Wilms' tumor


Wilms' tumor, also known as nephroblastoma, is a cancer of the kidneys that typically occurs in children, rarely in adults. It is named after Max Wilms, the German surgeon who first described it.
Approximately 650 cases are diagnosed in the U.S. annually. The majority of cases occur in children with no associated genetic syndromes; however, a minority of children with Wilms' tumor have a congenital abnormality. It is highly responsive to treatment, with about 9/10 children being cured.

Signs and symptoms

Typical signs and symptoms of Wilms' tumor include the following:
Wilms' tumor has many causes, which can broadly be categorized as syndromic and non-syndromic. Syndromic causes of Wilms' tumor occur as a result of alterations to genes such as the Wilms Tumor 1 or Wilms Tumor 2 genes, and the tumor presents with a group of other signs and symptoms. Non-syndromic Wilms' tumor is not associated with other symptoms or pathologies. Many, but not all, cases of Wilms' tumor develop from nephrogenic rests, which are fragments of tissue in or around the kidney that develop before birth and become cancerous after birth. In particular, cases of bilateral Wilms' tumor, as well as cases of Wilms' tumor derived from certain genetic syndromes such as Denys-Drash syndrome, are strongly associated with nephrogenic rests. Most nephroblastomas are on one side of the body only and are found on both sides in less than 5% of cases, although people with Denys-Drash syndrome mostly have bilateral or multiple tumors. They tend to be encapsulated and vascularized tumors that do not cross the midline of the abdomen. In cases of metastasis it is usually to the lung. A rupture of Wilms' tumor puts the patient at risk of bleeding and peritoneal dissemination of the tumor. In such cases, surgical intervention by a surgeon who is experienced in the removal of such a fragile tumor is imperative.
Pathologically, a triphasic nephroblastoma comprises three elements:
Wilms' tumor is a malignant tumor containing metanephric blastema, stromal and epithelial derivatives. Characteristic is 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. Dysfunction is caused when the tumor compresses the normal kidney parenchyma.
The mesenchymal component may include cells showing rhabdomyoid differentiation or malignancy.
Wilms' tumors may be separated into 2 prognostic groups based on pathologic characteristics:
Mutations of the WT1 gene which is located on the short arm of chromosome 11 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. This latter gene is found on short arm of chromosome 3.
Most cases do not have mutations in any of these genes.
Syndrome NameAssociated Genetic VariantRisk for Wilms tumorDescription of Syndrome
WAGR syndrome Gene deletion that includes both WT1 and PAX645-60%Characterized by Wilms tumor, aniridia, hemihypertrophy, genitourinary abnormalities, ambiguous genitalia, intellectual disability.
Denys-Drash syndrome WT1 74%Characterized by kidney diseases since birth leading to early-onset kidney failure, ambiguous genitalia.
Beckwith-Wiedemann SyndromeAbnormal regulation of chromosome 11p15.57%Characterized by macrosmia, macroglossia, hemihypertrophy, other tumors in body, omphalocele and visceromegaly.

An association with H19 has been reported. H19 is a long noncoding RNA located on the short arm of chromosome 11.

Diagnosis

The majority of people with Wilms’ tumor present with an asymptomatic abdominal mass which is noticed by a family member or healthcare professional. Renal tumors can also be found during routine screening in children who have known predisposing clinical syndromes. The diagnostic process includes taking a medical history, a physical exam, and a series of tests including blood, urine, and imaging tests.
Once Wilms’ tumor is suspected, an ultrasound scan is usually done first to confirm the presence of an intrarenal mass. A computed tomography scan or MRI scan can also be used for more detailed imaging. Finally, the diagnosis of Wilms’ tumor is confirmed by a tissue sample. In most cases, a biopsy is not done first because there is a risk of cancer cells spreading during the procedure. Treatment in North America is nephrectomy or in Europe chemotherapy followed by nephrectomy. A definitive diagnosis is obtained by pathological examination of the nephrectomy specimen.

Staging

Staging is a standard way to describe the extent of spread of Wilms' tumors, and to determine prognosis and treatments. Staging is based on anatomical findings and tumor cells pathology. According to the extend of tumor tissue at the time of initial diagnosis, five stages are considered.
In Stage I Wilms' tumor, all of the following criteria must be met:
In Stage II, 1 or more of the following criteria must be met:
In Stage III, 1 or more of the following criteria must be met:
Stage IV Wilms' tumor is defined by the presence of hematogenous metastases, or lymph node metastases outside the abdomenopelvic region.
Stage V Wilms' tumor is defined by bilateral renal involvement at the time of initial diagnosis.
For patients with bilateral involvement, an attempt should be made to stage each side according to the above criteria on the basis of extent of disease prior to biopsy.

Treatment/prognosis

The overall 5-year survival is estimated to be approximately 90%, but for individuals the prognosis is highly dependent on individual [|staging and treatment]. Early removal tends to promote positive outcomes.
Tumor-specific loss-of-heterozygosity for chromosomes 1p and 16q identifies a subset of Wilms' tumor patients who have a significantly increased risk of relapse and death. LOH for these chromosomal regions can now be used as an independent prognostic factor together with disease stage to target intensity of treatment to risk of treatment failure. Genome-wide copy number and LOH status can be assessed with virtual karyotyping of tumor cells.
Statistics may sometimes show more favorable outcomes for more aggressive stages than for less aggressive stages, which may be caused by more aggressive treatment and/or random variability in the study groups. Also, a stage V tumor is not necessarily worse than a stage IV tumor.
StageHistopathology4 Year relapse-free survival or event-free survival 4 Year overall survival Treatment
Stage IFavorable histology in children younger than 24 months or tumor weight less than 550g85%98%Surgery only
Stage IFavorable histology in children older than 24 months or tumor weight more than 550g94% RFS98%Nephrectomy + lymph node sampling followed by regimen EE-4A
Stage IDiffuse anaplastic68% EFS80%Nephrectomy + lymph node sampling followed by regimen EE-4A and radiotherapy
Stage IIFavorable histology86% RFS98%Nephrectomy + lymph node sampling followed by regimen EE-4A
Stage IIFocal anaplastic80% EFS80%Nephrectomy + lymph node sampling followed by abdominal radiotherapy and regimen DD-4A
Stage IIDiffuse anaplastic83% EFS82%Nephrectomy + lymph node sampling followed by abdominal radiotherapy and regimen I
Stage IIIFavorable histology87% RFS94%Nephrectomy + lymph node sampling followed by abdominal radiotherapy and regimen DD-4A
Stage IIIFocal anaplastic88% RFS100% Nephrectomy + lymph node sampling followed by abdominal radiotherapy and regimen DD-4A
Stage IIIFocal anaplastic 71% RFS71%Preoperative treatment with regimen DD-4A followed by nephrectomy + lymph node sampling and abdominal radiotherapy
Stage IIIDiffuse anaplastic46% EFS53%Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling and abdominal radiotherapy
Stage IIIDiffuse anaplastic65% EFS67%Immediate nephrectomy + lymph node sampling followed by abdominal radiotherapy and regimen I
Stage IVFavorable histology76% RFS86%Nephrectomy + lymph node sampling, followed by abdominal radiotherapy, bilateral pulmonary radiotherapy, and regimen DD-4A
Stage IVFocal anaplastic61% EFS72%Nephrectomy + lymph node sampling, followed by abdominal radiotherapy, bilateral pulmonary radiotherapy, and regimen DD-4A
Stage IVDiffuse anaplastic33% EFS33%Immediate nephrectomy + lymph node sampling followed by abdominal radiotherapy, whole-lung radiotherapy, and regimen I
Stage IVDiffuse anaplastic 31% EFS44%Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling followed by abdominal radiotherapy, whole-lung radiotherapy
Stage VOverall61% EFS80%
Stage VFavorable histology65%87%Preoperative treatment with regimen DD-4A, followed by nephron sparing surgery or nephrecomy, staging of tumors, and chemotherapy and/or radiotherapy based on pathology and staging
Stage VFocal anaplastic76%88%Preoperative treatment with regimen DD-4A, followed by nephron sparing surgery or nephrecomy, staging of tumors, and chemotherapy and/or radiotherapy based on pathology and staging
Stage VDiffuse anaplastic25%42%Preoperative treatment with regimen DD-4A, followed by nephron sparing surgery or nephrecomy, staging of tumors, and chemotherapy and/or radiotherapy based on pathology and staging

In case of relapse of Wilms' tumor, the 4-year survival rate for children with a standard-risk has been estimated to be 80%.

Epidemiology

Wilms tumor is the most common malignant renal tumor in children. There are a number of rare genetic syndromes that have been linked to an increased risk of developing Wilms Tumor. Screening guidelines vary between countries; however health care professionals are recommending regular ultrasound screening for people with associated genetic syndromes.
Wilms' tumor affects approximately one person per 10,000 worldwide before the age of 15 years. People of African descent may have slightly higher rates of Wilms' tumor. The peak age of Wilms' tumor is 3 to 4 years and most cases occur before the age of 10 years. A genetic predisposition to Wilms' tumor in individuals with aniridia has been established, due to deletions in the p13 band on chromosome 11.

History

Dr. Sidney Farber, founder of Dana–Farber Cancer Institute, and his colleagues achieved the first remissions in Wilms' tumor in the 1950s. By employing the antibiotic actinomycin D in addition to surgery and radiation therapy, they boosted cure rates from 40 to 89 percent.
The use of computed tomography scan for the diagnosis of Wilms' tumor began in early 1970s, thanks to the intuition of Dr. Mario Costici, an Italian physician. He discovered that in the direct radiograms and in the urographic images, you can identify determining elements for a differential diagnosis with the Wilms' tumor. This possibility was a premise for starting a treatment.

Notable cases

's daughter Skylar died from this cancer in August 1995, a month before he released his album, Carved in Stone, which includes the tribute track "Skylar's Song".