WILMS TUMOR

BY DR Amitabh

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.

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

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.

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

RaceWilms 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

SexAmong 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.

:

Age

• The median age at diagnosis is approximately 3.5 years

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.

WAGR syndrome

characterized by

Aniridia,

Genital anomalies, and

mental Retardation and a 33% chance of developing

Wilms tumor.

• 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,

anda contiguously deleted autosomal dominant gene for ANIRIDIA,

PAX6, both located on chromosome

11p13.

Patients with deletions restricted to

PAX6, with normal WT1 function,

develop sporadic ANIRIDIA,

but they are not at increased risk for Wilms tumors.

Denys- Drash syndromeA much higher risk for Wilms tumor (∼90%)

characterized by

GONADAL DYSGENESIS(male pseudohermaphroditism) and

EARLY-ONSET NEPHROPATHY leading to renal failure

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.

• 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

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.

Beckwith- Wiedemann

syndromecharacterized by

1. ENLARGEMENT OF BODY ORGANS (organomegaly)

2. MACROGLOSSIA3. 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

• 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.

11p15.5This 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.

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

• Moreover, the phenotype of BWS, including the predisposition to tumorigenesis, is

influenced by the specific “WT2” imprinting abnormalities present.

• 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.

• 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.

• 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.

• In addition to Wilms tumors, patients with BWS are also at increased risk for developing

HEPATOBLASTOMA,

•PANCREATOBLASTOMA,

•ADRENOCORTICAL TUMORS, and RHABDOMYOSARCOMAS.

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.

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.

• 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

• 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.

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.

HISTOLOGYANAPLASIA

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

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.

On cut sectionThe tumor is soft,homogeneous,and tan to gray withoccasionalfoci of hemorrhage,cyst formation,and necrosis.

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.

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.

HISTORY AND PHYSICAL EXAMINATION

• Detection of an asymptomatic

abdominal mass bulgingin the flank.

• Non specific systoms likeabdominal pain, fatigue

• Haematuria (in <10%)

• Hypertension (V. rare )

• Associated Urogenital anomalies,Aniridia, overgrowth Syndrome.

DIAGNOSTIC WORK - UP

Laboratory Studies• CBC count

• RBS

• Chemistry profile

• (KFT & LFT)

• Urinalysis

• Coagulation studies

• Cytogenetics studies

• (WT1 gene)

IMAGING STUDIES1. Abdominal USG Organ of origin

Identify contralateral KidneyPresence/absence of tumorthrombus in IVC

2. CT Scan Further evaluation of extentof tumor Extension into adjoiningstructures such asLiver spleen & colon.Visualisation and function ofcontralateral Kidney

3. X-ray chest PA Pulmonary Metasteses

• 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.

National Wilms Tumor Study (NWTS) staging Stage I : Tumor confined to the kidney & completely excisedStage II : Tumor outside the kidney but completely excised

Local tumor spillage during surgeryLymph nodes negative

Stage III : Non hematogenous disease confined to the abdomen

Perioperative rupture of renal capsuleDiffuse tumor spillage during surgeryPeritoneal implantsPositive lymph nodes

Stage IV : Hematogenous metastases to lungs or liverStage V : Bilateral Wilms’ tumor

GENERAL MANAGEMENT

• 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

Absolute Indications for

Prenephrectomy Chemotherapy1. Large tumor technically difficult to deliver at surgery.2. Presence of major tumor thrombus in the inferior venacava.3. Bilateral Wilm’s tumor4. Wilm’s tumor in a solitary Kidney or horse shoe Kidney.

Radiation TherapyWilms 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

RT - Indications : Post OP RT• WT - Favourable Histology

– Stage III:– residual T

Gross/Micro+ve MarginLocal Infiltration Vital Structures

- Abd / Pelv -Ly N +- peritoneal surface

PenetrationTumour implantsT 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

– 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

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.

RT Machines

• Telecobalt

• Linear Accelerator

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

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

RT Dose• Stage III

FH

• Stage I-III

Focal anaplasia

Diffuse anaplasia

CCSK

FLANK RT : 10.8Gy, 180cGy/ fx

• Stage III

Diffuse anaplasia

• Stage I-III

RTK

FLANK RT : 19.8Gy

(Infants -10.8Gy), 180cGy/ fx

• Whole Abdomen RT FH : 10Gy, 150cGy/ Fx

Gross Residual disease : Boost of + 10Gy

(Renal Shielding / Limit the dose to

remaining kidney <14.4Gy)

• 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

• Unresected Lymph nodes : 19.8Gy in 11#

• Bone ( mets.) : 25.2 Gy in 14#

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

Treatment Fields - Flank

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

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

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.

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.

THANKYOU