WILM"S TUMOR DAN PENATALAKSANAANNYA / Nephroblastoma

Wilm's tumor (Nephroblastoma)

A. INTRODUCTION

            Wilms tumor is the most malignancies and is the fifth most common renal tumor at the age of the children. These tumors most Appear at the age of three years and is rare after the age of 8 years. There are 250 cases of Wilms tumor ever reported. However, the preoperative diagnosis of Wilms' tumor in the adult 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 cystic part by focal necrosis and degeneration process. Sometimes radiological picture may resemble renal cysts hemorhagik. These tumors arise in one or two kidneys. (1) (7)

            Diabdomen large masses, especially in children aged 1-5 years should arouse suspicion Wilm tumors. This neoplasm is aggressive and metastasizes to various organs, but to respond to combination therapy. Wilms tumor when Diagnosed and receive NAMAs therapy has a cure rate is quite high, reaching 90%. (1) (7)

            The development of diagnostic imaging lately also play an important role in enhancing the efficacy and accuracy of the diagnosis of Wilms tumor and this is very important in designing the best combination therapy in children. (1) (7)

B. Epidemiology

            Wilms Tumour 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 it involves both kidneys. Risks incident to hit Wilm tumor is 1 in 10,000 births. Wilms tumor Occurs primarily in children under the age of 5 years. The incidence is highest between the ages of 1-3 years. It is estimated that these tumors in 7 Occurred between 1 million children in the United States and much of the African-American race. The ratio of female Patients and the male is almost balanced. (7)

Wilms tumor may occur as part of the syndrome:

·          Beckwith-Wiedemann syndrome (macroglossia, gigantism, umbilkalis hernia, omphalocele, organomegaly, hemihipertrophy, kidney cysts and adrenal sitomegali)

·          Congenital aniridia

·          Movements of trisomy 18

·          Denys-Drash Syndrome (2) (3)

Wilm's tumor Epidemiology / Nephroblastoma
Incidence Cases per year in the United States Afro-American race gender ratio bilateral tumors The average incidence (age) at unilateral tumors The average incidence (age) at the bilateral tumors	8.1 per 1 million children  460  The highest incidence  0.9 male: 1 female  0.6 male: 1 female  Male: age 41 months  Women: age 47 months  Male: 29 months  Women: age 33 monthsbulan

C. Pathogenesis

            Wilms tumors can occur sporadically, in association with a genetic syndrome and familial. Therefore, Wilm tumor predicted a genetic abnormality. However, the molecular pathophysiology of the disease is unclear. Tumors thought to be the caused by network failures blastema differentiate into normal renal structures. (4) (8)

Wilms tumor / Nephroblastoma: Cytogenetics

Tumor Suppressor Gene WT1: A Constitutional Deletion        chromosome 11p13            WAGR Syndrome            Nonhereditary Wilms tumor (33%)        10 exons encoding for a 45-49 kd protein            Homology to the Early Growth Response 1 (Egr1)        Sequence-specific DNA binding WT1 Role        gonadal development        WAGR Syndrome        Denysh-Drash Syndrome WT2: Tumor Suppressor Gene        chromosome 11p15.5        Linkage Analysis Associated with Beckwith-Weidemann Syndrome Candidates for WT2        Insulin-Like Growth Factor Type II             Embryonal tumors Growth Factor In Wilm WT3: Tumor-Specific 16q Loss of Heterozygosity       Associated with poor diagnosis       Involved with tumor progression

MOLECULAR GENETIC D.

            According to Knudsen and Strong, Wilms tumors such as retinoblastoma, two traumatized by the 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 indeed originate de novo. Postzigot mutation Occurs only in a few specific cells and is a predisposing factor in Patients with unilateral tumors are sporadic cases. (4) (8)

            WT1 gene on chromosome 11p13 is a tissue-specific genes for renal blastema cells and glomerular epithelial cell precursors with the notion that both the kidney is the site of origin of the tumor Wilm. Increased WT1 expression at birth, and decreases when the kidney has been increasingly mature. WT1 is a dominant oncogene that when there is a mutation that pda Occurs only 1 or 2 alleles have been Able to promote the occurrence of Wilms tumor. WT2 gene on chromosome 11p15 remained isolated is not compromised. (4) (8)

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

E. CLINICAL Symptoms

Wilm's tumor CLINICAL / Nephroblastoma
Bilateral tumors Mass in the abdomen Abdominal pain Acute abdominal pain hypertension fever hematuria Urogenital anomalies (renal Ectopia, unilateral agenesis, horseshoe kidney, ureteral duplication, hypospadias, kriptokismus) Hemihipertropi Aniridia	4.7% 84% 35-40% 12% 63% 23% 12-24% 5.3% 1.8% 1.1%

            Most unilateral Wilms tumor, but 5-10% of Wilms tumors in children is bilateral or tumors in the kidney, but multicentric (there are multiple tumors)

            Radiological features are not much help, Because this diagnostic tool can not distinguish renal cell carcinoma with tumor Wilm. Therefore, preoperative diagnosis is very difficult to enforce.

EXAMINATION F. Histopathology

            In pathology, the classic triphasic Nephroblastoma has three elements:

·          Blastema

·          mesenchyme

·          epithelium

Where only one among these elements will Become dominant.

            Basic microscopic pattern of Wilms tumor is a biphasic growth Consisting of blastema metanefrik islands separated by mesenchymal tissue. Blastema metanefrik a compact arrangement of cells, oval / polygonal with small hyperchromatic nuclei and little cytoplasm. Perhaps there is little differentiation of the epithelium, the which is usually in the form of tubukus with varying lumen formation. (4) (8)

            Preview typically is the abortive tubules and glomeruli surrounded by spindle cell stroma. Glomeruloid structure rarely found. Stroma may include striated muscle, cartilage, bone, fat tissue and fibrous connective tissue. These tumors suppress the normal renal parenchyma. Components include mesenchymal cell differentiation Showed rabdomyoid. Rabdomyoid component itself can show a picture of malignant (Rhabdomyosarkomatous Wilms). Rhaddomyomatous Wilm tumor that has many components immature striated muscle, growing niche to Appear at a young age, can be found prolapse into the renal pelvis and sometimes bilateral.

            When one component of Achieving> 65% of the total cross-sectional area of ​​the tumor, then this element is Considered as the dominant subtype, for example, blastema predominant, predominantly epithelial or stromal predominant. If there is no one dominant component or element of this tumor, then the tumor was designated a mixed pattern (mixed pattern). And this is a mixed pattern majority group.

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

• Good prognosis, the which contain a components or elements are well developed
• Anaplastic, where tumors contain a diffuse anaplasia (cells that are not growing well)

The histologic features are most important in terms of prognosis presence or absence of anaplasia. Anaplasia itself is defined as the presence of:

·          The core with the size of the cell nucleus similar adjoining 3xdiameter

·          Where is hyperchromatic nuclei

·          The presence of atypical mitotic

All three criteria must be met

            Anaplasia may be focal or diffuse. Definition of focal or diffuse anaplasia behind this has been revised where anplasia clear focal circumscribed within the limits of excision specimens but not found in the location ekstrarenal or residual tumor not Considered to worsen the prognosis.

Unfavorable / anaplasia

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

Wilms tumor / Nephroblastoma: histological morphology

Three Primary Elements     Blastema         Difusse pattern         Organoid pattern             Serpentine             nodular             Basaloid    -Lined epithelial tubules          tubular pattern          Glomeruloid pattern          papillary pattern          Pelvicalyceal pattern          Cysts / glands          Heterozygous (mucinous, squamous, neuroendocrine neural)         Primitive Stromal Cell Types          undifferentiated          Myxoid          Fiboblastic          smooth muscle          skeletal muscle          cartilage          osteoid          fat tissue          neural

TUMOR STAGING G. Wilm

According to the Children's Oncology Group

ST Adium I

Tumor is found only in the kidney and can be removed entirely

ST Adium II

The tumor has spread beyond the kidney, fatty tissue or to other soft tissue or blood vessels, but still can be lifted as a whole.

ST Adium III

Tumor has spread within the abdominal cavity and can not be removed completely. Also had metastatic nodes, vascular or peritoneal

STA DIUM IV

Distant metastases to the lungs, liver, bones, vertebrae and praspinal region, the brain or the KGB outside the abdomen and pelvis

STA DIUM V

Tumor cells were found in both kidneys when the tumor was first Diagnosed

            The spread to the renal pelvis or ureter is very rare, if any, and the case is a case of advanced causes polypoid mass out of the system that resembles pyelocalyceal botryoid rhabdomyosarcoma.

            Spread of WT can reach the adrenal gland, intestine, liver, vertebrae and praspinal. Location metastases are the most common lung, liver, peritoneum and CNS.

H. THERAPY

1.       Measures surgery

Indications for surgery are:

• Tumor limited to the kidney
• Tumor extends out the kidney but not cross the midline, and with or without expansion into vascular
• Postchemotherapy tumor excision is Indicated in Patients with bilateral tumors, tumors that extend beyond the center line and has shrunk, and tumors with vascular expansion. Operation not recommended for Wilms tumor, based on the results of studies NWTSG-5 (3) (5)

Contraindications to surgery are:

• Bilateral tumors and metastatic
• Large tumors that goes beyond the halfway line, has been expanding into vascular, or both is a relative contraindication, Because some surgeons prefer to get the network through surgical excision, but it 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 abdominal exploration through a transverse incision. Kidney Explored by Mobilizing the ipsilateral colon and Gerota's fascia opening. Exploration of the contralateral kidney is not currently recommended Because of the Increased use of imaging techniques (computed tomography [CT] scans, magnetic resonance imaging [MRI]). If bilateral disease is Diagnosed, nephrectomy is not done, but do it first biopsy specimen. The new protocol in the management of bilateral Wilms tumors is being Explored. If the location of the tumor unilateral, unilateral radical nephrectomy and regional lymph node dissection or sampling was performed. (5) (4)

• Partial nephrectomy

The role of partial nephrectomy remains 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 (eg, Denys-Drash syndrome WAGR syndrome). Partial nephrectomy may be worth doing at 10% -15% of Patients, Because most tumors are too large at initial diagnosis. The main concern regarding nephron-sparing procedure is the presence of local recurrence. NWTS-4 study Showed 8% rate of local recurrence after partial nephrectomy for Patients with bilateral tumors. Given the bilateral Wilms tumor, solitary kidney, or renal insufficiency, partial nephrectomy is a reasonable consideration. (3)

• Preoperative

If the tumor will be removed, and a biopsy performed nephrectomy deferred until after chemotherapy, the which in most cases, will shrink the tumor. Adjacent organ involvement is Often overdiagnosed. Overall complication rate of surgery for Wilms tumor is approximately 20%. If the thrombus is found inferior vena cava (IVC), preoperative chemotherapy will reduce by 50% the level cavotomy. (5)

In bilateral Wilms tumor (6% of cases) that do include surgical exploration, biopsy of both sides, and accurate tumor staging (including lymph node biopsies from both sides). This is then Followed by 6 weeks of chemotherapy According to the stage of the tumor anatomy and pathology picture. A review is then performed through 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, if good response to chemotherapy in tumors of the kidney again. This approach dramatically Reduces the rate of renal failure after bilateral Wilms tumor therapy. (10)

The survival rate for 2-year overall higher than 80% with this approach, and nephrectomy rate fell by 50% in Patients with bilateral Wilms tumor. Bilateral partial nephrectomy possible after chemotherapy or, if the tumor is in one side fully respond to chemotherapy, and does not need to be done again nephrectomy. (8)

Follow-up after surgery

Follow-up care after treatment must be long (if possible, for life), Because Wilms tumor can recur after several years. Follow-up consisted of chest x-ray and ultrasound, CT scan, or MRI of the 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

• Ileus obstruction (7%)
• Bleeding (6%)
• Surgical wound infection, hernia (4%)
• Complications in vascular (2%)
• Trauma to the spleen and intestine (1.5%)

2.       Chemotherapy and Radiation

            Effects of chemotherapy and radiation over the visible blastema components Compared to the mesenchyme or epithelium. The incidence of anaplasia also influenced by the modality of healing. (2) (3) (5) (10)

Stage and Histology	Surgery	Chemotherapy	Radiation Therapy *
Stage I or II favorable histology without loss of heterozygosity (LOH) 1p and 16q †	Nephrectomy	Vincristine, dactinomycin	No..
Stage I or II favorable histology with LOH 1p and 16q	Nephrectomy	Vincristine, dactinomycin, doxorubicin	No..
Stage III and IV favorable histology without LOH 1p and 16q	Nephrectomy	Vincristine, dactinomycin, doxorubicin	Yes
Stage III and IV favorable histology with LOH 1p and 16q	Nephrectomy	Vincristine, dactinomycin, doxorubicin, cyclophosphamide, etoposide	Yes
*  Currently the exact dose of radiation therapy for Wilms tumor is approximately 1080 cGy to 1200 cGy to the abdomen and lungs. Radiotherapy Carried out at 14 days post-nephrectomy. Stage IV Wilms tumor with pulmonary metastases of lung lesions Patients do not disappear after six weeks of radiation chemotherapy should be performed on all lung fields. † Some Evidence Suggests that in certain children with stage I can be treated with either by nephrectomy alone. Children aged less than 24 months with tumor weight (<550 g) with a good histologic included in the current COG protocols.

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 multimodal therapy, the prognosis of Wilms tumor to be better, and this is Considered as an example of success in cancer therapy. Overall survival rates in Patients with Wilms tumor is 90%. Cases of tumors with anaplasia picture spread and stage III or IV disease reappearing despite the complex therapy have a much 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 sparked increasing the survival rate of up to 50% -60%.

Prognosis depends on the following:

• Differentiation of tumor cells Compared to normal kidney cells
• Cancer stage
• The type and size of the tumor
• Age of children
• Whether the tumor can be completely resected by surgery
• Is this a new case Diagnosed or has happened before (relapse)
• Is there any abnormal chromosomes or genes
• Whether Patients are treated by doctors who have experience treating children 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. January 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. November 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. September 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. February 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. Considerations 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.