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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) Presentation Transcript

  • 1. Bilateral Wilms’ Tumor Samuel Anim MD 3/12/2010 I have nothing to disclose
  • 2. Case
    • CC: 13 m o F with progressive abdominal distension and constipation for 3 weeks
    • ROS: Intermittent fever, Dyspnea, vomiting, no weight loss, no hematuria
    • PMHx : Idiopathic dilated cardiomyopathy @ 4 months of age with LVFS of 16 % and EF 30 %
    • Meds : enalapril, carvidilol, digoxin
    • G&D : Appropriate
    • FHx : Negative for malignancy. Still birth in maternal Aunt
    • Birth Hx : Normal
  • 3. Examination
    • T: 38.5 F, HR: 101-140, BP: 108 – 143/56-100, RR: 40,
    • O 2 : 95 %
    • HEENT: No syndromic facies PERRL
    • NECK : Supple without lymphadenopathy
    • RESP : Slightly decreased at the bases, otherwise CTAB
    • CVS: S1 + S2 no murmurs
    • ABD: 12 cm mass below the right costal margin and 5 cm below the left costal margin
    • CNS: grossly intact
    • GEN: normal female pre pubertal external genitalia tanner stage I. No masses/hernia in the groin
    • SKIN: Intact
    • EXT: normal
  • 4. Blood work
    • CBC:
      • WBC: 19.2 (n- 59, l - 26 m 13); Hb: 12 g/dl; Plt - 606
    • CMP normal except for,
      • Na 134, BUN 21, Protein 5.4, albumin 2
    • Mg, Phos, Ca - normal
    • LDH - 650, ESR - 71
    • Urinalysis:
      • 2-3 + protein,
      • microscopy negative for RBC,
      • hyaline and granular casts present
    • Ur Protein – 265, Ucr – 25.7, Urine Prot/Cr - 10
    • Lipid panel normal
  • 5. Imaging
    • Initial US from OSH : Polycystic Kidney Disease
    • US:
      • 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.
      • 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.
    • CT Abdo/Pelvis – Bilateral renal masses
    • Chest CT: normal
    • Pathology : Nephroblastoma with intralobular nephrogenic rests and areas of focal necrosis bilateral
    • Special tests
      • DNA micro array – negative for genetic imbalance
      • WT 1 mutation: transition of G>A @ position 1186 0f codon 396 associated with Denys Drash syndrome
      • Karyotype – 46 XX
  • 6.
    • BILATERAL WILMS’ TUMOR
  • 7. Epidemiology
    • 1 st described by Dr Rance in 1814 with bilateral tumors
    • Max Wilms – 1899 also described bilateral presentations
    • Mean age of presentation earlier than unilateral Wilms’
    • Incidence
      • Unilateral: 6 % of all childhood cancers = 650 new cases /year
        • Bilateral 5- 8 % of all Wilms’ tumor
        • Equal sex distribution
        • AA>Caucasians>Asian
    • Metachronous Vrs Synchronus
  • 8. Clinical features
    • Abdominal mass – Commonest symptom
        • +/- pain, fever N &V constipation, weight loss
    • Hematuria – 30 %
        • Microscopic /macroscopic
    • Hypertension - 25 %
      • Cardiomyopathy
        • Hypereninemia and increased cathechol amines
        • Other vaso-active amines involved
    • Part of a syndrome - 20 %
      • Genital, eyes, MR,
    • Coagulopathy – 10 %
      • Acquired vWF
  • 9.  
  • 10. Pathology
    • 3 elements
        • Blastemal, stromal, epithelial
    • Anaplasia
        • Polypoid nuclei, > 3 X surrounding nuclei
        • Frequency of 5-7 %
        • Focal of diffuse
        • Marker of Resistance to chemotherapy
    • Nephrogenic Rests
        • Embryonal nephroblastic tissue
        • Intralobar or intralobular
        • Majority regress spontaneously
        • Remain dormant or progress to malignancy
  • 11. WT 1 Gene mutation
    • WT 1
      • 5-15% of all Wilms’ tumor
        • located on 11p13
        • 10 exons
        • Encodes transcription factors with 4 zinc finger regions
        • Alternative splicing may result in inclusion and exclusion of 3 amino acids (KTS) -
        • 4 main isoforms
          • +KTS bind to RNA and – KTS bind to DNA
          • High levels in Podocytes
        • Required in ureteric budding, nephron formation, differentiation of the podocytes
        • Complex phenotypes
        • In mice, involved in coronary vessels and epicarduim abnormalities
  • 12.  
  • 13. Wilms’ Tumor Genes cont
    • WT 2
      • 11p15.5
        • Region of genetic imprinting
      • BWS (5%) and IGF II expression
    • WT 3
      • 16 q
    • WT X
      • - located on the X chromosome
      • Tumor suppressor
      • ? Role as a prognostic factor in Wilms’ tumor (15/51)
    • FWT 1- 17 q, FWT2 – 19 q, p53, 1 P
  • 14. Genetic Syndrome
    • Denys Drash (DDS) – 95 %
    • Frazier’s syndrome – rare
        • complete gonadal dysgenesis, gonadoblastoma
        • Nephrotic syndrome with FSGC
        • Intron 9
    • WAGR – 30 %
        • Wilms tumor, Aniridiae, GU abnormalities MR
    • BWS and other over growth syndromes – 5 %
  • 15. Denys Drash Syndrome
        • Pseudohemaphroditism
          • With 46 XY or 46 XX
        • Congenital GN (Diffuse Messangial sclerosis) with progression to ESRD
          • Presents with Proteinuria
        • Wilms’ tumor
          • usually bilateral
        • Exon 8/9
          • Part of the zinc finger encoding region
  • 16.  
  • 17. Cardiomyopathy and WT1 mutation Wagner et al 2008
    • Case report of a 4 month old F with sever HTN 220/140, FTT oliguria, RF
    • HTN unresponsive to multi drug therapy with Nicardipine, enalapril, labetalol. Associated with cardiogenic shock and Anemia, thrombocytopenia
    • US consistent with hypertrophy and moderate signs of heart failure and pericarditis
    • Bilateral nephrectomy performed – dialysis dependent and awaiting transplant. Required minoxidil after nephrectomies
    • Pathology
      • Persistence of metanephric blastema with focal calcifications. No wilms’ tumor
      • Imunno staining with antibodies against podocytes (WT1 neprine) revealed no uptake when compared to controls of normal and wilms tumor patients
      • further testing revealed complete absence of glomerulii
    • Sequennce analysis of WT1 mutation revealed C-T at BP 29 of exon 9 in blood and blastema tissue
    • No abnormality identified in parents – de novo mutation
  • 18.  
  • 19.  
  • 20. Prognostic factors Asch et al 1985 (1966-1981)
    • Age at presentation
    • Stage – kidney with the highest stage
    • Biologic markers –
      • LOH 1p and 16 q (NWTS - 5)
    • Histology
      • Favorable Vs. unfavorable
      • Anaplasia
    • Synchronous Vs. Metachronus
    • Metastasis to the lungs
  • 21.  
  • 22. Prognostic factors
  • 23. Treatment
    • Aim
      • Eradication of neoplasm
      • Preservation of Renal function
        • Synchronous – 9 % have RF
        • Metachronous – 18 %
        • Unilateral Wilms' – 1 %
        • Recurrent or Persistent disease commonest cause
        • Treatment related – Rad, Chemo, Surg, Genetics
      • Decreasing toxicity from Chemotherapy
  • 24. Treatment
    • Surgery
        • Timing
        • Nephron sparing surgery
    • Chemo therapy
        • DACT, VCR. DOXO,
        • IFOS, Carboplatin and Etoposide
    • Radiation
        • Dependent on stage
        • Tumor bed Vs. whole abdominal vs. chest for metastasis
    • Complications
        • Recurrence – 8.2 %
        • ESRD
  • 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
  • 26. UK study Kumar et al 1998
    • Aim: Conservative treatment using initial biopsy, chemotherapy and definite surgery compared to Surgery up front followed by chemo therapy (1980 - 1995)
    • N- 71 children with Bilateral Wilms
        • 57 - biopsy, chemo and surgery
        • 13 - surgery and chemo
        • 1 - bilateral renal cyst Excluded
        • All patients had synchronous tumors
    • OS – 69 % in both groups
    • Renal function normal in 80 % of both groups
    • Mean preserved renal mass 45 % in conservative Vs. 35 %
  • 27. Current Bilateral Wilms tumor study
    • Aims : to improve 4 y EFS to 73 %
    • Prevent removal of at least 1 kidney in 50 % of patients
    • Definitive surgery by 12 week of chemotherapy
    • Open Biopsy discouraged
      • Avoid misdiagnosis
      • Detection of anaplasia
        • Positive in 30 %
    • Open/Needle Biopsy upstages tumor to stage III
      • increased incidence of abdominal recurrence
    • Intensified chemotherapy for anaplasia
  • 28. Progress
    • Received 12 weeks of chemotherapy with DACT and VCR
    • Doxo: Held because of Hx idiopathic dilated Cardiomyopathy
        • Cardiomyopathy resolved with LV EF – 57 % and FS – 29 %
    • Good response with decrease in tumor volume of >50 %
    • Proteinuria resolved
    • Maintained normal renal function
    • Surgery after 12 weeks of chemotherapy
    • Biopsy of normal renal tissue consistent with DMS
    • Will follow closely with
        • scans
        • renal function
  • 29. Concerns
    • ESRD with dialysis dependence
      • Peritoneal Vrs CVVH
    • Recurrence
    • Will not need abdominal radiation
  • 30. References
    • 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
    • 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
    • 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
    • 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 .
  • 31.
    • Thank You
  • 32.  
  • 33.