Pediatric Surgery, AlSadik Hospital, Qatif, Saudi Arabia
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Renal tumors are rare in children, with some of them being highly treatable and usually curable.
The type of tumor found through pathological examination is very predictive of the outcome of children with renal tumors.
The determination of tumor type is very important so that the children can receive the appropriate therapy.
Renal tumors in children comprise a spectrum ranging from the benign neonatal congenital mesoblastic nephroma to the highly malignant anaplastic Wilms’ tumor and Rhabdoid tumor of the kidney.
Many pediatric renal tumors were previously lumped together and categorized as Wilms tumor.
However, in recent years several specific tumors have been recognized as distinct pathologic entities.
These are separate from the classic Wilms tumor.
Wilms tumor (nephroblastoma) is the commonest renal tumor and accounts for 87 % of pediatric renal tumors.
Although Wilms tumor is the most common pediatric renal malignancy, it is often indistinguishable from other rare but more aggressive tumors like rhabdoid tumor of the kidney and renal clear cell sarcoma or the more benign tumors like mesoblastic nephroma.
Currently, as a result of better understanding of these tumors and the multimodal approach to therapy, survival of these patients has improved to its current rate of more than 80 %.
The diagnosis of renal tumors of childhood is based on:
The clinical presentation and radiographic appearance of these tumors are not unique to each tumor, and the diagnosis can only be confirmed by histological evaluation.
The histological diagnosis is also important to decide the most appropriate adjuvant treatment of these tumors as these tumors range from chemosensitive Wilms’ tumors to nonchemosensitive renal cell carcinoma.
As with most tumors, a staging system has been developed to categorize patients for the appropriate treatment.
Age at Presentation for Renal Malignancies
Unilateral Wilms tumor: 1–11 year (Mean 3.5 year)
Bilateral Wilms tumor: 2 months–2 year (Mean 15 months)
Nephroblastomatosis: 6–18 months
Renal cell carcinoma: 6 months–60 year (Commonly 10–20 year)
Mesoblastic nephroma: 0–1 year (Commonly 1–3 months)
Multilocular cystic renal tumor
Cystic nephroma: Adult female
Cystic partially differentiated nephroblastoma: 3 months–4 year (Commonly 1–2 year)
Clear cell sarcoma: 1–4 year (Mean 2 year)
Rhabdoid tumor: 6 months–9 year (Commonly 6–12 months)
Angiomyolipoma: 6–41 year (Mean 10 year)
Renal medullary carcinoma: 10–39 year (Mean 20 year)
Ossifying renal tumor of infancy: 6 days–14 months (Commonly 1–3 months)
Metanephric adenoma: 15 months–83 year
Hodgkin lymphoma: >10 year (Commonly late teens
Non-Hodgkin lymphoma: Any age (Commonly child <10 year)
Patients with tumors confined to the kidney that can be removed completely have the best survival rate.
Patients who have unfavorable histology are not very responsive to chemotherapy or radiation therapy and complete surgical excision is essential.
There are several renal tumors in children and these include:
Cystic partially differentiated nephroblastoma
Renal cell carcinoma
Clear cell sarcoma
Rhabdoid tumor of the kidney
Ossifying renal tumor of infancy
Neuroepithelial tumors of the kidney
Renal medullary carcinoma
Desmoplastic small round cell tumor of the kidney
Others (Fibroma, Leiomyoma, Leiomyosarcoma, Primary renal synovial sarcoma, Anaplastic sarcoma of the kidney)
4.2 Wilms’ Tumor
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).
A clinical photograph showing Wilms tumor arising from the upper part of the kidney
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:
At the same time (synchronous bilateral Wilms tumor).
Or one after the other (metachronous bilateral Wilms tumor).
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.
This is attributed to The National Wilms’ Tumor Study Group (NWTSG) and the International Society of Pediatric Oncology (SIOP) who have identified several chemotherapeutic agents through their clinical trials.
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:
Favorable: The tumor contains well developed components.
Anaplastic: The tumor contains diffuse anaplasia (poorly developed cells).
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:
Cryptorchidism (2.8 %)
Hemihypertrophy (2.5 %)
Hypospadias (1.8 %)
Two loci on chromosome 11 have been implicated in the genesis of Wilms tumors.
Locus 11p13 is known as the WT1gene
Locus 11p15 is known as the WT2 gene.
An abnormal WT1 gene is present in patients with WAGR syndrome:
An abnormal WT1 gene is present in patients with Denys-Drash syndrome:
An abnormal WT2 gene is present in patients with Beckwith-Wiedemann syndrome or hemihypertrophy.
The genetics of Wilms tumor appear to be multifactorial, and abnormalities at other sites, including chromosomes 1, 12, and 8, are also recognized.
Familial Wilms tumor is rare, occurring in approximately 1 % of cases and is not associated with mutations in chromosome 11.
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”:
This is a Wilms tumor characterized by tissue differentiation within the tumor cells such as bone, cartilage, and muscle.
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:
A double collecting system
WT1 gene and other genetic loci
WT1 encodes a transcription factor critical to normal renal and gonadal development.
WT1, the first Wilms tumor suppressor gene at chromosomal band 11p13, was identified in children with Wilms tumor who also had aniridia, genitourinary anomalies, and mental retardation (WAGR syndrome).
Karyotypic analysis revealed constitutional deletions within the short arm of 1 copy of chromosome 11.
The 11p13 locus was subsequently demonstrated to encompass numerous contiguous genes, including the aniridia gene PAX6 and the Wilms tumor suppressor gene WT1.
A second gene that predisposes individuals to develop Wilms tumor has been identified at chromosomal band 11p15.
This locus was proposed on the basis of studies in patients with both Wilms tumor and Beckwith-Wiedemann syndrome (BWS).
Loci at 16q, 1p, 7p, and 17p have also been implicated in the biology of Wilms tumor, although these loci do not seem to predispose individuals to develop a Wilms tumor.
Beckwith-Wiedemann syndrome (BWS):
This is an overgrowth syndrome characterized by visceromegaly, macroglossia, and hyperinsulinemic hypoglycemia.
Patients with BWS are predisposed to have several embryonal neoplasms, including Wilms tumor.
Several loci for Wilms tumor and BWS have been proposed. These loci include:
The insulinlike growth factor II gene (IGFII)
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):
Figs. 4.2, 4.3, and 4.4
Clinical photographs showing Wilms tumor. Note the compressed renal tissue at the periphery
A clinical photograph showing an excised Wilms tumor. Note the fleshy, homogenous and Tan-gray in color tumor
A photograph of a resected Wilms’ tumor. Note the gross appearance of Wilms’ tumor with the normal part of the kidney being compressed by the tumor
A clinical photograph showing an excised Wilms tumor. Note the areas of hemorrhage within the tumor
Is usually a large, solitary and encapsulated tumor.
It compresses the remaining normal kidney parenchyma.
On cut section, Wilms’ tumor is soft, homogenous and Tan-gray in color and may contain areas of hemorrhage and necrosis.
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):
A histological photograph of Wilms’ tumor showing blastema () tubules () and spindle cells ()
Figs. 4.9 and 4.10
Histological picture of Wilms’ tumor showing tubules and spindle cells
Figs. 4.11 and 4.12
Histological pictures showing anaplastic Wilms’ tumor. Note the large cells with large nuclei
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.
The mesenchymal stroma may also include cells showing rhabdomyoid differentiation. The rhabdomyoid component may itself show features of malignancy. When this feature is present, it is called rhabdomyosarcomatous Wilms’ tumor. This particular sub-type shows poor response to chemotherapy.
Wilms’ tumors may be separated into two prognostic groups based on pathologic characteristics:
Favorable: This contains well developed components.
Anaplastic (unfavorable): This contains anaplastic cells which could be focal or diffuse. This is associated with higher frequencies of relapse and death especially those with diffuse anaplasia.
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:
This is also called Wilms tumor suppressor gene.
It has been found to make a protein that is found mostly in the fetal kidney and in tissues that give rise to the genitourinary system.
Inactivation of this gene may be responsible for the occurrence of Wilms tumor.
Mutations of the WT1 gene on chromosome 11 p 13 are observed 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.
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).
Figs. 4.13 and 4.14
Abdominal CT-scan showing bilateral nephroblastomatosis and Wilms’ tumor
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:
Dormant, sclerosing, hyperplastic, or neoplastic.
Dormant and sclerosing rests are usually microscopic and are not considered to have malignant potential.
Hyperplastic and neoplastic rests are grossly visible as small tan nodules surrounded by normal parenchyma.
There are two pathologic subtypes of nephrogenic rest based on location (perilobar and intralobar):
Perilobar rest (90 %)
Intralobar rest (10 %). This is more associated with Wilms’ tumor.
They are found in subcapsular location with well demarcated low power margins.
They are associated with Beck-with-Wiedemann syndrome and hemihypertrophy, Perlman syndrome (visceromegaly, gigantism, cryptorchidism, polyhydramnios, characteristic facies), and trisomy 18.
Malignant degeneration into Wilms tumor is most common in patients with Beckwith-Wiedemann syndrome and hemi-hypertrophy, occurring in 3 % of cases.
These are considerably less common than the perilobar nephrogenic rest.
They present anywhere within the kidney and often have a more irregular and intermixed margins.
They have a higher association with Wilms tumor development.
These rests are found in 78 % of patients with Denys-Drash syndrome and nearly 100 % of patients with sporadic aniridia and are also seen in patients with WAGR syndrome.
Ultrasonographic detection of these rests is possible, but sonography lacks the sensitivity of CT and MRI.
On CT, macroscopic nephrogenic rests appear as low-attenuation peripheral nodules with poor enhancement relative to that of adjacent normal renal parenchyma.
On MRI, the nodules demonstrate low-signal-intensity foci on both T1-weighted and T2-weighted images.
On sonograms, the affected kidney may be enlarged and lobulated with multiple hypoechoic areas. Corticomedullary differentiation may be lost.
After such findings are discovered, three monthly ultrasound examinations should be performed to detect their progression to a Wilms’ tumor.
Lymphoma can mimic the appearance of nephroblastomatosis but is unusual in infants and young children.
Treatment for nephrogenic rests:
This is controversial.
Some investigators recommend chemotherapy, whereas others maintain that close serial radiologic evaluation of enlarging masses is sufficient.
Screening for Wilms tumor in patients with syndromes associated with nephrogenic rests should be performed.
Ultrasound is a good follow-up investigation, cheap, readily available and can be done easily without anesthesia, however CT-scan is the method of choice for follow-up.
On imaging, nephroblastomatosis appear as discrete, homogeneous, non-enhancing renal masses.
Any rapid growth, inhomogeneity, or heterogeneous enhancement should be taken seriously and worrisome for development of Wilms.
4.2.5 Clinical Features
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):
Figs. 4.15 and 4.16
Clinical photographs showing children with left and right Wilms tumors
A clinical photograph showing a very large Wilms tumor filling almost the whole abdomen
A clinical photograph showing a very large Wilms tumor. This proved by abdominal CT-scan to be secondary to hemorrhage inside the tumor
Abdominal swelling or distension
Nausea and vomiting
Urinary tract infection
Wilms’ tumor can grow rapidly as a result of bleeding into the tumor or from actual tumor growth.
Bleeding into the tumor will lead to anemia and if severe will result in heart failure.
May be seen in 10–15 % of cases.
This can be microscopic or gross hematuria.
This is seen often after a relatively minor trauma and injury of the enlarged kidney by the tumor.
Hematuria may be seen as a late presentation that is usually associated with tumor invasion of the calyces and considered a bad prognostic sign.
As many as one third of patients with Wilms tumor present with hypertension. Their blood pressure usually normalizes after nephrectomy, but they occasionally require prolonged therapeutic intervention
Increased blood pressure may be present in 20 % of Wilms’ tumor cases.
Hypertension in Wilms’s tumor results from pressure effect of the tumor on the renal vessels leading to increased secretion of rennin.
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:
WAGR syndrome. This syndrome includes:
Abnormalities of the genitals and urinary system.
Denys-Drash syndrome. This syndrome includes:
These patients mostly have bilateral or multiple tumors.
Beckwith-Wiedemann syndrome. This syndrome includes:
A large tongue (macroglossia).
Enlarged internal organs (visceromegaly).
4.2.6 Risk Factors for Wilms’ Tumor
Girls are slightly more likely to develop Wilms’ tumor than are boys.
Black children have a slightly higher risk of developing Wilms’ tumor than do children of other races.
People of African descent have the highest rates of Wilms’ tumor.
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:
Aniridia (partial or total absence of the iris)
A genetic predisposition to Wilms’ Tumor in individuals with aniridia has been established, due to deletions in the p13 band on chromosome 11.
A double collecting system
Wilms’ tumor can occur as part of rare syndromes, including:
WAGR syndrome: This syndrome includes Wilms’ tumor, aniridia, abnormalities of the genitals and urinary system, and mental retardation.
Denys-Drash syndrome: This syndrome includes Wilms’ tumor, kidney disease and male pseudohermaphroditism.
Beckwith-Wiedemann syndrome (BWS):
BWS is an overgrowth syndrome characterized by visceromegaly, macroglossia, omphalocele and hyperinsulinemic hypoglycemia.
Patients with BWS are predisposed to have several embryonal neoplasms, including Wilms’ tumor.
Few candidate loci for Wilms’ tumor and BWS have been proposed. These loci include the insulinlike growth factor II gene (IGFII), H19 (for an untranslated ribonucleic acid [RNA]), and that encoding for p57kip2.
WT1, the first Wilms’ tumor suppressor gene at chromosomal band 11p13, was identified as a direct result of the study of children with Wilms’ tumor who also had aniridia, genitourinary anomalies, and mental retardation (WAGR syndrome).
WT1 encodes a transcription factor critical to normal renal and gonadal development.
The WT1 gene is the specific target of mutations and deletions in a subset of patients with sporadic Wilms’ tumors, as well as in the germline of some children (e.g., those with Denys-Drash syndrome) with a genetic predisposition to develop this cancer.
Additional genetic loci:
A second gene that predisposes individuals to develop the Wilms’ tumor has been identified (but has not yet been cloned) telomeric of WT1, at 11p15. This locus was proposed on the basis of studies in patients with both Wilms’ tumor and Beckwith-Wiedemann syndrome (BWS), another congenital Wilms’ tumor predisposition syndrome linked to chromosomal band 11p15.
Loci at 16q, 1p, 7p, and 17p have also been implicated in the biology of Wilms tumor, although these loci do not seem to predispose individuals to develop a Wilms’ tumor. Instead, they seem to be associated with the phenotype or the outcome.
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:
WAGR syndrome (Wilms tumor, aniridia, abnormal genitourinary system, and mental retardation)
Beckwith-Wiedemann syndrome (visceromegaly, macroglossia, and hyperinsulinemic hypoglycemia)
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.
4.2.7 Staging of Wilms Tumor
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)
Tumor is limited to the kidney and is completely excised.
The surface of the renal capsule is intact.
The tumor is not ruptured or biopsied (open or needle) prior to removal.
No involvement of extrarenal or renal sinus lymph-vascular spaces
No residual tumor apparent beyond the margins of excision.
Metastasis of tumor to lymph nodes not identified.
Stage II (23 % of patients)
Tumor extends beyond the kidney but is completely excised.
No residual tumor apparent at or beyond the margins of excision.
Any of the following conditions may also exist:
Tumor involvement of the blood vessels of the renal sinus and/or outside the renal parenchyma.
The tumor has been biopsied prior to removal or there is local spillage of tumor during surgery, confined to the flank.
Extensive tumor involvement of renal sinus soft tissue.
Stage III (20 % of patients)
Inoperable primary tumor.
Lymph node metastasis.
Tumor is present at surgical margins.
Tumor spillage involving peritoneal surfaces either before or during surgery, or transected tumor thrombus.
Stage IV (10 % of patients)
Stage IV Wilms tumor is defined as the presence of hematogenous metastases (lung, liver, bone, or brain), or lymph node metastases outside the abdomenopelvic region (Fig. 4.19).
CT-scan of the chest showing secondaries from Wilms tumor
Stage V (5 % of patients)
Stage V Wilms tumor is defined as bilateral renal involvement at the time of initial diagnosis (Figs. 4.20 and 4.21).
Figs. 4.20 and 4.21
Abdominal CT-scan in two patients with bilateral Wilms’ tumor. The sizes of both tumors is different
In term of treatment and prognosis, for patients with bilateral Wilms tumor, it is important to stage each side separately according to the above criteria on the basis of extent of disease and plan treatment according to the side with the more advanced stage.
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:
Extent of the tumor
Presence or absence of secondaries
Presence or absence of synchronous Wilms tumors
It is also important to make sure that there is a normally functioning contralateral kidney
There are general and specific investigations.
The general investigations include:
A complete blood count
Liver function tests
BUN and creatinine
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):
Figs. 4.22 and 4.23
Abdominal radiograph showing a soft tissue density in two patients with right and left Wilms tumor. Note the mass compressing and pushing the bowel downward and to the other side
This often shows a soft tissue density with displacement of bowel loops inferiorly and to the contralateral side.
Occasionally calcification (<10 %) is seen.
The calcification usually is located on the edge of the tumor whereas calcification in neuroblastoma is speckled throughout.
Chest radiograph (Figs. 4.24, 4.25, and 4.26):
Figs. 4.24, 4.25, and 4.26
Chest x-rays showing pulmonary secondaries from Wilms’ tumor
This is to confirm or exclude the presence of secondaries in the lungs.
Distant metastasis in Wilms’ tumor is commonly seen in the lungs.
CT-scan of the chest is more informative for the presence or absence of secondaries.
In children with Wilms’ tumor. CT-scan of the chest and abdomen should be done simultaneously.
Abnormalities seen on chest CT-scan however, needs to biopsied to confirm the diagnosis.
Abdominal ultrasound (Figs. 4.27, 4.28, 4.29, and 4.30):
Figs. 4.27, 4.28, 4.29, and 4.30
Abdominal ultrasound showing left renal Wilms tumor in the upper one and bilateral Wilms tumor in the lower two pictures
This is valuable in determining the origin of the tumor, whether the mass is cystic or solid; and indicates if the tumor extends into the renal veins and inferior vena cava.
It is also useful in evaluating the contralateral kidney and whether a synchronous tumor is present or not.
Doppler ultrasound is a valuable investigation in detecting tumor extension in the renal vein and inferior vena cava and the extent of extension.
This shows a solid intrarenal mass.
The mass has heterogeneous echogenicity, which represents hemorrhage, fat, necrosis, or calcification.
Abdominal and thoracic CT-scan (Figs. 4.31, 4.32, 4.33, 4.34, and 4.35):
Figs. 4.31 and 4.32
Abdominal CT-scan showing a very large left Wilms tumor
Abdominal CT-scan showing a very large right Wilms tumor
Figs. 4.34 and 4.35
Abdominal CT-scans showing bilateral Wilms tumor
This defines the tumor site; identifies the presence of enlarged lymph nodes; evaluates the contralateral kidney for possible presence of a second Wilms’ tumor; assesses extension of the tumor into the renal veins, inferior vena cava and right atrium, and determines if the patient has intra-abdominal secondaries to the liver.
It is also valuable in detecting nodal metastases as well hemorrhage and areas of calcification within the tumor.
It is important to visualize the contralateral kidney and document that it is functioning using contrast.
Thoracic CT-scan is important to detect pulmonary metastasis. Sometimes pulmonary metastasis are not seen on chest x-ray and appear only on CT-scan.
Intravenous urography (Figs. 4.36, and 4.37):
Figs. 4.36 and 4.37
Intravenous urography showing left and right Wilms tumors. Note the normal functioning contralateral kidney. Note also the distortion of the calcyeal system of the affected kidney
In the past, this was one of the radiological investigation used to evaluate children with Wilms’ tumor.
This is also useful to show that a normal functioning contralateral kidney is present.
Currently, this is replaced by CT-scan and MRI.
MRI scanning (Figs. 4.38, 4.39, 4.40, 4.41, 4.42, and 4.43):
Figs. 4.38 and 4.39
Abdominal MRI showing left Wilms tumor. Note the normally functioning right kidney
Figs. 4.40 and 4.41
Abdominal MRI showing a large left side Wilms’ tumor with areas of hemorrhage and or necrosis. Note also an associated congenital pancreatic cyst
Figs. 4.42 and 4.43
Abdominal MRI showing a large right side Wilms’ tumor
Abdominal magnetic resonance imaging (MRI) is reportedly the most sensitive imaging modality for determination of caval patency and may be important in determining whether the inferior vena cava is directly invaded by the tumor or not.
Wilms’ tumor demonstrates low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.
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):
CT-scan of the chest showing pulmonary metastasis from Wilms tumor
CT-scan of the chest showing liver metastasis from Wilms tumor
Figs. 4.46 and 4.47
CT-scans of the abdomen showing local recurrence following resection of Wilms tumor
Abdominal CT-scan showing bilateral Wilms’ tumor
Abdominal CT-scan showing left side Wilms’ tumor. Note the patent IVC and the presence of an enlarged lymph node
Abdominal CT-scan showing a large left Wilms’ tumor. Note the areas of hemorrhage or necrosis in the center
Aspiration cytology showing cells of Wilms’ tumor
The origin of the tumor
Involvement of the regional lymph nodes and local recurrence
Bilateral renal involvement
To visualize the contralateral kidney and document that it is functioning using contrast.
Invasion into the renal vein and inferior vena cava
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 National Wilms Tumor Study Group (NWTSG):
Patients with unilateral Wilms tumor undergo nephrectomy immediately.
During the procedure, the contralateral kidney is explored to ensure that the disease is indeed unilateral.
Lymph node biopsy samples are obtained for staging purposes. Lymph node dissection is not indicated.
The International Society of Pediatric Oncology (SIOP)
The diagnosis of Wilms tumor is presumptive based on imaging findings alone.
Administration of chemotherapy
4.2.9 Prognosis and Complications of Wilms Tumor
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
Survival rates in patients with favorable-histology Wilms tumor
Relapse-free survival %
Overall survival, %
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.
Children with unilateral Wilms tumor who undergoes nephrectomy have a minimal risk for impaired contralateral renal function.
There is usually a compensatory postnephrectomy hypertrophy of the remaining kidney.
The function of the remaining kidney may be affected in those who receive postoperative radiotherapy (Radiation-induced renal damage).
Renal function can be impaired in those with bilateral Wilms tumor.
The risk factors for renal damage include:
Stromal predominant histology
Age at diagnosis of younger than 24 months
Metachronous bilateral Wilms tumor
WT1 mutation etiology.
Hepatic damage in patients with Wilms tumor can be caused by radiation therapy and the use of cytotoxic drugs particularly dactinomycin and vincristine.
The dactinomycin hepatotoxicity is dose-related.
Radiotherapy is the main cause of hepatic toxicity but this rare nowadays.
Hepatic toxicity was reported in 2.8–14.3 % of children who did not receive radiotherapy.
Some patients with Wilms tumor have developed hepatic veno-occlusive disease.
Hepatic veno-occlusive disease is characterized by hepatomegaly or pain in the right upper quadrant, jaundice, ascites, and unexplained weight gain.
It is seen in children with Wilms tumor undergoing nephrectomy first and in those receiving combination chemotherapy before surgery.
Other complications include:
Congestive heart failure is a well-known complication of the administration of anthracyclines (e.g. doxorubicin).
Radiation-induced pulmonary complications. This is more commonly seen in those who receive bilateral pulmonary irradiation.
Women who received whole-abdomen irradiation in childhood can develop ovarian failure.
Male patients are at risk for testicular failure after whole-abdomen radiation therapy or certain types of chemotherapy, most notably that involving alkylating agents.
Radiation therapy may affect the growth of any given bone but the spine is most notably affected. The effect is dose related and can lead to scoliosis.
There is an increased risk for second malignant neoplasm following chemotherapy and or radiotherapy.
Most secondary malignant neoplasms reported (e.g., bone tumors, breast and thyroid cancers) have occurred in irradiated areas.
Certain chemotherapeutic agents, including doxorubicin, dactinomycin, and vincristine, may contribute to an increased risk for secondary malignancies.
A recent interesting finding was that female survivors of Wilms tumor have a 9.1-fold increased risk of developing invasive breast cancer and had an estimated cumulative risk of invasive breast cancer at age 40 of 4.5 %. The risk was highest among children who had been treated with chest radiotherapy.
4.2.10 Surgical Considerations
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.
Postoperative radiotherapy is started within 14 days of nephrectomy.
The current dose for radiation therapy for favorable histology Wilms tumor is approximately 1,080 cGy for the abdomen and 1,200 cGy for the lung.
Patients with stage IV favorable histology Wilms tumor and lung metastases whose pulmonary lesions do not disappear after 6 weeks of chemotherapy receive whole-lung radiation therapy.
In North America:
Patients with suspected Wilms’ tumor undergo nephrectomy immediately.
During this procedure, the contralateral kidney is explored to ensure that Wilms’ tumor is unilateral.
Currently, may surgeons will not explore the contralateral kidney and will depend on preoperative CT-scan or MRI evaluation.
Lymph node biopsy samples are obtained for staging purposes.
Immediate nephrectomy is not performed in patients with bilateral Wilms’ tumor or those with very large unresectable Wilms tumor.
In most European centers:
A presumptive diagnosis of Wilms’ tumor is made based on imaging findings alone.
Administer chemotherapy before nephrectomy.
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:
Inoperable tumors (Figs. 4.52, 4.53, 4.54, 4.55, 4.56, and 4.57):
Figs. 4.52 and 4.53
CT-can showing large Wilms Tumors that appear inoperable
Figs. 4.54 and 4.55
CT-scan showing large left sided Wilms tumor
Figs. 4.56 and 4.57
Radiological evaluation of a large left Wilms tumor that was treated with preoperative chemotherapy showing an excellent response
Large tumors that involve vital structures make resection difficult; the complication rate is high, and the incidence of tumor rupture and spill is also high.
Intracaval tumor extension:
This occurs in 5 % of cases of Wilms’ tumor.
This is associated with a 40 % rate of surgical complications.
Chemotherapy after staging and biopsy is beneficial in reducing the tumor and thrombus size.
Bilateral Wilms’ tumor (Figs. 4.58, 4.59, 4.60, 4.61, 4.62, and 4.63).
Figs. 4.58, 4.59, 4.60, and 4.61
Abdominal CT-scans showing bilateral Wilms tumors
Figs. 4.62 and 4.63
Abdominal CT-scans showing bilateral Wilms tumor before and after chemotherapy. Note the excellent response to chemotherapy with complete disappearance of Wilms tumor on one side and marked reduction of the tumor on the other side
SIOP advocates chemotherapy without previous laparotomy and biopsy. The NWTSG suggests that this approach results in a 1–5 % risk of treating a benign disease.
Chemotherapy without proper surgical staging (e.g., staging by means of imaging studies only) may alter the actual initial stage of the disease by the time of surgery and may subsequently alter decisions regarding the adjuvant chemotherapy and radiation therapy, which is based on the surgical staging.
Postoperative chemotherapy and radiotherapy protocols are based on the surgical staging and follow the guidelines of the NWTSG.
Nephrectomy ±18 weeks of chemotherapy depending on age of the patient and weight of tumor.
A child less than 2 years old and a tumor less than 550 g only requires Nephrectomy and observation.
Nephrectomy + abdominal radiation + 24 weeks of chemotherapy.
Abdominal radiation + 24 weeks of chemotherapy + nephrectomy after tumor shrinkage.
Nephrectomy + abdominal radiation + 24 weeks of chemotherapy + radiation of metastatic site as appropriate.
Individualized therapy based on tumor burden.
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.
The initial procedure should be biopsies of both kidneys to establish the diagnosis and histological types in both kidneys.
Approximately 4 % of cases have different types between the two kidneys.
The patient is treated with chemotherapy and restudied by abdominal CT or MRI to evaluate tumor response and determine whether a surgical procedure would be beneficial.
If considerable tumor persists in both kidneys, additional chemotherapy is administered, and surgery is delayed.
Radiation therapy is withheld if possible in these cases to reduce the risk of radiation injury to the remaining kidney tissue.
In some patients, the tumor persists in both kidneys, and resection of the tumor with preservation of functioning kidney tissue is not possible. The only remaining option for these rare patients ultimately is removal of both kidneys.
Stage I–IV Anaplasia:
Children with stage I anaplastic tumors can be managed with the same regimen given to stage I favorable histology patients.
Children with stage II through stage IV diffuse anaplasia, however, represent a higher-risk group.
These tumors are more resistant to the chemotherapy traditionally used in children with Wilms’ tumor (favorable histology), and require more aggressive regimens.
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:
Absorption of the von Willebrand factor (vWF) by tumor cells.
Hyperviscosity caused by elevated serum levels of hyaluronic acid.
An immunoglobulin G (IgG)–type antibody that prevents aggregation of normal platelet cells.
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):
Figs. 4.64 and 4.65
Abdominal and chest x-ray in a patient with right Wilms tumor and normal looking chest x-ray and chest CT-scan showing a single secondary in the chest
Chest CT-scan showing multiple bilateral pulmonary secondaries in a child with Wilms tumor
A normal chest x-ray during initial evaluation does not exclude the presence of pulmonary metastasis and a chest CT-scan should be done as part of their evaluation.
Children with normal looking chest radiography and positive findings on chest CT-scan require tissue diagnosis of the lung nodules.
It is important to have tissue diagnosis of the lung nodules because several conditions (e.g. histoplasmosis, atelectasis, pseudotumor, intrapulmonary lymph node, pneumonia) can mimic pulmonary metastases.
These secondaries can be single or multiple.
A biopsy can be performed percutaneously or thoracoscopically.
Single secondaries can be excised totally while multiple lesions are biopsied.
Patients with favorable histology Wilms’ tumor with lung metastasis and no other sites of distant spread or presence of 1p and 16q deletion are treated with 6 weeks of actinomycin-D, doxorubicin, and vincristine.
A clinical intraoperative photograph showing radical nephrectomy for Wilms tumor. Note also the ureter which should be excised as low as possible
A clinical intraoperative photograph showing radical nephrectomy for Wilms tumor
The first step in the treatment of Wilms’ tumor is surgical staging followed by radical nephrectomy, if possible.
Begin the abdominal exploration through a transverse incision.
The kidney is explored by mobilizing the ipsilateral colon and opening the Gerota fascia.
Exploration of the contralateral kidney is currently not recommended because of the improvement in imaging techniques (computed tomography [CT] scanning, magnetic resonance imaging [MRI]).
If the tumor is unresectable, biopsies are performed and the nephrectomy is deferred until after chemotherapy, which, in most cases, will shrink the tumor.
Radical nephrectomy is the treatment of choice.
If bilateral disease is diagnosed, nephrectomy is not performed, but biopsy specimens are obtained.
New protocols in the management of bilateral Wilms’ tumor are being explored. If the disease is unilateral, radical nephrectomy and regional lymph node dissection or sampling are performed.
The role of partial nephrectomy remains controversial.
Partial nephrectomy may be feasible in only 10–15 % of patients, as most tumors are too large at initial diagnosis.
The main concern regarding a nephron-sparing procedure is that of local recurrence.
The NWTS-4 study showed an 8 % local recurrence rate following partial nephrectomy for patients with bilateral disease.
In the presence of bilateral Wilms’ tumors, solitary kidney, or renal insufficiency, partial nephrectomy is a reasonable consideration.
If inferior vena cava (IVC) thrombus is present, preoperative chemotherapy will reduce the cavotomy rate by 50 %.
Stage and histology
Stage I or II favorable histology without loss of heterozygosity (LOH) 1p and 16q
Stage I or II favorable histology with LOH 1p and 16q
Vincristine, dactinomycin, doxorubicin
Stage III and IV favorable histology without LOH 1p and 16q
Vincristine, dactinomycin, doxorubicin
Stage III and IV favorable histology with LOH 1p and 16q
Doxorubicin, cyclophosphamide, etoposide
Bilateral Wilms’ tumor:
With bilateral Wilms’ tumor (6 % of cases), surgical exploration, biopsy of both sides, and accurate surgical staging (including lymph node biopsy of both sides) are performed.
This is followed by 6 weeks of chemotherapy that is appropriate to the stage and histology of the tumor.
Reassessment is then performed using imaging studies, followed by definitive surgery which can be any of the followings:
Unilateral radical nephrectomy and partial nephrectomy on the contralateral side.
Bilateral partial nephrectomy.
Unilateral nephrectomy only, if the response was complete on the opposite side. This approach dramatically reduces the renal failure rate following bilateral Wilms’ tumor therapy.
The overall 2-year survival rate is higher than 80 % with this approach, and the nephrectomy rate drops by 50 % in patients with bilateral Wilms’ tumor.
4.2.11 Surgical Complications
The overall surgical complication rate for Wilms’ tumor is approximately 15–20 %.
Surgical complications may include the following:
Small-bowel obstruction (7 %)
Hemorrhage (6 %)
Wound infection, hernia (4 %)
Vascular complications (2 %)
Splenic and intestinal injury (1.5 %)
Currently, Patients with High Risk Wilms’ Tumor Are Treated as Follows
Focal anaplastic stage I–III Wilms’ tumors and diffuse anaplastic stage I Wilms’ tumors:
Nephrectomy followed by vincristine, actinomycin-D, and doxorubicin in addition to local radiotherapy.
Focal anaplastic stage IV Wilms’ tumors and diffuse anaplastic stage II–III tumors:
Nephrectomy followed by chemotherapy including vincristine, actinomycin-D, doxorubicin, cyclophosphamide, etoposide, and carboplatin in addition to local radiotherapy
Stage IV diffuse anaplastic Wilms’ tumors:
More aggressive treatment is delivered; nephrectomy is followed by initial irinotecan and vincristine administration, which in turn is followed by actinomycin-D, doxorubicin, cyclophosphamide, carboplatin, etoposide, and radiotherapy.
4.2.12 Prognosis and Outcome
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.
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