NEPHROBLASTOMA.pptxin pediatric medicine

Nephroblastoma

1. NEPHROBLASTOMA PRESENTATION BY BYEKWASO CLARISSA 2020-08-00157

2. INTRODUCTION Renal tumors account for 7% of all childhood cancers. While 80% of these are nephroblastoma others including clear cell sarcoma of the kidney (6%), renal call carcinoma(4%) and congenital mesoblastoma(2%) Nephroblastoma also known as Wilm’s tumor is a malignant kidney cancer predominantly affecting children

3. Epidemiology Approximately 600 children and adolescents are diagnosed with renal tumors in the US each year and of the about 80% are Wilm’s tumor. The median age for diagnosis is approximately 3 years old with variation based on gender and ethnic group amd symptoms presenting earlier in boys Majority of nephroblastoma cases occur before the age of 5 years and are rare in children over 10 years In 2014 study at Mulago hospital reported nephroblastoma accounting for 12% of pediatric cancers

4. Epid cont. Wilm’s tumor has been linked to various genetic syndromes and birth defects such as WAGR syndrome (genetic disorder characterized with Wilm’s tumor, aniridia, genitourinary anomalies and mental retardation Beckwith-Wiedemann syndrome (genetic disorder characterized by macrosomia, macroglossia, umbilical hernia) Denys-Drash syndrome (Wilm’s tumor, pseudohemaphoditism and glomerulopathy) Children with these genetic syndromes should be screened for WT every 3 months until the age of 8 years

5. Pathophysiology Wilm’s tumor IS described as a mixed tumor that is comprised of three distinct components; epithelial, blastemal and stromal `Wilm's tumor cells developed from a common undifferentiated germ cell. In development, the fetal kidney arises from the ureteric bud( which forms the collecting duct and the ureter) plus the metanephric mesenchyme/blastema (which is responsible for the formation of the stroma and the remaining tubular structures (glomeruli, proximal and distal tubules and the collecting duct)

6. The blastema usually disappears by 36 weeks of gestation however in 1% of infants the blastema components are retained after birth known as nephrogenic rests Nephrogenic rests are a cluster of embryonic kidney cells that persist beyond normal development Germline mutations and other inciting events result in nephrogenic rests that in turn develop into Wilm’s tumor

7. Genetics Wilm’s Tumor 1 gene(WT1) is a tumor suppressor gene. Its mutation is associated with the development of WT. This gene located on chromosome 11p13 and binds to transcription regulatory sequence of DNA where it acts as a transcription factor for WT1 protein WT1 protein is involved in the differentiation and development of the gonads and kidneys specifically. It is involved in the production of ureteric bud branching signals and nephrogenic progenitor cell response to ureteric bud derived nephrogenic signals causing Mesenchymal to Epithelial transition

8. Mutation in the WT1 gene ( impairs its function to regulate other genes e.g. MYC, Cyclin E, EPO that can lead to uncontrolled cell proliferation and hindered differentiation contributing to tumor formation Certain syndromes such as Beckwith-Wiedemann syndromes are associated with genetic and epigenetic alteration in genes located on chromosome 11p15.5 that contain a number of imprinting genes located in this region i.e. ( IGF2, H19 and CDKN1C) In normal cells,IGF2 is expressed by the paternal allele while in WT, uniparental isodisomy where paternal derived chromosome is duplicated leading to loss of imprinting this causes over expression of IGFR2( Insulin Like growth factor 2)

9. The excessive IGF2 activity contributes to unchecked cell division and tumor formation Another pathway involved in WT development is the WNT signaling pathway. This pathway is involved in the activation of CTNNBI gene that encodes for β -catenin protein.15% of patients with Wilm’s tumor cells with WT1 mutation have concurrent mutation with CTNNBBI

10. Pathology WT are mostly solitary lesions but can be multifocal in 12% of cases Majority of WT are unilateral affecting one kidney Bilateral WTs comprises7% total cases and is more common in individuals with genetic predisposition syndromes

11. Gross appearance Uniform pale grey color. They are sharply demarcated and are surrounded by a distinct intrarenal pseudocapsule composed of compressed atrophic renal tissue. Cysts are also commonly encountered Histology Wilm’s tumor is composed of three cell types Blastemal: undifferentiated small blue cells Epithelial: usually seen as abortive glomeruli and tubules Stromal :usually seen as immature spindled cells or can manifest as cartilage, osteoid or fat

12. Depending on presence of different types of cell types, Wilm’s tumor can be termed as triphasic or monophasic Based on histology WT can be separated into two prognostic groups i.e. Favorable histology; there is absence of anaplasia in the tumor Unfavorable histology; presence of an enlarged polyploid nucleus within the tumor. Anaplasia is associated with resistance to chemotherapy

13. Clinical presentation Abdominal mass Symptoms can include; Constipation Abdominal pain and/or distension Hematuria Clinical signs; Hypertension anemia

14. Presentation showing large abdominal mass

15. Differential diagnosis Renal cysts Dysplastic kidneys Renal abscess Neuroblastoma Benign renal tumors egg cystic nephroma, metanephric tumors

16. Diagnosis History and physical examination Thorough history taken including family history of cancer predisposition, congenital anomalies, urogenital defects as well as child’s birth and developmental history to assess for WT associated syndromes Physical examination should include blood pressure measurements given risk of hypertension. Evaluation of dysmorphic features is assessed On physical examination, the typical finding is a palpable, firm, nontender, smooth abdominal mass that is large

17. Diagnosis cont. Imaging Abdominal ultrasound Doppler US; for thorough examination off the renal vasculature an IVC MRI or CT used to better define the anatomy of the tumor and aid in surgical planning WT is consistent with “claw sign” on imaging due to the tumor displacing the normal kidney

18. Diagnosis cont. Laboratory evaluation CBC Blood urea nitrogen and creatinine(to evaluate kidney function) LFT Urinalysis; shows hematuria

19. CHILDRENS ONCOLOGY GROUP STAGING OF PEDIATRIC RENAL TUMORS

20. Treatment Surgical Chemotherapy Radiotherapy

21. Surgical Surgical removal of primary tumor Radical nephrectomy is recommended for unilateral WT Partial nephrectomy is recommended for patients with bilateral WT to spare as much normal renal parenchyma as possible

22. Chemotherapy For stage I and II WT; the primary chemotherapy agents are Vincristine and Dactinomycin these can be given on an outpatient basis and are nor associated with long terms side effects A small subset of patients less than 2 years old with stage I WT weighing <550g does not require chemotherapy at all but can be treated with surgical therapy Patients with stage III or IV WT receive Doxorubicin

23. Chemotherapy cont. Patients with stage IV WT with ling metastases that do not resolve completely after 6 weeks of chemotherapy benefit from addition of Cyclophosphamide and Etoposide into their treatment regimen

24. Special considerations Patients with stage V or bilateral disease are initially given chemotherapy for 6-12 weeks preceding surgery. This done to optimize tumor shrinkage prior to nephron-sparing surgery or partial nephrectomy

25. RADIOTHERAPY Radiotherapy is very effective in treatment of higher WT due to the risk of acute and long term toxicities. Patients with local stage III WT receive either flank or whole abdominal radiation depending on local extent of spread

26. Complications Risk of congestive heart failure at 20 years due to exposure to radiotherapy and Doxorubicin Decline in cardiac ffunction End stage renal disease in survivors of unilateral WT Infertility due to exposure to cyclophosphamide

27. Prognostic factors Histology; tumors with anaplastic histology have a favorable histology compared to aplastic histology Age; increasing patient age is associated with increased risk of recurrence for WT . Some younger children <2 years old with stage I WT and tumors <550g have an outstanding prognosis with surgery alone without adjuvant chemotherapy/radiotherapy Tumor staging; higher stages(I-V) are associated with more extensive disease and poorer outcome when compared to lower stage disease (I and II)

28. THANK YOU FOR LISTENING REFERENCES Rudolph’s pediatrics 23 rd edition Nelson textbook of pediatrics 21 st edition Hutchisons pediatrics