1. WILMS TUMOR
BY DR Amitabh

2. Max Wilms, MD
• German surgeon Max Wilms, born
in Hünshoven, Germany
• At the start of his medical career,
Wilms examined children’s kidney
tumors, added seven cases to a
thorough review of the literature,
and produced what was the
definitive work on the subject in
1899
• He may be best remembered for
his thorough work with childhood
cancer
• This tumor derived the name from
MAX WILMS
• In May 1918, during World War l
Wilms died of diphtheria.

3. EPIDEMIOLOGY
• WT most common malignant renal tumor of
childhood
• Wilms’ tumor affects approximately 7 children per 1
million before the age of 15 years.
• Accounts for 6-7% of all childhood cancers in North
America.
• About 450-500 new cases are diagnosed each year

4. FACTS
• Most WTs are solitary lesions , multifocal within
a single kidney in 12 % and bilateral in 7 %
• In only 1% of the children who have a kidney
removed due to Wilms’ tumor, does the cancer
re-appear later in the other kidney.
• There is a family history of the disease in only 1%
of cases.

5. Mortality/Morbidity
Before the multimodality
approach was available, the
survival rate of patients was less
than 50%. With the current
NWTSG and SIOP strategies,
survival rates are approaching
90%. Most survivors of Wilms
tumor have good functional
outcomes and quality of life

6. Race
Wilms tumor is relatively more common in blacks than
in whites and is rare in East Asians. Estimates
suggest 6-9 cases per million person years in whites,
3-4 cases per million person years in East Asians
and more than 10 cases per million person years
among black populations.
10 cases
per million
6-9 cases
per million 3-4 cases
per million

7. Sex
Among patients with unilateral Wilms tumor
enrolled in all NWTSG protocols, the male-
to-female ratio was 0.92:1. For patients with
bilateral disease, the male-to-female ratio
was 0.60:1.
:

8. Age
• The median
age at
diagnosis is
approximately
3.5 years

9. Pathogenesis and Genetics
The risk of Wilms tumor is
increased in association with at least
four recognizable groups of
congenital malformations
associated with distinct chromosomal
loci.

10. WAGR syndrome
characterized by
Aniridia,
Genital anomalies, and
mental Retardation and a 33% chance of developing
Wilms tumor.

11. • Individuals with WAGR syndrome carry constitutional
(germline) deletions of 11p13. Studies on these
patients led to the identification of the first
Wilms tumor–associated gene, WT1,
and
a contiguously deleted autosomal dominant gene for
ANIRIDIA,
PAX6, both located on chromosome
11p13.

12. Patients with deletions restricted to
PAX6, with normal WT1 function,
develop sporadic ANIRIDIA,
but they are not at increased
risk for Wilms tumors.

13. Denys- Drash syndrome
A much higher risk for Wilms tumor (∼90%)
characterized by
GONADAL DYSGENESIS
(male pseudohermaphroditism) and
EARLY-ONSET NEPHROPATHY leading to
renal failure

14. Denys- Drash syndrome
The characteristic glomerular
lesion in these patients is a
diffuse mesangial sclerosis. As in
patients with WAGR, these
patients also demonstrate
germline abnormalities in WT1.

15. • In patients with the Denys- Drash
syndrome, however, the genetic
abnormality is
• A DOMINANT NEGATIVE
MISSENSEMUTATION in the zinc-
finger region of the WT1 gene
that affects its DNA BINDING
PROPERTIES

16. Despite the importance of WT1 in
NEPHROGENESIS and its unequivocal role as a
TUMOR SUPPRESSOR GENE, only about 10%
of patients with sporadic (nonsyndromic) Wilms
tumors demonstrate WT1 mutations, suggesting
that the majority of these tumors arise by
GENETICALLY DISTINCT
PATHWAYS.

17. Beckwith- Wiedemann
syndrome
characterized by
1. ENLARGEMENT OF BODY ORGANS (organomegaly)
2. MACROGLOSSIA
3. HEMIHYPERTROPHY
4. OMPHALOCELE
5. ABNORMAL LARGE CELLS IN THE ADRENAL
CORTEX (adrenal cytomegaly)
6. Genitourinary abnormalities
7. Ear creases ; Hypoglycemia
8. A predisposition to WT

18. • BWS has served as a model for a
nonclassical mechanism of
tumorigenesis in HUMANS—
GENOMIC IMPRINTING
• The chromosomal region implicated
in BWS has been localized to band
11p15.5 (“WT2”), distal to the WT1
locus.

19. 11p15.5
This region contains multiple genes that are
normally expressed from only one of the two
parental alleles, with transcriptional silencing
(i.e., imprinting) of the other parental
homologue by METHYLATION of the promoter
region.

20. Unlike WAGR or Denys- Drash
syndromes, the genetic basis for
BWS is considerably more
HETEROGENEOUS in that NO
SINGLE 11P15.5 GENE IS INVOLVED
IN ALL CASES.

21. • Moreover, the phenotype of BWS, including
the predisposition to tumorigenesis, is
influenced by the specific “WT2”
imprinting
abnormalities present.

22. • One of the genes in this region—
•insulin-like growth
factor-2 (IGF2)—is
normally expressed solely from the
PATERNAL ALLELE, while the
maternal allele is silenced by
imprinting.

23. • In some Wilms tumors, loss of imprinting
(i.e., re-expression of the maternal IGF2
allele) can be demonstrated, leading to
overexpression of the IGF-2 protein.
• In other instances there is a selective
deletion of the imprinted maternal
allele, combined with duplication of the
transcriptionally active paternal allele in
the tumor (uniparental paternal disomy),
which has an identical functional effect
in terms of overexpression of IGF-2.

24. • Since the IGF-2 protein is an
embryonal growth factor, it could
conceivably explain the features of
OVERGROWTH associated with BWS,
as well as the increased risk for Wilms
tumors in these patients.
• Of all the “WT2” genes, imprinting
abnormalties of IGF2 have the
strongest relationship to tumor
predisposition in BWS.

25. • In addition to Wilms tumors, patients
with BWS are also at increased risk for
developing
HEPATOBLASTOMA,
•PANCREATOBLASTOMA,
•ADRENOCORTICAL
TUMORS, and
RHABDOMYOSARCOMAS.

26. β- catenin
• Recent genetic studies have also elucidated the
role of β- catenin in Wilms tumor. It will be
recalled that β- catenin belongs to the
developmentally important WNT (wingless)
signaling pathway.
• Gain-of-function mutations of the gene
encoding β -catenin have been demonstrated in
approximately 10% of sporadic Wilms tumors;
there is a significant overlap between the
presence of WT1 & β- catenin mutations,
suggesting a synergistic role for these events in
the genesis of Wilms tumors.

27. Nephrogenic Rests
• Nephrogenic rests are putative precursor
lesions of Wilms tumors and are seen in the
renal parenchyma adjacent to approximately
25% to 40% of unilateral tumors;
this frequency rises to nearly 100%
in cases of bilateral Wilms tumors.

28. • Nephrogenic rests consists of
embryonal nephroblastic tissue
and are found in 35 % of kidneys
with unilateral WT and in nearly
100 % of kidneys with bilateral WT
• Most nephrogenic rests undergo
spontaneous regression and only a
small proportion 1 % to 5 %
transform into WT

29. • In many instances the nephrogenic rests
share GENETIC ALTERATIONS with the
adjacent Wilms tumor, underscoring their
preneoplastic status.
• The appearance of nephrogenic rests varies
from EXPANSILE MASSES that resemble
Wilms tumors (hyperplastic rests) to
SCLEROTIC RESTS consisting predominantly
of fibrous tissue and occasional admixed
immature tubules or glomeruli.

30. It is important to document the
presence of nephrogenic rests in
the resected specimen, since these
patients are at an increased risk of
developing Wilms tumors in the
contralateral kidney and require
frequent and regular surveillance
for many years.

31. HISTOLOGY
ANAPLASIA
Focal or Diffuse : reflect the
distribution of anaplastic cells in
tumor and are of prognostic
significance
The 4 year survival rates for patients
with stages ll , lll , lV FA were 90%
,100% and 100% compared with 55%,
45%, and 4% for patient with similar
stage DA WT

32. Morphology
Grossly, Wilms tumor tends to
present as a large, solitary, well-
circumscribed mass, although
10% are either bilateral or
multicentric at the time of
diagnosis.

33. On cut section
The tumor is soft,
homogeneous,
and tan to gray with
occasional
foci of hemorrhage,
cyst formation,
and necrosis.

34. Microscopy
• Microscopically, Wilms tumors are characterized
by recognizable attempts to recapitulate
different stages of nephrogenesis.
• The classic triphasic combination of
• BLASTEMAL,
• STROMAL, &
• EPITHELIAL cell types is observed in the vast
majority of lesions, although the percentage of
each component is variable.

35. 1. Sheets of small blue cells with few
distinctive features characterize the
BLASTEMAL component.
2.EPITHELIAL
DIFFERENTIATION is usually in
the form of abortive tubules or
glomeruli.
3. STROMAL CELLS are usually
fibrocytic or myxoid in nature,
although skeletal muscle
differentiation is not uncommon.

36. HISTORY AND PHYSICAL EXAMINATION
• Detection of an
asymptomatic
abdominal mass bulging
in the flank.
• Non specific systoms like
abdominal pain, fatigue
• Haematuria (in <10%)
• Hypertension (V. rare )
• Associated Urogenital anomalies,
Aniridia, overgrowth Syndrome.

37. DIAGNOSTIC
WORK - UP

38. Laboratory Studies
• CBC count
• RBS
• Chemistry profile
• (KFT & LFT)
• Urinalysis
• Coagulation studies
• Cytogenetics studies
• (WT1 gene)

39. IMAGING STUDIES
1. Abdominal USG Organ of origin
Identify contralateral Kidney
Presence/absence of tumor
thrombus in IVC
2. CT Scan Further evaluation of extent
of tumor Extension into adjoining
structures such as
Liver spleen & colon.
Visualisation and function of
contralateral Kidney
3. X-ray chest PA Pulmonary Metasteses

40. • 4. Bone scan & X-ray Skelatal
survey Bone mets in clear cell Sarcoma of
Kidney (CCSK)
• 5. Brain imaging (MRI / CT-Scan)
Intracranial mets in Rhabdiod Tumor (RT) &
CCSK
• 6. Fine needle aspiration cytology
of mass Cytological confirmation of
diagnosis prior to prenephrectomy
Chemotherapy.

41. National Wilms Tumor Study (NWTS) staging
Stage I : Tumor confined to the kidney & completely
excised
Stage II : Tumor outside the kidney but completely
excised
Local tumor spillage during surgery
Lymph nodes negative
Stage III : Non hematogenous disease confined to the
abdomen
Perioperative rupture of renal capsule
Diffuse tumor spillage during surgery
Peritoneal implants
Positive lymph nodes
Stage IV : Hematogenous metastases to lungs or liver
Stage V : Bilateral Wilms’ tumor

42. GENERAL
MANAGEMENT

43. • The diagnosis of WT is usually made
before surgery and confirmed at
surgery.
• A TRANSVERSE TRANSABDOMINAL ,
TRANSPERITONEAL INCISION is
recommonded
• Lymph node sampling from para –aortic
, celiac and iliac areas must be
performed

44. Absolute Indications for
Prenephrectomy Chemotherapy
1. Large tumor technically difficult to deliver at
surgery.
2. Presence of major tumor thrombus in the
inferior venacava.
3. Bilateral Wilm’s tumor
4. Wilm’s tumor in a solitary Kidney or horse
shoe Kidney.

45. Radiation Therapy
Wilms Tumors - high sensitivity – ionizing radiation
RT Management varies according to:
Age of patient (avoided in < 6 months
infants / <2yrs FH)
Preoperative extent on imaging
Operative stage
Post operative histology

46. RT - Indications : Post OP RT
• WT - Favourable Histology
– Stage III:
– residual T
Gross/Micro
+ve Margin
Local Infiltration Vital Structures
- Abd / Pelv -Ly N +
- peritoneal surface
Penetration
Tumour implants
T Spillage (pre / intro OP)
- Bx – trucut, Bx, FNAC
- T removed in Pieces : eg - extra
adrenal , T thrombus in renal vein
• Standard Risk FH WT
without LOH at 1p & 16q
• Higher Risk FH with LOH at
1p & 16q
• WT Unfavourable Histology
– Anaplasia
• Stage I – diffuse
• Stage II-IV – diffuse
• Stage I-IV - Focal
– Clear cell CCSK
• Stage I-III
• Stage IV
– Rhabdoid RTK
• Stage I -IV

47. –Stage IV
• Rapid responders of
lung metastasis at
week 6 on DD4A
• (Possibility of no-RT to
rapid complete
responders on CT scan)
• Slow responders
(lungs) & non-
pulmonary metastasis

48. RT Technique
• Timing of RT : not later than 9
days after surgery (max 14 days)
• Delay of >10dys – significantly
higher abdominal relapse rate ,
particularly UH.

49. RT Machines
• Telecobalt
• Linear Accelerator

50. RT Techniques
• Flank RT
• Whole Abdomen RT (WAI):
– Indicated –
• diffuse tumor spillage - Pre-OP / Intra OP Tumor Rupture
• Peritoneal T seeding
• Ascites +ve Cytology
• Whole Lung RT
– Localized foci of lung disease persisting 2 weeks after 12 Gy can be
excised or given additional 7.5 Gy
– Treat both lungs regardless of the number or location of visible
metastases
– Patients with CT only pulmonary mets – at the discretion of the
treating institution

51. General Principles : RT planning
• Pt position : Supine
• Immobilization: Vacuum Cushion
• Sedation / Anesthesia during RT / Simulation
• Simulation:
– Simulator – X –Ray + IVP (to Exclude Opposite kidney)
– CT Simulation
• Ensure – Anesthesia & Patient monitoring equipments in the RT
Bunker
• Opposed AP:PA fields
– Field Shaping : 3DCRT / Contouring
– Shielding opposite kidney & selected normal structures
– Complete Vertebrae to be included in the RT field

52. RT Dose
• Stage III
FH
• Stage I-III
Focal anaplasia
Diffuse anaplasia
CCSK
FLANK RT : 10.8Gy, 180cGy/ fx

53. • Stage III
Diffuse anaplasia
• Stage I-III
RTK
FLANK RT : 19.8Gy
(Infants -10.8Gy), 180cGy/ fx

54. • Whole Abdomen RT
 FH : 10Gy, 150cGy/ Fx
 Gross Residual disease : Boost of + 10Gy
(Renal Shielding / Limit the dose to
remaining kidney <14.4Gy)

55. • Lung (mets.)
FH / UH : 12Gy WLI in 8#
• Liver (mets.) : 19.8Gy whole liver in 11#
• Brain (mets.) : 36.6Gy WB in 17#
Or 21.6Gy WB + 10.8Gy IMRT
/Stereotactic Boost

56. • Unresected Lymph nodes : 19.8Gy in 11#
• Bone ( mets.) : 25.2 Gy in 14#

57. Flank Radiation
• Treatment Portal design :
– Should encompass the tumor bed and the site of
the excised kidney
– 2-3 cm margins should be given circumferentially
• 3D Plans: Pre OP CT/MRI – CTV : kidney +
Tumor with 1cms Margin
• Field sizes ~ 10 x 10 / 12 x 12 cms
• Beam energy : 4-6 MV

58. Treatment Fields - Flank

59. Whole Abdomen Radiation
• Indicated in few patients now a days
• energy - 4-6 MV photons
• Shielding :
– Opposite kidney
– Acetabulum and femoral heads – both AP-PA shields
• Superior border : dome of diaphragm (nipples)
• Inferior border : inferior border of the obturator foramen(
pubis symphysis )
• Lateral border : to the lateral peritoneal reflection

62. Lung Irradiation
• Superior border : 3cm above the middle 1/3 rd
of clavicle
• Inferior border : ( below the costophrenic
angles) Below the xiphisternum / level of L1
(transpyloric plane)
• Lateral borders : Lateral border of areola of
nipple
• Shielding
– humeral head
– larynx

64. bilateral Wilms’
• Dose to more than 1/3 of the
contralateral kidney or residual kidney
should not exceed 14.4 Gy
• Inoperable Bilateral WT- role of Cyber
Knife, Tomotherapy, Rapid Arc, True
Beam, IMRT to be considered . PET based
planning.

65. Evaluation in Late effect Clinic
. Evaluation of Renal Functions on annual basis
. Evaluation of Anthracycline related
cardiotoxicity with 2 DEcho on annual/biennial
basis
. Assessment of growth and Sexual development.
. Assesment of musculoskeletal development in
irradiated patients.
. Assesment of fertility
. Watch out for second Malignant Neoplasia.

66. THANK
YOU