1. Chrissy Zoon December 11th 2014 Pediatric Surgery
Interesting Case
Chrissy Zoon
December 11th 2014
Pediatric Surgery

2. PMH: hemihypertrophy, asthma, eczema FH: none
6 yo AAF
PMH: hemihypertrophy, asthma, eczema
FH: none
SH: lives at home with mom, siblings
US/MRI at 3 mo left kidney mass – nephroblastomatosis
Plan for Q3mo US/MRIs alternating but lost to follow up
Presented 8/2014 to OSH with right abdominal pain, nausea, vomiting
AF VSS
On physical exam was felt to have abdominal mass
CT scan performed
Beckwith-wiedemann syndrome
Macroglossia
Macrosomia
Midline abdominal wall defects
Ear creases/pits
Neonatal hypoglycemia
Nevus flammeus
Midface hypoplasia
Hemihypertrophy
Enlarged kidneys
Cardiac anomalies
Musculoskeletal abnormalities
Hearing loss

3. 7/31/14

4. 7/31/14

5. 7/31/14

6. 7/31/14

7. 7/31/14

8. Concern for bilateral Wilms tumors Started on neoadjuvant protocol
COG protocol for the treatment of bilateral Wilms tumor, on Aug 2, 2014.

9. After ~ 1 month chemotherapy
9/9/14

10. 9/9/14

11. Per protocol requirements
After ~ 1.5 months chemotherapy
Open Biopsy right
Wilms tumor with favorable histologic characteristics regarding effect of treatment
FNA biopsy left
Negative for malignancy
Surgical Pathology Microscopic Interpretation
Submitted as "?Wilms tumor right kidney" (specimen #1); wedge biopsy:
- Benign renal parenchyma with no significant histopathologic abnormalities.
Submitted as "normal kidney, right lower pole" (specimen #2); wedge biopsy:
Submitted as "tumor, upper pole, right kidney" (specimen #3); wedge biopsy:
Submitted as "is this tumor ?" (specimen #4); wedge biopsy:
- Effective post therapy changes on Wilms Tumor consisting only of residual scattered well-differentiated tubules and bland stroma with rare rhabdomyomatous cells, see Comment.
- Other treatment related changes including fibrosis and foamy and hemosiderin laden macrophages are additionally present.
Paracaval node (specimen #5); excision:
- One benign lymph node (0/1).
Paraaortic node (specimen #6); excision:
- Two benign lymph nodes (0/2).
Submitted as "suspected tumor, far upper pole, right kidney" (specimen #7); wedge biopsy:
- No viable tumor seen.
- Organizing hematoma.
Dictated By: ASHRAF MD, NABIL
Verified By: JAKOWSKI MD, JOSEPH D
(Electronically reviewed and signed)
: NA 09/24/14
Surgical Pathology Special Studies
Immunohistochemical stains for CD57, MYOD-1, desmin, WT1, EMA, S100, and vimentin are performed on block 4A. The stroma cells are positive for WT1 and negative for S100. Desmin is positive rhabdomyomatous cells but negative for MYOD-1. The tubules are strongly positive with EMA. CD57 is negative. Vimentin is diffusely positive. Control slides stain appropriately.
The immunoperoxidase or in situ hybridization tests were developed and their performance characteristics determined by the Special Studies Laboratory of the Department of Pathology at the Medical College of Virginia Hospitals of Virginia Commonwealth University. They have not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. These tests are used for clinical purposes and should not be regarded as investigational or for research.
Surgical Pathology Comment
There are effective post treatment changes in this tumor and this precludes any further classification of the histology. No blastema is seen.
The intraoperative consultations for specimens #1, #3, and #4 are corroborated.
SP Teaching Physician Statement
The attending pathologist whose name appears on this report has personally reviewed the diagnostic slides and where appropriate has edited the gross and/or microscopic portion of the report in rendering the interpretation.

12. After ~ 3 months chemotherapy
11/12/14

14. Definitive surgery Right radical nephrectomy
Nephrectomy, lymph node sampling (hilar, pericaval, periaortic), ureter
Intraoperative US of left kidney (peds urology assisting)
No gross or US abnormalities seen
Pathology
Wilms tumor with prominent treatment effects
0/7 nodes positive for metastatic disease
Stage III – tumor(changes) present at margins and h/o biopsy before definitive surgery
Surgical Pathology Microscopic Interpretation
Right kidney (Specimen #1), nephrectomy:
- Nephroblastoma (Wilms tumor, 4.5cm) with prominent treatment effect.
- Please see Comment and Synoptic Report.
"Right hilar lymph node" (Specimen #2); lymphadenectomy:
- No metastatic nephroblastoma identified in two lymph nodes (0/2).
"Periaortic lymph node" (Specimen #3); lymphadenectomy:
- No metastatic nephroblastoma identified in three lymph node fragments (0/3).
"Paracaval lymph node" (Specimen #4); lymphadenectomy:
- No metastatic nephroblastoma identified in one lymph node (0/1).
"portal lymph node" (Specimen #5); lymphadenectomy:
Dictated By: SMITH MD, STEVEN C
Verified By: SMITH MD, STEVEN C
(Electronically reviewed and signed)
: SCS 12/02/14
Surgical Pathology Comment
Case held for consensus and review of multiple deeper sections taken from multiple tissue blocks sampling the renal hilar resection margin.
Review of the morphology of this case demonstrates a broad area of involvement by microscopic foci of treated nephroblastoma involving the renal sinus soft tissue, including extending multifocally to the inked cauterized renal hilar resection margin. The pattern seen is of prominent hyalinization of the stroma, with patchy areas of "maturing tubules" in this scarred background. Scattered foci of stromal component rhabdomyoblastic differentiation are seen, consistent with the treated milieu. Numerous patches of "atrophic pattern" blastema are identified. There are foci where this component in particular extends to the margin. Importantly, metastasis, vascular invasion, and anaplasia are not identified in this extensively sampled tumor.
Case discussed with Dr. Timothy Harris on 12/2/2014.
Case also reviewed by Dr. Ema Dragoescu, who agrees with the above diagnostic interpretation.
Surgical Pathology Synoptic Report
SPECIMEN:
Procedure: Not specified
Specimen Size:
Kidney dimension: cm
Kidney dimension: cm
Kidney dimension: cm
Weight: 80 g
Specimen Laterality: Right
Tumor Site(s): Other: Microscopic foci of treated residual nephroblastcoma predominantly in the soft tissue of the renal sinus.
Tumor Focality: Cannot be assessed (Multiple microscopic residual foci.)
TUMOR:
Histologic Type: Wilms tumor, favorable histology
EXTENT:
Tumor Size: Greatest dimension: cm (Multiple microscopic foci of residual/treated nephroblastoma in the renal sinus soft tissue.)
Macroscopic Extent of Tumor:
Gerota's Fascia: Cannot be assessed
Renal Vein: Renal vein invasion not identified
Renal Sinus: Tumor extensively involves renal sinus soft tissue
Adjacent Organ Involvement: Cannot be assessed
MARGINS:
Margin(s) involved by tumor: Other: Renal sinus soft tissue resection margin multifocally positive for residual/treated nephroblastoma with atrophic post-treatment pattern.
ACCESSORY FINDINGS:
Nephrogenic Rests: Nephrogenic rests not identified
LYMPH NODES:
Lymph Nodes: Regional lymph node metastasis not identified
Number of Lymph Nodes Examined: 7
Number of Lymph Nodes Involved: 0
METASTASIS: Not applicable
STAGE:
Children's Oncology Group Staging System for pediatric renal tumors other than renal cell carcinoma (select all that apply under the appropriate stage):
Stage III: Residual tumor:
Tumor present at margin(s) of resection
History of renal tumor biopsy before definitive surgery

15. Epidemiology
2nd most common pediatric solid abdominal tumor and most common renal malignancy
Incidence is 8 cases per million in children <15yo
500 new cases annually
6% all childhood malignant tumors
Most present between ages 1-5
66% before 5, 95% before 10
Survival has increased dramatically over the years
1930s: 30%
2010s: >90%
Multidisciplinary approach

16. Clinical Presentation
No tumor-specific symptoms
1/3rd with anorexia, malaise, vomiting
HTN in 25%, hematuria in ~30%
Most commonly found as painless abdominal mass
Exam:
Smooth, palpable large mass
Associated findings if
syndrome related

17. Associated Congenital Abnormalities
WAGR Syndrome
Wilms Tumor (30%)
Aniridia
Genitourinary malformations
Mental Retardation
Denys-Drash Syndrome
Progressive renal disease: mesangial sclerosisproteinurianephrotic syndromeESRD
Male pseudohermaphrotidism
Wilms tumor (90%)
Beckwith-Wiedemann Syndrome
Macroglossia, hemihypertorphy, visceromegaly, omphalocele
Wilms Tumor (5%)

18. Pathology Majority of Wilms tumors are solitary.
5-7% bilateral kidney involvement.
10% multifocal loci within a kidney.
Favorable histo contains 3 cell types
Blastemal (undifferentiated cells)
Stromal (immature spindle cells)
Epithelial cells (glomeruli and tubules)
Unfavorable histo contains
anaplastic cells

19. Differential Dx Neuroblastoma Clear cell sarcoma of kidney
Rhabdoid tumor of kidney
Congenital mesoblastic sarcoma of kidney
Renal medullary carcinoma
Wilms v. Neuroblastoma: contrast enhanced CT
Wilms v. other renal cell tumors: histology
Differentiate Wilm’s from Neuroblastoma with contrast enhanced CT
Differentiate Wilm’s from other renal cell tumors with histology

20. Prognostic factors Tumor histology (increased anaplasia) Tumor stage
Molecular and genetic markers
The presence of anaplasia is the most important predictor of adverse outcome in children with Wilms tumor [2,3]. Anaplasia is defined as the presence of multipolar polypoid mitotic figures and marked nuclear enlargement with hyperchromasia, and it can be further classified as either focal (defined as tumors with anaplasia confined to one or a few discrete loci within the primary tumor, with no anaplasia or marked nuclear atypia elsewhere) or diffuse [2].
Staging criteria for Wilms tumor are based on the anatomic extent of the tumor without consideration for genetic, histologic, or biologic markers [8]. Higher stages (stages III through V) are associated with more extensive disease and a poorer outcome when compared with patients with lower stage disease (I and II) [4,9-12]. (See 'Outcome' below.)

21. NWTSG vs SIOP
Two major approaches and therefore staging systems are used
National Wilms’ Tumor Study Group (NWTSG)
Surgery first approach
Staging is based off of surgical findings
Postoperative chemoradiation
International Society of Pediatric Oncology (SIOP)
“Societe Internationale D'oncologie Pediatrique”
Staging after chemotherapy
Ultimately, staging based on tumor extent

22. Combined Efforts Only 500 cases diagnosed annually
Single or small groups of institutions do not provide enough patients to study
Investigators and institutions agreed to combine efforts
Goal was to get answers in a short period of time
Improve survival
Study long-term outcomes
Epidemiology and biology of the tumors
Multimodal approach with varying physicians

23. National Wilms’ Tumor Study Group
North American group, started in 1969
5 NWTSG trials to improve outcomes in Wilms’ patients
First four randomized, whereas last was used more for biologic prognostic factors
More than 400 children entered in these studies annually (70% of all Wilms’ cases in US)
In 2001, NWTS merged with other pediatric oncology groups to create Children’s Oncology Group (COG)
Enrollment in NWTSG ended in 2002, now COG

24. NWTS #1: To determine effect of surgical technique #2: Prognosis
#3: Reduce treatment for low-risk patients and improve chemotherapy regimens
#4: Evaluate toxicity, efficacy, cost
#5: Identify biologic prognostic factors

25. NWTS NWTS #1 Conclusions: NWTS #2 Conclusions:
Radiation not to be given in low risk Stage I diagnosis
Treatment combining two drugs more effective
Identified favorable/unfavorable histologic classifications
NWTS #2 Conclusions:
Group I can be treated for 6 mo (instead of 15)
Adriamycin for stages II and III
Smaller babies can be treated with 50% reduction in CTx doses
Histology coincided with clinical outcome (favorable did better)
Updated staging- lymph nodes now increased to Stage III
Each study identified objectives: overall objective to improve survival. New study built on results of previous study.

26. NWTS #3 Conclusions: NWTS #4 Conclusions:
More focused histology/pathology, especially regarding definitions of favorable vs unfavorable (diffuse, focal anaplasia, clear cell, rhabdoid)
Children with Stage I favorable or focal anaplasia may be treated the same and do not need XRT to flank
Children with Stage III favorable best treated with 3 drugs (actinomycin D, vincristine, adriamycin) and XRT
Children with II-IV anaplastic are best treated with 4 drugs (above plus cyclophosphamide)
NWTS #4 Conclusions:
New treatment method including “pulse intensive” doses with same results and decreased toxicities
Cost therapy decreased with pulse regimen

27. NWTS #5 Conclusions: Present Day:
Tumor genetics: loss for either 1p or 16q associated with adverse outcome in favorable histology Wilms compared to those without the loss of heterozygosity
Loss of 1p associated for worse outcome for Stages I/II but not III/IV
Surgery alone may be adequate for some kids: younger than 2 at diagnosis with stage I favorable histology that way less that 550g
Those with pulmonary mets detected by CT (not CXR) may benefit from doxorubicin in addition to vincristie/dactinomycin instead of whole lung irradiation
Present Day:
Late effects study
Includes only those enrolled in one of the original NWTS trials
Determines risks and mortality rates
Contributions to genetic epidemiology

28. SIOP International Society of Pediatric Oncology
Strategy of giving preoperative therapy reduces risk of tumor rupture during surgery reduce likelihood of local and distant recurrence
Succession of studies beginning in 1971 to determine optimal preoperative therapy regimen
UKCCSG completed randomized comparison of pre/post operative therapies in UKW3
Showed more favorable tumor stage distribution and signficant reduction in overall burden of therapy and surgical complications in prenephrectomy chemotherapy
Metzger ML, Dome JS. Current therapy for Wilms’ tumor. Oncologist 2005; 10:815-26

29. Powis, Mark “Surgical complications after immediate nephrectomy versus preoperative chemotherapy in non-metastatic Wilms’ tumour: Findings from the United Kingdom Children’s Cancer Study Group UKW3 Trial. J Ped Surg (2013) 48,

30. Staging Based exclusively on anatomic extent of the tumor
Staging is based on 1 of 2 systems:
NWTSG upfront surgery
SIOP upfront chemotherapy
Both are valuable at predicting outcomes, but the difference in timing of nephrectomy limits stage-wise comparisons

31. .

32. NWTSG vs SIOP NWTSG Strengths: Primary strength of SIOP:
Up-front resection allows accurate assessment of histologic diagnosis and tumor extent
Most patients on SIOP Wilms’ tumor studies do NOT undergo biopsy before therapy
On SIOP 93-01, 5% of lesions treated with chemotherapy were ultimately NOT Wilms’ and 1.8% benign
SIOP may obscure prognostic clues (interfering with LN involvement, etc)
Primary strength of SIOP:
Preoperative chemo reduces tumor volume, thereby decreasing risk of spillage and “downstaging” the tumor
Because of this, fewer XRT in SIOP-9 than NWTS-5
Additionally, response to neoadjuvant may provide prognostic indicator
Anaplastic features do not regress with neoadjuvant tx

33. Surgical Resection Accurately assess tumor spread Avoid tumor spillage
Lymph node sampling
Avoid tumor spillage
Increases risk of local abdominal relapse and subsequent poor outcome
Complications (from NWTS 4)
Bowel obstruction (5.1%)
Extensive vascular injury (1.4%)
Infection (1.9%)
Risk Factors
Tumor extension into IVC, atrium or both
Tumor >10cm

34. Surgery The main responsibility of the surgeon is to:
Remove the tumor completely, without spillage
Accurately assess the extent to which the tumor has spread
Pay particular attention to adequately assessing the lymph node involvement

35. Role of Laparoscopy
Minimally invasive surgery in pediatric cancers is gaining popularity
Biopsies, diagnosis of tumor extent, second-look, complete excision
Laparoscopic Unilateral Nephrectomy or Partial Nephrectomy described for treatment of Wilms’tumor.
Case reports, particularly performed in Europe where children get neoadjuvant chemotherapy.
Currently not endorsed in US.

36. Who gets chemotherapy first?
Solitary kidney
Tumor in a horseshoe kidney
Bilateral Wilms’ tumors
Tumors with IVC and intra-atrial involvement
Patients with massive tumors considered to be unresectable by operating surgeon
Respiratory distress from extensive pulmonary metastasis
Size of tumor alone is NOT an indication for preop chemoradiation therapy
Shamberger RC. Pediatric renal tumors. Semin Surg Oncol 1999; 16:

37. Resources
D'angio GJ, Evans A, Breslow N, et al. The treatment of Wilms' tumor: results of the Second National Wilms' Tumor Study. Cancer. 1981;47(9):
Green DM, Breslow NE, Beckwith JB, et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol. 1998;16(12):
Grovas A, Fremgen A, Rauck A, et al. The National Cancer Data Base report on patterns of childhood cancers in the United States. Cancer. 1997;80(12):
Kalapurakal JA, Dome JS, Perlman EJ, et al. Management of Wilms' tumour: current practice and future goals. Lancet Oncol. 2004;5(1):37-46.
Perlman EJ. Pediatric renal tumors: practical updates for the pathologist. Pediatr Dev Pathol. 2005;8(3):
Zuppan CW, Beckwith JB, Luckey DW. Anaplasia in unilateral Wilms' tumor: a report from the National Wilms' Tumor Study Pathology Center. Hum Pathol. 1988;19(10):
Shamberger RC. Pediatric renal tumors. Semin Surg Oncol 1999; 16:
Wilimas JA, Magill L, Parham DM et al. Is renal salvage feasible in unilateral Wilms’ tumor? Proposed computed tomographic criteria and their relation to surgicopathologic functions. Am J Pediatr Hematol Oncol 1990; 12:
Ladd WE. Embyroma of the kidney (Wilms’ tumor). Ann Surg 1938; 108:
Shamberger RC, Guthrie KA, Rictchey ML et al. Surgery-related factors and local recurrence of Wilms’ tumor in National Wilms’ Tumor Study 4. Ann Surg 1999; 220:
Metzger ML, Dome JS. Current therapy for Wilms’ tumor. Oncologist 2005; 10:815-26