Wilms' TumourWilms' TumourModerator:Moderator:

Lt Col MS Vinod ( Cl Spl Surg & Paediatric Lt Col MS Vinod ( Cl Spl Surg & Paediatric Surgeon)Surgeon)

Resident:Resident:Dr SD SanyalDr SD Sanyal

Epidemiology

• Annual incidence in US = 7.6 cases/ million ( amongst children < 15 years)

• 6% of Paediatric tumors • Commonest abdominal pediatric tumor• 5th most common childhood cancer• Frequency - Blacks > Asians• Male to female ratio is:• 0.92:1.00 for unilateral disease

• 0.60:1.00 for bilateral disease

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Epidemiology

• Mean age of diagnosis:• 46.9 months for females (29.5 mths for B/L tumors)

• 41.5 months for males (32.6 mths for B/L tumors)

• Scanty Indian population based data• Largest study by Thiruanathapuram - Wilms' Tumors account for 5.4% of all

pediatric malignancies• Likely to be the 2nd most common solid

pediatric tumor in India (after HD)

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Pathogenesis

Renal Development5

Metanephric blastema

Nephrogenic Rests

• Perinephric rests are persistent mesoblastic tissues beyond the 36th week of gestation

• Two types:• Intralobular (assoc. with

WAGR, DDS etc)

• Perilobular (assoc. with BWS)

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Wilms Tumorigenesis

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Tumor Components

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Tumor Components

• Blastema• Mesenchyme• Epithelium

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Genetics of Wilms Tumor

• Three candidate gene loci :• Chromosome 11p13 (WT-1 gene):

• WAGR syndrome

• Denys Drash Syndrome

• Chromosome 11q15(WT- 2 gene):

• Beckwith -Wiedemann Syndrome

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Classification

• Favourable - Contains well developed components

• Anaplastic - Diffuse anaplasia present

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Clinical Clinical FeaturesFeatures

Symptoms

• Classically appears as a silent abdominal mass during childhood (60-90%)

• Other symptoms:• Pain Abdomen (30-40%)

• Flank pain and rapid enlargement of the mass (2° to bleeding in the tumor)

• Hematuria (25%)

• Fever (20%)

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Physical Examination• Primary tumor• Smooth, rounded lobulated mass in the

loin

• Attached kidney may be felt

• Doesn't move with respiration

• Other features:• Hypertension (25%)

• Varicocele (tumor thrombus in IVC)

• Associated genitourinary abnormalities

• Associated stigmataof congenital anomalies

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Congenital Anomalies

• Congenital anomaly : 9 - 10% of individuals with Wilms

• Long term F/U: Syndrome in 17% patients

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WAGR Syndrome

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Wilms TumorWilms Tumor

AniridiaAniridia

Genitourinary abnormalitiesGenitourinary abnormalities

Mental RetardationMental Retardation

Denys Drash Syndrome

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Diffuse Mesangial SclerosisDiffuse Mesangial Sclerosis

Male Male PseudohermaphorditismPseudohermaphorditismWilms TumorWilms Tumor

Beckwith-Wiedemann Syndrome

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MicrocephalyMicrocephaly

Umbilical HerniaUmbilical Hernia

Ear lobe creaseEar lobe crease MacroglossiaMacroglossia

HemihypertrophyHemihypertrophy

WorkupWorkup

Investigations

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◄ To establish the diagnosis

◄ Delineate tumor extent

◄ Confirm contralateral renal functional status

◄ Discover any metastasis

◄ Assess fitness for surgery / anaesthesia

AIMS

Routine Investigations

• Hemogram:• Anemia: 2° to tumor bleed

• Thromobocytosis: 2° to tumor bleed

• Coagulogram:• Association with Von Willebrand Disease (5 -8%)

• Urinanalysis:• Protein

• Catecholamines: Exclude neuroblastoma & for anesthesia

• Renal Function

Imaging• USG abdomen:• Imaging investigation of choice for

local disease

• Organ of origin,

• Extent of any spread

• Patency of the IVC

• Detecting any involved lymph nodes

• To assess renal function:• IVP

• DTPA renal scan

• CT - IVP

• CT scans:• Accurate delineation of intra-

abdominal tumor.

• Extension into surrounding organs

• Detection of lung mets (?)

• Plain X-rays:• PA views are adequate for

detection of lung mets.

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Special investigations

• CT brain:• Rhabdoid tumor of kidney

• Bone scan:• Clear cell sarcoma

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D/D of Pediatric Renal Mass• Neuroblastoma• Hydronephrosis• Renal cell carcinoma• Multilocular cystic renal tumor • Clear cell sarcoma• Rhabdoid tumor• Renal medullary carcinoma• Ossifying renal tumor of

infancy• Lymphoma.

• Nephroblastomatosis• Mesoblastic nephroma• Angiomyolipoma,• Metanephric adenoma,

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StagingStaging

Stage I

• SIOP System:• Tumor

confined to the kidney

• Completely excised

• Capsule intact

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Tumor

NWTS System:Tumor confined to

the kidney

Completely excised

Capsule intact

Stage II

• SIOP System• Tumor extending beyond

the kidney• Extra-renal vessel /ureteric

invasion • Adjacent organ or vena

caval invasion • Regional lymph node

involvement (IIN)**• Resected completely

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Tumor

NWTS SystemLocal extension beyond the

renal capsule

No invasion of adjacent viscera / mets

Only microscopic residual tumor

Tumor in renal vessels not beyond the renal sinus

Bx before resection (except FNAC)**

Completely resected

Stage III

• SIOP System:• Invasion beyond capsule

with incomplete excision• Pre/peri-op Bx• Peritoneal mets• Pre/per-op rupture• PAN below renal artery

origin

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NWTS System:Macroscopic residual

disease in nodes &/or abdomen

Preop rupture

Diffuse spillage

Peritoneal implants

Stage IV

• SIOP System:• Hematogenou

s metastasis• LAD beyond

the abdomen/pelvis

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NWTS System:

Hematogenous metastasis

LAD beyond the abdomen/pelvis

Stage V

• SIOP System:• Bilateral

tumor

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NWTS System:

Bilateral Tumor

N.B.: Both systems specify that the tumors should be individually staged.

Overview of the recent system

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TreatmenTreatmentt

Multimodality Management

• Wilms Tumors = highly chemo and radiosensitive

• Large mass and propensity for metastasis (hematogenous)

• Surgery = bulk of the disease • Chemotherapy = For metastatic disease • Radiation therapy = eliminates the risk of

local recurrence

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Treatment outline Immediate Nephrectomy

Adjuvant Chemotherapy as per Stage and Histological features

Radiation as per abdominal stage*

* Radiation generally avoided below 06 months

SurgerySurgery

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 (RPLND doesn't alter outcome)

• Renal vein and IVC (6% involvement) should be palpated to exclude intravascular tumor extension

• Exploration of the opposite kidney

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Issues in surgery• 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

• Not to be used routinely, however part of protocol in NTWS 1-4

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Nephrectomy alone

• Presently indicated in:• Age < 2 yrs

• Favourable Histology

• Stage I tumors

• Weight < 550 gms

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Surgical Complications• Surgical mortality < 1% • Complications of nephrectomy : • Small bowel obstruction (7%)

• Hemorrhage (6%)

• Wound infection, hernia (4%)

• Vascular complications (2%)

• Risk factors associated with increased surgical complications:• Higher local tumor stage

• Incorrect preoperative diagnosis

• Intravascular extension

• En bloc resection of other visceral organs39

Post nephrectomy management40

Histology Stage Chemotherapy Radiation therapyFavourable I

Not neededIIIII – IV Stage adapted radiation therapyI Not neededIIIII–IV Stage adapted radiation therapyI Not neededII-IV Regimen I Stage adapted radiation therapy

CSSK I-IV Regimen I Stage adapted radiation therapy

I-IV Regimen RTK Stage adapted radiation therapy

Actinomycin D + Vincristine (EE4A)

Act-D + VCR+ Dox (DD4A)Focal Anaplasia

Actinomycin D + Vincristine (EE4A)

Act-D + VCR+ Dox (DD4A)

Diffuse Anaplasia

Actinomycin D + Vincristine (EE4A)

Rhabdoid Tumors

Chemotharapy

Chemotherapy• Initially single agent Dactinomycin was used by

Faber et al in 1966. • Tan et al showed that it was associated with a CR

rate of 37.5%

• Another study from UK in 1965 showed that administration of 120 μg/Kg over 12 days improved the 2 yr EFS from 11% to 62%

• Single agent Vincristine was also used in 1960s• It was associated with an ORR of 61.5% in patients

with relapsed WT who had received Act-D

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Neoadjuvant Chemotherapy

• Indicated is 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

• Unilateral kidney

• Presence of genetic syndromes

• Horseshoe kidneys

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Neoadjuvant Chemotherapy

• The current protocol followed in the West includes Actinomycin D + Vincristine

• 4 weeks of chemotherapy = Adequate• Some centres in India using 4-6 wks of

Vincristine + Etoposide prior to surgery

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Radiation

Radiation Therapy

• Highly radiosensitive tumor• Adjuvant radiotherapy = Survival• In 1940s surgery attained 5 yr survival rates

of 15 -20% in all stages• Addition of postoperative radiation therapy

increased the survival to 47% (Gross and Neuhauser, 1940)

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Role of Radiotherapy• Historical• Definitive radiation therapy

• Contemporary• Preoperative Radiation

• Flank

• Whole Abdomen

• Postoperative Radiation

• Flank

• Whole Abdomen

• Lung bath

• Treatment of recurrence• Abdomen (localized abdominal

recurrence)

• Treatment of metastasis• Lung

• Brain

• Bone

• Liver

• Lymph nodes

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Wilms Tumor in special situations

Relapsed / Refractory WT• The most frequent site of relapse overall = Lung• The overall survival following relapse = 24 -30 % • Best results reported with: - ICE regimen Ifosfamide Carboplatin Etoposide)• Children + relapse - remission = High dose

chemotherapy + stem cell transplantation(alternative)

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Bilateral Wilms Tumor• Account for 7% of all WT – 6% synchronous• Associated in 20% with genetic syndromes• Both sides staged seperately• Metachronous tumors fare worse than

synchronous• Long term survival rates 70 -80%.

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Initial open biopsy / Trucut biopsy and staging

Downstaging with Chemotherapy

Bench Surgery*

Partial nephrectomy

Wilms Tumor in Adults

• Median age at presentation = 25 years• MC presenting symptom Pain• Stage III and IV disease > in childhood• Poor prognosis• Survival = 24% at 3 years.

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Wilms Tumor in Horseshoe Kidneys

• Abnormal fusion of metanephric blastema of the lower pole of the future kidneys at 6th -7th weeks of gestation.

• 50 -60 cases recorded in literature• 2 fold increased risk of development of WT• Partial nephrectomy / bench surgery typically

used for reduction of disease burden• Preoperative chemotherapy = Bulk reduction• Post operative adjuvant radiation involved

flank 52

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

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Follow up Protocol54

Imaging Study Schedule

Abdominal ultrasound

CT chest

CT abdomen and pelvis

Starting 2 years from end of therapy: every 6 months × 4

Every 3 months × 4, then every 6 months × 2

Abdominal ultrasound or CT abdomen

Bone scan Every 6 months × 6

MRI brain Every 6 months × 6

Patient Character-istics

Favorable-histology Wilms' tumor  

Chest radiograph CT chest Every 6 weeks until complete remission is documented; then every 3 months × 8 times, then every 6 months × 4 timesPostoperatively after 6 weeks and 3 months; then every 3 months × 8, then every 6 months × 4

Anaplastic Wilms' tumor; rhabdoid tu-mor  

Every 6 weeks until complete remission is documented; then every 3 months × 8Postoperatively after 6 weeks and 3 months; then every 3 months × 8

Abdominal ultrasound and chest ra-diographMRI brain (for rhabdoid tumor only)

Clear cell sarcoma; renal cell carcino-ma  

Chest radiograph or CT chest Every 6 weeks until complete remission is documented; every 3 months × 8, then every 6 months × 6Every 6 weeks until complete remission is documented; every 3 months × 8, then every 6 months 3 6

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