Wilms Tumor: Gaurav Nahar DNB Urology (STD) MMHRC, Madurai

WILMS TUMOR
Gaurav Nahar
DNB Urology(Std)
MMHRC, Madurai
INTRODUCTION
Wilms tumor - Nephroblastoma.
Most common primary malignant renal tumor
of childhood.
This embryonal tumor develops from remnants
of immature kidney.
EPIDEMIOLOGY
Accounts for 6% to 7% of all childhood
cancers.
Children<15 yrs: annual incidence rate 7 to 10
cases per million.
More than 80% of cases are diagnosed before
5 years of age, with a median age of 3.5 years.
B/L Wilms tumors present at earlier age.

Incidence lower in East Asian populations &
higher in black populations compared with
North American and European whites.
Environmental risk factors play a minor role.
ETIOLOGY
Majority of Wilms tumors arise from somatic
mutations restricted to tumor tissue.
A much smaller percentage originate from
germline mutations.
Several genetic events result in Wilms tumor
development.
10% tumors- have coexistent congenital

anomalies and syndromes.
5% to 10% tumors- bilateral/multicentric.
1% to 2% are familial.
WT1:
1st Wilms tumor gene to be identified.
Gross deletions at chromosome 11p13.
Associated syndromes:
1.WAGR syndrome
2.Denys-Drash syndrome
3.Frasier syndrome
WT1 gene is important for normal kidney &

gonadal development.
WT1 encodes a zinc-finger transcription factor
expressed in kidney, gonads, spleen, &
mesothelium
WT1 is necessary for ureteric bud outgrowth
and nephrogenesis.
WAGR (Wilms tumor, Aniridia, Genital

anomalies, mental Retardation) syndrome.
Aniridia, found in 1.1% of Wilms tumor
patients, is caused by an abnormality of the
PAX6 gene located adjacent to WT1.
Wilms tumor develops in 40% to 70% of
aniridia patients with deletions of WT1.
Denys-Drash syndrome (DDS): specific

association of male pseudohermaphroditism,
renal mesangial sclerosis, and nephroblastoma.
Caused by point mutations in zinc finger DNA
binding region of WT1.
>90% of DDS patients harbor germline point
mutations in only one WT1 allele.
WAGR and DDS patients- more likely to have

bilateral tumors & are diagnosed at a younger age.
WAGR patients- increased risk of renal failure if they
survive into puberty.
Genitourinary anomalies- renal fusion anomalies,
cryptorchidism, hypospadias are present in 4.5% of
patients with Wilms tumor.
WT2:
11p15 locus- LoH(Loss of Heterozygosity)
a/w Beckwith-Wiedemann Syndrome.
Genes involved- H19 & IGF-2.
Beckwith-Wiedemann syndrome(BWS)
characterized by excess growth at cellular,
organ (macroglossia, nephromegaly,
hepatomegaly), or body segment
(hemihypertrophy) levels.
Adrenocortical neoplasms and hepatoblastoma
also occur in BWS.
Most cases sporadic; 15% heritable- AD.
WTX:
Tumor suppressor gene, Wilms Tumor gene on
the X chromosome, at Xq11.1,
Inactivated in up to one third of Wilm's
tumors.
Targets single X chromosome in males &
active X chromosome in females with tumors.
Familial Wilm's Tumor : (FWT1, FWT2)

1% to 2% of Wilms tumor patients have a
family h/o Wilms tumor.
Earlier age of onset & increased frequency of
B/L disease.
TP53 mutations- increased frequency in

anaplastic histology.
LoH at 1p and 16q are associated with an
increased risk of tumor relapse and death.
SCREENING
Ultrasound surveillance- from time of
diagnosis until 5 years of age, with a
frequency of every 3 to 4 months.
BWS, Simpson-Golabi-Behmel, and familial
Wilms- continue to 7 years.
Screening recommended when WT incidence
> 5%.
Screening of contralateral kidney after
nephrectomy for U/L Wilm's.
CT or MRI if USG shows any suspicious lesion.

7-fold increased risk of Wilm's tumor in HK.
an increased risk of mllerian duct anomalies in girls
with Wilms tumor- Approx.10% girls will have
abnormalities, such as duplication of cervix or uterus,
or bicornuate uterus.
PATHOLOGY
Favorable-Histology Wilms Tumor(FH):
Wilms tumor compresses adjacent normal
renal parenchyma, forming an "intrarenal
pseudocapsule."
Tremendous histologic diversity.
90% of all renal tumors have favorable
histology.
Classical Wilms tumor is characterized by

islands of compact undifferentiated blastema,
presence of variable epithelial differentiation
in the form of embryonic tubules, rosettes, and
glomeruloid structures,
separated by a significant stromal component.
Predominantly epithelial differentiation- low

degree of aggressiveness, majority are stage I
tumors,
But may be more resistant to therapy, if they
present as advanced-stage disease.
Survival Rates in Patients with Favorable-Histology Wilms

Tumor
Anaplastic Wilms Tumor:

Anaplasia is characterized by the presence of
three abnormalities:
1.nuclear enlargement to three or more times the
diameter of adjacent cells,
2.hyperchromasia of enlarged nuclei, and
3.abnormal mitotic figures.
Rarely seen in children< 3 years.
Resistant to chemotherapy.
Poor prognosis.
Further divided into focal & diffuse patterns.
Nephrogenis Rests:
Precursor lesions; still most don't form Wilm's
tumor.
A rest can undergo maturation, sclerosis,
involution, or complete disappearance.
Two types based on location: Perilobar &
Intralobar(PLNRs & ILNRs).
Perilobar NRs- found only in the lobar

periphery, elaborated late in embryogenesis.
Subcortical, sharply demarcated, and contain
predominantly blastema & tubules.
Usually found in BWS, linked to 11p15 locus.
Intralobar NRs found anywhere within the

lobe, renal sinus and wall of PCS.
Result of earlier gestational aberrations.
ILNRs are commonly stroma rich.
Typically seen in aniridia, WAGR, DDS or
other features a/w WT1.
CLINICAL PRESENTATION
A palpable smooth abdominal mass- 90%.
Incidentally discovered.
Abdominal pain, gross hematuria & fever- less
frequent.
Tumor rupture with hemorrhage into peritoneal
cavity- mimics acute abdomen.
Extension into renal vein & IVC- varicocoele,
hepatomegaly due to hepatic vein obstruction, ascites,
and congestive heart failure- <10%.
Hypertension- common at diagnosis, d/t

elevated plasma renin levels; resolves shortly
after removal.
Acquired von Willebrand disease found in 8%
of newly diagnosed Wilms tumor.
IMAGING
FOUR FIELD CHEST RADIOGRAPHY:
may show lung metastasis.
RENAL ULTRASOUND:
1st study to evaluate child with abd.mass.
demonstrate solid nature of the lesion.
Doppler USG helps to exclude intracaval
tumor extension, & its proximal extent.
Solid renal tumor: CT demonstrates that lesion is amenable to renal-sparing

surgery
CT SCAN:
helps to determine origin of the tumor, lymph
node involvement, B/L kidney involvement,
invasion into major vessels (IVC), and liver
metastases.
CT chest to rule out lung metastasis.
CT scan of a left Wilms tumor with a small rim of

functioning renal parenchyma
MRI ABDOMEN:
Most sensitive imaging modality for caval
patency, to determine tumor extension into
IVC.
low signal intensity on T1-weighted images
and high signal intensity on T2-weighted
images.
MRI depicting extension of Wilms tumor into the

inferior vena cava.
STAGING
DIFFERENTIAL DIAGNOSIS
Mesoblastic nephroma - Most common renal tumor in the first

month of life.
Renal cell carcinoma
Clear cell sarcoma of the kidney
Rhabdoid tumor of the kidney
Nonmalignant mass
Hydronephrosis
Multicystic kidney disease
Renal cyst
Renal thrombosis
Dysplastic kidney
Renal hemorrhage
Differential Diagnoses
Neuroblastoma
Polycystic Kidney Disease
Rhabdomyosarcoma
PROGNOSTIC FACTORS
Most Important determinants of outcome:
histopathology & tumor stage.
Chromosomal Abnormalities: LOH for
chromosome 16q and/or 1p (20% of Wilms
tumors) a/w increased risk for relapse & death.
High telomerase activity- an unfavourable
prognostic feature.
DNA Content: Aneuploidy & DNA index . 1.5strongly a/w anaplastic histology.
Cytokines: VEGF angiogenic cytokine.
TREAMENT
Usual approach- nephrectomy followed by
chemotherapy, with or without postoperative
radiotherapy.
Multiple RCTs to determine therapeutic protocols by:
1. National Wilm's Tumor Study Group/Children's
Oncology Group(NWTSG/COG),
2. International Society of Pediatric Oncology(SIOP),
and
3. United Kingdom Childrens Cancer Study Group
(UKCCSG) .
COG AREN0321 protocol for high risk Wilms

tumor
Focal anaplastic stage I-III Wilms tumors and diffuse

anaplastic stage I Wilms tumors - Nephrectomy followed by
vincristine, actinomycin-D, and doxorubicin in addition to local
radiotherapy
Focal anaplastic stage IV Wilms tumors and diffuse
anaplastic stage II-III tumors Patients undergo the same
treatment, with the addition of cyclophosphamide, etoposide,
and carboplatin
Stage IV diffuse anaplastic Wilms tumors - More aggressive
treatment is delivered; nephrectomy is followed by initial
irinotecan and vincristine administration, which in turn is
followed by actinomycin-D, doxorubicin, cyclophosphamide,
carboplatin, etoposide, and radiotherapy.
SURGICAL CONSIDERATIONS:
Radical nephrectomy by transperitoneal approach.
Thorough exploration of the abdominal cavity to
exclude local tumor extension, liver and nodal
metastases, or peritoneal seeding.
Accurate staging to determine appropriate
chemotherapy & need for radiation therapy.
Selective sampling of suspicious nodes is essential.
Formal RPLND is not recommended.
Risk factors for local tumor recurrence

(Shamberger):
1.tumor spillage,
2.unfavorable histology,
3.incomplete tumor removal, and
4.absence of any lymph node sampling.
PREOPERATIVE CHEMOTHERAPY:
Situations where preoperative chemotherapy is
recommended:1. Children for whom renal-sparing surgery is planned,
2. Tumors are inoperable at surgical exploration, and
3. There is tumor extension into IVC above hepatic
veins.
An inoperable tumor should be considered stage III
and treated accordingly.
Inoperability should not be based on

preoperative imaging studies, which can
overestimate local tumor extension.
Pretreatment with chemotherapy almost
always reduces the bulk of tumor and renders
it resectable.
Majority of reduction in tumor volume occurs
in first 4 weeks of chemotherapy.
A, MRI of a Wilms tumor that was pretreated with chemotherapy.

B, After 6 weeks of chemotherapy, the tumor is much smaller in size
MANAGEMENT OF LUNG METASTASIS:

CXR negative but CT positive: tissue
diagnosis of lung nodules because several
conditions (eg, histoplasmosis, atelectasis,
pseudotumor, intrapulmonary lymph node,
pneumonia) can mimic pulmonary metastases.
WT FH with lung mets, no other mets/1p or

16q deletion: 6 weeks of actinomycin-D,
doxorubicin, and vincristine.
Complete resolution- No radiation required.
No resolution- cyclophosphamide and
etoposide in addition + radiation therapy.
MANAGEMENT OF B/L WILMS TUMORS:

No initial radical nephrectomy.
Preoperative chemotherapy for 6 weeks.
tumors amenable to renal-sparing procedures
can proceed with surgery.
Tumors not responding- B/L open biopsy &
additional chemo based on biopsy findings.
Proceed to Sx at 12 weeks of therapy (no

benefit beyond 12 weeks).
Partial nephrectomy, tumor enucleation or
wedge excision of tumor.
In FH tumors, even with positive margins or
large B/L residual masses, adjuvant therapy
provides a good outcome.
LATE EFFECTS OF Rx
RADIATION:
Musculoskeletal problems like scoliosis.
Reduction in stature.
Hypogonadism & temporary azoospermia.
Delayed sexual maturation.
Ovarian failure.
Adverse pregnancy outcomes with increased
risk for miscarriage, LBW, prematurity &
congenital malformations.
Increased risk of 2nd malignant neoplasms.
CHEMO:
Congestive heart failure caused by
anthracyclines(DOX)
FOLLOW-UP
THANK
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WILMS TUMOR

B/L Wilms tumors present at earlier age.

10% tumors- have coexistent congenital

WT1 gene is important for normal kidney &

WAGR (Wilms tumor, Aniridia, Genital

Denys-Drash syndrome (DDS): specific

WAGR and DDS patients- more likely to have

Familial Wilm's Tumor : (FWT1, FWT2)

TP53 mutations- increased frequency in

CT or MRI if USG shows any suspicious lesion.

Classical Wilms tumor is characterized by

Predominantly epithelial differentiation- low

Survival Rates in Patients with Favorable-Histology Wilms

Anaplastic Wilms Tumor:

Perilobar NRs- found only in the lobar

Intralobar NRs found anywhere within the

Hypertension- common at diagnosis, d/t

Solid renal tumor: CT demonstrates that lesion is amenable to renal-sparing

CT scan of a left Wilms tumor with a small rim of

MRI depicting extension of Wilms tumor into the

Mesoblastic nephroma - Most common renal tumor in the first

COG AREN0321 protocol for high risk Wilms

Focal anaplastic stage I-III Wilms tumors and diffuse

Risk factors for local tumor recurrence

Inoperability should not be based on

A, MRI of a Wilms tumor that was pretreated with chemotherapy.

MANAGEMENT OF LUNG METASTASIS:

WT FH with lung mets, no other mets/1p or

MANAGEMENT OF B/L WILMS TUMORS:

Proceed to Sx at 12 weeks of therapy (no

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