Pediatric urology : Wilms tumour

D E P T O F U R O L O G Y
G O V T R O Y A P E T T A H H O S P I T A L A N D K I L P A U K M E D I C A L C O L L E G E
C H E N N A I
WILMS TUMOUR
1

Moderators:
Professors:
 Prof. Dr. G. Sivasankar, M.S., M.Ch.,
 Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
 Dr. J. Sivabalan, M.S., M.Ch.,
 Dr. R. Bhargavi, M.S., M.Ch.,
 Dr. S. Raju, M.S., M.Ch.,
 Dr. K. Muthurathinam, M.S., M.Ch.,
 Dr. D. Tamilselvan, M.S., M.Ch.,
 Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai.
2

INTRODUCTION
 Nephroblastoma
 most common primary malignant renal tumour of
childhood
 embryonal tumour that develops from remnants of
immature kidney
.
3

EPIDEMIOLOGY
 6% to 7% - all childhood cancers.
 95% of all kidney cancers in children under age of 15
 AI : 7-10/ million
 > 80% of patients are diagnosed before 5 years of age,
with a median age of 3.5 years.
 The median age at diagnosis is lower in children with
bilateral Wilms tumour (Breslow et al, 1993).
4

 frequency in females > males
 Several epidemiologic studies have investigated
occupational, environmental, and lifestyle factors
as risk factors for Wilms
 Incidence lower in Asian population & higher in
black populations compared with North American
& European whites.
5

BIOLOGY AND GENETICS
 Majority of Wilms tumours arise from somatic
mutations restricted to tumour tissue and a much smaller
percentage originate from germline mutations.
 10% of children with Wilms tumour have congenital
anomalies and syndromes
 5% to 10% of tumours are bilateral and multicentric
 1% to 2% are familial
6

 CONGENITAL ANOMALY A/W wilms TUMOUR
1. Cryptorchidism
2. Duplex renal collecting system
3. Horse shoe kidney
4. hypospadias
7

8

WT 1
 The first gene mutation described (both somatic and
germline mutations )
 gross deletions at chromosome 11p13
 WT1 encodes a zinc finger transcription regulating
mesenchymal to epithelial transition in kidney
development.
 WT1 is necessary for ureteric bud outgrowth,
nephrogenesis & normal gonadal development
9

 associated with beta-catenin (CTNNB1) mutations,
defining a specific genetic subset of Wilms tumour
called the ideal type 1 Wilms tumour
 stromal-predominant, favorable histology,
intralobar nephrogenic rests (ILNRs)
 early onset of Wilms tumour, and genitourinary
abnormalities in males.
10

 Associated Syndromes
1. WAGR syndrome
2. Denys-Drass Syndrome
3. Frasier Syndrome
11

WAGR syndrome
o Wilms tumour
o Aniridia
o genital anomalies
o mental retardation
 Aniridia, found in 1.1% of Wilms tumour patients & caused by an
abnormality of the PAX6 gene located adjacent to the WT1 gene
 Wilms tumour will develop in 40% to 70% of aniridia patients
with deletions of WT1.
 WAGR patients and those with genitourinary abnormalities have
an increased risk of renal failure if they survive into puberty
12

DDS
1. Male pseudohermaphroditism,
2. renal mesangial sclerosis,
3. nephroblastoma
 caused by point mutations in the zinc finger DNA binding
region of WT1 (Coppes et al, 1993).
 > 90% of DDS patients harbor germline point mutations in
only one WT1 allele, Therefore the WT1 mutation acts
dominantly with respect to genitourinary abnormalities
13

 Denys-Drash mutations do not result in inactivation of
the WT1 protein, but rather in the production of a
dysfunctional WT1 protein
 The majority of these patients progress to end-stage
renal disease.
 Nephropathy usually manifests early in life, and renal
biopsy demonstrates mesangial sclerosis.
 Some WT1 mutations can lead to an incomplete DDS
phenotype, with varying degrees of genitourinary
anomalies, renal pathologies, and penetrance of Wilms
tumour
14

 WAGR and DDS patients have bilateral tumours and are
diagnosed at a younger age
 The incidence of WT1 mutations in patients with wilms
tumour not associated with any genitourinary
abnormality is approximately 2%
15

 FRASIER SYNDROME
1. WILMS Tumour (5%)
2. Gonadoblastoma (50%)
3. Male pseudohermaphroditism
4. Nephropathy ( FSGS-LATER)
16

WTX
 tumour suppressor gene targeted by somatic mutations -
30%
 role in the Wnt/beta-catenin signaling pathway
 Most have deletions of the entire WTX gene, but 1/3
carry truncating mutations or missense mutations
 Location Xq11.1
17

 it is inactivated by a monoallelic or “single-hit”
event rather than by the classical biallelic
inactivation of autosomal tumour suppressor
genes.
 It targets the single X chromosome in males and
the active X chromosome in females with tumours
18

WT 2
 LOH or loss of imprinting (LOI) on 11p15 occurs in 70%
 Gene involved H19 & IGF-2
 Wilms tumour associated with epigenetic alterations in
the 11p15 region has been termed the ideal type 2 Wilms
tumour
 A type 2 Wilms tumour is characterized by limited
nephrogenic differentiation and blastemal or epithelial-
type histology
19

 develop tumours at later age and have heavier birth
weight.
 21% - bilateral disease at presentation
 A/W Beckwith-Wiedemann syndrome (BWS) and other
syndromes with overgrowth features including
hemihypertrophy, which may occur alone or as part of
BWS or Perlman, Soto, and Simpson-Golabi-Behmel
syndromes
20

BWS
 Excess growth at cellular, organ ( macroglossia,
nephromegaly,hepatomegaly) or body segment
( hemihypertrophy ) level
 Most cases are sporadic, 15% heritable – AD
 The risk of nephroblastoma - 4% to 10%;
21

 Adrenocortical neoplasms and hepatoblastoma
occur with increased frequency
 increased Wilms tumour risk - ICR1 gain of
methylation and 11p15 uniparental disomy.
 In contrast, the tumour risk is lower - ICR2 loss of
methylation and CDKN1C mutations.
22

FAMILIAL WILMS tumour
 1% to 2% of Wilms tumour
 earlier age of onset and an increased frequency of
bilateral disease.
 Two familial Wilms tumour genes have been localized
(Ruteshouser and Huff, 2004).
FWT1 is located at 17q12-q21
FWT2 at 19q13.4
23

Other Chromosomal Abnormalities
 TP53 mutations - 75% of Wilms tumour with AHWT
 favorable-histology tumour may progress to an anaplastic
tumour by acquiring a disruption of TP53 function.
 The TP53 mutations correlated with advanced-stage disease
 Loss 16q - 20%
 loss of 1p - 10%
 Both A/w increased risk of tumour relapse and death
24

SCREENING
 Screening recommended when WT incidence > 5 %
 Infants younger than 12 months found to have NRs in the
resected kidney are at the greatest risk for metachronous
tumours.
 USG surveillance is performed at time of diagnosis until 5
years of age, with a frequency of every 3 to 4 months
 BWS, Simpson-Golabi-Behmel syndrome, and familial Wilms
continue to 7 years
 Early detection can provide an opportunity for NSS because
these children are at an increased risk for bilateral disease. But
not improved survival.
25

 Screening of the contralateral kidney after nephrectomy
for unilateral Wilms tumour
 CT or MRI should be performed if ultrasonography
demonstrates a suspicious lesion
 An association between Wilms tumour and horseshoe
kidney has been noted ….7 X also in MCDK
 risk of müllerian duct anomalies in girls - 10% of girls
such as duplication of the cervix or uterus or bicornuate
uterus.
26

27

PATHOLOGY
Favorable-Histology Wilms tumour (90%)
 compresses adjacent normal renal parenchyma, forming a
intrarenal pseudocapsule composed of compressed atrophic
renal tissues.
 The texture of the tumours varies depending on the
predominant histologic pattern.
 Many are soft and friable with necrotic or hemorrhagic areas
frequently noted which increases the risk of intraoperative
tumour rupture during primary nephrectomy
28

 Extrarenal Wilms tumour - displaced metanephric
elements or mesonephric remnants
 tremendous histologic diversity, often contains tissues such
as skeletal muscle, cartilage, and squamous epithelium.
 “Classic” Wilms tumour
1. islands of compact undifferentiated Blastema
2. presence of variable Epithelial differentiation in the
form of embryonic tubules, rosettes, and glomeruloid
structures
3. separated by a significant STromal component
29

 Wilms tumours with predominantly epithelial differentiation
have a low degree of aggressiveness and the majority are
stage I tumours
 more resistance to therapy, If they are present at advanced
stage disease
30

31

 SURVICAL RATE IN FAVORABLE HISTOLOGY
STAGE RELAPSE FREE
SURVIVAL
OS
1 92 98
2 85 96
2 90 95
4 80 90
32

 ANAPLASTIC WILMS tumour
 Anaplasia is characterized by presence of 3 abnormalities
1. nuclear enlargement to three or more times the diameter of
the adjacent cells
2. hyperchromasia of enlarged nuclei
3. abnormal mitotic figure.
 rarely seen in children < 2 years (incidence about 2% )
 resistance to chemotherapy.
 poor prognosis even when the tumour is apparently confined
to the kidney, stage I
33

 PATHOLOGY AFTER PREOPERATIVE CHEMOTHERAPY
 Stroma and Epithelial predominant tumours are found more
often after chemotherapy
 poor clinical response to therapy but have an excellent
prognosis if the tumour is completely excised
 The proportion of blastemal-predominant tumours is
decreased after chemotherapy, have a high rate of relapse
34

 SIOP classifies tumours with complete tumour necrosis after
preoperative chemotherapy as “low-risk.”
 Children with stage I low risk tumours after post-
chemotherapy nephrectomy receive no further chemotherapy
 Tumours with diffuse anaplasia and blastemal predominance
after chemotherapy are classified as “high-risk”
 SIOP “intermediate-risk” tumours consist of all other
histologies.
35

 NEPHROGENIC RESTS
 Precurson lesions ; most do not form wilms tumour.
 A rest can undergo maturation, sclerosis, involution, or
complete disappearance.
 NRs can be separated into two fundamentally distinct
categories,
1. perilobar nephrogenic rests (PLNRs)
2. intralobar nephrogenic rests (ILNRs)
36

 PLNRs
1. found only in the lobar periphery
2. elaborated late in embryogenesis
3. Subcortical
4. sharply demarcated
5. predominantly blastema & tubules
6. found in children with BWS, linked to 11p15
37

 ILNRs
1. anywhere within the lobe, as well as renal sinus
and the wall of PCS
2. result of earlier gestational aberrations
3. stroma rich and intermingle with the adjacent
renal parenchyma.
4. seen in children with aniridia, WAGR, and DDS
or other features associated with WT1
38

 Multiple rests in one kidney usually implies that NRs are
present in the other kidney
 Hyperplastic NRs can produce a renal mass that can be
mistaken for a small Wilms tumour (Beckwith, 1998)
.
 Wilms tumour will have a spheric shape, whereas
hyperplastic rests will retain the appearance of the original
rest and be more elliptical or lenticular in shape
 Nephroblastomatosis refers to the presence of multiple NRs.
 Diffuse overgrowth of PLNRs may produce a thick rind that
enlarges the kidney but preserves its original shape
39

40

PREOPERATIVE EVALUATION AND
STAGING
 > 90% asymptomatic smooth abdominal mass discovered
incidentally by a family member or physician
 The mass may be extremely large relative to the size of child
 20% - hematuria
 25% - hypertension d/t elevated plasma renin; resolves after
nephrectomy
 fever, anorexia, and weight loss in 10% of patients.
41

 ACUTE abdomen from tumour rupture into the
peritoneal cavity or bleeding within the tumour
42

 Extension into IVC & renal vein (10%) - A persistent
varicocele in the supine position, hepatomegaly d/t hepatic
vein obstruction, ascites
 Atrial thrombus may manifest as HTN / CHF
 Acquired WVD – 8 % newly diagnosed
 Physical examination reveals firm, nontender mass that
classically does not cross the midline.
43

 blood count, liver enzymes, and serum electrolytes, including
blood urea nitrogen, creatinine, and calcium
 Coagulation profile
 This defect can be corrected preoperatively with the
administration of 1-desamino-8-D-arginine-vasopressin
(DDAVP)
44

IMAGING
 All of the solid renal tumours of childhood have some common
radiographic features including renal cell carcinoma (RCC)
 important role - confirm that the contralateral kidney is
functioning before performing a nephrectomy
 CHEST RADIOGRAPHY – may show lung metastasis
 ULTRASONOGRAPHY
o 1 st study to evaluate children with an abdominal mass
o will demonstrate the solid nature of the lesion.
o Doppler ultrasonography is helpful to exclude intracaval tumour
extension that occurs in 4% of Wilms tumour.
45

All patients should undergo either CECT OR MRI of the
abdomen and pelvis with gadolinium
 CT SCAN
 origin of the tumour
 SIZE
 C/L kidney involvement
 LN involvement
 invasion into major vessels
 liver metastasis
46

 has moderate specificity but poor sensitivity in the detection
of preoperative tumour rupture
 Ascites beyond the cul-de-sac was most strongly associated
with tumour rupture
 CT CHEST to rule out lung metastasis
 MRI abdomen
o can reliably identify extension of tumour into the IVC
o T1 –low signal intensity
o T2 - high signal intensity
47

48

PROGNOSTIC FACTORS
•Most important determinant of outcome – Histopathology
and tumour stage
•Clinical trials are now incorporating biological factors that
predict tumour behaviour
•LOH for a portion of chromosome 16q and/or 1p has been
noted in 20% of Wilms tumours. This is associated with an
increased risk for relapse
•High telemerase activity – unfavourable prognostic feature
49

 DNA content : Aneuploidy & DNS index 1.5 strongly a/w
anaplastic histology
 lung metastases were far more likely to occur in animals
with VEGF-positive tumours.
 Anti-VEGF therapy has been shown to suppress tumour
growth in mice and can prevent development of metastases.
 Antiangiogenesis treatment would appear to be a promising
adjunctive future treatment for patients with Wilms
tumour.
50

Treatment
 Usual approach – Nephrectomy followed by chemotherapy
with or without postoperative radiotherapy
 Multiple RCT to determine therapeutic protocol by :
1. NWTSG / COG
2. SIOP
3. UKCCSG
51

52

COG PROTOCOL FOR HIGH RISK
Focal anaplastic stage stage 1-3
Diffuse anaplastic stage 1
Nephrectomy
Vincristine, Dactinomycin, Doxo
+ local RT
Focal Anaplastic stage 4
Diffuse anaplastic stage 2-3
Diffuse anaplastic stage 4
SAME
+ Cyclo, Eto, Carbo
More aggressive t/t
Nephrectomy
Irinitacan & Vincristine
Dactinomycin, doxo,cyclo, carbo, eto,
RT
53

Surgical Considerations
 Radical Nephrectomy via transperitoneal approach.
 Thorough exploration of the abdominal cavity to exclude
local tumour extension, liver and nodal metastases, and
peritoneal seeding.
 Accurate staging to determine appropriate chemotherapy &
need for radiation therapy.
 Formal RPLND is not recommended but selective sampling
of suspicious nodes is essential.
54

 Exploration of the contralateral kidney is no longer
mandatory if preoperative CT or MRI demonstrates a normal
kidney
 The renal vein and IVC are palpated to exclude intravascular
tumour extension before vessel ligation.
 The adrenal gland can be spared without increasing the risk
for tumour spill or recurrence if it is not in close proximity to
the tumour (Kieran et al, 2013a)
 Extensive lymph node dissection, particularly above the renal
hilum, can result in chylous ascites
55

 major responsibility - complete removal of the tumour
without contamination of the operative field.
 A recent COG study reported intraoperative tumour
spillage in 9.7% of patients undergoing primary nephrectomy
…….. common with right-sided tumours and larger tumours.
 risk factors for local tumour recurrence
1. tumour spillage
2. unfavorable histology
3. incomplete tumour removal
4. absence of any lymph node sampling
56

 This study included both stage II and III disease. The risk of
recurrence was highest in patients with stage II disease.
 recent COG studies treated all spill patients - stage III
disease.
 laparoscopic nephrectomy - done in conjunction with
preoperative chemotherapy and is likely more feasible after
the tumour is reduced in size (Duarte et al, 2009).
 open nephrectomy after chemotherapy - less prone to
tumour spillage.
57

 Preoperative chemotherapy may influence surgical
complication rates by producing tumour shrinkage.
 A recent report from the UKCCSG - significantly fewer
complications in those undergoing delayed nephrectomy (1%
vs. 5.8%). Performed after 6 weeks of CT.
58

PREOPERATIVE CHEMOTHERAPY
(Children’s Oncology Group Recommendations)
 COG protocols - treatment is dependent on surgical and
pathologic staging after immediate nephrectomy.
 preoperative chemotherapy is recommendation
1. children for whom RSS is planned
2. tumours inoperable at surgical exploration
3. tumour extension into the IVC above the hepatic veins.
59

 Inoperablility should not be based on preoperative imaging
studies, which can overestimate local tumour extension.
 IF unresectable - pretreatment with chemotherapy almost
always reduces the bulk of tumour and renders it resectable
 inoperable tumour should be considered stage III disease
and should be treated accordingly
 Experience in SIOP shown - majority of reduction (48%)
in tumour volume occurs in the first 4 weeks of therapy but
that reduction extends out through 8 weeks.
60

SIOP
61

 Repeat imaging is performed after 6 weeks of chemotherapy.
 After adequate shrinkage of the tumour, definitive resection can
be completed.
 A clinically good response (by imaging) is usually associated
with a pathologically good response in terms of regressive
histologic changes
 The distribution of histologic subtypes is different after
preoperative chemotherapy compared with primary surgery,
with differentiation of the tumour occurring after CT.
62

 Stromal- and epithelial predominant tumours are
found more often after treatment with preoperative
chemotherapy.
 These histologic subtypes may demonstrate a poor
clinical response to therapy but have an excellent
prognosis if the tumour is completely excised.
 Failure to achieve a reduction in volume is the result of
tumour differentiation
63

64

BILATERAL WILMS tumourS
 Synchronous bilateral Wilms tumours - 5% to 7%
 no initial radical nephrectomy.
 preoperative CT for 6 weeks - current COG protocol
 tumour response is assessed after 6 weeks with CT or MRI to
determine the reduction in tumour volume and feasibility of
RSS
• tumours not responding to therapy require bilateral open
biopsy to determine histology & additional chemo based on
biopsy findings
65

• bilateral biopsies are recommend because anaplasia is found
to be discordant between the two kidneys in 83% of children
• proceed to surgical resection within 12 weeks of starting
therapy ( no benefit beyond 12 weeks )
• Even when large bilateral masses remain after initial
chemotherapy, a high percentage of children can be
successfully managed with RSS ( partial nephrectomy, wedge
resection)
• The kidney with the lower tumour burden is addressed first.
66

 It is easy to underestimate the amount of renal
parenchyma that can be salvaged as a result of
compression by the tumour therefore NSS should be
considered in all patients
67

68

 tumour enucleation may be considered in lieu of a
formal partial nephrectomy - for large centrally located
tumours when removal of a margin of renal tissue
would compromise the vascular supply to the kidney
 enucleation more likely to result in positive surgical
margins.
- favorable-histology tumours - adjuvant therapy may
still achieve a good outcome
- Anaplasia - positive margin will adversely affect
survival and requires additional resection
69

• Radical nephrectomy may be needed in a kidney with
extensive tumour involvement.
• Bilateral nephrectomies and dialysis are rarely required
when the tumours fail to respond to CT / RT
• anephric patients can still be administered chemotherapy
with some modifications
• renal transplant - 2 years to ensure that the patient does
not develop metastatic disease
70

 renal failure after RSS - removal of the remaining renal tissue
before transplant to prevent tumour recurrence after starting
immunosuppression
 Need long term follow up ( SIOP - late relapse - more than 4
years after treatment )
 These patients should also have frequent assessment of renal
function, urine protein, and blood pressure
71

PARTIAL NEPHRECTOMY FOR UNILATERAL tumourS
 the incidence of renal failure after nephrectomy
0.6% at 20 years
 The risk of renal failure is higher for patients with
genitourinary anomalies, DDS, and WAGR.
 Syndromic patients likely have smaller tumours &
more amenable to renal-sparing surgery
 Most Wilms tumours are too large at diagnosis to
allow partial nephrectomy.
72

 After preoperative chemotherapy, partial nephrectomy can
be performed in 10% to 15% of patients.
 Patients who develop intra-abdominal relapse have a
markedly decreased survival
 The COG is conducting a renal-sparing protocol for select
patients with unilateral Wilms tumours known to be at risk
for bilateral disease or at increased risk for renal failure.
73

 The lesion should be completely excised with a margin of
normal renal parenchyma.
 patients should not undergo partial nephrectomy if the
tumour cannot be removed at stage I.
 Patients with high-risk histologic patterns such as anaplasia
or persistent blastemal-predominant tumour after
chemotherapy should be treated with complete nephrectomy
because these tumours have resistance to chemotherapy
74

LATE EFFECTS OF TREATMENT
Fertility and Pregnancy
 Gonadal radiation - hypogonadism and temp.
azoospermia
 severity of damage - dose dependent.
 Leydig cells are more radioresistant but higher doses can
result in inadequate production of testosterone….result
in delayed sexual maturation
 Chemotherapeutic agents adversely affect testicular
function
75

 Pelvic irradiation and exposure to alkylating agents -
ovarian failure and premature menopause
 offspring of irradiated female - risk for LBW &
premature birth.
 Radiation risk miscarriage
 Musculosceletal problem like scoliosis
76

Second Malignancies
 1% cumulative incidence at 10 years post-diagnosis
 greatest risk factors is prior irradiation, and most
tumours occur in the radiation field
 The incidence of leukemia is highest during the first 5
years after Wilms tumour treatment.
 The incidence of solid tumours increases fivefold from
age 15 to 40 years
77

Cardiac Effects
 CHF- 4.4% among DOX-treated patients who received
this drug as part of their initial chemotherapy regimen
(Green et al, 2001b).
 The risk was increased if the patient received whole-lung
or left-flank irradiation.
78

79

Thank you
80

Pediatric urology : Wilms tumour

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