Childhood Diseases:

Diagnosis, Treatments and Follow-up

Clinical Research Education Lecture Series

Wilms Tumor

23 January 2015
Wilms Tumor
Rachel C. Brennan, MD
Department of Oncology – Solid Tumor Division
January 23, 2015
Rachel C. Brennan, MD
Dr. Jocelyn Lewis gave a talk on Wilms Tumor on 1-23-2012…
Thank you to her for some of these slides!

Objectives Medical History

• Recognize the clinical findings associated with Carl Max Wilhelm Wilms
Wilms tumor German pathologist and surgeon

Research: nephrology
• Recognize common treatments and side effects
encountered during Wilms tumor therapy Proposed that tumor cells
originate during the
development of the embryo
• Understand the prognosis for a patient who has
Wilms tumor Die Mischgeschwülste der Niere

Nephroblastoma = Wilms tumor

http://ihm.nlm.nih.gov/luna/servlet/view/
search?q=B010870

Cancer in Children: Incidence by Age Epidemiology

• All renal tumors
o Wilms tumor 92%
• 500 cases/year
o Clear cell sarcoma 3.4%
o Congenital mesoblastic nephroma 1.7%
o Malignant rhabdoid tumor 1.6%

Age at diagnosis - Unilateral: 42mo (M), 47mo (F)

6% bilateral at diagnosis: 24mo (M), 31mo (F)
Male:Female = 1:1.1
African American > Caucasian > Asian

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 Genetics and Molecular Biology
• Chromosome 11p13 (WT-1), 11p15 (WT-2 locus)
Associated Syndromes
• Denys-Drash
• Chromosome xq26: GPC3 deletions or mutations
oKidneys/Genitalia
• Scar tissue leads to
• BRCA2 (FANCD1) predisposition to Wilms tumor
renal failure in
• BUB1B – auto recessive 25% risk of Wilms tumor
childhood
• TP53 – mutations Li Fraumeni
• Males with
ambiguous genitalia
• Non-syndromic familial Wilms tumor (Auto Dom) geneticpeople.com
o 17q12-21 FWT1
o 19q13.3-4 FWT2 oWilm’s Tumor risk > 90%

• Syndromic…

Associated Syndromes Associated Syndromes

WAGR Fanconi Anemia
o Wilms tumor
Aniridia o Bone marrow failure
Genitourinary anomalies Short stature
Radial ray defects (thumbs)
Renal failure Microcephaly
Hip displasia
Rocker bottom feet
o Wilms tumor risk = 30%
o Wilms tumor risk = 20%
http://www.reviewofophthalmology.com/content/i/1353/c/25860/

Nathan DG, Oski FA, eds. Hematology of Infancy and Childhood, 4th ed

Associated Syndromes “Predisposed** to WT”

Beckwith-Wiedemann
• Nephrogeneic Rests (NR)
Syndrome (BWS) o Nephroblastomatosis: kidneys with multiple NR
o “Gigantism”
o Organomegaly
o Fetal tissue persisting into infancy = nephrogenic rest (NR)
Large birth weight
Macroglossia
Omphalocele o <1% of NR will transform into malignant Wilms Tumor, but
Hemihypertrophy 36% of WT have NR
Ear pits and creases
Neonatal hypoglycemia
o Perilobar rests, located along the perimeter of a renal lobe,
are associated with synchronous bilateral Wilms tumors
atlasgeneticsoncology.org o Wilms tumor risk = 5%
o Also risk for ACC, HBL, RMS
o **Intralobar rests (within the renal lobe) show a strong
association with metachronous tumor
Other overgrowth syndromes (Perlman, 33%)
or idiopathic hemihypertrophy (<3%) also associated with WT

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 Clinical Presentation Imaging – Ultrasound
• Abdominal mass 75%
• Abdominal pain 28%
• Hypertension ~20%
• Gross hematuria 18%
• Microscopic hematuria 24%
• Fever 22%

• CONSTIPATION

Met sites: LUNGS

IVC tumor thrombus via renal vein

Imaging Imaging

Imaging Imaging

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 Imaging Imaging

Work-up for Renal Tumor Staging

• History and Physical Exam I Completely resected
o Family history of congenital syndromes, renal failure, other tumors Limited to the kidney
o Vital signs: hypertension
o Examination: any stigmata, hypertrophy, lungs, vascular compromise
II Completely resected
• GENTLE abdominal exam, avoid rupture of tumor
Extension outside the kidney
o Current symptoms: constipation, pain, headaches/HTN symptoms

• Laboratory Information III Residual tumor in abdomen

o Basic CBC and electrolytes
• Anemia resulting from intra-tumoral bleeding
• BUN/Creatinine as measure of renal function IV Distant Disease
• Consider cystatin C (baseline) Distant metastatic disease
o Urinalysis: blood? Protein? Lymph nodes outside abd/pelvis

• Imaging
o Ultrasound with doppler: renal mass, IVC and liver evaluation V Bilateral disease
o CT chest/abdomen/pelvis with contrast

• Surgical consultation

Poor Prognostic Factors Staging

• Loss of Heterozygosity = LOH I Completely resected
Limited to the kidney
o LOH 1p and 16q
o Need more aggressive chemo 2 drugs
II Completely resected
Extension outside the kidney

• Unfavorable histology (anaplasia) III Residual tumor in abdomen Surgery

o Need more aggressive chemo
o Need radiation
IV Distant Disease
Distant metastatic disease 3 drugs
• Blastemal predominant after chemo Lymph nodes outside abd/pelvis Radiation
o If surgical resection not possible upfront (bilateral)
o European approach
V Bilateral disease

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 Treatment Treatment
• Surgery and Observation only • Surgery then chemotherapy
o <24 months old o Everyone else except
o Tumor weight <550g • Bilateral tumors
o Any LOH • Thrombus in the IVC above hepatic veins
o Very Low Risk • Invasion of adjacent organs
• Not an upfront surgical candidate (use chemo to shrink)
• Respiratory distress from multiple lung metastases

Wilms Tumor
Treatment
RENBIO
TBANK / MAST • EE4A – Low Risk
FH Wilms High o Vincristine and Dactinomycin x 18 weeks
Higher Risk :
Risk :
Very Low Risk: FH Wilms Focal Anaplasia, Stage IV
Low Risk :
FH, Stage I-II + LOH
Diffuse Anaplasia, Stage II-
IV
o Stage I and II, favorable histology
Stage I/II
observation FH, Stage III-IV
Or
Regimen I
EE4A Focal Anaplasia, I-III;
Diffuse Anaplasia, I

Bilateral or
DD4A + XRT
predisposed
unilateral WT

REN534
Pre-surgery
chemo

Treatment Treatment
• DD4A – Standard Risk and High Risk • Regimen I – Higher Risk
o Vincristine, Dactinomycin, Doxorubicin
o Vincristine, Dactinomycin, Doxorubicin, Etoposide,
o 25 weeks Cyclophosphamide
o 25 weeks
o Favorable histology
• Stage I or II with LOH at 1p and 16 q
• Stage III – IV
• UH-1: chemo + radiation
**Toxicity with this combination noted on last COG trial
o Anaplasia
• Focal anaplasia, Stage I-III
• Diffuse anaplasia, Stage I o Anaplasia: focal stage IV or diffuse stage II-IV

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 Radiation Stage V Wilms Tumor
• Indications • AREN0534
o Flank radiation
• Upfront chemotherapy
• Stage III and IV disease o Biopsy discouraged (could “upstage” tumors)
• Positive lymph nodes, surgical margins, or tumor spillage
= 10.8Gy to the flank • Vincristine, Dactinomycin and Doxorubicin (VAD)
o Whole abdomen radiation o Evaluate at 6 weeks for surgical resection
• If not, consider biopsy to be sure no anaplasia
• Diffuse tumor spillage or peritoneal seeding
o Surgery at week 6 or 12
= 10.8 Gy to the entire abdomen
• Based on post-chemo pathology, continue with:
o Boost to tumor bed
o EE4A
• Gross residual disease
o DD4A
o Pulmonary radiation: lung mets o Regimen I
• May NOT require radiation if mets resolve at week 6**

Chemo: Side Effects Wilms Tumor Late Effects

Serious chronic health conditions 25 yr after dx in 25% of
• Vincristine survivors (Termuhlen et al, 2011 PBC [CCSS study])
o Peripheral neuropathy, constipation, vocal cord paralysis, jaw
pain, leg pain, hair loss o Cardiotoxicity - Doxorubicin
• Actinomycin-D (dactinomycin) • risk of CHF ~4.4%
o Nausea, vomiting (N/V), liver dysfunction, veno-oclusive disease • Increased risk in female patients and after chest radiation
(liver), radiation recall, pancytopenia, hair loss o Impaired fertility – Cyclophosphamide
• Doxorubicin (Adriamycin) o Secondary malignancies
o N/V, color change of tears/urine/sweat, cardiac damage, mouth • MDS, leukemia, sarcomas, carcinomas – alkylating agents and
sores, pancytopenia, hair loss topoisomerase inhibitors
• Cyclophosphamide o Renal failure – 0.6%
o N/V, blood in urine, hair loss, pancytopenia • Increased in patients with WAGR syndrome and Denys Drash
• Etoposide • Increased in non-syndromic bilateral Wilms tumor
o N/V, Allergic reaction/hypotension • Associated with increased therapy/abdominal radiation

Wilms Tumor EFS and OS

Wilms Tumor
(from Dome et al, PBC 2013)
Prognosis/outcomes
• Favorable histology, localized or completely
resected, non-metastatic, no LOH: OS >90%

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 Childhood Diseases: Childhood Diseases:
Diagnosis, Treatments and Follow-up Diagnosis, Treatments and Follow-up
Clinical Research Education Lecture Series Clinical Research Education Lecture Series

? ?

Questions & Answers Questions & Answers

Some questions were asked without a Some questions were asked without a
microphone nearby and may be difficult to microphone nearby and may be difficult to
hear, but they are presented here. hear, but they are presented here.

Childhood Diseases: Childhood Diseases:

Diagnosis, Treatments and Follow-up Diagnosis, Treatments and Follow-up
Clinical Research Education Lecture Series Clinical Research Education Lecture Series

? ?

Questions & Answers Questions & Answers

Some questions were asked without a Some questions were asked without a
microphone nearby and may be difficult to microphone nearby and may be difficult to
hear, but they are presented here. hear, but they are presented here.

Childhood Diseases:
Diagnosis, Treatments and Follow-up
Clinical Research Education Lecture Series

Rachel C. Brennan, MD

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