Wilms Tumor:

useful guidelines for

pathologists
October 2008
 Wilms’ Tumor (nephroblastoma)

• Pediatric renal tumors comprise 6.3% of

all childhood cancers (<15 years)
• Most common primary malignant renal
tumor of childhood.
• 500 cases/year nationally
• Highest incidence the first 2 years of life
• 7% of children with WT have bilateral
involvement
• Rare cases in extrarenal sites.
• Beckwith-Wiedemann, WAGR, Denys-
Drash, isolated hemihypertrophy…
Wilms Tumor 1
• (WT1) gene - chromosome 11p13
• Tumor suppressor gene
• Plays role in development of gonads
• Accounts for ~10% of Wilms tumors
Associated syndromes
• WAGR syndrome (del 11p13, WT1 gene)
• Aniridia, GU abnormalities, Mental retardation, Wilms' tumor
• Renal impairment (glomerular filtration rate <80 mL per min) and
proteinuria or End-stage renal disease (ESRD)
• Denys-Drash syndrome (point mutation in 8th or 9th exon of WT1 gene)
• Progressive renal disease, male pseudohermaphroditism, and Wilms'
tumor
• Underlying pathology is diffuse mesangial sclerosis, which presents in
infancy with proteinuria and progresses to nephrotic syndrome and
renal failure.
• Beckwith-Wiedemann syndrome (microduplication mutations in the
11p15.5 region, site of the WT2 gene)
• Macrosomia, macroglossia, omphalocele, prominent eyes, ear
creases, large kidneys, pancreatic hyperplasia, and hemihypertrophy.
• Other congenital anomalies
• Perlman syndrome, Sotos syndrome, Isolated hemihypertrophy
Diagnosis
Presentation:
• Palpable abdominal mass
• Abdominal pain 30%
• Hematuria 12 - 25%
• Hypertension – due to renin secretion by tumor

Physical examination:
• Firm, nontender, smooth mass that rarely crosses the midline and
generally does not move with respiration. (versus neuroblastoma or
splenomegaly)
• Look for associated anomalies, such as aniridia, hemihypertrophy, and
genitourinary anomalies.
Role of imaging
• Establish the presence of a renal tumor
(vs. hydronephrosis or multicystic kidney
disease)
• Size and extent of the tumor
• Intravascular tumor thrombosis (Doppler
U/S)
• Evaluate contralateral kidney
• Presence and function
• Tumor involvement
• Nephrogenic rests
• Lung metastases
• Guides management decisions
• Surgical approach
• Preoperative chemotherapy
Treatment
Europe:
• Preoperative neoadjuvant chemotherapy
• Postoperative chemotherapy based on pathologic
response

United States:
• Primary nephrectomy
• Postoperative chemotherapy based on diagnosis and
stage
• Central Pathology Review (“center of excellence”)
• COG registry into Tumor Classification and Banking
protocol
• Recut slides, pathology report, frozen tissue (normal
and tumor), paraffin block, other samples
Therapeutic protocols:
1. Low- and standard-risk FHWT
2. High-risk FHWT
3. Bilateral Wilms tumor, unilateral Wilms tumor with high risk
for renal failure, and nephroblastomatosis
4. High-risk renal tumors (CCSK, MRT, anaplastic Wilms
Tumor, renal cell carcinoma)
Staging of pediatric renal tumors
In the gross room
• A solitary well circumscribed
or lobular mass with gray to
pink variegated appearance.
• Cystic changes (PPE! And stand back! )
• Necrosis and hemorrhage
are common
• Location in kidney
• Nodules – number and size
• Friable – drag artifact

• Snap frozen tissue

• Electron microscopy
• Touch preps
• Flow cytometry -
• Cytogenetics -
Sampling:
what you need to document
• Weight (protocol eligibility factor)
• Margins (radial, vascular, ureter)
• Invasion: renal vein, ureter or
adipose tissue.
• Renal sinus
• One section per cm of tumor
• In relation to capsule, normal
kidney and possible vascular
involvement
• Each nodule should be sampled
• Non-contiguous
• Nephrogenic rests
• Other lesions if present
• Normal kidney
• Adrenal
• Lymph nodes
Histology
Malignant growth of primitive
metanephric blastema
Three major components:
• Undifferentiated blastema
• Mesenchymal (stromal)
• “heterologous elements”
• Skeletal muscle, cartilage
• Epithelial
• Usually tubules
• Can be biphasic or monophasic
Blastema
• Resemble the condensed mesenchyme from
which the kidney develops.
• Small, closely packed, and mitotically active,
with minimal evidence of differentiation.
• Prominent overlapping of adjacent nuclei
• Nuclei are relatively small and regular, with
evenly distributed, slightly coarse chromatin
and small nucleoli.
• Cytoplasm is scanty
• Cell borders are often indistinct
Multiple blastemal patterns

Invasive diffuse blastemal pattern Central epithelial pattern

Nodular blastemal pattern Basaloid blastemal pattern

Epithelial differentiation

Tubules Glomerular Mucinous epithelium

Stromal differentiation
• Most commonly skeletal muscle
• Almost any type of stromal differentiation, including adipose
tissue, cartilage, osteoid, mature ganglion cells, and
neuroglial tissue, may be observed in nephroblastomas

Skeletal muscle Ganglion cells Cartilage

Favorable histology vs. Anaplasia
• Anaplasia (4% of all cases)
• Marked nuclear enlargement
• 3 fold enlargement
• In two perpendicular axes
• Hyperchromasia of enlarged nuclei
• Enlarged, usually multipolar mitotic figures
• unequivocal increase in the total
amount of DNA
• Large prophase chromosome spreads
equivalent
• Associated with increased resistance to
chemotherapy but not increased tumor
aggressiveness
• “Nuclear unrest”: “background nuclear
enlargement and histologic disarray”
• Grade 3/Severe: Striking background
atypia and disarray just short of anaplasia
 Focal vs. diffuse

**This is why we take non-contiguous

sections when sampling

Faria P, Beckwith JB, Mishra K, et al. Focal Versus Diffuse Anaplasia in Wilms Tumor – New Definitions With Prognostic
Significance. A Report from the National Wilms Tumor Study Group. Am J Surg Path 1996:20(8);909-920.
Nephrogenic rests
• Abnormally persistent foci of
embryonal cells that are capable
of developing into
nephroblastomas
• Perilobar
• Intralobar
• Combined

Perilobar – at periphery Intralobar – mingles with normal

Types of rests and evolution to WT

WT

• Distinction between nephrogenic rest and nephroblastoma can be made

with confidence pathologically only when the shape of the lesion is known
and the interface between the lesion and the surrounding kidney is
included in the surgical excision
Diffuse perilobar nephroblastomatosis

• Treated as a low stage, favorable histology nephroblastoma

• Reduces the number of proliferating cells that may develop a clonal transformation into
nephroblastoma
• ½ who receive chemotherapy have complete resolution of the process and never develop
tumors subsequently.
• The remaining patients have a waxing and waning course, both in the development and
size of their rests and in the development of nephroblastoma, over a period of 5 to 10 years.
• The most critical determinant of long-term survival is the utilization of a treatment regimen
that preserves the renal parenchyma.
• 32 percent risk of developing anaplastic nephroblastoma
Don’t confuse with:

Mesoblastic nephroma

Rhabdoid tumor

• Neuroblastoma
• Synovial sarcoma
• Primitive neuroectodermal tumor
• Rhabdomyosarcoma

Clear cell sarcoma of kidney

 References / Reading list:
• CAP Tumor Protocol for Wilms Tumor:
http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2005/wilms05_pw.pdf

• Perlman EJ. Pediatric Renal Tumors: Practical Updates for the Pathologist. Pediatric and
Developmental Pathology 2005;8:320–338

• Faria P, Beckwith JB, Mishra K, et al. Focal Versus Diffuse Anaplasia in Wilms Tumor – New
Definitions With Prognostic Significance. A Report from the National Wilms Tumor Study
Group. Am J Surg Path 1996:20(8);909-920.

• Tumors of the Kidney, Bladder, and Related Urinary Structures. AFIP Atlas of Tumor Pathology
– 4th Series

• Lester SC. Manual of Surgical Pathology pp. China:Elsevier; 2006. pp. 380-385.

• Bernstein L, Linet M, Smith MA, Olshan AF. RENAL TUMORS National Cancer Institute 79 SEER Pediatric Monograph IN:
Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR (eds). Cancer Incidence and Survival among
Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub. No.
99-4649. Bethesda, MD, 1999.

• Beckwith JB. Wilms’ Tumor and Other Renal Tumors of Childhood: a selective review from the National Wilms’ Tumor Study
Pathology Center. Human Pathology. 1983:14(6);481-492.

• Zuppan CW, Beckwith B, Luckey DW. Anaplasia in Unilateral Wilms’ tumor: a report from the National Wilms’ Tumor Study
Pathology Center. Human Pathology. 1988:19(10);1199-1209.