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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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