Wilms Tumor Overview

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, DenysDrash, 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 •

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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 • • • •

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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. 2. 3. 4.

Low- and standard-risk FHWT High-risk FHWT Bilateral Wilms tumor, unilateral Wilms tumor with high risk for renal failure, and nephroblastomatosis 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 • • • • •

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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 • • • •

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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 •

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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 •

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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

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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

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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

• • • • Clear cell sarcoma of kidney

Neuroblastoma Synovial sarcoma Primitive neuroectodermal tumor Rhabdomyosarcoma

References / Reading list: •

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

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

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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.

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

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

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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.

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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.

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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.