wilms tumour staging and it's management

Wilms tumor

1. WILMS TUMOUR By, DR.ISHRATH ANJUM

2. INTRODUCTION Aka NEPHROBLASTOMA Most common primary Renal Tumour of childhood Peak incidence Between 2-5 years of age 95% tumours occur less than 10 years of age 5-10 % of Wilms tumour are Bilateral (synchronous/metachronous) Age of onset – 10 months earlier than tumours Restricted to one kidney Usually harbour Germ line mutation (Familial)

3. PATHOGENESIS & GENETICS Associated with 3 important syndromes WAGR SYNDROME DENYS- DRASH SYNDROME BECKWITH WEIDMANN SYNDROME

4. WAGR SYNDROME Wilms tumour, aniridia , genital anomalies and mental retardation Lifetime risk of development of wilms tumor – 33% Associated with Germline deletion on ch 11p13 Deleted chromosome segments contains WT1 gene and Aniridia genes i.e PAX – 8 gene WT1 encodes for a Transcription factor important for normal Renal and Gonadal development 1 st Hit – Germline mutation in WT1 2 nd Hit – Frame shift mutation or Nonsense mutation

5. DENYS – DRASH SYNDROME Very high risk of development of wilms tumour – 90% Characterised by – Gonadal dysgenesis ( Male pseudohermaphrotidism) Nephropathy ( Diffuse mesangial sclerosis) Leading to renal failure In this syndrome – Dominant Negative missense mutation in one allele in WT1 – which interferes with working of other normal allele Only single allele mutation – Causes Genitourinary Anomalies not wilms tumour For wilms tumour it requires Bi- allelic inactivated of WT1 gene Increased risk of development of GCT - Gonadoblastoma

6. BECKWITH-WIEDEMANN SYNDROME Organomegaly Macroglossia Hemihypertrophy Omphalocoele Adrenal Cytoegaly Predisposition to develop wilms tumour CHR region involved – 11p15.5 ( WT2 Locus) – distal to WT1 locus Basic genetic abnormality associated with genomic imprinting

7. Due to defective imprinting – Increased expression of IGF2 gene Located on 11p15.5 Region Which leads to overexpression of IGF-2 protein – leads to organomegaly and overgrowth and increased risk for wilms tumour

8. 90% cases of Wilms tumour – Sporadic in nature – molecular abnormality not studied extensively Only 10% patients with sporadic wilms tumour have Mutation in WT1 gene Gain of function mutation in beta- catenin – 10% sporadic tumours Other mutations involve genes encoding proteins , involved in micro – RNA processing ( DROSHA, DGCR8, DICER1) – accounts for 15-20% of wilms tumour with Blastemal Histology Mutations in RNA processing genes leads to decreased levels of mature MRNA

9. These genes are normally involved in Mesenchymal to Epithelial Transformation during renal development – if this is effected it leads to Blastemal rests Tumours with TP- 53 mutation are associated with Poor prognosis

10. MORPHOLOGY GROSS – Large , solitary , well circumcised mass (Pseudocapsule) On cut section – Soft , homogenous , tan to grey Occasional occurrence of haemorrhages, cyst formation and necrosis

11. MACROSCOPIC Large masses more than 5cms in diameter cut surface- solid /soft / cystic/ greyish/ pinkish Foci of haemorrhage and necrosis are present

12. MICROSCOPIC EXAMINATION Triphasic combination – Blastemal cells – sheets of small blue cells Epithelial Differentiation – Form of small abortive tubules or glomeruli Stromal cells – usually fibroblastic/myxoid / skeletal muscle differentiation Heterogenous differentiation – squamous /mucinous Epithelium/ smooth muscle/adipose tissue/ Cartilage/osteoid/Neurogenic tissue 5% tumours – Anaplasia – Defined as presence of cells with large hyperchromatic , pleomorphic nuclei with abnormal mitosis. Co related with TP- 53 Worst prognosis

13. Concept of Nephrogenic Rests Precursor lesion of wilms tumour Present adjacent to Renal parenchyma in 25- 40% of Unilateral wilms tumour and 100% in bilateral wilms tumour Same genetic abnormality as adjacent wilms tumour Importance lies in documenting the presence of nephrogenic rests in resected specimens as these patients have increased risk of developing wilms tumour in contralateral kidney

14. CLINICAL FEATURES Wilms tumour – 90% sporadic and 10% familial Familial tumours – B/L multicentric Asymptomatic abdominal mass (m/c) Abdominal pain Hypertension Fever Hematuria (rare) Intestinal obstruction Pulmonary mets at presentation

15. PROGNOSIS Anaplasia In microscopic examination- worse prognosis Presence of TP – 53 mutation and resistance to chemotherapy – associated with Anaplasia and worse prognosis Loss of heterozygosmy at CHR 1p and 16q gain of Chr 1q in tumour cells Increased survival rate in wilms tumour patients due to better treatment modalities but patients develop secondary primary tumours like bone and Soft tissues sarcomas, Leukemias and lymphomas and lymphomas, Breast cancers as a consequence of Radiation therapy used for wilms tumour