Wilm's tumor, also known as nephroblastoma, is a type of kidney cancer that typically affects children under the age of 5. It makes up about 6% of all childhood cancers. The tumor is caused by the abnormal growth of kidney cells that would normally develop into mature kidney tissue. Wilm's tumor is associated with genetic syndromes that involve mutations in genes like WT1. Patients with certain birth defects like WAGR or Beckwith-Wiedemann syndrome have a higher risk of developing Wilm's tumor. The cancer presents as a soft, homogeneous mass in the kidney and is characterized by the presence of blastemal, stromal, and epithelial cells under the microscope. Treatment involves

1. Wilm’s
tumor
Nephroblastoma
Lecture 54

2. Wilms’ tumor
• The peak incidence for Wilms tumor is
between 2 and 5 years of
age , and
95%
of tumors occur before the age of
10
years.

3. Wilms’ tumor
• Approximately 5% to 10% of Wilms tumors
both kidneys,
• either simultaneously (synchronous)
involve
or one after the other
metachronous).
(

4. • Bilateral Wilms tumors have a median age of
onset approximately
10 months earlier
than tumors restricted to one kidney, and
• these patients are presumed to harbor a
germline mutation in
one of the Wilms tumor–predisposing genes.

5. The biology of this tumor illustrates several
important aspects of childhood neoplasms, such as
• The relationship between malformations and
neoplasia,
• The histologic similarities between organogenesis
and oncogenesis,
• The two-hit theory of recessive tumor suppressor
genes,
• The role of premalignant lesions, and
• The potential for judicious treatment
modalities to dramatically affect prognosis
and outcome.

6. 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.

7. I. W AGR syndrome
characterized by
Aniridia,
Genital anomalies,
mental
Retardation
and
and a 33% chance of developing
Wilms tumor.
Aniridia is the absence of the

8. • 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.

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

10. The presence of germline WT1
deletions in WAGR syndrome represents
first hit
the “
”; the development of Wilms
tumor in these patients frequently correlates with
the occurrence of a nonsense
or
frameshift mutation in the
second WT1 allele
(“second hit”).

11. II. 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.

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

13. II. Denys-Drash syndrome
• In patients with the Denys-Drash syndrome,
however, the genetic abnormality is
• a dominant-negative missense mutation
in the zinc-finger region of the WT1 gene
that affects its DNA-binding properties.

14. II. Denys-Drash syndrome
• This mutation interferes with the function of
the remaining wild-type allele, yet strangely,
it is sufficient only in causing genitourinary
abnormalities, but not tumorigenesis; Wilms
tumors arising in Denys-Drash syndrome
demonstrate bi-allelic inactivation of WT1.

15. II. Denys-Drash syndrome
• In addition to Wilms tumors, these
individuals are also at increased risk for
developing germ cell tumors called
GONADOBLASTOMAS,
almost certainly a consequence of disruption
in normal gonadal development.

16. II. Denys-Drash syndrome
• WT1 encodes a DNA-binding transcription factor
that is expressed within SEVERAL tissues, including
THE KIDNEY &GONADS,
during embryogenesis.
• The WT1 protein is critical for normal renal and
gonadal development.

17. II. Denys-Drash syndrome
WT1 has MULTIPLE BINDING PARTNERS, &
the choice of this partner can affect whether WT1
functions as a TRANSCRIPTIONAL
ACTIVATOR or REPRESSOR
in a given cellular context.

18. II. Denys-Drash syndrome
• Numerous TRANSCRIPTIONAL TARGETS
of WT1 have been identified, including
GLOMERULAR PODOCYTE-SPECIFIC
PROTEINS, and GENES ASSOCIATED WITH
INDUCING DIFFERENTIATION.

19. II. Denys-Drash syndrome
•
Despite the importance of WT1 in
and its unequivocal role as a
NEPHROGENESIS
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.

20. III. Children with Beckwith-Wiedemann
syndrome
characterized by
1. ENLARGEMENT OF BODY ORGANS
(organomegaly),
2.
3.
4.
5.
MACROGLOSSIA,
HEMIHYPERTROPHY,
OMPHALOCELE, and
ABNORMAL LARGE CELLS IN THE ADRENAL
CORTEX (adrenal cytomegaly).

21. Beckwith-Wiedemann syndrome
• BWS has served as a model for a nonclassical
mechanism of tumorigenesis in HUMANS
—GENOMIC IMPRINTING.

22. Beckwith-Wiedemann syndrome
• The chromosomal region implicated in BWS
has been localized to band
11p15.5
(“WT2”), distal
to the WT1 locus.

23. 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.

24. Beckwith-Wiedemann syndrome BWS
• Unlike WAGR or Denys-Drash syndromes, the
genetic basis for BWS is considerably more
HETEROGENEO
US in that NO SINGLE
11P15.5 GENE IS
INVOLVED IN ALL CASES.

25. Beckwith-Wiedemann syndrome
BWS
• Moreover, the phenotype of BWS, including
the predisposition to tumorigenesis, is
influenced by the specific
“WT2”
imprinting
abnormalities present.

26. Beckwith-Wiedemann syndrome
BWS
• One of the genes in this region—
• insulin-like growth factor2 (IGF2)—is normally expressed solely
from the PATERNAL ALLELE, while the
maternal allele is silenced by imprinting.

27. • 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.

28. • 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.

29. • 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.

30. • Of all the “WT2” genes, imprinting
abnormalties of
IGF2
strongest relationship to tumor
predisposition in BWS.
have the

31. • A subset of patients with BWS harbor mutations of
cell cycle
regulator
CDKN1C
the
(also
p57 or KIP2
known as
); however, these
patients have a significantly lower risk for
developing Wilms tumors.

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

33. 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.
WNT - Wingless-related integration

34. • 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
events in the genesis of Wilms tumors.
for these

35. 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.

36. • In many instances the nephrogenic rests
share GENETIC
ALTERATIONS with the
adjacent Wilms tumor ,
underscoring their preneoplastic
status.

37. • The appearance of nephrogenic rests varies
from EXPANSILE MASSES that
resemble Wilms tumors (hyperplastic rests)
SCLEROTIC RESTS
to
consisting
predominantly of fibrous tissue and
occasional admixed immature tubules or
glomeruli.

38. • 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.

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

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

41. Microscopy
• Microscopically, Wilms tumors are
characterized by recognizable attempts to
recapitulate
different stages
of nephrogenesis.

42. • The classic triphasic combination of
1.BLASTEMAL ,
2.STROMAL , &
3.EPITHELIAL
cell types is
observed in the vast majority of lesions,
although the percentage of each component
is variable.

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

44. • Rarely, other heterologous elements are
identified, including
• Squamous or mucinous epithelium,
• Smooth muscle,
• Adipose tissue,
• Cartilage,
• Osteoid and
• Neurogenic tissue.

45. • Approximately 5% of tumors reveal
ANAPLASIA,
defined as the
presence of cells with
• large, hyperchromatic, pleomorphic NUCLEI
and ABNORMAL MITOSES.

46. • The presence of ANAPLASIA correlates
with the presence of
• p53 mutations and
• the emergence of
resistance to
chemotherapy.

47. • Recall that p53 elicits pro-apoptotic signals in
response to DNA damage.
• The loss of p53 function might explain
the relative unresponsiveness of anaplastic
cells to
cytotoxic chemotherapy.

48. Wilms' tumor in the lower pole of the kidney with the characteristic
tan-to-gray color and well-circumscribed margins.

50. Clinical Features.
•
•
•
•
•
Abdominal mass
Hematuria,
Pain in the abdomen,
Intestinal obstruction,
Hypertension

51. • In a considerable number of these patients,
pulmonary
metastases
are present at the
time of primary diagnosis.

52. Prognosis
• Cure Rate 85 %
• Anaplastic histology remains a critical
determinant of adverse prognosis.
• Even anaplasia restricted to the kidney (i.e.,
without extra-renal spread) confers an
increased risk of recurrence and death.

53. • Molecular parameters that correlate with
adverse prognosis include
• loss of genetic material on chromosomes
11q and 16q, and
• gain of chromosome 1q in the tumor cells.

54. • Along with the increased survival of individuals
with Wilms tumor have come reports of an
increased relative risk of developing second
primary tumors, including
• Bone and soft-tissue
SARCOMAS,
• Leukemia
Lymphomas,
• Breast cancers.
and
and

55. • While some of these neoplasms
represent the presence of a germline
mutation in a cancer predisposition
gene,
• others are a consequence of
therapy, most commonly
RADIATION administered to the
cancer field.

56. BACHA KHAN MEDICAL COLLEGE MARDAN KPK PAKISTAN