and hyperchromasia. Focal anaplasia is defined as the presence of a few distinct and localized regions of anaplasia within a primary tumor without other sites of 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 correlates with age, occurring primarily in children older than 2 years. Diffuse anaplasia is associated with chemotherapy resistance. The poor prognosis (higher rates of relapse and death) with diffuse anaplasia may be related to the association with TP53 (tumor suppressor gene) mutations.

Salient features of the anaplastic Wilms tumor variant with H&E staining. Anaplasia is defined by three requisite criteria that are all depicted in the image: atypical mitotic figures ( dotted arrow ) (often tripolar or multipolar), nuclear enlargement ( solid arrows ) to greater than three times the size of resident cell nuclei of the same type, and nuclear hyperchromicity present in some of the cells. Enlargement and hyperchromicity reflect the fact that anaplastic WTs contain nearly twice the amount of DNA as normal cells with duplication of many whole chromosomes in each cell.

Two principal staging systems are used for children with WTs. The COG system is based on pretreatment findings (prior to administration of chemotherapy or radiotherapy). Patients are given a local stage and a disease stage. The local stage defines the extent of abdominal disease, and the disease stage considers both the local extent of disease and distant metastasis. Both factors determine adjuvant therapy.

The COG staging system includes five stages:

• Stage I: The tumor is limited to one kidney and is completely resected. The surface of the renal capsule is intact, there is no involvement of renal sinus vessels, and the tumor was not biopsied prior to removal.

• Stage II: The tumor extends beyond the renal capsule but is completely resected. This may include extension into the renal sinus blood vessels or infiltration into the perirenal fat. However, there is no residual tumor apparent beyond the margins of resection.

• Stage III: Residual nonhematogenous tumor remains postsurgery. This may be due to tumor disruption localized to the flank before or during surgery, involvement of lymph nodes within the abdomen, or tumor removal in more than one piece (including prenephrectomy biopsy). This stage may also include tumors that are unresectable because of local infiltration into vital structures.

• Stage IV: Hematogenous metastases or lymph node metastases outside of the abdomen, such as to the lungs, liver, bone, or brain. There is also a local (abdominal) stage assigned in the setting of stage IV disease.

• Stage V: Bilateral renal involvement at the time of initial diagnosis. Each side should be staged separately according to the above criteria based on the extent of tumor spread as seen at surgery (each side has a local stage and may also include a separate stage IV designation if there are metastases).

The SIOP stages WT through a slightly different process than COG, with preoperative chemotherapy followed by surgery, with staging at the time of nephrectomy. Further chemotherapy or radiotherapy follows, if necessary.

• Stage 1: The tumor is confined to the kidney or surrounded with fibrous pseudocapsule. If outside the normal contours of the kidney, the renal capsule or pseudocapsule may be infiltrated with the tumor, but it does not reach the outer surface and is completely resected. The tumor may be protruding into the pelvic system and “dipping” into the ureter (but it is not infiltrating their walls). The vessels of the renal sinus are not involved. Intrarenal vessel involvement may be present.

• Stage 2: Tumor has spread beyond the kidney to nearby structures but has been completely removed. The tumor extends beyond kidney or penetrates through the renal capsule and/or fibrous pseudocapsule into perirenal fat but is completely resected. The tumor infiltrates the renal sinus and/or invades blood and lymphatic vessels outside the renal parenchyma but is completely resected. The tumor infiltrates adjacent organs or vena cava but is completely resected.

• Stage 3: Incomplete excision of the tumor, which extends beyond resection margins (gross or microscopic tumor remains postoperatively). Stage 3 includes involvement of abdominal lymph nodes, tumor rupture pre- or intraoperatively (irrespective of other criteria for staging), or tumor has penetrated through the peritoneal surface. This stage includes tumor thrombi present at resection margins of vessels or ureter, transected or removed piecemeal by the surgeon, or surgical biopsy was done prior to preoperative chemotherapy.

• Stage 4: Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdominopelvic region.

• Stage 5: There are tumors in both kidneys.

Tumors are also risk-stratified by SIOP using the postchemotherapy nephrectomy pathology as completely necrotic (low-risk tumor), other histology (intermediate-risk tumors), and blastemal (high-risk tumor).

A combination of histology, molecular genetics, and patient characteristics is used to determine prognosis, and subsequently treatment, for patients with WTs. ^{, , ,} With reference to histology, prognosis centers on favorable histology compared with anaplasia. Staging is as described above, and is determined by a combination of imaging studies, operative findings, and histologic findings on pathology review. Regarding molecular genetics, in COG trials, LOH at 1p and 16q have been used to assess prognosis and stratify for treatment; 1q gain will be used in future COG trials.

Response to chemotherapy has also been evaluated as a prognostic factor to stratify treatment. In COG trial AREN0533, children who had complete resolution of pulmonary metastases, as determined by computed tomography at 6 weeks, could avoid pulmonary radiation. The 4-year EFS for these patients was 78%.

Most children with renal tumors present with an asymptomatic abdominal mass, often noted by a pediatrician or parent during routine examination or care. The differential diagnosis of such abdominal masses includes pediatric renal tumors, but also neuroblastoma, hepatoblastoma, rhabdomyosarcoma, and other malignancies such as lymphoma. While renal tumors often present asymptomatically, patients may have hematuria, although this is more common in patients with RCC than WT. Additionally, about a quarter of patients with renal malignancies may present with hypertension.

Diagnosis of a renal tumor involves radiographic imaging. The initial study is often ultrasound, which can help determine the site of origin as well as assess for intravascular extension into the renal vein or inferior vena cava (IVC) ( Fig. 62.6 ). Renal vein thrombus is present in about 11% of patients with WTs, and further extension to the IVC occurs in 4%. While US is a common modality used to evaluate for vascular involvement, CT scan can be used to accurately identify tumor thrombus. Cross-sectional imaging, with either CT or MRI, aids further with diagnosis to determine the extent of the mass, as well as the presence or absence of bilateral disease. While it was previously recommended to routinely explore the contralateral kidney in a patient with WT to intraoperatively evaluate for bilateral disease, improved radiographic imaging with CT and MRI now demonstrates that <0.25% of bilateral tumors are missed radiographically. A “claw sign” may also be seen on cross-sectional imaging, helping to differentiate tumors of renal origin from neuroblastoma ( Fig. 62.7 ).

A transverse cut of a CT scan demonstrating a left Wilms tumor ( asterisk ) that extends into the inferior vena cava ( arrow ).

CT scan of a 4-year-old boy found on routine physical examination demonstrating a very large left renal tumor and the classic “claw sign” of a Wilms tumor that occurs with extension of the thin lip of renal parenchyma ( arrow ) over the tumor.

Cross-sectional imaging of the chest is also indicated in the staging evaluation to determine whether there is evidence of pulmonary metastasis, which is the most common site of spread for renal tumors. Intraabdominal imaging is not particularly useful for determination of local stage as the sensitivity and specificity of imaging for preoperative rupture or lymph node metastasis is low.