Bilateral Wilms’ Tumor
Samuel Anim MD
3/12/2010
I have nothing to disclose
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
Examination
• T: 38.5 F, HR: 101-140, BP: 108 – 143/56-100, RR: 40,
O2: 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
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
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
BILATERAL WILMS’ TUMOR
Epidemiology
• 1st 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
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
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
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
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
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%
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
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
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
Prognostic factors
Treatment
• Aim
1. Eradication of neoplasm
2. 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
3. Decreasing toxicity from Chemotherapy
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
Surgery Vs. Biopsy +Chemo
1970- 1990 @ L A Children’s
Surgery Biopsy + chemo
N- 8 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 No difference No difference
recurrence
Renal Failure 3 1
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
%
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
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
Concerns
• ESRD with dialysis dependence
– Peritoneal Vrs CVVH
• Recurrence
• Will not need abdominal radiation
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.
Thank You