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  • WT 1 gene is an important regulator of renal and gonadal and cardiac development development
  • 1980 and 2001 in France. Involving patients with DDS FS, WAGR WT 1 mutation. 20 patients were identified. Median age if diagnosis of was 9 months and mean agoe of 13.5month. 5 were bilateral and 15 unilateral
  • Non syndromic
  • Asch et all in 1998 reviewed charts of patients between 1966 and 1981. they did review pathology slides using classify tumors as favourable and unfavorable. 15 girls and 6 boys with age at diagnosis from 3 months to 6 years with a mean of 28.8 months. All patients had favorable histology, and received DACT and VCR and DOX. 11 required radiation. To the abdomen or tumor bed or lungs/mediastinum p value of <0.03
  • P value of <0.02
  • (PowerPoint)

    1. 1. Bilateral Wilms’ Tumor Samuel Anim MD 3/12/2010 I have nothing to disclose
    2. 2. Case <ul><li>CC: 13 m o F with progressive abdominal distension and constipation for 3 weeks </li></ul><ul><li>ROS: Intermittent fever, Dyspnea, vomiting, no weight loss, no hematuria </li></ul><ul><li>PMHx : Idiopathic dilated cardiomyopathy @ 4 months of age with LVFS of 16 % and EF 30 % </li></ul><ul><li>Meds : enalapril, carvidilol, digoxin </li></ul><ul><li>G&D : Appropriate </li></ul><ul><li>FHx : Negative for malignancy. Still birth in maternal Aunt </li></ul><ul><li>Birth Hx : Normal </li></ul>
    3. 3. Examination <ul><li>T: 38.5 F, HR: 101-140, BP: 108 – 143/56-100, RR: 40, </li></ul><ul><li>O 2 : 95 % </li></ul><ul><li>HEENT: No syndromic facies PERRL </li></ul><ul><li>NECK : Supple without lymphadenopathy </li></ul><ul><li>RESP : Slightly decreased at the bases, otherwise CTAB </li></ul><ul><li>CVS: S1 + S2 no murmurs </li></ul><ul><li>ABD: 12 cm mass below the right costal margin and 5 cm below the left costal margin </li></ul><ul><li>CNS: grossly intact </li></ul><ul><li>GEN: normal female pre pubertal external genitalia tanner stage I. No masses/hernia in the groin </li></ul><ul><li>SKIN: Intact </li></ul><ul><li>EXT: normal </li></ul>
    4. 4. Blood work <ul><li>CBC: </li></ul><ul><ul><li>WBC: 19.2 (n- 59, l - 26 m 13); Hb: 12 g/dl; Plt - 606 </li></ul></ul><ul><li>CMP normal except for, </li></ul><ul><ul><li>Na 134, BUN 21, Protein 5.4, albumin 2 </li></ul></ul><ul><li>Mg, Phos, Ca - normal </li></ul><ul><li>LDH - 650, ESR - 71 </li></ul><ul><li>Urinalysis: </li></ul><ul><ul><li>2-3 + protein, </li></ul></ul><ul><ul><li>microscopy negative for RBC, </li></ul></ul><ul><ul><li>hyaline and granular casts present </li></ul></ul><ul><li>Ur Protein – 265, Ucr – 25.7, Urine Prot/Cr - 10 </li></ul><ul><li>Lipid panel normal </li></ul>
    5. 5. Imaging <ul><li>Initial US from OSH : Polycystic Kidney Disease </li></ul><ul><li>US: </li></ul><ul><ul><li>Right kidney is almost entirely replaced by mass. The larger upper pole mass measures 9.4 x 8.2 x 11.2 cm. and lower pole mass measuring 3.0 x 3.5 cm. This mass is solid and contains multiple focal cystic areas, likely representing necrosis. </li></ul></ul><ul><ul><li>The left lower pole renal mass measures 3.3 x 3.4 x 2.8 cm. The parenchyma of the left kidney is otherwise normal. </li></ul></ul><ul><li>CT Abdo/Pelvis – Bilateral renal masses </li></ul><ul><li>Chest CT: normal </li></ul><ul><li>Pathology : Nephroblastoma with intralobular nephrogenic rests and areas of focal necrosis bilateral </li></ul><ul><li>Special tests </li></ul><ul><ul><li>DNA micro array – negative for genetic imbalance </li></ul></ul><ul><ul><li>WT 1 mutation: transition of G>A @ position 1186 0f codon 396 associated with Denys Drash syndrome </li></ul></ul><ul><ul><li>Karyotype – 46 XX </li></ul></ul>
    6. 6. <ul><li>BILATERAL WILMS’ TUMOR </li></ul>
    7. 7. Epidemiology <ul><li>1 st described by Dr Rance in 1814 with bilateral tumors </li></ul><ul><li>Max Wilms – 1899 also described bilateral presentations </li></ul><ul><li>Mean age of presentation earlier than unilateral Wilms’ </li></ul><ul><li>Incidence </li></ul><ul><ul><li>Unilateral: 6 % of all childhood cancers = 650 new cases /year </li></ul></ul><ul><ul><ul><li>Bilateral 5- 8 % of all Wilms’ tumor </li></ul></ul></ul><ul><ul><ul><li>Equal sex distribution </li></ul></ul></ul><ul><ul><ul><li>AA>Caucasians>Asian </li></ul></ul></ul><ul><li>Metachronous Vrs Synchronus </li></ul>
    8. 8. Clinical features <ul><li>Abdominal mass – Commonest symptom </li></ul><ul><ul><ul><li>+/- pain, fever N &V constipation, weight loss </li></ul></ul></ul><ul><li>Hematuria – 30 % </li></ul><ul><ul><ul><li>Microscopic /macroscopic </li></ul></ul></ul><ul><li>Hypertension - 25 % </li></ul><ul><ul><li>Cardiomyopathy </li></ul></ul><ul><ul><ul><li>Hypereninemia and increased cathechol amines </li></ul></ul></ul><ul><ul><ul><li>Other vaso-active amines involved </li></ul></ul></ul><ul><li>Part of a syndrome - 20 % </li></ul><ul><ul><li>Genital, eyes, MR, </li></ul></ul><ul><li>Coagulopathy – 10 % </li></ul><ul><ul><li>Acquired vWF </li></ul></ul>
    9. 10. Pathology <ul><li>3 elements </li></ul><ul><ul><ul><li>Blastemal, stromal, epithelial </li></ul></ul></ul><ul><li>Anaplasia </li></ul><ul><ul><ul><li>Polypoid nuclei, > 3 X surrounding nuclei </li></ul></ul></ul><ul><ul><ul><li>Frequency of 5-7 % </li></ul></ul></ul><ul><ul><ul><li>Focal of diffuse </li></ul></ul></ul><ul><ul><ul><li>Marker of Resistance to chemotherapy </li></ul></ul></ul><ul><li>Nephrogenic Rests </li></ul><ul><ul><ul><li>Embryonal nephroblastic tissue </li></ul></ul></ul><ul><ul><ul><li>Intralobar or intralobular </li></ul></ul></ul><ul><ul><ul><li>Majority regress spontaneously </li></ul></ul></ul><ul><ul><ul><li>Remain dormant or progress to malignancy </li></ul></ul></ul>
    10. 11. WT 1 Gene mutation <ul><li>WT 1 </li></ul><ul><ul><li>5-15% of all Wilms’ tumor </li></ul></ul><ul><ul><ul><li>located on 11p13 </li></ul></ul></ul><ul><ul><ul><li>10 exons </li></ul></ul></ul><ul><ul><ul><li>Encodes transcription factors with 4 zinc finger regions </li></ul></ul></ul><ul><ul><ul><li>Alternative splicing may result in inclusion and exclusion of 3 amino acids (KTS) - </li></ul></ul></ul><ul><ul><ul><li>4 main isoforms </li></ul></ul></ul><ul><ul><ul><ul><li>+KTS bind to RNA and – KTS bind to DNA </li></ul></ul></ul></ul><ul><ul><ul><ul><li>High levels in Podocytes </li></ul></ul></ul></ul><ul><ul><ul><li>Required in ureteric budding, nephron formation, differentiation of the podocytes </li></ul></ul></ul><ul><ul><ul><li>Complex phenotypes </li></ul></ul></ul><ul><ul><ul><li>In mice, involved in coronary vessels and epicarduim abnormalities </li></ul></ul></ul>
    11. 13. Wilms’ Tumor Genes cont <ul><li>WT 2 </li></ul><ul><ul><li>11p15.5 </li></ul></ul><ul><ul><ul><li>Region of genetic imprinting </li></ul></ul></ul><ul><ul><li>BWS (5%) and IGF II expression </li></ul></ul><ul><li>WT 3 </li></ul><ul><ul><li>16 q </li></ul></ul><ul><li>WT X </li></ul><ul><ul><li>- located on the X chromosome </li></ul></ul><ul><ul><li>Tumor suppressor </li></ul></ul><ul><ul><li>? Role as a prognostic factor in Wilms’ tumor (15/51) </li></ul></ul><ul><li>FWT 1- 17 q, FWT2 – 19 q, p53, 1 P </li></ul>
    12. 14. Genetic Syndrome <ul><li>Denys Drash (DDS) – 95 % </li></ul><ul><li>Frazier’s syndrome – rare </li></ul><ul><ul><ul><li>complete gonadal dysgenesis, gonadoblastoma </li></ul></ul></ul><ul><ul><ul><li>Nephrotic syndrome with FSGC </li></ul></ul></ul><ul><ul><ul><li>Intron 9 </li></ul></ul></ul><ul><li>WAGR – 30 % </li></ul><ul><ul><ul><li>Wilms tumor, Aniridiae, GU abnormalities MR </li></ul></ul></ul><ul><li>BWS and other over growth syndromes – 5 % </li></ul>
    13. 15. Denys Drash Syndrome <ul><ul><ul><li>Pseudohemaphroditism </li></ul></ul></ul><ul><ul><ul><ul><li>With 46 XY or 46 XX </li></ul></ul></ul></ul><ul><ul><ul><li>Congenital GN (Diffuse Messangial sclerosis) with progression to ESRD </li></ul></ul></ul><ul><ul><ul><ul><li>Presents with Proteinuria </li></ul></ul></ul></ul><ul><ul><ul><li>Wilms’ tumor </li></ul></ul></ul><ul><ul><ul><ul><li>usually bilateral </li></ul></ul></ul></ul><ul><ul><ul><li>Exon 8/9 </li></ul></ul></ul><ul><ul><ul><ul><li>Part of the zinc finger encoding region </li></ul></ul></ul></ul>
    14. 17. Cardiomyopathy and WT1 mutation Wagner et al 2008 <ul><li>Case report of a 4 month old F with sever HTN 220/140, FTT oliguria, RF </li></ul><ul><li>HTN unresponsive to multi drug therapy with Nicardipine, enalapril, labetalol. Associated with cardiogenic shock and Anemia, thrombocytopenia </li></ul><ul><li>US consistent with hypertrophy and moderate signs of heart failure and pericarditis </li></ul><ul><li>Bilateral nephrectomy performed – dialysis dependent and awaiting transplant. Required minoxidil after nephrectomies </li></ul><ul><li>Pathology </li></ul><ul><ul><li>Persistence of metanephric blastema with focal calcifications. No wilms’ tumor </li></ul></ul><ul><ul><li>Imunno staining with antibodies against podocytes (WT1 neprine) revealed no uptake when compared to controls of normal and wilms tumor patients </li></ul></ul><ul><ul><li>further testing revealed complete absence of glomerulii </li></ul></ul><ul><li>Sequennce analysis of WT1 mutation revealed C-T at BP 29 of exon 9 in blood and blastema tissue </li></ul><ul><li>No abnormality identified in parents – de novo mutation </li></ul>
    15. 20. Prognostic factors Asch et al 1985 (1966-1981) <ul><li>Age at presentation </li></ul><ul><li>Stage – kidney with the highest stage </li></ul><ul><li>Biologic markers – </li></ul><ul><ul><li>LOH 1p and 16 q (NWTS - 5) </li></ul></ul><ul><li>Histology </li></ul><ul><ul><li>Favorable Vs. unfavorable </li></ul></ul><ul><ul><li>Anaplasia </li></ul></ul><ul><li>Synchronous Vs. Metachronus </li></ul><ul><li>Metastasis to the lungs </li></ul>
    16. 22. Prognostic factors
    17. 23. Treatment <ul><li>Aim </li></ul><ul><ul><li>Eradication of neoplasm </li></ul></ul><ul><ul><li>Preservation of Renal function </li></ul></ul><ul><ul><ul><li>Synchronous – 9 % have RF </li></ul></ul></ul><ul><ul><ul><li>Metachronous – 18 % </li></ul></ul></ul><ul><ul><ul><li>Unilateral Wilms' – 1 % </li></ul></ul></ul><ul><ul><ul><li>Recurrent or Persistent disease commonest cause </li></ul></ul></ul><ul><ul><ul><li>Treatment related – Rad, Chemo, Surg, Genetics </li></ul></ul></ul><ul><ul><li>Decreasing toxicity from Chemotherapy </li></ul></ul>
    18. 24. Treatment <ul><li>Surgery </li></ul><ul><ul><ul><li>Timing </li></ul></ul></ul><ul><ul><ul><li>Nephron sparing surgery </li></ul></ul></ul><ul><li>Chemo therapy </li></ul><ul><ul><ul><li>DACT, VCR. DOXO, </li></ul></ul></ul><ul><ul><ul><li>IFOS, Carboplatin and Etoposide </li></ul></ul></ul><ul><li>Radiation </li></ul><ul><ul><ul><li>Dependent on stage </li></ul></ul></ul><ul><ul><ul><li>Tumor bed Vs. whole abdominal vs. chest for metastasis </li></ul></ul></ul><ul><li>Complications </li></ul><ul><ul><ul><li>Recurrence – 8.2 % </li></ul></ul></ul><ul><ul><ul><li>ESRD </li></ul></ul></ul>
    19. 25. Surgery Vs. Biopsy +Chemo 1970- 1990 @ L A Children’s Surgery N- 8 Biopsy + chemo N - 7 Age 3.6 y +/- 2.2 2.3 y +/- 2.2 % renal mass preserved 52 +/- 12 73 +/- 16 ( p – 0.03 ) Survival No difference No difference Metastasis/ Local recurrence No difference No difference Renal Failure 3 1
    20. 26. UK study Kumar et al 1998 <ul><li>Aim: Conservative treatment using initial biopsy, chemotherapy and definite surgery compared to Surgery up front followed by chemo therapy (1980 - 1995) </li></ul><ul><li>N- 71 children with Bilateral Wilms </li></ul><ul><ul><ul><li>57 - biopsy, chemo and surgery </li></ul></ul></ul><ul><ul><ul><li>13 - surgery and chemo </li></ul></ul></ul><ul><ul><ul><li>1 - bilateral renal cyst Excluded </li></ul></ul></ul><ul><ul><ul><li>All patients had synchronous tumors </li></ul></ul></ul><ul><li>OS – 69 % in both groups </li></ul><ul><li>Renal function normal in 80 % of both groups </li></ul><ul><li>Mean preserved renal mass 45 % in conservative Vs. 35 % </li></ul>
    21. 27. Current Bilateral Wilms tumor study <ul><li>Aims : to improve 4 y EFS to 73 % </li></ul><ul><li>Prevent removal of at least 1 kidney in 50 % of patients </li></ul><ul><li>Definitive surgery by 12 week of chemotherapy </li></ul><ul><li>Open Biopsy discouraged </li></ul><ul><ul><li>Avoid misdiagnosis </li></ul></ul><ul><ul><li>Detection of anaplasia </li></ul></ul><ul><ul><ul><li>Positive in 30 % </li></ul></ul></ul><ul><li>Open/Needle Biopsy upstages tumor to stage III </li></ul><ul><ul><li>increased incidence of abdominal recurrence </li></ul></ul><ul><li>Intensified chemotherapy for anaplasia </li></ul>
    22. 28. Progress <ul><li>Received 12 weeks of chemotherapy with DACT and VCR </li></ul><ul><li>Doxo: Held because of Hx idiopathic dilated Cardiomyopathy </li></ul><ul><ul><ul><li>Cardiomyopathy resolved with LV EF – 57 % and FS – 29 % </li></ul></ul></ul><ul><li>Good response with decrease in tumor volume of >50 % </li></ul><ul><li>Proteinuria resolved </li></ul><ul><li>Maintained normal renal function </li></ul><ul><li>Surgery after 12 weeks of chemotherapy </li></ul><ul><li>Biopsy of normal renal tissue consistent with DMS </li></ul><ul><li>Will follow closely with </li></ul><ul><ul><ul><li>scans </li></ul></ul></ul><ul><ul><ul><li>renal function </li></ul></ul></ul>
    23. 29. Concerns <ul><li>ESRD with dialysis dependence </li></ul><ul><ul><li>Peritoneal Vrs CVVH </li></ul></ul><ul><li>Recurrence </li></ul><ul><li>Will not need abdominal radiation </li></ul>
    24. 30. References <ul><li>Prognostic factors and outcome in bilateral Wilms' tumor, Morris J. Asch, Stuart Siegel, Leslie White, Eric Fonkalsrud, Daniel Hays, Hart Isaacs, Cancer, 56 (10), Pages 2524 - 2529 </li></ul><ul><li>Treatment of bilateral Wilms’ tumor: Comparison of initial biopsy and chemotherapy to initial surgical resection in the preservetion of renal mass and funcion. Journal of Pediatric Surgery , Volume 27, Issue 8 , August 1992 , Pages 1009-1015 Donald B. Shaul, Myur M. Srikanth, Jorge A. Ortega, G.Hossein Mahour </li></ul><ul><li>Conservative surgical management of Bilateral Wilms tumor: results of the United Kingdom Childrens Cancer Study Group. The Journal of Urology , Volume 160, Issue 4 , October 1998 , Pages 1450-1453 Rajendra Kumar, Ray Fitzgerald, Fin Breatnach </li></ul><ul><li>A novel wilms tumor 1 gene mutation in a achild with severe renal dysfunction and persistent renal blastema, Pediatric Nephrology , Sep2008, Vol. 23 Issue 9, p1445-1453. Wagner, Nicole; Wagner, Kay-Dietrich; Afanetti, Mickael; Nevo, Fabien; Antignac, Corinne; Michiels, Jean-Francois; Schedl, Andreas; Berard, Etienne . </li></ul>
    25. 31. <ul><li>Thank You </li></ul>