Wilms Tumor (Nephroblastoma)

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Definition of Wilms Tumor

Wilms tumor (or nephroblastoma) is a rare malignant renal tumor in children with develops from remnants of immature tissue from the renal development (Graf et al, 2003) (Metzger et al, 2005) (Kalapurakal et al, 2004) (Wu et al, 2005). The tumor was described in 1899 by the German surgeon Max Wilms (1867–1918).

Epidemiology

Incidence 1/100.000 in children under 15 years, median age at diagnosis is 3.5 years. Balanced sex ratio.

Association of Wilms tumor with rare genetic syndromes:

10% of Wilms tumors are associated with congenital anomalies and syndromes:

Denys-Drash syndrome:

Male pseudohermaphroditism, renal mesangial sclerosis, Wilms' tumor (50% risk) and WT1 mutations (see below).

WAGR syndrome:

WILMS tumor in 50%, Aniridia, Genital anomalies, mental Retardation, WT1 mutations (see below).

Beckwith-Wiedemann syndrome:

4–10% risk for Wilms tumor, excessive growth at the cellular level, organ level (macroglossia, nephromegaly, hepatomegaly) or body segment level (hemihypertrophy), WT2 mutations (see below).

Perlman syndrome:

Very rare genetic syndrome characterized by among other polyhydramnios, macrosomia, bilateral renal tumors with a high risk for Wilms tumor.

Fanconi anemia D1:

generally increased risk of tumors, 20% risk of Wilms tumor.

Horseshoe kidney:

2–7-fold increased risk of Wilms tumor.

Causes (Etiology) of Nephroblastoma

Tumor suppressor genes:

Wilms tumor is a classic example for loss of function mutations of tumor suppressor genes. Due to the diploid chromosome status, at least two genetic events are necessary for the complete loss of function of a tumor suppressor. In genetic syndromes or familiar Wilms tumor, the first mutation is inherited from the parents, the second mutation occurs spontaneously or during the further development.

Wilms tumor suppressor gene 1 (WT1):

WT1 is located on chromosome 11p13. The gene product regulates the expression‎ of other genes during normal kidney development.

WT2:

WT2 is located on chromosome 11p15. The gene product is not known.

Further molecular changes:

p53 mutations, WTX mutations, LOH at 1p and 16q.

Wilms Tumor Pathology

Classical Wilms tumor:

The classical Wilm tumor (also called favorable-histology Wilms tumor) is a triphasic tumor consisting of islands of metanephritic blastema with variable epithelial and stromal components.

Anaplastic Wilms tumor:

Prominent nuclear enlargement with hyperchromasia and abnormal mitotic figures are the hallmarks of anaplastic Wilms tumor. Approximately 10% of Wilms tumors are anaplastic, they exibit a poor prognosis even in tumor stages confined to the kidney due to their resistance to chemotherapy.

Wilms tumor with nephrogenic rests:

30% of kidneys with Wilms tumor contain embryonic cells (nephrogenic rests) within the normal renal tissue. Nephrogenic rests are differentiated according to their localization: perilobar nephrogenic rests (PLNR) or intralobar nephrogenic rests (ILNR). The presence of PLNR or ILNR leads to an increased risk of bilateral disease or developing contralateral disease in the future. Regular surveillance is recommended.

Sarcomatoid kidney tumors:

Sarcomatoid tumors have to be separated from Wilms tumors, but sometimes pathological differentiation is difficult. Initial treatment is analogous to Wilms tumors (see below).

Metastases:

10% of children with Wilms tumor present with distant metastases at diagnosis, most commonly in the lungs, liver, bone and brain.

Tumor Staging according to NWTS/COG

Staging classification is done after radical nephrectomy and before chemotherapy.

Stage I:

• (a) Tumor is limited to the kidney and completely excised
• (b) The tumor was not ruptured before or during removal
• (c) The vessels of the renal sinus are not involved beyond 2 mm
• (d) There is no residual tumor apparent beyond the margins of excision

Stage II:

• (a) Tumor extends beyond the kidney but is completely excised
• (b) No residual tumor is apparent at or beyond the margins of excision
• (c) Tumor thrombus in vessels outside the kidney is stage II if the thrombus is removed en bloc with the tumor
• Although tumor biopsy or local spillage confined to the flank were considered stage II by NWTSG in the past, such events will be considered stage III in upcoming COG studies.

Stage III:

Residual tumor confined to the abdomen:

• (a) Lymph nodes in the renal hilum, the periaortic chains, or beyond are found to contain tumor
• (b) Diffuse peritoneal contamination by the tumor
• (c) Implants are found on the peritoneal surfaces
• (d) Tumor extends beyond the surgical margins either microscopically or grossly
• (e) Tumor is not completely resectable because of local infiltration into vital structures

Stage IV:

Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdomino-pelvic region.

Stage V:

Bilateral renal involvement at diagnosis

Tumor Staging according to SIOP

Staging classification is done after neoadjuvant chemotherapy and radical nephrectomy.

Stage I:

• (a) Tumor is limited to kidney or surrounded with fibrous pseudocapsule if outside of the normal contours of the kidney, the renal capsule or pseudocapsule may be infiltrated with the tumor, but it does not reach the outer surface, and is completely resected (resection margins “clear”)
• (b) The tumor may be protruding into the pelvic system and “dipping” into the ureter (but it is not infiltrating their walls)
• (c) The vessels of the renal sinus are not involved
• (d) Intrarenal vessel involvement may be present

Stage II:

• (a) The tumor extends beyond kidney or penetrates through the renal capsule and/or fibrous pseudocapsule into perirenal fat but is completely resected (resection margins “clear”)
• (b) The tumor infiltrates the renal sinus and/or invades blood and lymphatic vessels outside the renal parenchyma but is completely resected
• (c) The tumor infiltrates adjacent organs or vena cava but is completely resected

Stage III:

• (a) Incomplete excision of the tumor, which extends beyond resection margins (gross or microscopical tumor remains postoperatively)
• (b) Any abdominal lymph nodes are involved
• (c) Tumor rupture before or intraoperatively (irrespective of other criteria for staging)
• (d) The tumor has penetrated through the peritoneal surface
• (e) Tumor thrombi present at resection margins of vessels or ureter, transsected or removed piecemeal by surgeon
• (f) The tumor has been surgically biopsied (wedge biopsy) prior to preoperative chemotherapy or surgery

Stage IV:

Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdomino-pelvic region.

Stage V:

Bilateral renal involvement at diagnosis

Signs and Symptoms

Abdominal tumor, abdominal pain and hematuria are typical findings. Hypertension may be caused by renin secretion in 25%. Vomiting, fever or varicoceles are rarely present. It is important to search for associated malformations such as aniridia, hemihypertrophy and genital anomalies.

Diagnostic Work-Up

Laboratory investigations:

Tumor marker are not available. 24-hour urine collection and test for catecholamines and metanephrines, if neuroblastoma is possible.

Ultrasound imaging:

Imaging reveals a mass of the kidney. A tumor thrombus may be seen in the renal vein or vena cava.

CT or MRI of the abdomen:

Radiological differentiation between the possible solid tumors in childhood is not always possible (neuroblastoma, renal lymphoma). Imaging is important to detect bilateral disease and to eval‎uate renal function.

Chest x-ray or CT thorax:

for Staging.

MIBG-Scintigraphy:

if neuroblastoma is possible.

Intravenous Urography:

IVP is a historical investigation and is not indicated any more for suspected renal tumor in childhood. Signs of a nephroblastoma are an enlarged kidney shadow and displacement of the pyelocaliceal system.

Tumor biopsy:

The NWTS protocoll recommends biopsy if chemotherapy is necessary before surgery.

Genetic testing:

If above-mentioned clinical syndromes are suspected.

Treatment of Wilms Tumor

Due to the small number of cases, treatment should be done according to the recommendations of multinational study groups. There are two different therapeutic approaches:

NWTS / COG Recommendations:

In National Wilms Tumor Study Group / Children Oncology Group in the United States, primary surgical resection of the tumor is the initial treatment of most children. The postoperative histology and tumor stage decides on adjuvant chemotherapy and radiotherapy. Neoadjuvant chemotherapy is recommended for bilateral Wilms tumor, if a complete tumor resection is not possible (intraoperative decision) or with involvement of the inferior vena cava above the hepatic veins. Before neoadjuvant chemotherapy, the correct diagnosis should be verified with a (bilateral) biopsy.

SIOP Recommendations:

In International Society of Pediatric Oncology (SIOP) studies preval‎ent in Europe, neoadjuvant chemotherapy before surgical treatment is recommended for most children. A primary tumor biopsy is not recommended, if imaging is straightforward in children over six months and younger than 16 years. Neoadjuvant therapy leads to a lower tumor stage and reduces the rate of incomplete resections or tumor rupture. After nephrectomy, postoperative tumor stage and histology decides on adjuvant chemotherapy and radiotherapy. Primary surgery is recommended for patients under the age of 6 months or over 16 years, since malignant tumors other than Wilms tumor are more likely.

Radical Nephrectomy:

Radical nephrectomy is done via a transperitoneal approach. Key points of the operative technique are complete resection and accurate intraoperative staging of lymph nodes, liver, peritoneum and vena cava.

Chemotherapy:

Chemotherapy is always administered as a combination chemotherapy. The most effective drugs are actinomycin-D and vincristine. If high risk tumor stages are present, anthracyclines (epirubicin, doxorubicin) are added.

Radiotherapy:

The indication is based on the histology and the local stage after nephrectomy. Indications for radiotherapy are intermediate risk for stage III and high risk tumors for stage II. The local dose is 15–30 Gy.

Screening:

Sonographic screening tests every 3 to 4 months should be performed in children with more than 5% risk of Wilms tumor (e.g. children with WAGR syndrome, Beckwith-Wiedemann syndrome or familial Wilms tumor).

Prognosis

90% of all children with Wilms tumor can be cured. Prognosis is dependent on tumor stage and histology. Unfavorable prognostic factors are metastases present at diagnosis and tumors with high malignancy (e.g. anaplastic Wilms tumor or blastema-dominant Wilms tumor).