WILMS TUMOR

OR

NEPHROBLASTOMA
Wilms tumor is a childhood embryonal tumor of the
kidney that arises from embryonal nephric mesenchyme
and typically has a triphasic histology with :
1) Blastemal
2) Epithelial
3) stromal elements
EPIDEMIOLOGY
*Most common primary malignant renal tumor of
childhood(>95%).
*2nd most common abdominal tumor.(1st-neuroblastoma)
 6% Of all pediatric maliganancies
 Peak incidence - 2-3 yrs of age
 Can be unilateral or bilateral
 Mostly sporadic, 2% with family history
 Wilms tumors often become quite large before they are noticed.
 The average newly found Wilms tumor is many times larger than the
kidney in which it started.
ETIOLOGY
 The kidneys develop very early as a fetus grows in the uterus.

 Some of the cells that are supposed to develop into mature kidney cells
sometimes stay as early kidney cells(nephrogenic rests) instead, and might
remain even after the baby is born.

 Usually, these cells mature by the time the child is 3 to 4 years old. But if
this doesn’t happen, the cells might somehow begin to grow out of control,
which might result in a Wilms tumor.
 Derived from incompletely differentiated renal mesenchyme
 Tumor composed of cells reminiscent of the undifferentiated and partially
differentiated cells that normally arise from renal mesenchyme.
Types of Wilms tumor
2 major types based on their histology

Favorable histology:
 Cancer cells in these tumors don’t look quite normal, but there is no anaplasia.
 About 9 of 10 Wilms tumors have a favorable histology.
 The chance of curing children with these tumors is very good.

Anaplastic histology:
 the look of the cancer cells varies widely,and the cells’ nuclei tend to be very large and
distorted - anaplasia.
 In general, tumors in which the anaplasia is spread throughout the tumor ( diffuse
anaplasia) are harder to treat than tumors in which the anaplasia is limited just to
certain parts of the tumor (focal anaplasia).
 GENETICS
• Three candidate gene loci identified:

• Chromosome 11p13 (WT-1 gene):

• WAGR syndrome (gene deletions)
• Denys Drash Syndrome (point mutations)

• Chromosome 11p15(WT- 2 gene):

• Beckwith -Wiedemann Syndrome (gene deletions)

• Other loci, including 1p, 2q, 7p, 9q, 14q, 16q, and 22, have also been
implicated in the etiology of Wilms tumor through studies of loss of
heterozygosity, loss of imprinting, and constitutional chromosomal defects
• CTNNB1, the gene encoding β-catenin, is also mutated in about 15%
of Wilms tumors .
• Most tumors with mutations in WT1 also carry mutations in CTNNB1,
and CTNNB1 mutations rarely occur in the absence of WT1 mutation
PATHOLOGY

• Usually a large tumor compressing the normal renal parenchyma

• Tumor usually has a intact fibrous capsule with prominent veins
• Lymphatic / vascular invasion common.
• Yellowish colour with heterogeneous appearance – hemorrhagic/cystic areas.
HISTOLOGY

• WT reflects the
development of the
normal kidney, consisting
of three components:
blastemal, epithelial
(tubules), and stromal
elements, in varying
proportions
• Triphasic nature of tumor allows diversity in histology

• Pathological features associated with poor prognosis:

• Diffuse anaplasia
• Anaplasia in extra-renal tumor
• Predominant blastemal pattern
CLINICAL FEATURES
• Classically appears as a silent abdominal mass during
childhood

• Other symptoms:
• Pain Abdomen
• Flank pain and rapid enlargement of the mass (2° to
bleeding in the tumor)
• Hematuria
• Fever
SYNDROMES ASSOCIATED WITH WILMS TUMOR
CONGENITAL ANOMALIES

• Around 10%-13% of individuals with Wilms tumour have a

congenital anomaly

• Long term follow up of individuals reveals a syndrome in 17%

patients
 CONGENITAL ANOMALIES
•High risk (>20%)


WT1 deletions (including WAGR syndrome)

Truncating and pathogenic missense WT1 mutations (including Denys-Drash syndrome)

Familial Wilms tumour

Perlman syndrome

Mosaic variegated aneuploidy

Fanconi anaemia D-1/Biallelic BRCA2 mutations
•Moderate risk (5–20%)

WT1 intron 9 splice mutations (Frasier syndrome)

Beckwith-Wiedemann syndrome

Simpson-Golabi-Behmel syndrome caused by GPC3 mutations/deletions

•Low risk (<5%)


Isolated hemihypertrophy

Bloom syndrome

Li-Fraumeni syndrome
DIFFERENTIAL DIAGNOSIS
• Other malignant childhood lesions of the kidney
• Neuroblastoma
• Hydronephrosis
• Polycystic disease, and
• Splenomegaly in left-sided tumors.
DIAGNOSTIC WORKUP
TREATMENT
 MULTIMODALITY MANAGEMENT

• Wilms Tumors are highly chemo and radiosensitive

• However they typically present with a large size and have a propensity for
metastasis (hematogenous)
• Surgery to remove the bulk of the disease and Chemotherapy to eliminate
metastatic disease forms the basis of therapy
• Radiation therapy is now a days indicated in a selected few to eliminate
the risk of local recurrence
• Multimodality, stage and risk adapted approach is the standard of care.
 TREATMENT OUTLINE

• Patients are classically treated with immediate nephrectomy

followed by adjuvant Chemotherapy as per the stage and
histological features
• Radiation therapy is delivered according to the abdominal stage.
• Radiation therapy and Chemotherapy are classically avoided in
very young infants (< 6 months)
 NEOADJUVANT CCT
• Indicated in some select situations like:

• Tumor is deemed inoperable:

• Tumor thrombus in Rt Atrium / IVC
• Extensive tumor with anticipated morbidity
• Invasion of surrounding organs (Liver/ Spleen/ intestines)

• Disseminated disease (Stage IV)

• WT occurring in some special situations:

• Bilateral WT
• WT in single kidney
• WT in presence of genetic syndromes
• WT in horseshoe kidneys
 SURGERY

• Operability should be determined on the table – imaging

overestimates inoperability
• Surgical excision is done through a transverse abdominal incision
• The standard procedure includes:
• Unilateral radical nephrectomy
• Selective sampling of nodes
• Renal vein and IVC (6% involvement) should be palpated to exclude
intravascular tumor extension
• Exploration of the opposite kidney
• Role of nephron-sparing surgery
• Indicated in bilateral Wilms tumor
• WT in patients with genetic predisposition
• Also in WT in solitary functional kidney / renal failure
• Always preceded by CCT
• Very young infants < 6 months age

• Role of biopsy of opposite kidney

• Condemned for unilateral involved kidney
• May be indicated in the opposite kidney if there is suspicion of nephrogenic
rests on preop imaging
 NEPHRECTOMY ALONE

• Presently indicated in:

• Age < 2 yrs
• Favourable Histology
• Stage I tumors
• Weight < 550 gms
 Preoperative Chemotherapy: Merits

• Achieves down-staging of the tumor

• Allows better surgical resection
• Reduces surgical morbidity
• Reduces risk of local relapse
• Reduction in need for radiation therapy in event of tumor spillage
• Assessment of tumor response to CCT important predictive factor in selecting
future therapy
• Allows reduction in CCT/RT intensity in the postoperative period
SURGICAL COMPLICATIONS
• Surgical mortality is < 1% in modern day series
• Most common complications of nephrectomy are:
• Small bowel obstruction (7%)
• Hemorrhage (6%)
• Wound infection, hernia (4%)
• Vascular complications (2%)
• Risk factors associated with increased surgical complications:
• Higher local tumor stage
• Intravascular extension
• En bloc resection of other visceral organs
 Relapsed / Refractory WT

• The most frequent site of relapse overall is the lungs

• 54% of all relapses were isolated pulmonary events

• Factors that indicate an increased likelihood of salvaging relapsed tumors :

• Tumors with favourable histology

• Recurred only in the lungs

• Relapse in the abdomen where radiotherapy had not been included in the primary
treatment;
• Relapse that occurred more than 12 months from diagnosis.

• The overall survival following relapse was only 24 -30 % .

 Relapsed / Refractory WT
• Best results till date have been reported with the use of ICE regimen (Ifosfamide /
Carboplatin / Etoposide) – given initially by the SFOP.

• Doses for Ifosfamide were 1.8 g/m2/d x 5 days, Carboplatin 400 mg/m2/d x 2 days,
and etoposide 100 mg/m2/d x 5days
• Survival – 50 -60 % at 3yrs
• Recent St Jude study evaluated modified doses of carboplatin to reduce the toxicity.

• Investigational chemotherapeutic agents: Irinotecan and oxaliplatin

• In children with relapse without remission High dose chemotherapy with stem cell
transplantation is an alternative.
RT for Recurrent Tumors

• For recurrent tumors recommendations are:

• < 12 mo of age: 12.6–18 Gy

• In older children 21.6 Gy if previous radiation dose is ≤ 10.8 Gy.
• A boost dose of up to 9 Gy to gross residual after surgery.
• Total dose including previous irradiation not to exceed:
• 30.6 Gy (<1 y of age)
• 39.5 Gy in older children.
Bilateral Wilms Tumor
• Account for 7% of all WT – 6% synchronous
• Associated in 20% with genetic syndromes
• Both sides staged seperately
• Metachronous tumors far worse than synchronous
• Long term survival rates 70 -80%.
 Treatment Toxicity

• Chemotherapy
• Vincristine: Neurotoxicity (7-8%)
• Actinomycin D: Hepatic Veno-occlusive disease
• Anthracyclines: Long term cardiotoxicity (10 -25% with cumulative doses of 300 mg/m2)
• Surgery
• 32% have some renal dysfunction in opposite kidney after 10 yrs
• 9% proteinuria
• 11% hypertension
• Radiation therapy
• Loss in potential height (loss of potential height 7cm at 1 yr)
• Second malignancies
 Conclusion

• MC renal tumor of childhood

• Usually has a large size on presentation and high chance of distant spread
• However prognosis is excellent with modern day therapy
• Surgery with adjuvant chemotherapy is the mainstay of therapy
• Radiation therapy given judiciously can reduce recurrences and improve QOL
• Treatment deintensification has been the theme of successive RCTs.
 Conclusion

• MC renal tumor of childhood

• Usually has a large size on presentation and high chance of distant spread
• However prognos is excellent with modern day therapy
• Surgery with adjuvant chemotherapy is the mainstay of therapy
• Radiation therapy given judiciously can reduce recurrences and improve QOL
• Treatment deintensification has been the theme of successive RCTs.