BY DR.AHMED, R.

O 15th June,2012

 Wilms Tumour otherwise known as Nephroblastoma

is an embryonal neoplasm arising from the kidney. Nephroblastoma is named after Dr. Max Wilms, the German surgeon (18671918) who first described this kind of tumor. Commonest abdominal malignancy in childhood; accounting for 20% of childhood malignancies International collaborative research over the last 30 years has resulted in cure rates rising from 50% to almost 90% currently.

 The Urogenital system develop primarily from the intermediate

mesoderm of the 3 germ cell layers of Embryonic life i.e Ectoderm, Mesoderm and Endoderm) The development of the kidney proceeds through a series of successive phases, each marked by the development of a more advanced kidney: the pronephros, mesonephros, and metanephros. The pronephros is the most immature form of kidney, while the metanephros is most developed. The metanephros persists as the definitive adult kidney. Metanephric blastema: are cells which are involved in the development of the child's kidneys while in the womb. These cells usually disappear at birth, but in many children with Wilms' tumour, cells called nephrogenic rests can still be found.
Pronephros Metanephros

Mesonephros

 Incidence 8.1 cases/million Caucasian children less

than 15 years of age Peak incidence is at 3-4 years of age, most occuring before 5 years of age Around 70 cases/annum in the UK, about 450 new cases/annum in North America Male:Female ratio 1 Rarer after 10 years; and occurs occasionally in adults

 Development of Wilms

Tumour linked with some cells called NEPHROGENIC RESTS Nephrogenic rests are small, microscopic cluster of blastemal cells, tubules and stromal cells found at the periphery and within the renal lobe. Nephrogenic rests are said to be the precursor lesions for Wilms Tumour. They are found in 30% Unilateral tumours and almost 100% in bilateral Wilms Tumour. Inactivation/Deletion of a Tumour Suppressor gene; WT-1, located on Chromosome 11, is linked to Wilms Tumour. WT-1 encodes for transcription factor for normal kidney development.

 WT-1 deletion is associated with WAGR syndrome

(Wilms Tumour associated with Aniridia, Genitourinary abnormalities and Mental Retardation) and Denys-Drash syndrome (pseudohermaphroditism, mesangial sclerosis, renal failure and Wilms Tumour) WT-2 gene deletion is also culpable. This is associated with development of Beckwith Wiederman syndrome. Familial WT genes(FWT1 and FWT2) on loci of chromosomes 17 & 19 confers poor prognosis of Wilms Tumour especially with loss of heterozygosity.

 Symptoms and signs include:

Abdominal mass or swelling, smooth, rounded or lobulated, non-tender arising in the loin Abdominal pains Gross haematuria Pyrexia and weight loss Hypertension DIFFERENTIALS Neuroblastoma Benign conditions like Hydronephrosis, Polycystic Kidney Disease & Spenomegaly

 Abdominal CT/Ultrasonography- enables determination of extent of tumour spread and patency of the IVC vessel. Duplex colour or Doppler Ultrasound also may determine presence of radiological abnormality in the other kidney Chest X-ray or better still CT - to rule out pulmonary metastasis Full Blood Count- may show anaemia

Serum E/U/Cr & LFTs- may show a derangement

Urinalysis- may show blood & protein in the urine Urinary catecholamines - to exclude Neuroblastoma Intravenous Urography- to check the function,especially of the contralateral kidney. However CT has replaced IVU as the diagnostic imaging of choice in Nephroblastema Most common sites of metastasis of Wilms Tumour are Lungs ,Lymph nodes and Liver.

 2 broad groups of Wilms tumours are recognized by their

histological appearances; Favourable Histology and Unfavourable Histology A.) Favourable Histology (90%): It consists of classical triphasic histological pattern- B.E.S {Blastemal,Epithelial and Stromal Elements} B.)Unfavourable Histology (10%): This consists of -Anaplastic type: made up gigantic polypoid cells within tumour samples. Anaplastic type may be FOCAL or DIFFUSE. Focal type has higher survival rate while Diffuse has a poor prognosis. - Clear Cell Sarcoma of the Kidney (CCSK) - Rhabdoid Tumour of the Kidney (RTK) It should be noted that both CCSK & RTK are no longer considered as true Wilms Tumours. In fact, RTK is now regarded as the most lethal renal neoplasm in children.

Computed tomography scan of the abdomen demonstrating bilateral renal tumors.

 The National Wilms Tumour Study Group (NWTSG)

staging system is commonly used: STAGE I Tumour completely excised and retained within the capsule STAGE II Tumour completely excised but extending beyond capsule STAGE III Tumour incompletely excised but no blood borne metastasis (but lymph nodes invlvement) STAGE IV Blood-borne distant metastasis e.g to Lungs, Liver, Bone or Brain STAGE V Bilateral Renal Tumours

 SURGERY :
This remains the cornerstone in the treatment of Wilms

Tumours. Transabdominal/Transperitoneal incision is used for adequate exposure. Laparotomy & radical resection of the tumour (Nephroureterectomy+Regional node dissection) is done. Excision of all tumours without spillage Contralateral kidney is palpated & visualized to exclude Bilateral Wilms Tumour before nephrectomy Lymph node sample (para-aortic,celiac & iliac areas) must be performed.

 CHEMOTHERAPY AND RADIOTHERAPY: These are

used as adjuvant to surgery postoperatively. Treatment is tailored to the stage and pathology of the tumour. For Favourable Histology:
Short course of Vincristine & Actinomycin D over 18 weeks

STAGE I & II

STAGE III & IV

Vincristine, Actinomycin D & Adriamyci n + XRT to renal bed

 For Unfavourable Histology (Anaplastic tumours):

STAGE I Short course of Vincristine and Actinomycin D

STAGE II,III & IV

2nd line of Vincristine, Adriamycin, Etoposide & Cyclophosphamide + XRT to renal bed &metastatic sites (if px responds well to chemorx)

 For STAGE V, it is a more difficult and specialized

case:
STAGE V Initial chemotherapy + partial nephrectomy + adjuvant treatment

Bilateral nephrectomy+ chemotherapy + renal transplant (is the last resort)

 SURGERY VERSUS CHEMOTHERAPY, BEFORE OR

AFTER?! Surgery and chemotherapy are used for all stages of Wilms Tumour. According to the advocates of Chemorx (e,g SIOP) before Surgery, pre-nephrectomy chemorx reduces tumour rupture rate thereby preventing relapse. It also leads to identification of good prognostic group based on tumour response. Advocates of surgery before chemorx ( e.g NWTSG) believe that this avoids modification of histology or staging and administration of chemorx to non-Wilms Tumour or Benign diseases. Non of the views is said to be superior as at present.

 RADIOTHERAPY TREATMENT : XRT delay is not good especially for Unfavourable Histology

Tumours XRT should start not later than Day 9 after surgery Parallel-opposed fields using 4- or 6-MV photons are preferred. Post-op treatment to flank (renal bed) for STAGE III patients: Favourable Histology 14.4Gy in 8# Unfavourable Histology 25.2 Gy in 14# During planning,full width of vertebral body will be added to avoid asymetric spinal growth and scoliosis CTV Tumour + Kidney & a margin of 2cm

Simulation film of an anteroposterior portal of the flank in a 2-year-old child with a left-sided stage III favorable-histology Wilms' tumor (WT), showing inclusion of the entire width of the vertebral body in the irradiated volume. The outline of the right kidney (RK) and the WT from the preoperative computed tomography scan is shown.

Occasionally, whole abdominal XRT is done for those with intra-abdominal tumour spread. Femoral heads and acetabulum must be shielded for this procedure.
Anteroposterior portal for the whole abdomen used in irradiation of patients with stage III Wilms' tumor and diffuse peritoneal tumor spillage. The upper margin of the abdominal field must include the diaphragm. The acetabulum and femoral head should be excluded from the irradiated volume to decrease the probability of slipped femoral capital epiphysis. The pants zipper can be seen low on the hips. In general, it is advisable to remove the trousers completely to ensure a reproducible setup.

 For those with Pulmonary Metastasis, whole lung

irradiation is given. The fields are costophrenic recess with lower border extending to the lower border of T12. Humeral heads are shielded. The dose for whole lung irradiation are as below: 12Gy in 8 daily # of 1.5Gy specified to mid-plane without lung correction OR 15Gy in 10 daily # of 1.5Gy with a lung density correction

Simulation film of a patient with stage IV favorable histology Wilms' tumor receiving wholelung irradiation. A lateral radiograph of the chest should be obtained at simulation to ascertain inclusion of the anterior and posterior costophrenic angles at the inferior edge of the treatment volume.

Outline of Childrens Oncology Group Renal Tumor Study

Tumor Risk Classification Very low-risk FH Wilms tumor <2 yr, stage I, tumor weight <550 g Low-risk FH Wilms tumor <2 yr, stage I, tumor weight <550 g Stage II without LOH at 1p and 16q Standard-risk FH Wilms tumor Nephrectomy, no RT, regimen EE4A Multimodality Treatment Nephrectomy without adjuvant therapy, if node sampling and central pathology review has been performed.

Stage I and II with LOH at 1p and 16q

Stage III without LOH at 1p and 16q

Nephrectomy, no RT, regimen DD4A

Nephrectomy, RT, regimen DD4A

Stage IV FH: Rapid responders of lung metastases at week 6 Nephrectomy, RT, regimen DD4A; no WLI with regimen DD4A

FH, favorable histology; LOH, loss of heterozygosity; RT, flank or abdominal irradiation; regimen EE4A (VA); regimen DD 4A (V [vincristine] A [dactinomycin] D [doxorubicin]); WLI, whole-lung irradiation; regimen M (VAD/Cy [cyclophosphamide] E [etoposide]); UH, unfavorable histology; CCSK, clear cell sarcoma of kidney; RTK, rhabdoid tumor of kidney; regimen I (alternating VDCy/CyE); regimen UH1 (alternating VDCy/CyC [carboplatin] E).

Tumor Risk Classification

Higher-risk FH Wilms tumor Stage III with LOH at 1p and 16q Stage IV slow responders (lung) and nonpulmonary metastases High-risk UH renal tumors Stages I-IV focal anaplasia Stage I diffuse anaplasia Stage I-III CCSK Stage II-IV diffuse anaplasia Stage IV CCSK Stage I-IV RTK

Multimodality Treatment

Nephrectomy, RT, regimen M Nephrectomy, RT, regimen M, WLI and RT to metastases

Nephrectomy, RT, regimen DD 4A

Nephrectomy, RT, regimen I Nephrectomy, RT, regimen UH1, RT to all metastatic sites

FH, favorable histology; LOH, loss of heterozygosity; RT, flank or abdominal irradiation; regimen EE4A (VA); regimen DD 4A (V [vincristine] A [dactinomycin] D [doxorubicin]); WLI, whole-lung irradiation; regimen M (VAD/Cy [cyclophosphamide] E [etoposide]); UH, unfavorable histology; CCSK, clear cell sarcoma of kidney; RTK, rhabdoid tumor of kidney; regimen I (alternating VDCy/CyE); regimen UH1 (alternating VDCy/CyC [carboplatin] E).

Abdominal Tumor Stage and Histology Stage I and II FH Wilms tumor Stage III FH, stage I-III focal anaplasia, stage I-II diffuse anaplasia, stage I-II CCSKc Stage III diffuse anaplasia, stage I-III RTK Recurrent abdominal Wilms tumor

RT Dose/RT Fielda None 10.8 Gy to the flankb 19.8 Gy (infants 10.8 Gy) flankbRT 12.618 Gy (<12 months of age)b or 21.6 Gy (older children) if previous radiation dose is 10.8 Gy. Boost dose of up to 9 Gy to gross residual tumor after surgery 12 Gy WLI in 8 fractionsd

Lung metastases (favorable histology)

Lung metastases (unfavorable histology)

Brain metastases Liver metastases Bone metastases Unresected lymph node metastases

12 Gy WLI in 8 fractions
30.6 Gy whole brain in 17 fractions, or 21.6 Gy whole brain + 10.8 Gy IMRT or stereotactic boost 19.8 Gy whole liver in 11 fractions 25.2 Gy to the lesion plus 3-cm margin 19.8 Gy

RT radiation therapy; FH, favorable histology; CCSK, clear cell sarcoma of the kidney; RTK, rhabdoid tumor of kidney; WLI, wholelung irradiation; IMRT, intensity-modulated RT. aTiming of RT (RT delay): RT should begin as close to the beginning of chemotherapy as possible, preferably by day 9 (surgery is day 10), but no later than day 14, unless medically contraindicated or when there is a delay in central pathology review. bWhole-abdomen irradiation (WAI) is indicated when there is diffuse tumor spillage, preoperative or intraperitoneal tumor rupture, peritoneal tumor seeding, and cytology positive ascites. When WAI dose is >10 Gy, renal shielding is required to limit the dose to the remaining kidney to <14.4 Gy. Gross residual disease after surgery should receive a boost of 10 Gy.

FIGURE 83.1. Computed tomography scan of a 4-year-old girl with a large right-sided Wilms' tumor measuring 10.5 8.4 13.5 cm. The left kidney did not show any lesions. At laparotomy, the tumor was found to invade the diaphragm. She underwent a right radical nephrectomy. Surgical margins of resection were positive and she had metastases in the para-aortic lymph nodes. The tumor was classified as stage III favorable histology and received 10.8 Gy to the right flank and chemotherapy with vincristine, dactinomycin, and doxorubicin.

 Wilms Tumour is both radio- and chemosensitive

Prognosis for localized disease is very good.

80-90% of Stage I or II disease can be cured Even Stage IV disease with distant metastases have a

cure rate of 40%. TREATMENT COMPLICATIONS Scoliosis Congestive Heart Failure 2nd Malignant Neoplasm End Stage Renal Disease

References 1.Bethesda Handbook of Clinical Oncology(2 nd Edition) 2.Clinical Oncology by Dr Anthony J.Neal et al(4 th Edition) 3.Manual of Clinical Oncology by Dennis A.Casciato(5 th edition) 4.Perez & Bradys Principles and Practice of Radiation Oncology (5th edition) 5.Treatment of Cancer(4th edition) by Pat Price & Karol Sikora 6.Oxfords Handbook of Clinical Oncology(2ndEdition)