Wilms' tumor

Wilms' tumor
Classification and external resources
Cut section showing two halves of a nephroblastoma specimen. Note the prominent septa subdividing the sectioned surface and the protrusion of tumor into the renal pelvis, resembling botryoid rhabdomyosarcoma.
ICD-10	C64
ICD-9	189.0
ICD-O:	M8960/3
OMIM	194070 607102
DiseasesDB	8896
eMedicine	med/3093 ped/2440
MeSH	D009396

CT Scan of 11 cm Wilms' tumor of right kidney in 13-month-old patient.

Wilms' tumor or nephroblastoma is cancer of the kidneys that typically occurs in children, rarely in adults.^[1] Its common name is an eponym, referring to Dr. Max Wilms, the German surgeon (1867–1918) who first described this kind of tumor.^[2]

Approximately 500 cases are diagnosed in the U.S. annually. The majority (75%) occurs in otherwise normal children; a minority (25%) is associated with other developmental abnormalities. It is highly responsive to treatment, with about 90% of patients surviving at least five years.

Pathology

Micrograph showing the characteristic triphasic pattern consisting of tubules, solid sheets of small round cells, and stroma. H&E stain.

High magnification micrograph showing the epithelial component (tubules). H&E stain.

Most nephroblastomas are unilateral, being bilateral in less than 5% of cases, although patients with Denys-Drash syndrome mostly have bilateral or multiple tumors.^[3] 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 hemorrhage 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:

• blastema
• mesenchyme
• epithelium

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, fibrous tissue. The tumor is compressing the normal kidney parenchyma.

The mesenchymal component may include cells showing rhabdomyoid differentiation. The rhabdomyoid component may itself show features of malignancy (rhabdomyosarcomatous Wilms).

Wilms' tumors may be separated into 2 prognostic groups based on pathologic characteristics:

• Favorable - Contains well developed components mentioned above
• Anaplastic - Contains diffuse anaplasia (poorly developed cells)

Symptoms

Typical symptoms are:

• an abnormaly large abdomen
• abdominal pain
• fever
• nausea and vomiting
• blood in the urine (in about 20% of cases)
• high blood pressure in some cases

Diagnosis

The first sign is normally a painless abdominal tumor that can be easily felt by the doctor. An Ultrasound, Computed Tomography, or MRI are done first. Once a kidney tumor is found, a surgical biopsy is done. A sample of tissue from the tumor is sent to a pathologist, who looks at it under a microscope to check for signs of cancer.

Prognosis

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 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.^[4][5] Genome-wide copy number and LOH status can be assessed with virtual karyotyping of tumor cells (fresh or paraffin-embedded). The overall prognosis with surgical removal is positive. Early removal tends to promote positive outcomes.

Molecular biology

Mutations of the WT1 gene on chromosome 11 p 13 are observed in approximately 20% of Wilms' tumors.^[6][7] At least half of the Wilms' tumors with mutations in WT1 also carry mutations in CTNNB1, the gene encoding the proto-oncogene beta-catenin.^[8]

A gene on the X chromosome, WTX, is inactivated in up to 30% of Wilms' tumor cases, according to research published in 2007.^[9]

Most cases do not have mutations in any of these genes.^[10]

Staging and treatment

Staging is determined by combination of imaging studies and pathology findings if the tumor is operable (adapted from www.cancer.gov). Treatment strategy is determined by the stage:

Stage I (43% of patients)

For stage I Wilms' tumor, 1 or more of the following criteria must be met:

• 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.

Treatment: Nephrectomy +/- 18 weeks of chemotherapy depending on age of patient and weight of tumor. EG: less than 2 years old and less than 550g only requires Nephrectomy with observation

Outcome: 98% 4-year survival; 85% 4-year survival if anaplastic

Stage II (23% of patients)

For Stage II Wilms' tumor, 1 or more of the following criteria must be met:

• 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.

Treatment: Nephrectomy + abdominal radiation + 24 weeks of chemotherapy

Outcome: 96% 4-year survival; 70% 4-year survival if anaplastic

Stage III (23% of patients)

For Stage III Wilms' tumor, 1 or more of the following criteria must be met:

• Unresectable 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.

Treatment: Abdominal radiation + 24 weeks of chemotherapy + nephrectomy after tumor shrinkage

Outcome: 95% 4-year survival; 56% 4-year survival if anaplastic

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.

Treatment: Nephrectomy + abdominal radiation + 24 weeks of chemotherapy + radiation of metastatic site as appropriate

Outcome: 90% 4-year survival; 17% 4-year survival if anaplastic

Stage V (5% of patients)

Stage V Wilms’ tumor is defined as bilateral renal involvement at the time of initial diagnosis. Note: For patients with bilateral involvement, an attempt should be made to stage each side according to the above criteria (stage I to III) on the basis of extent of disease prior to biopsy. The 4-year survival was 94% for those patients whose most advanced lesion was stage I or stage II; 76% for those whose most advanced lesion was stage III.

Treatment: Individualized therapy based on tumor burden

Stage I-IV Anaplasia

Children with stage I anaplastic tumors have an excellent prognosis (80-90% five-year survival). They 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.

Treatment

In general, this type of cancer is curable. If the tumor is only in the kidney (typical), it can be removed along with the whole kidney (a nephrectomy). During the operation, the surgeon checks if the other kidney has a tumor. If there are tumors in both kidneys, a piece of the tumor will be removed. After the surgery, the child is given some chemotherapy drugs like antinomicin D, vincristine, or doxorubicin.

Children 16 years old or older have higher mortality rates within their stages. This is due to them being treated less aggressively and consistently.^{[citation needed]}

Adjuvant chemotherapy is sometimes used.^[11]

Risk factors

People of African descent have the highest rates of Wilms' tumor. Most instances of cancer occur among children between 3 to 3.5 years old.^{[citation needed]}

See also

• Beckwith-Wiedemann syndrome
• Denys-Drash syndrome
• Hemihypertrophy
• National Wilms Tumor Study Group (NWTS)
• Virtual Karyotype for 1p and 16q LOH
• WAGR syndrome
• Perlman syndrome

References

1. ^ EBSCO database verified by URAC; accessed from Mount Sinai Hospital, New York
2. ^ WhoNamedIt.com: Max Wilms
3. ^ Guaragna, M. S.; et al., Fernanda Caroline; Assumpção, Juliana Godoy; Zambaldi, Lílian de Jesus Girotto; Cardinalli, Izilda Aparecida; Yunes, José Andrés; De Mello, Maricilda Palandi; Brandalise, Silvia Regina et al. (2010). "The Novel WT1 Gene Mutation p. H377N Associated to Denys-Drash Syndrome". Journal of Pediatric Hematology/Oncology 32 (6): 486–488. doi:10.1097/MPH.0b013e3181e5e20d. PMID 20562648. 
4. ^ Messahel, B.; Williams, R.; Ridolfi, A.; et al., Roger; Warren, William; Tinworth, Lorna; Hobson, Rachel; Al-Saadi, Reem et al. (2009). "Allele loss at 16q defines poorer prognosis Wilms tumour irrespective of treatment approach in the UKW1-3 clinical trials: a Children's Cancer and Leukaemia Group (CCLG) Study". Eur J Cancer 45 (5): 819–826. doi:10.1016/j.ejca.2009.01.005. PMID 19231157. 
5. ^ Grundy, P. E.; Breslow, N. E.; Li, S.; et al., E; Beckwith, JB; Ritchey, ML; Shamberger, RC; Haase, GM et al. (2005). "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 23 (29): 7312–7321. doi:10.1200/JCO.2005.01.2799. PMID 16129848. 
6. ^ Call K, Glaser T, Ito C, Buckler A, Pelletier J, Haber D, Rose E, Kral A, Yeger H, Lewis W (1990). "Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus". Cell 60 (3): 509–20. doi:10.1016/0092-8674(90)90601-A. PMID 2154335. 
7. ^ Huff V (1998). "Wilms tumor genetics". Am J Med Genet 79 (4): 260–7. doi:10.1002/(SICI)1096-8628(19981002)79:4<260::AID-AJMG6>3.0.CO;2-Q. PMID 9781905. 
8. ^ Maiti S, Alam R, Amos CI, Huff V (2000). "Frequent association of beta-catenin and WT1 mutations in Wilms tumors". Cancer Res 60 (22): 6288–92. PMID 11103785. 
9. ^ Rivera M, Kim W, Wells J, Driscoll D, Brannigan B, Han M, Kim J, Feinberg A, Gerald W, Vargas S, Chin L, Iafrate A, Bell D, Haber D (2007). "An X chromosome gene, WTX, is commonly inactivated in Wilms tumor". Science 315 (5812): 642–5. doi:10.1126/science.1137509. PMID 17204608. 
10. ^ Ruteshouser EC, Robinson SM, Huff V (June 2008). "Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumors". Genes Chromosomes Cancer 47 (6): 461–70. doi:10.1002/gcc.20553. PMID 18311776. 
11. ^ Metzger ML, Dome JS (2005). "Current therapy for Wilms' tumor". Oncologist 10 (10): 815–26. doi:10.1634/theoncologist.10-10-815. PMID 16314292. http://theoncologist.alphamedpress.org/cgi/content/full/10/10/815?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=wilms&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT. 

External links

• GeneReviews/NCBI/NIH/UW entry on Wilms Tumor Overview
• Information from National Cancer Institute
• Wilms' tumor at the Open Directory Project