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

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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.
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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).

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Introduction to Wilms tumorand high risk renal
tumors

• Robert E. Ruiz, M.D., Ph.D.
• University of Michigan
• Ann Arbor, MI

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Outline

• General characteristics of Wilms tumor
• Anaplasia in Wilms tumor
• Childrens Oncology Group
• Brief overview of other high risk tumors
• Practical Considerations
• Processing pediatric renal tumors
• Signing out pediatric renal tumors

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1. General characteristics of Wilms tumor
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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
  gtWhitesgtAsians)
• Accounts for 80 of primary renal tumors in
  children

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

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External surface
Cross-section of mass
Typical Wilms tumor gross appearance
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Nephroblastoma (Wilms tumor)Microscopic features

• Histologically quite diverse
• Typical pattern is triphasic pattern
• Blastema (Metanephric)
• Epithelium
• Stroma

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Nephroblastoma (Wilms tumor)Microscopic features
(contd.)

• 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

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What does term blastema mean?
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5th week
Blastema resembles the metanephric mesoderm
from Langmans Medical Embryology
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Kidney from 17 week fetus
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Cortical neogenic zone
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Wilms tumor Blastema
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Wilms tumor Epithelium - tubules
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Wilms tumor Epithelium - glomeruli
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Primitive mesenchyme surrounding collecting system
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Triphasic Wilms tumor
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2. Anaplasia in Wilms tumor
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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

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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)

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Anaplasia
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Anaplasia
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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

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from Faria P, et al. Am J Surg Pathol 20
909-920, 1996
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from Faria P, et al. Am J Surg Pathol 20
909-920, 1996
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Case 12 Markedly enlarged, hyperchromatic nuclei
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Case 12 Multipolar mitotic figures
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How does this impact treatment?
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3. Children's Oncology Group
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CureSearch

• Two components
• Childrens 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

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COG

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

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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

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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

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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

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AREN0321 Therapeutic approaches to high risk
pediatric renal tumors
from Perlman EJ, Ped Dev Pathol 8 320-338, 2005
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4. Non-Wilms high risk renal tumors
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Clear cell sarcoma of kidney

• Bone metastasizing renal tumor of childhood
• Comprises 4 of primary pediatric renal tumors
• Predilection for metastasis to bone and numerous
  other sites, including LN, brain, lungs, liver,
  skeletal muscle, soft tissues

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from AFIP Atlas of Tumor Pathology, 3rd Series,
Fascicle 11
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Clear cell sarcoma of kidneyGross features

• Solitary, unilateral masses
• Size 126 - 3000 gm median 520 gm
• Usually arise from medullary or central regions
  of kidney
• Homogeneous cut surface, often mucoid
• Mass often irregularly shaped, cystic

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Clear cell sarcoma
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Clear cell sarcoma of kidneyMicroscopic features

• Homogeneous, pale blue appearance
• Many histologic patterns
• Most have classic pattern monomorphous,
  forming cords or nests (6 - 10 cells wide) of
  cells with clear cytoplasm, uniform, finely
  granular to empty nuclei, and inconspicuous
  nucleoli, separated by thin vascular septa, often
  with infiltrative margins and entrapped renal
  elements

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Low magnification
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Cystic areas
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Rhabdoid tumor

• Comprises 2 of primary pediatric renal tumors
• Association with separate intracranial primitive
  neuroepithelial tumors has been seen in 15 of
  cases
• Very aggressive neoplasm with early dissemination
  and wide metastasis, hematogenous and lymphatic

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from AFIP Atlas of Tumor Pathology, 3rd Series,
Fascicle 11
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Rhabdoid tumorGross features

• Generally unicentric, unilateral, but multiple
  nodules representing 2 implants possible
• Size lt 500 gm
• Smaller tumors arise in medulla
• Pale, soft, bulging cut surface
• Relatively well demarcated from kideny, but
  generally no capsule

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Rhabdoid tumor
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Rhabdoid tumorMicroscopic features

• Sheets of monomorphous, large, loosely cohesive
  cells with large, vesicular nuclei, prominent
  nucleoli, abundant eosinophilic cytoplasm,
  distinct cell borders
• Characteristic cytoplasmic inclusions not present
  in all cases, tend to be clustered rather than
  diffuse

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Rhabdoid tumor
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Lymphovascular invasion common, unencapsulated
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Rhabdoid morphology
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Rhabdoid tumor

• Characteristic feature is mutation or deletion of
  hSNF1/INI1 gene (chromosome 22q11.2, 80)
• Immunohistochemistry gives variable results, but
  can be helpful
• INI-1 - negative
• Vimentin, cytokeratins - positive
• EMA - usually positive
• Desmin, actin - sometimes positive
• Electron microscopy prominent aggregates of
  filaments form tightly whorled structures next to
  nucleus

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Renal epithelial tumors

• Overall, more than 5 of pediatric renal tumors
• Two predominant groups
• Clear cell carcinomas, in particular the
  translocation associated carcinomas TFE3 gene
  at Xp11, PRCC gene on chromosome 1
• Papillary carcinomas same genetic features as
  in adults (gains of chromosomes 7, 17), and
  cytokeratin 7 positivity by IHC

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5. Practical considerations

• Processing pediatric renal tumors
• Signing out pediatric renal tumors

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Renal tumor processing

• Initial processing of fresh specimen should
  emphasize obtaining tissue for special studies.
• Snap frozen tumor and normal kidney (for
  determination of LOH for 1p or 16q - this is for
  FH Wilms protocols)
• Cytogenetics (if untreated tumor should cancel
  if signed out as Wilms)

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• Fresh specimen
• Always weigh the specimen
• Always measure overall dimensions and tumor
  size
• Always photograph uncut specimen, describe
  any defects in capsule
• Ink surface and bivalve
• Always photograph cut surface
• If thick, add additional cuts parallel to
  bivalve, so slices no more than 1 cm thick
• Put gauze or paper towel between all slices
  to fix
• For renal PTP, need to take fresh and snap
  freeze
• Two samples of tumor
• Two samples of uninvolved kidney

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Samples for cytogenetics and snap freezing, from
either a resection specimen or a reasonably
large biopsy (greater than 1 cm3 ), should be
about the size of a standard pencil eraser.
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Sectioning the pediatric renal tumor

• Take standard ureteral and vascular margins. Look
  for tumor thrombus in the renal vein.
• Use photographs or diagrams of the tumor to map
  sections! This is important for the distinction
  between focal and diffuse anaplasia.
• Fix the tumor in abundant formalin. Wilms tumors
  are often very friable, and optimal histologic
  evaluation depends upon excellent fixation.

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Sectioning the pediatric renal tumor

• Sections for histologic review must provide
  information about morphology, anaplasia, and
  staging
• Sample the nephrectomy resection margins
  (superior, inferior, medial, lateral, anterior,
  and posterior). Describe sections in gross
  description refer to map inadequate if map is
  lost
• Extensively sample the renal sinus (area
  immediately around the pelvis, including soft
  tissue and vessels). Very important to consider
  extensions of sinus into the kidney.
• Sample interface of intrarenal tumor capsule,
  extrarenal tumor capsule, renal capsule.

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Sectioning the pediatric renal tumor (contd)

• Additional sections should emphasize the
  periphery of the mass, as tumor is most likely to
  be viable there, and information about the
  tumor/kidney interface (e.g., well-circumscribed
  vs. infiltrative) and the possibility of
  nephrogenic rests can be obtained.
• Approximately 1 cassette per cm of tumor greatest
  dimension should be submitted.
• Any hilar lymph nodes should be sampled.
• Uninvolved kidney should also be sampled (1
  cassette).

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• Always sample
• Ureteral and vascular margins
• Nephrectomy resection margins
• Area of renal sinus
• Interface of external tumor capsule, internal
  tumor capsule, renal capsule (triangular section
  in diagram)
• 5. Periphery of mass
• 6. Normal kidney

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Signing out pediatric renal tumors

• Always need to include
• Type of tumor
• Weight of nephrectomy specimen
• Intactness of capsule grossly
• Greatest dimension of tumor
• Favorable vs. unfavorable histology
• Focal vs. diffuse anaplasia (if applicable)
• Margin status
• Local pathologic stage, with details of
  determining features

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Signing out pedi
Signing out pediatric renal tumors

• Stage I Tumor is confined to the kidney and
  completely resected capsule intact, no previous
  biopsy, renal sinus not involved
• Stage II Tumor extends beyond kidney, but
  completely resected penetrates renal capsule,
  extensively invades renal sinus soft tissue,
  lymphovascular invasion outside parenchyma

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Signing out pedi
Signing out pediatric renal tumors

• Stage III Residual tumor is present, limited to
  abdomen peritoneal implants, resection margins
  positive, previous biopsy, tumor rupture
  abdominal or pelvic lymph nodes positive
• Stage IV Metastatic tumor present lymph nodes
  positive outside abdomen and pelvis, distant
  metastases
• Stage V Bilateral tumor at diagnosis also need
  to stage each side individually

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Summary

• Reviewed the general pathologic features of Wilms
  tumor
• Discussed the concepts of favorable vs.
  unfavorable histology, and focal vs. diffuse
  anaplasia
• Introduced the COG and the current high risk
  pediatric renal tumor protocol
• Briefly covered non-Wilms high risk renal tumors
• Considered practical aspects of renal tumor
  processing and signout which will contribute to
  greater understanding and more effective
  treatment of these tumors

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