Wilms’ (/vɪlmz/) tumor, or nephroblastoma is one of the commonest tumors of the kidneys that typically occurs in children.

It is named after Dr. Max Wilms, the German surgeon (1867–1918) who first described it.

Wilms’ tumor, or nephroblastoma is a malignant tumor of the kidneys that typically occurs in children (Fig. 4.1).

It makes up 87 % of pediatric renal tumors.

Wilms tumor is the fourth most common childhood cancer.

It is also the most common abdominal malignancy in children.

Wilms’ tumor accounts for 6–7 % of all childhood cancers.

In North America about 450–500 new cases of Wilms tumor are diagnosed each year.

Wilms tumor is relatively more common in blacks than in whites and is rare in East Asians.

For unknown reasons, Wilms tumor is more common among children of African descent.

Most cases of Wilms’ tumor occur among children between 3 and 3.5 years old.

Girls are slightly more likely to develop Wilms’ tumor than are boys.

The majority (75 %) of Wilms’ tumor cases occur in otherwise normal children.

In about 25 % of cases, Wilms’ tumors are associated with other developmental abnormalities.

Most nephroblastomas are unilateral affecting one kidney only.

This however is not the case in patients with Denys-Drash syndrome who mostly have bilateral or multiple tumors.

The majority of nephroblastomas are unilateral and bilateral Wilms tumor are seen in 5–10 % of cases.

In 5–10 % of patients, both kidneys are affected:

Wilms’ tumor has a classic histologic picture which is called triphasic composed of epithelial, blastemal, and stromal elements.

Approximately 80–90 % of Wilms’ tumors have favorable histology.

About 3–7 % of Wilms’ tumors are characterized by anaplastic changes. If these changes are present diffusely throughout the tumor (diffuse anaplasia), they are predictive of a poor outcome.

Wilms’ tumors are usually encapsulated and vascularized and in cases of metastasis it is usually to the lungs.

Two renal tumor types (Clear cell sarcoma of the kidney and Rhabdoid tumor of the kidney) were previously included in the category with unfavorable Wilms’ tumors. Currently, these are considered separate malignant entities.

The overall prognosis of Wilms’ tumor following surgical excision is excellent and the survival of these patients has improved markedly over the years.

At present, with early diagnosis and current multimodality therapy, approximately 80–90 % of children with Wilms tumor survive.

Wilms tumor arises from persistent metanephric blastemal.

Pathologically, Wilms tumors are described as being triphasic made up of three elements:

Add to this the presence of abortive tubules and glomeruli surrounded by a spindled cell stroma. The stroma may include striated muscle, cartilage, bone, fat tissue, and fibrous tissue.

The mesenchymal component may include cells showing rhabdomyoid differentiation or malignancy (rhabdomyosarcomatous Wilms).

Pathologically, Wilms tumors is divided into two prognostic groups:

It was shown that mutations of the WT1 gene on chromosome 11p13 are seen in approximately 20 % of Wilms tumors.

At least half of the Wilms tumors with mutations in WT1 also carry mutations in CTNNB1, the gene encoding the proto-oncogene beta-catenin.

It was shown also that a gene on the X chromosome, WTX, is inactivated in up to 30 % of Wilms tumor cases.

A tumor biopsy is not typically performed due to the risk of creating fragments of cancer tissue and seeding the abdomen with malignant cells.

Children with Beckwith-Wiedemann syndrome, WAGR syndrome and Denys-Drash syndrome, have increased risk of Wilms tumor.

There is a definite genetic predisposition to Wilms’ Tumor in children with aniridia. This is due to deletions in the p13 band on chromosome 11.

The treatment of unilateral Wilms’ tumor is nephrectomy followed by chemotherapy, with or without postoperative radiotherapy. Chemotherapy regimens typically comprise vincristine and dactinomycin; doxorubicin and then cyclophosphamide and etoposide are added for increasingly high-risk disease.

Wilms tumor may spread to the lungs, liver, or nearby lymph nodes.

Wilms tumor is known to be associated with congenital anomalies:

Two loci on chromosome 11 have been implicated in the genesis of Wilms tumors.

Screening for Wilms tumor in patients with associated syndromes should begin at 6 months of age with initial computed tomography (CT) followed by serial ultrasonography (US) every 3 months up to 7 years of age because the risk of developing Wilms tumor after the age of 7 years decreases significantly.

Wilms tumor occasionally arises in the extrarenal retroperitoneum, presumably within mesonephric remnants (Extra Renal Wilms Tumor).

The “teratoid Wilms tumor”:

The vast majority of Wilms tumors demonstrate favorable rather than unfavorable histopathologic findings and anaplasia correlates directly with a negative prognosis and resistance to chemotherapy. It is characterized by atypical mitoses or hyperchromatic cells with large nuclei.

Wilms tumor is thought to be caused by alterations of genes responsible for normal genitourinary development.

This is supported by the common congenital urological anomalies associated with Wilms tumor including:

WT1 gene and other genetic loci

Beckwith-Wiedemann syndrome (BWS):

Wilms tumor arise as a solid intrarenal mass with a pseudocapsule.

The tumor may also arise from one pole of the kidney.

The tumor compresses the normal renal parenchyma and leads to distortion of the collecting system.

Wilms tumor typically spreads by direct extension causing displacement but no encasement of tissues.

There may be vascular invasion of the renal vein and inferior vena cava with occasional extension into the right atrium.

Metastases are most commonly found in the lungs (85 % of cases), liver, and regional lymph nodes, and metastatic disease may also produce vascular invasion.

Pathologically, Wilms’ tumor (Figs. 4.2, 4.3, 4.4, 4.5, 4.6, and 4.7):

Histologically, Wilms’ tumor is a malignant tumor composed of three elements (a triphasic nephroblastoma) (Figs. 4.8, 4.9, 4.10, 4.11, and 4.12):

One of the characteristic histological features of Wilms’ tumor is the presence of abortive tubules and glomeruli surrounded by a spindled cell stroma.

The stroma may include striated muscles, cartilage, bone, fat tissue, and fibrous tissue.

Rhabdomyosarcomatous Wilms:

Wilms’ tumors may be separated into two prognostic groups based on pathologic characteristics:

The anaplasia in Wilms’ tumor is classified into two types depending on the extent:

Approximately 90 % of all Wilms tumors have favorable histology.

About 3–7 % of Wilms tumors are characterized by anaplastic changes.

The presence of diffuse anaplasia throughout the tumor is a predictive of poor outcome.

Clear cell sarcoma of the kidney and rhabdoid tumor of the kidney were included in the unfavorable histology in the past and currently these are considered as separate malignant tumors.

The presence of nephrogenic rests, and dysplastic lesions of metanephric origin, are now believed to represent precursor lesions of Wilms tumor. These lesions are observed in approximately one third of kidneys affected by Wilms tumors.

It was also shown that children younger than age 12 months diagnosed with perilobar nephrogenic rests have a markedly increased risk of developing a contralateral Wilms tumor.

The National Wilms Tumor Study (NWTS) and Societe Internationale D’Oncologie Pediatrique (SIOP) have made large contributions to the modern multimodal treatment, which consists of surgical excision, radiotherapy, and chemotherapy (adjuvant and/or neoadjuvant). These oncologic treatments achieve a remarkable long-term overall survival rate of 90 %.

Most cases of Wilms tumor do not have mutations in any of the genes.

A gene on the X chromosome, WTX, is inactivated in up to 30 % of Wilms’ tumor cases.

The gene WT1:

The fetal kidney is formed by the development of nephrons from fetal metanephric blastema surrounding the ureteric bud.

The fetal renal tissue matures into normal renal parenchyma during gestation, but, occasionally, fetal tissue persists into infancy as microscopic foci called nephrogenic rests (renal blastema).

Renal blastema and nephroblastomatosis are interrelated conditions closely related to Wilms tumors (Figs. 4.13 and 4.14).

The persistence of primitive renal blastema beyond 4 months of age is abnormal except in small microscopic rests.

Nephroblastomatosis is defined as the presence of multifocal nephrogenic rests.

Nephrogenic rests are foci of metanephric blastema that persist beyond 36 weeks gestation and have the potential for malignant transformation into Wilms’ tumor.

Nephrogenic rest are found incidentally in 1 % of infants.

It is currently believed that nephrogenic rests give rise to approximately 30–40 % of Wilms’ tumors.

Nephrogenic rests are found in up to 99 % of bilateral Wilms’ tumors.

Nephrogenic rests are classified histologically as:

There are two pathologic subtypes of nephrogenic rest based on location (perilobar and intralobar):

Treatment for nephrogenic rests:

The usual presentation of Wims’ tumor is with a painless abdominal mass discovered accidently by the parents or by a physician during a routine physical examination. It is not uncommon for the mother to discover the mass while giving bath to her child. This is the presentation in more than 80 % of children with Wilms tumor.

The mass is discovered after coincidental trauma in up to 10 % of cases.

Abdominal pain (25 %)

Wilms’ tumor can present with (Figs. 4.15, 4.16, 4.17, and 4.18):

Hematuria:

Hypertension:

Rarely, the tumor may produce erythropoietin leading to increased red blood cells production and polycythemia.

Patients with Wilms tumor can present with hemorrhage into their tumor leading to hypotension, anemia, and fever.

Rarely patients with Wilms tumor and lung metastases may present with respiratory symptoms.

Wilms’ tumor can occur as part of rare genetic syndromes, including:

Female gender

Black children have a slightly higher risk of developing Wilms’ tumor than do children of other races.

Children of Asian descent appear to have a lower risk of developing Wilms’ tumor than do children of other races.

A family history of Wilms’ tumor increases the risk of developing Wilms’ tumor.

Wilms’ tumor occurs more frequently in children with certain congenital abnormalities, including:

Wilms’ tumor can occur as part of rare syndromes, including:

WT1 gene:

Additional genetic loci:

Wilms tumor may be part of a genetic syndrome and certain birth defects can also increase a child’s risk for developing Wilms tumor.

The following genetic syndromes and birth defects have been linked to Wilms tumor:

It is recommended that children with these genetic syndromes and birth defects should be screened for Wilms tumor every 3 months until age 8 years.

Staging of Wilms tumor is based on anatomical findings and tumor cells pathology.

The Children’s Oncology Group staging of Wilms tumors:

Stage I (43 % of patients)

Stage II (23 % of patients)

Stage III (20 % of patients)

Stage IV (10 % of patients)

Stage V (5 % of patients)

The National Wilms Tumor Study Group (NWTSG) and the International Society of Pediatric Oncology (SIOP) have contributed to the overall improved survival of children with Wilms tumors. They improved our understanding of the molecular mechanisms that contribute to the development of Wilms tumor and identified several chemotherapeutic agents through clinical trials.

Children with bilateral Wilms tumor are treated with preoperative chemotherapy. This is important because each kidney is staged separately, and preoperative chemotherapy may lead to complete resolution of disease in one kidney or reduction in the size of both tumors. This will make it possible to subsequently do nephrectomy on one side only or bilateral partial nephrectomies.

It is important to investigate children with Wilms tumor.

The aim of the specific investigations is to evaluate the:

There are general and specific investigations.

The general investigations include:

It is of great importance to exclude extension of the tumor into the renal vein as well as the inferior vena cava.

A plain abdominal radiograph (KUB) (Figs. 4.22 and 4.23):

Chest radiograph (Figs. 4.24, 4.25, and 4.26):

Abdominal ultrasound (Figs. 4.27, 4.28, 4.29, and 4.30):

Abdominal and thoracic CT-scan (Figs. 4.31, 4.32, 4.33, 4.34, and 4.35):

Intravenous urography (Figs. 4.36, and 4.37):

MRI scanning (Figs. 4.38, 4.39, 4.40, 4.41, 4.42, and 4.43):

Tumor extension into the renal vein and IVC is seen in 5–10 % of patients with Wilms tumor.

A cystic variant of Wilms tumor may mimic benign multilocular cystic nephroma.

Small abnormalities seen on chest x-ray are suggestive of secondaries but those seen on CT-scan may need to be confirmed by biopsy.

With the current radiological investigations, physical inspection of the opposite kidney by opening Gerota’s fascia as suggested previously to check for synchronous tumor is no longer necessary.

Abdominal and chest CT-scan is useful in determining (Figs. 4.44, 4.45, 4.46, 4.47, 4.48, 4.49, 4.50, and 4.51):

Diagnostic biopsy of lesions noted on the chest CT scan is recommended to confirm the diagnosis.

Histopathologic confirmation of Wilms tumor is essential.

Transcutaneous biopsy is not usually recommended as this may complicate treatment by causing preoperative tumor spill, requiring whole abdominal radiotherapy.

The prognosis is highly dependent on individual staging, histology and treatment.

The overall 5-year survival is estimated to be approximately 80–90 %.

Tumor-specific loss-of-heterozygosity (LOH) for chromosomes 1p and 16q identifies a subset of Wilms tumor patients who have a significantly increased risk of relapse and death. Children with loss of heterozygosity at 1p and 16q are treated with more aggressive chemotherapy.

Approximately 80–90 % of children with a diagnosis of Wilms tumor survive with current multimodality therapy.

Patients who have tumors with favorable histology have an overall survival rate of at least 80 % at 4 years after the initial diagnosis, even in patients with stage IV disease.

The 4-year relapse-free and overall survival rates in patients with favorable-histology Wilms tumor are as follows

Patients with synchronous bilateral tumors have a 70–80 % survival rate, whereas those with metachronous tumors have a 45–50 % survival rate.

Patients with anaplastic Wilms tumor have a worse prognosis compared with favorable histology Wilms tumor; the 4-year overall survival rates are 83 %, 83 %, 65 % and 33 % for stages I, II, III, and IV, respectively.

Children with a loss of heterozygosity at 1p and 16q have a worse prognosis than do children without this heterozygosity loss.

The prognosis for patients who have a relapse is not as good as it is for those with a newly diagnosed Wilms tumor, with 40–80 % of relapse patients expected to survive after salvage therapy.

Chemotherapy and radiation therapy can induce second malignant neoplasms.

Renal complications:

Hepatic complications:

Other complications include:

According to Children’s Oncology Group (COG), the treatment of Wilms tumor is nephrectomy followed by chemotherapy, with or without postoperative radiotherapy.

Certain children with stage I disease and favorable histology do well with nephrectomy alone.

Radiotherapy:

In North America:

In most European centers:

Transcutaneous biopsy is not usually recommended and may in fact complicate treatment by causing preoperative tumor spill, requiring whole abdominal radiotherapy.

Aspiration cytology is a valuable investigation to diagnose Wilms’ tumor but it requires a good pathologist to read it (Fig. 4.51).

The usual approach in most patients is nephrectomy followed by chemotherapy, with or without postoperative radiotherapy.

Children found to have loss of heterozygosity at 1p and 16q receive more aggressive chemotherapy because they have a worse prognosis than do children without this heterozygosity loss.

Children younger than age 12 months diagnosed with perilobar nephrogenic rests have a markedly increased risk of developing a contralateral Wilms’ tumor.

The National Wilms’ Tumor Study Group (NWTSG) and the International Society of Pediatric Oncology (SIOP) have identified several chemotherapeutic agents through their clinical trials.

At present, survival rates of children with Wilms’ tumor are approximately 80–90 %.

Chemotherapy without initial surgical resection can be used in the following situations:

Postoperative chemotherapy and radiotherapy protocols are based on the surgical staging and follow the guidelines of the NWTSG.

Stage I:

Stage II:

Stage III:

Stage IV:

Stage V:

The management of bilateral Wilms’ tumor must be individualized according to the extent of tumor present in both kidneys with a goal to preserving adequate kidney tissue to avoid kidney failure.

Stage I–IV Anaplasia:

About 5–10 % of patients with Wilms tumor present with acquired von Willebrand disease at the time of diagnosis.

The reason for this acquired von Willebrand disease is not known ad several hypothesis have been postulated including:

The presence of acquired von Willebrand disease in these patients will lead to excessive bleeding during surgery and should be treated preoperatively.

Desmopressin (DDAVP), a drug that promotes the release of vWF from storage sites, is recommended.

If DDAVP is ineffective, cryoprecipitator (a specific vWF concentrate) should be administered.

Management of lung metastasis (Figs. 4.64, 4.65, and 4.66):

The overall surgical complication rate for Wilms’ tumor is approximately 15–20 %.

Surgical complications may include the following:

The overall 5-year survival in children with Wilms’ tumor is estimated to be approximately 90 %.

This however is variable and the prognosis is highly dependent on the stage and treatment of tumor.

Tumor-specific loss-of-heterozygosity (LOH) for chromosomes 1p and 16q identifies a subset of Wilms’ tumor patients who have a significantly increased risk of relapse and death.

LOH can now be used as an independent prognostic factor together with disease stage to give intensive treatment.