A 6 year old boy with fatigue Abdalla Zarroug MD, FACS, FAAP Consultant Pediatric Surgeon Mayo Clinic. Rochester, MN USA Edited by SAMA and the Surgical club of SAMA Abdalla Zarroug MD, FACS, FAAP Consultant Pediatric Surgeon Mayo Clinic. Rochester, MN USA Edited by SAMA and the Surgical club of SAMA

6 year old boy with fatigue Chief Complaint

Previously healthy 35 kg boy with abdominal pain for months Seen at outside emergency room and diagnosed with constipation, with no imaging studies Several weeks later presented to pediatrician with fever and fatigue Weight loss 9 kg Previously healthy 35 kg boy with abdominal pain for months Seen at outside emergency room and diagnosed with constipation, with no imaging studies Several weeks later presented to pediatrician with fever and fatigue Weight loss 9 kg History of Present Illness

Past medical/surgical history asthma Family history no childhood oncology disorders Social second grade lives with mother and 3 brothers No known drug allergies Immunizations up-to-date Past medical/surgical history asthma Family history no childhood oncology disorders Social second grade lives with mother and 3 brothers No known drug allergies Immunizations up-to-date History

Neck No lymphadenopathy Chest Cleat to auscultation bilaterally CV No murmurs, rubs, gallops Abdomen Soft, slightly distended, massive masses in both right and left abdomen Extremities No cyanosis or edema Neck No lymphadenopathy Chest Cleat to auscultation bilaterally CV No murmurs, rubs, gallops Abdomen Soft, slightly distended, massive masses in both right and left abdomen Extremities No cyanosis or edema Physical Exam

Labs Prolonged ptt Abdominal X-ray No calcifications CT scan Bilateral Abdominal Masses Labs Prolonged ptt Abdominal X-ray No calcifications CT scan Bilateral Abdominal Masses Results

CT: Bilateral Renal Tumors Possible IVC thrombus Renal vein to lower half of kidney

MRI: No Tumor Thrombus 3 dimensional reconstruction

Impression Bilateral Wilms Tumor Workup revealed factor XI deficiency Plan Bilateral Open Biopsy Port-a-cath placement Chemotherapy Pathology Bilateral Wilms tumor with favorable histology Impression Bilateral Wilms Tumor Workup revealed factor XI deficiency Plan Bilateral Open Biopsy Port-a-cath placement Chemotherapy Pathology Bilateral Wilms tumor with favorable histology Evaluation

Regimen DD4A (favorable histology) Vincristine Actinomycin Doxorubicin Tolerated well Repeat CT Decreased tumor size Regimen DD4A (favorable histology) Vincristine Actinomycin Doxorubicin Tolerated well Repeat CT Decreased tumor size Chemotherapy

Right nephrectomy Left heminephrectomy Double J stent through the left ureter Lymph node biopsy Right nephrectomy Left heminephrectomy Double J stent through the left ureter Lymph node biopsy Definitive Operation

Operation Left renal arteries and vein to normal kidney to be salvaged Left Wilms tumor Left Native kidney

Operation Left Wilms tumor Cut surface of left native kidney in situ with J stent in ureter

Pathology Diffuse anaplasia Negative margins Epithelial/blastemal predominant Switched to AREN0321 regimen (aggressive chemotherapy for non-favorable anaplasia) Vincristine Adriamycin Cytoxan Carboplatin Etoposide Pathology Diffuse anaplasia Negative margins Epithelial/blastemal predominant Switched to AREN0321 regimen (aggressive chemotherapy for non-favorable anaplasia) Vincristine Adriamycin Cytoxan Carboplatin Etoposide Post Op

No surgical complications Normal urine output and creatinine Dialysis catheter removed Double J stent removed at 3 months post-op No surgical complications Normal urine output and creatinine Dialysis catheter removed Double J stent removed at 3 months post-op Post Op

Repeat Imaging CT at 6 month post-op No evidence of disease Creatinine normal GFR 87ml/min/bsa No evidence of disease Creatinine normal GFR 87ml/min/bsa

Case finalized now some information on Wilms Tumor Wilms Tumor

Renal tumors represent 6% of all pediatric cancers Most common malignant renal tumor in children 450 cases diagnosed per year in US 1 in 10,000 children in US Peak incidence is 3 years of age M:F equal for unilateral; 0.6:1 for bilateral Renal tumors represent 6% of all pediatric cancers Most common malignant renal tumor in children 450 cases diagnosed per year in US 1 in 10,000 children in US Peak incidence is 3 years of age M:F equal for unilateral; 0.6:1 for bilateral

Congenital Anomalies AnomalyRate (per 1000) Aniridia7.6 Beckwith-Wiedemann8.4 Hemihypertrophy33.8 Genitourinary anomalies Hypospadias13.4 Cryptorchidism37.3 Both12.0

Congenital Anomalies Incidence in patients with Wilms Tumor: Aniridia - 1.1% Hemihypertrophy - 3% Genitourinary anomalies - 4.5% Beckwith-Wiedemann syndrome has an incidence of 10-20% with tumor development Incidence in patients with Wilms Tumor: Aniridia - 1.1% Hemihypertrophy - 3% Genitourinary anomalies - 4.5% Beckwith-Wiedemann syndrome has an incidence of 10-20% with tumor development

Cytogenetics of Wilms’ Tumor Cytogenetics is the study of the chromosomal changes that occur in diseases Karyotypes are photographs of matching pairs of chromosomes during metaphase Most interest in Wilms’ tumor has been in the familial occurrence of changes in chromosome 11 Cytogenetics is the study of the chromosomal changes that occur in diseases Karyotypes are photographs of matching pairs of chromosomes during metaphase Most interest in Wilms’ tumor has been in the familial occurrence of changes in chromosome 11

Wilms’ Tumor Genes 11p 11q 11p13 WT1 gene WAGR Syndrome Denys-Drash Syndrome Wilms’ tumor, Aniridia, Genitourinary malformations, Mental Retardation Wilms’ tumor, Intersexual disorders, nephropathy

Wilms’ Tumor Genes 11p 11q 11p15 WT2 gene Beckwith-Wiedemann Syndrome Macroglossia, Organomegaly, Hemihypertrophy, Neonatal hypoglycemia, Embryonal tumors

WT2 Gene BWS shows duplication of the paternally derived 11p15 and others show inhertance of two paternally derived chromosomes 11 without maternal contribution = genomic imprinting IGF2 - encodes a growth factor thought important in fetal overgrowth syndrome p57 - inactivating mutations lead to loss of cellular growth control leading to organomegaly Nontranslated RNA H19 - regulates IGF2 expression and may suppress cellular proliferation BWS shows duplication of the paternally derived 11p15 and others show inhertance of two paternally derived chromosomes 11 without maternal contribution = genomic imprinting IGF2 - encodes a growth factor thought important in fetal overgrowth syndrome p57 - inactivating mutations lead to loss of cellular growth control leading to organomegaly Nontranslated RNA H19 - regulates IGF2 expression and may suppress cellular proliferation

NWTSG Staging for Wilms’ DescriptionStage Stage ILimited to kidney and completely excised Capsule intact No rupture, vessel, node Stage IIExtends beyond kidney but is completely excised No residual tumor is at or beyond margin Maybe regional extension, bx only, local spillage Stage IIIResidual tumor confined to abdomen as defined: L. node, diffuse peritoneal contamination, peritoneal implants, tumor beyond surgical margin, or local infiltration into vital structures Stage IV Hematogenous mets: Includes lung, liver, bone, brain Stage V Bilateral renal involvement

Management Options Nephrectomy followed by adjuvant chemotherapy ± radiotherapy If tumour deemed unresectable to proceed with initial chemotherapy Gow et al (J Pediatr Surg, 2000)

Parameters to be assessed A. CT Scan may assess: Size of tumor Margin Nodal involvement Vascular invasion Contralateral involvement Gow et al (J Pediatr Surg, 2000)

Pathology Triphasic pattern: Blastemal, stromal, epithelial Blastemal predominant behave aggressively Stromal component may differentiate into muscle, cartilage, or fat Unfavorable histology = Anaplastic Triphasic pattern: Blastemal, stromal, epithelial Blastemal predominant behave aggressively Stromal component may differentiate into muscle, cartilage, or fat Unfavorable histology = Anaplastic

Investigations Goal of establishing diagnosis, stage, and function of contralateral kidney Ultrasound is the first imaging modality CT scan is often the next investigation used Chest radiograph or CT scan is done to assess pulmonary involvement Goal of establishing diagnosis, stage, and function of contralateral kidney Ultrasound is the first imaging modality CT scan is often the next investigation used Chest radiograph or CT scan is done to assess pulmonary involvement

Management of Wilms’ Tumor Surgical resection is advocated as the primary procedure when resectable Along with this, insertion of central line for chemotherapy Biopsies are performed for use in bilateral tumors Surgical resection is advocated as the primary procedure when resectable Along with this, insertion of central line for chemotherapy Biopsies are performed for use in bilateral tumors

Abdalla Zarroug MD, FACS, FAAP Pediatric Surgery Assistant Professor of Surgery and Pediatrics Mayo Clinic Abdalla Zarroug MD, FACS, FAAP Pediatric Surgery Assistant Professor of Surgery and Pediatrics Mayo Clinic