UROLOGY / PAEDIATRIC SURGERY SERIES : WILM'S TUMOR/ NEPHROBLASTOMA. ( Definition, etiology, stadium, sign, symptoms, diagnosis, and management)

Wilm Tumor (Nephroblastoma)

A. INTRODUCTION

Definition of Wilm tumor is malignant and the most to the five most common renal tumor at the age of the children. These tumors appear most at the age of three years and is rarely found after 8 years of age. There are 250 cases of Wilm tumor ever reported. However, preoperative diagnosis of Wilm tumor in adults is quite difficult. These tumors usually appear as a solid renal mass with or without accompanied by hematuria. This solid mass may be accompanied by the process of cystic degeneration and focal necrosis. Sometimes the radiological picture may resemble renal cysts hemorhagik. These tumors appear in one or two kidneys. (A) (7)

The existence of large masses diabdomen, especially in children aged 1-5 years should arouse suspicion Tumor Wilm. This is an aggressive neoplasm and metastasis to different organs, but to respond to combination therapy. Wilm tumor when diagnosed and get appropriate therapy has a high cure rate is as high as 90%. (A) (7)

Development of diagnostic imaging in recent years also plays an important role in enhancing the efficacy and accuracy of diagnosis of Wilm tumor and it is extremely important in designing the best combination therapy in children. (A) (7)

B. EPIDEMIOLOGY

Wilm Tumor incidence was 0.8 cases per 100,000 people. There are 500 new cases each year in the United States, and as much as 6% of which involve both kidneys. Exposed to risks incident to Wilm Tumor is about 1 in 10,000 births. Wilm tumor mainly occurs in children under age 5. The highest incidence occurs between the ages of 1-3 years. This tumor is estimated to occur in 7 between 1 million children in the United States and more about the African-American race. Ratio of female patients and male is almost balanced. (7)

Wilm tumor can occur as part of the syndrome:

• Beckwith-Wiedemann syndrome (makroglosia, gigantism, umbilkalis hernia, omphalocele, organomegaly, hemihipertrophy, cystic kidney and adrenal sitomegali)

•  Congenital aniridia

•  Mutation Trisomy 18

•  Denys-Drash Syndrome (2) (3)

C. Pathogenesis

Wilm tumors can occur sporadically, in association with genetic syndromes and familial nature. Therefore, it is estimated Wilm tumor genetic abnormalities. However, the molecular pathophysiology of this disease is as yet unclear. Tumors thought to be caused by network failures blastema differentiate into normal kidney structure. (4) (8)

D. MOLECULAR GENETICS

According to Knudsen and Strong, as the retinoblastoma tumor Wilm, two trauma caused by gene mutations in tumor suppressor genes. The first mutation is the first cell inactivation of tumor suppressor genes and related aspects postzigot prezigot. Prezigot mutations (germline mutations) inherited or originated by de novo. Postzigot mutations occur only in some specific cells and is a predisposing factor in patients with unilateral tumors that are sporadic cases. (4) (8)

WT1 gene on chromosome 11p13 is a network of genes specific for epithelial cells and glomerular renal blastema with the allegation that the precursor cells from the kidney is the site of tumor Wilm. WT1 expression increased at birth, and decreases when the kidneys have been more mature. WT1 is a dominant oncogene so that when there are mutations that occur only pda 1 or 2 alleles have been able to promote the occurrence of Wilm tumor. WT2 gene on chromosome 11p15 remained isolated undisturbed. (4) (8)

In addition, some genetic factors might be expected to prognostic factors, such as loss of heterozigositi (LOH) on chromosomes 1p and 16q. This factor showed a significant relationship with risk of relapse and death. (4) (8)

E. CLINICAL SYMPTOMS

Most tumors are unilateral Wilm, but 5-10% Wilm Tumor in children are bilateral or tumor on one kidney, but multicentric (there are multiple tumors)
Radiological picture is not much help, because this diagnostic tool can not distinguish renal cell carcinoma with tumor Wilm. Therefore, preoperative diagnosis is very difficult to enforce.

F. Histopathology Examination
In pathology, a classic triphasic Nephroblastoma has three elements:

• Blastema

• mesenchyme

• epithelium

Where only one of these elements will be dominant.

Basic microscopic pattern of Wilm Tumor growth was biphasic consisting of blastema metanefrik islands separated by mesenchymal tissue. Blastema metanefrik a compact arrangement of oval cell / small polygonal nucleus and cytoplasm hiperkromatik a bit. Perhaps there is little differentiation of the epithelium, which is usually in the form tubukus with varying lumen formation. (4) (8)

Typical picture is the presence of abortive tubules and glomeruli are surrounded by spindle cell stroma. Glomeruloid structures are rarely found. Stroma may include striated muscle, cartilage, bone, fat tissue and fibrous connective tissue. The tumor is pressing the normal renal parenchyma. Mesenchymal components include cells that show differentiation rabdomyoid. Rabdomyoid component itself can show a picture of malignant (Rhabdomyosarkomatous Wilms). Rhaddomyomatous Wilm tumor that has a lot of immature striated muscle component, tends to appear at a young age, can be found to prolapse into the renal pelvis and is sometimes bilateral.

When a component reaches> 65% of the total cross sectional area of ​​the tumor, then these elements are considered to be the dominant subtype, for example, blastema predominant, predominantly epithelial or stromal predominant. If there is no one dominant component or element on this tumor, the tumor is called a mixed pattern sebgai (mixed pattern). And pattern of this mixture is the largest group.

Wilm tumor can also be divided into two prognostic groups based on characteristics of the pathology, namely:

• Prognosis good, which contain components or elements that are well developed

• Anaplastic, in which tumors contain anaplasia difuse (cells that are not well developed)

Histologic prognosis is important in terms of presence or absence of anaplasia. Anaplasia is defined as the presence of:

• The core with a size similar to the cell nucleus 3xdiameter the adjoining

• Where this core hiperkromatik

• The presence of atypical mitosis

These three criteria must be met

Anaplasia may be focal or diffuse. Focal or diffuse anaplasia definition has been revised back where anplasia focal clearly demarcated within the boundaries of the excision specimen but does not exist at the location of residual tumor ekstrarenal or not considered to worsen the prognosis.

Unfavourable / anaplasia

Anaplasia often found in non-white people, children and older with metastatic tumors to the KGB. Anaplasia is also believed to be a manifestation of genetic instability and drug resistance mutipel.

G. Wilm tumor staging

According to the Children's Oncology Group
I STADIUM
Tumor is found only in the kidneys and can be removed entirely

STADIUM II
Tumor has spread beyond the kidney, which is the fatty tissue or other soft tissue or blood vessels, but can still be removed in its entirety.

STADIUM III
The tumor has spread within the abdominal cavity and can not be removed completely. Also had metastatic lymph nodes, blood vessels or the peritoneum

IV STADIUM
Distant metastases to the lung, liver, bones, vertebrae and praspinal region, brain or lymph nodes outside the abdomen and pelvis

STADIUM V
Tumor cells are found in both kidneys when the tumor was first diagnosed

Spread to the renal pelvis or ureter is rare, if any, the case is a case of advanced and lead to polypoid mass that comes out of the system pyelocalyceal resembling botryoid rhabdomyosarcoma.

WT deployment can reach the adrenal gland, intestine, liver, vertebrae and praspinal. Location of the most common metastasis is the lung, liver, peritoneum and CNS.

H. THERAPY

A. Surgery
Surgical indications are:
• The tumor is confined to the kidney
• Kidney Tumor extends out but does not cross the midline, and with or without expansion of the vascular
• Postchemotherapy tumor excision is indicated in patients with bilateral tumors, tumors extending beyond the center line and has been shrinking, and with the expansion of the vascular tumor. Surgery alone is not recommended for Wilms tumor, based on the results of the study-5 NWTSG (3) (5)

Contraindications to surgery are:
• bilateral and metastatic tumors
• large tumors beyond the center line, has expanded into vascular, or both, is a relative contraindication, because some surgeons prefer to get the network through surgical excision, but this may expose the patient to increased surgical risk (6) (10)

Surgical technique
• Radical nephrectomy
According NWTSG protocol, the first step in the treatment of Wilms tumor is a biopsy followed by radical nephrectomy, if possible. Begin exploration of the abdomen through a transverse incision. Kidney explored by mobilizing the ipsilateral colon and unlock Gerota fascia. Exploration of the contralateral kidney is not currently recommended because of increased use of imaging techniques (computed tomography [CT] scanning, magnetic resonance imaging [MRI]). If diagnosed with bilateral disease, nephrectomy is not performed, but performed a biopsy specimen first. The new protocol in the management of bilateral Wilms tumors is being explored. If the location of unilateral tumors, radical nephrectomy and unilateral regional lymph node dissection or sampling. (5) (4)

• Partial nephrectomy
The role of partial nephrectomy is still controversial. Although end-stage renal disease after unilateral radical nephrectomy rare (0.25% in NWTSG trial), maintaining a healthy kidney tissue can prevent these complications, especially in patients with intrinsic renal disease (for example, WAGR syndrome, Denys-Drash syndrome). Partial nephrectomy might be worth doing at 10% -15% of patients, because most tumors are too large at initial diagnosis. The main concern of nephron-sparing procedures is the presence of local recurrence. NWTS-4 study showed 8% rate of local recurrence after partial nephrectomy for patients with bilateral tumors. In the presence of bilateral Wilms tumor, solitary kidney, or renal insufficiency, partial nephrectomy is a reasonable consideration. (3)

• Preoperative
If the tumor be removed, the biopsy was done and nephrectomy is deferred until after the chemotherapy, which in most cases, will shrink the tumor. Involvement of adjacent organs is often overdiagnosed. Overall complication rate of surgery for Wilms tumor is about 20%. If a thrombus was found inferior vena cava (IVC), preoperative chemotherapy will reduce the rate by 50% cavotomy. (5)

On bilateral Wilms tumor (6% of cases) who carried out such surgical exploration, biopsy of both sides, and accurate tumor staging (including lymph node biopsies from both sides). This was then followed by six weeks of chemotherapy according to stage of tumor anatomy and pathology. Then conducted through a review of imaging techniques, followed by definitive surgery with (1) unilateral radical nephrectomy and partial nephrectomy on the contralateral side, (2) bilateral partial nephrectomy, and (3) unilateral nephrectomy alone, if the tumor response to chemotherapy either in a single kidney anymore. This approach dramatically reduces the level of renal failure after treatment of bilateral Wilms tumor. (10)

The survival rate for 2 years as a whole is higher than 80% with this approach, and nephrectomy rate fell by 50% in patients with bilateral Wilms tumor. Possible bilateral partial nephrectomy after chemotherapy or, if the tumor on one side completely respond to chemotherapy, and nephrectomy is not necessary anymore. (8)

Follow-up after surgery
Follow-up care after treatment should be long (if possible, for life), because Wilms tumor may recur after several years. Follow-up consisted of chest x-rays and ultrasound, CT scan, or MRI abdomen every 3 months for the first 2 years, every 6 months for 2 years, and every 2 years thereafter. (6) (10)

Complications of surgery

• Obstruction ileus (7%)
• bleeding (6%)
• wound infection, hernia (4%)
• Complications of blood vessels (2%)
• Trauma to the spleen and intestine (1.5%)

2. Chemotherapy and Radiation
Effects of chemotherapy and radiation is more visible on the component compared to the mesenchymal blastema or epithelium. Anaplasia incident also was not affected by the modality of healing. (2) (3) (5) (10)

I. Prognosis

The success rate and Prognosis
Biomarkers of tumor, histology, and tumor stage is the most important prognostic factor in unilateral Wilms tumor

With the existence of multimodal therapy, the prognosis for the better Wilms tumor, and is regarded as an example of success in cancer therapy. Overall survival rate in patients with Wilms tumor was 90%. Cases of tumors with anaplasia picture spread and stage III or IV disease who came back though with a complex therapy had a significantly worse prognosis. However, the addition of new chemotherapeutic agents, such as cyclophosphamide, ifosfamide, cisplatin, carboplatin, and etoposide, especially the combination of ICE (ifosfamide, carboplatin, etoposide), has triggered an increase in survival rate by 50% -60%.

Prognosis depends on the following:
• Differentiation of tumor cells than from normal kidney cells
• Staging of cancer
• Type and size of the tumor
• Age of child
• Whether the tumor can be completely resected by surgery
• Is this a case of newly diagnosed or had never happened before (relapse)
• Are there any abnormal chromosomes or genes
• Does the patient is treated by the doctors caring for children who have experienced Wilms tumor patients.

REFERENCES

1. Ehrlich PF, Ritchey ML, Hamilton TE, Haase GM, Ou S, Breslow N, et al. Quality assessment for Wilms' tumor: a report from the National Wilms' Tumor Study-5. J Pediatr Surg. Jan 2005;40(1):208-12; discussion 212-3.

2. Kubiak R, Gundeti M, Duffy PG, Ransley PG, Wilcox DT. Renal function and outcome following salvage surgery for bilateral Wilms' tumor. J Pediatr Surg. Nov 2004;39(11):1667-72. 

3. Haecker FM, von Schweinitz D, Harms D, Buerger D, Graf N. Partial nephrectomy for unilateral Wilms tumor: results of study SIOP 93-01/GPOH. J Urol. Sep 2003;170(3):939-42; discussion 943-4.

4. Metzger ML, Dome JS. Current therapy for Wilms' tumor. Oncologist. Nov-Dec 2005;10(10):815-26.

5. Ritchey ML. The role of preoperative chemotherapy for Wilms' tumor: the NWTSG perspective. National Wilms' Tumor Study Group. Semin Urol Oncol. Feb 1999;17(1):21-7. 

6. Bogaert GA, Heremans B, Renard M, Bruninx L, De Wever L, Van Poppel H. Does preoperative chemotherapy ease the surgical procedure for Wilms tumor?. J Urol. Oct 2009;182(4 Suppl):1869-74.

7. Breslow N, Olsham A, Beckwith JB, Green DM. Epidemiology of Wilm’s Tumor. MPO,   1993; 21 : 172-181.

8. Cassady JR, Tefft M, Filler RM. Consideration in the radiation therapy of Wilm’s tumor. Cancer, 1973; 32 : 598-607.

9. Cowell JK, Wadey RB, Buckle BB, Pritchard J. The aniridia-Wilm’s tumor association : molecular and genetic analysis of chromosome deletions on the short arm of chromosome 11. Hum Genet, 1989; 82 : 123-6.

10. Ehrlich RM, Goodwin WE. The surgical treatment of nephroblastoma (Wilm’s tumor). Cancer, 1973; 32 : 1145-9.