Wilm's Tumor Power Notes [1]

What was Sidney Farber's contribution to the field of oncology?
Sidney Farber was the first to us adjuvant chemotherapy (Actinomycin D) to treat cancer (Wilm's tumor).

What syndromes is WT associated with and how often?
In 10% of cases, WT is associated with:
1. sporadic aniridia
2. isolated hemihypertrophy
3. Denys-Drash syndrome
4. genital anomalies
5. Beckwith-Wiedemann syndrome
6. WAGR (60% develop WT)

What are the main genes associated with WT, and what is the role of the protein produced by those genes?
WT1 and WT2 (reside on chromosome 11) are tumor suppressor genes that code for proteins that suppress growth inducing genes. Deletions in WT1 and WT2 predispose to WT.
WAGR is associated with WT1 and Beckwith-Wiedemann syndrome is associated with WT2

How often is WT bilateral in WAGR?
60% of patients with WAGR develop WT which is bilateral in 17% of cases

What is the relationship between Beckwith-Wiedemann syndrome and WT?
Kids with BW syndrome have a 40% chance of developing WT

How often is WT familial?
in up to 2% of cases

How does loss of heterozygosity (LOH) affect prognosis?
LOH (of chromosomes 1 or 16) is associated with increased risk of relapse and mortality.
LOH-16 present in 15-20% of WT, LOH-1 present in 10%

What is screening protocol for patient with syndromes associated with WT?
Ultrasound of kidneys every three months until the age of 5 YO

What are nephrogenic rests (NR) and what are their two distribution patterns?
NRs are persistent metanephric tissue beyond 36 weeks of gestation. The vase majority of NRs involute. They are found in two main distribution patterns.
1. Perilobular (PLNR): more common
2. Intralobular (ILNR)

What is the autopsy incidence of NRs?
~1%
PLNR: 0.9%
ILNR: 0.1%

What are the three histologic groups of NRs?
1. Incipient (infants)/Dormant (Older children): composed of blastemal and primitive epithelial cells that resemble embryonic kidney tissue and WT, but are microscopic and have sharp margins.
2. Regressing/Sclerosing (most common): show maturation of cellular elements. Progress to become obsolete rests composed of hyaline stromal elements (acellular proteinaceous material).
3. Hyperplastic: These are difficult to distinguish from WT, except based on architecture. They have uniform growth components that result in enlargement of the entire rest (preserving it's shape), as opposed to the neoplatic growth (WT) that results in a spherical expanding nodule within a rest.

How are hyperplastic NRs differentiated from WT?
The shape of the NR is preserved in hyperplastic NRs, and there is now surrounding pesudocapsule (which is found in WT). The importance of architectural characteristics makes a needle biopsy insufficient for differentiation unless they contain a part of the lesion's margin.

What is the association between WT and NRs?
41% of unilateral WT have NRs vs 99% of bilateral WT. NRs are increased in patients with WT associated with syndromes.

What is diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) and what is it's radiologic characteristic?
DHPLN is an entity that can be confused with WT. Infants with DHPLN have unilateral or bilateral enlarged kidneys that maintain their their normal shape and lack necrosis. DHPLN can become WT (in ~50% of cases despite neoadjuvant chemotherapy) so they should be monitored closely. Changes in CT/MRI characteristics or evidence of growth of DHPLNs should raise concern for WT.

what is the treatment and prognosis of DHPLN?
Chemotherapy is used to decrease the size of DHPLNs, which may cause respiratory compromise by virtue of their size, but has not been shown to decrease the risk of malignant transformation. 100% transformation to WT in the absence of chemotherapy, vs 55% when biopsy/chemotherapy performed.
A high proportion of patients with DHPLN and WT will have anaplastic WT

Is nephrectomy justified in multicystic dysplastic kidneys?
No. Only 4% of these patients will have NRs and the risk of WT too low to justify prophylactic nephrectomies

What defines unfavorable histology WT (UH)?
Presence of focal or diffuse anaplasia. Anaplastic cells have large, pleomorphic, hyperchromatic nuecleii with abnormal mitotic figures. Focal anaplasia confers a better prognosis than diffuse anaplasia. Anaplasia is aassoicated more with respnse to therapy than tumor aggressiveness.

What are the two tumors that were considered WT UH and where split into a different category?
Clear cell sarcoma of the kidney (CCSK) and malignant rhabdoid tumors

What is the main difference between NWTSG and SIOP classifications?
NWTSG is a pre-treatment staging system while the SIOP assesses post treatment characteristics of the tumor.

What difference between Stage II and Stage III in terms of spillage?
Spillage is now considered Stage III regardless of whether it is local or diffuse, from a biopsy or tumor rupture. The extent of spillage affects the field of radiation given. Local spillage in the renal fossa is treated with local flank radiation; spillage outside the tumor bed mandates total abdominal radiation [2]

Is there a difference in terms of gross or microscopic post resection residual tumor in terms of staging?
No. Both are considered Stage III

How are tumors classified into risk groups based on neoadjuvant chemotherapy?
Based on histology at resection AFTER neo-adjuvant chemotherapy.
Low risk tumors are those that are completely necrotic (>99%)at time or resection
Blastemal predominant tumors (high risk) are those with more than 1/3 of tumor viable, and at least 2/3 of the viable tumor consists of blastemal cells.
Intermediate risk tumors are those with a variety of histologic charactaristics in between the low and the high risk categories.

What are the main pathologic characteristics of WT and how are they related to outcome?
WT is an embryonal neoplasm with blastemal, stromal, and epithelial components. Each of these can have variable levels of differentiation, including anaplasia.

What is particular about fetal rhabdomyomatous nephroblastoma and diffuse blastemal type WT?
Both these subtypes of WT. Fetal rhabdomyomatous nephroblastoma has poor response to chemotherapy, but excellent prognosis. Diffuse blastemal type has rapid response to chemotherapy, but characteristically presents with advanced disease

Which kids are at risk for anaplastic WT?
Kids older than 2 YO. Mortality from anaplastic WT ~ 60%. Outcome better for focal vs diffuse anaplasia.

What is the rate of metachronous contralateral disease and what are risk factors?
The rate of metachronous disease is 1% (synchornous is 5%). This is increased:
1. In the presence of NRs
2. Kids younger than two years
3. associated syndromes

What are the main characteristics of clear cell sarcoma of the kidney?
metastasis to bones and brain. Unclear cell origin

What are the main characteristics of malignant rhabdoid tumors of the kidney?
average age 11 months
characteristic involvement of perihilar renal parenchyma
second primary neurglial tumor in the brain

What are the main chemotheraputic agents used with WT?
Dactinomycin, vincristine, doxorubicin

When is doxorubicin added?
Stage III disease or in the presence of anaplasia

What are the aims of the main SWTS studies?
SWTS3: Use of Dox for Stage III dz
NWTS4: Dose intensification (less frequent) adequate with less hematologic toxicity
NWTS5: Effect of LOH on outcome in stage 1 and 2: decreased EFS
looked at management of relapse

What chemotheraputic agents are used for anaplasia?
Focal anaplasia: Vincristine/Dactinomycin/Doxorubicin
Diffue anaplasia: add cyclophosphamide +/- etoposide


What agents are used for CCSK and malignant rhabdoid tumors?
CCSK: Doxorubicin
Malignant rhabdoid: cyclophos/carbaplatin/etoposide (non of the basic WT agents)

What are the disadvantages of the routine use of neoadjuvant chemotherapy (SIOP)?
1. risk of losing staging information
2. risk of treating benign disease
3. modification of tumor histology by chemotherapy
4. Clear cell/rhabdoid will not respong
up to 10% rate of benign or altered malignant diagnosis in kids with pre-nephrectomy diagnosis of WT

What are the complications of doxorubicin?
1. cardiomyopathy in 1.2%
2. secondary malignancies (AML) in 1.6%

What are risk factors for a secondary malignancy?
1. doxorubicin
2. irradiation
3. prior treatment for relapsed tumor

What are the current guidelines for radiation therapy to lungs?
low dose radiation if lunges involved.

What is the significance of CT only lung lesions? [3]
Up to a third of lung lesions found on CT in patients with WT are not malignant.
Patients who are stage I or II FH WT should undergo biopsy of CT only lesions to gauge therapy. Those who are FH stage III or IV who are on AREN0533 protocol trial receive chemotherapy and then are reevaluated after 6 weeks. At that time, any residual lesions will get radiation, preferably after biopsy

What are guidelines for abdominal irradiation? [2]
Local Stage III disease. 10cGy


What are the main things that need to be assessed on imaging?
1. contralateral kidney involvement
2. two functioning kidneys
3. vascular involvement

What is the incidence of synchronous contralateral lesions?
5%

Is there a need for contralateral exploration and why?
No. Although 10% of lesions on the other side may be missed by imaging, these lesions do not affect outcome and recurrence, especially that some are NRs and not WT.

What are the false positive and false negative rates of clinical assessment of LN involvement?
The false positive rate of clinical assessment is ~20% and a false negative rate is 30%. Thus routine sampling of LN's (even when not suspicious) is mandatory for proper staging.

Why is cystoscopy important in the presence of hematuria?
Cystoscopy is important to rule out tumor extension into the bladder, where cutting through the ureter would result in cutting through the tumor, thus upstaging the patient.

What are factors related to increased risk of tumor recurrence?
Stage III
Intraoperative rupture
Anaplasia

What are indications for neoadjuvant chemotherapy (NWTSG)?[2]
1. solitary kidney
2. bilateral tumors: all bilateral tumors are treated with upfront chemotherapy. Any attempts at partial nephrectomy should be with held until week 6 or 12 [2]
3. horseshoe kidney
4. unresectable tumor
a.intravascular extension of tumor thrombus above hepatic veins
b.involvement of contiguous structures that would need to be sacrificed
c.if resection risks unnecessary morbidity and mortality per surgeon judgement
d.pulmonary compromise due to extensive pulmonary metastasis
5. respiratory distress form mass

Should both kidneys be biopsied in bilateral WT? [2]
No. Initially, and because of the risk of discordant pathology between the two kidneys, it was recommended that both kidneys be biopsied.
Per new COG protocol, renal biopsy is not necessary in stage V disease. Protocol calls for upfront 3 drub chemotherapy followed by possible OPEN biopsy (<50% reduction in size which may suggest presence of anaplastic tumor) or resection (tumor rendered resectable) or continued chemotherapy and resection at 12 weeks When is a core needle biopsy vs an open biopsy acceptable?
A core needle biopsy is acceptable to obtain a tissue diagnosis when a suspected WT tumor is deemed unresectable. An open biopsy is mandatory in the setting of bilateral WT that does not decrease in size by more than 50% after 6 weeks of chemotherapy.

How often is intravascular extension identified?
The renal vein is involved in 11% of children, the vena cava in 5% [2]. The Renal vein and VC should be palpated for the presence of tumor intraoperatively, even when preoperative imaging studies are normal.

Which patients are candidates for resection alone without adjuvant chemotherapy?
patients who are younger than two years, stage I, and <550 grams. LN's MUST be sampled and found negative for children to qualify. If LN's are not sampled, the child does not qualify for the surgery only protocol [2]
90% 4 year disease free survival

References: Ashcraft unless otherwise specified
1. Ashcraft's Pedatric Surgery. 5th edition. Chapter 67: Renal Tumors
2. COG renal biology protocol handbook. Accessed July 2011. Available at http://www.childrensoncologygroup.org/_files/disc/Surgery/RenalTumorsHandbook.pdf
3. Ehlrich et al. The value of surgery in directing therapy for patients with Wilm's tumor with pulmonary disease. A report from the National Wilm's Tumor Study Group (NWTS-5). Journal of Pediatric Surgery (2006);41:162-167