Case 12: Diagnosis

1. The patient is a 3 year old female who presented to her primary care practitioner for a well child examination and was found to have a palpable left abdominal mass. She was referred to the University of Michigan for consultation with Pediatric Hematology-Oncology. Abdominal ultrasound and follow up CT showed an approximately 7 cm left renal mass in the lower pole of the kidney. A smaller periaortic mass was also noted. Laboratory studies showed normal uric acid, alpha fetoprotein, beta HCG, CEA, and urinary catecholamines. Her LDH was slightly elevated. She subsequently underwent a left radical nephrectomy and periaortic lymph node dissection. The virtual slide is from the nephrectomy specimen.

12. Case 12: Diagnosis Left renal mass, nephrectomy (163 gm): • Nephroblastoma (Wilms tumor), 6.7 cm in greatest dimension, with diffuse anaplasia. • Tumor involves renal sinus vessels. • Tumor penetrates the renal capsule, and is focally present at the inked surgical margin (local pathologic stage 3).

13. Introduction to Wilms tumorand high risk renal tumors Robert E. Ruiz, M.D., Ph.D. University of Michigan Ann Arbor, MI

14. Outline • General characteristics of Wilms tumor • Anaplasia in Wilms tumor • Children’s Oncology Group • Brief overview of other high risk tumors • Practical Considerations • Processing pediatric renal tumors • Signing out pediatric renal tumors

15. 1. General characteristics of Wilms tumor

16. Nephroblastoma (Wilms tumor) • One of the most common malignant solid tumors of childhood (extracranial), accounting for about 8% of pediatric malignancies • Approximately 1/10,000 children (Blacks >Whites>Asians) • Accounts for 80% of primary renal tumors in children

18. from AFIP Atlas of Tumor Pathology, 3rd Series, Fascicle 11

19. Nephroblastoma (Wilms tumor)Gross features • Usually solitary, rounded masses • Multicentric 12 - 15% • Bilateral 5 - 6% • Size: 60 - 6350 gm; median 550 gm • Pale tan or gray, pseudocapsule, bulging cut surface, generally soft • Lobulation, cysts, hemorrhage, necrosis possible

20. External surface Cross-section of mass Typical Wilms tumor gross appearance

21. Nephroblastoma (Wilms tumor)Microscopic features • Histologically quite diverse • Typical pattern is triphasic pattern: • Blastema (Metanephric) • Epithelium • Stroma

22. Nephroblastoma (Wilms tumor)Microscopic features (cont’d.) • Triphasic is classic pattern, but monophasic or biphasic pattern also possible • If one component comprises greater than 2/3 of tumor, designate accordingly • Mixed (no component predominates) - 41% • Blastema-predominant - 39% • Epithelium-predominant - 18% • Stroma-predominant - 1.4%

23. What does term “blastema” mean?

24. 5th week Blastema resembles the metanephric mesoderm from Langman’s Medical Embryology

25. Kidney from 17 week fetus

26. Cortical neogenic zone

27. Wilms tumor Blastema

28. Wilms tumor Epithelium - tubules

29. Wilms tumor Epithelium - glomeruli

30. Primitive mesenchyme surrounding collecting system

31. Triphasic Wilms tumor

32. 2. Anaplasia in Wilms tumor

33. Favorable vs. unfavorable histology • Terminology reflects interest in histologic classification that provides prognostic information • Usually used in reference to Wilms tumor and neuroblastoma • Conclusion is based on different criteria in these two tumors • In Wilms tumor, distinction between favorable and unfavorable histology is based upon anaplasia

34. Anaplasia • Two histologic features (seen with 10x objective) • Markedly enlarged, hyperchromatic nuclei (at least 3-fold increase in nuclear diameter) • Multipolar mitotic figures (correlate with polyploid chromosomal content)

35. Anaplasia

36. Anaplasia

37. Anaplasia • Most important prognostic histologic feature in Wilms tumor • Appears to be correlated with response or resistance to therapy • When widely distributed (diffuse) is associated with worse prognosis than when localized (focal) • Anaplastic Wilms is a high risk renal tumor

38. from Faria P, et al. Am J Surg Pathol 20: 909-920, 1996

39. from Faria P, et al. Am J Surg Pathol 20: 909-920, 1996

40. Case 12: Markedly enlarged, hyperchromatic nuclei

41. Case 12: Multipolar mitotic figures

42. How does this impact treatment?

43. 3. Children's Oncology Group

44. CureSearch • Two components • Children’s Oncology Group (COG) • Supported by National Cancer Institute to conduct cooperative research and clinical trials for children with cancer • Develops and coordinates clinical trials at more than 240 member institutions in U.S. and Canada, and sites in Europe and Australia • National Childhood Cancer Foundation • Raises private funds for childhood cancer research carried out by the COG

45. COG • Formed in 2000 by merger of four pre-existing cooperative research and clinical trial organizations • Children’s Cancer Group (CCG) • Intergroup Rhabdomyosarcoma Study Group (IRSG) • National Wilms Tumor Study Groups (NWTSG) • Pediatric Oncology Group (POG)

46. COG Clinical Trials • Currently over 150 ongoing trials, with over 40,000 patients receiving treatment on a COG protocol • All data about diagnosis, treatment, and results goes to Group Operations Center for analysis • Tissue samples and cell lines may be collected and stored for use in research • Laboratories important for diagnosis, treatment and research are also maintained • Research findings are shared with entire group and used to develop next steps and protocols

47. Kidney Tumors Committee • Descendant of the NWTSG, founded in 1969 • One of the four organizations that merged to form COG in 2000 • About 70% of children with Wilms tumors have been treated on these protocols in past 20 years • Cure rate has improved from 40% to 85-90%, while decreasing the amount of chemotherapy and radiation therapy • Other renal tumors are also studied, and can require different treatment than Wilms • Biological and genetic insights are also being obtained

48. Current emphases • Low risk patients: Surgery only? • Standard (intermediate) risk patients: Continue to study, find ways to identify 10-15% who recur • High risk patients: Less than 75% cure rate with some tumors, including resistant forms of Wilms (anaplastic Wilms); need to develop improved treatments

49. AREN0321: Therapeutic approaches to high risk pediatric renal tumors from Perlman EJ, Ped Dev Pathol 8: 320-338, 2005

50. 4. Non-Wilms high risk renal tumors