Wilms Tumour

Epidemiology and Etiology:

· 2-5y usually

·

Common sites:

·

Gross features:

· 5-10% bilateral (synchronous or metachronous)

· Large

· Well-circumscribed

· Soft

· Homogenous

· Tan to gray

· Hemorrhage maybe

· Cyst maybe

· Necrosis maybe

Histologic features:

· Attempts to recapitulate different stages of nephrogenesis

· Classic triphasic combination

· Blastemal

· Sheets of small blue cells with little distinctive features

· Stromal

· Fibrocytic or myxoid usually

· Skeletal muscle maybe

· Rarely:

· Smooth muscle

· Adipose

· Cartilage

· Osteoid

· Neurogenic tissue

· Epithelial

· Abortive tubules or glomeruli

· Squamous or mucinous elements rarely

· Nephrogenic rests in adjacent renal parenchyma of ~40% of unilateral tumours and nearly 100% of bilateral Wilms

· Hyperplastic rest:

· Expansile mass that resembles Wilms tumour (hyperplastic rest)

· Sclerotic rest:

· Predominantly fibrous tissue and occasional admixed immature tubules or glomeruli

· Anaplasia (5%)

· Cells with large, hyperchromatic, pleomorphic nuclei

· Abnormal mitoses

· Correlates with p53 mutations

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

· 3 recognizable groups of congenital malformations associated with distinct chromosomal loci (10% of Wilms)

· WAGR syndrome (deletion 11p13 including WT1):

· Aniridia (PAX6 deletion at 11p13)

· Genital anomalies

· Mental retardation

· 33% chance of Wilms

· Requires 2^nd hit – usually a nonsense or frameshift mutation in the second WT1 allele

· Denys-Drash syndrome (dominant negative mis-sense WT1 mutation in the zinc finger region)

· Gonadal dysgenesis (male pseudohermaphroditism)

· Early-onset nephropathy leading to renal failure

· Diffuse mesangial sclerosis

· Wilms tumours increased risk

· Requires bi-allelic inactivation

· Gonadoblastoma increased risk

· Consequence of a disruption in normal gonadal development

· Beckwith-Wiedemann syndrome (11p15.5, distal to WT1 locus)

· Sometimes called “WT2” locus

· The gene involved in tumorigenesis has not been identified.

· Also predisposes to hepatoblastoma, adrenocortical tumours, rhabdomyosarcomas, and pancreatic tumours

· These syndromes are mostly de novo (not familial)

· Sporadic Wilms

· WT1 mutations (15%)

· Beta-catenin mutations (15%) (often present with WT1 mutations)

· P53 mutations (correlates with anaplasia histologically)

· WT1

· Encodes a transcription factor expressed in the kidney and gonads of developing fetus

· Transcriptional targets include p21 (inhibit cell cycle), amphiregulin (EGF family), BCL2 (antiapoptotic), connective tissue growth factor (vitamin D receptor)

· Critical for normal renal and gonadal development

Other features:

· Presence of nephrogenic rests increases risk of developing contralateral Wilms

· Presence of anaplasia correlates with p53 mutations and resistance to chemo

· Pulmonary mets often present at time of diagnosis

· Very good prognosis

· Nephrectomy and chemo is treatment

· Survival for 2 years usually implies a cure

· 90% 2 year survival

· Worse prognosis for anaplasia, especially with extrarenal spread

· Increased risk of second primary tumours:

· Bone and soft tissue

· Leukemia and lymphoma

· Brain tumours

· Genitourinary tumours

References:

· Kumar V, Fausto N, Abbas A. Robbins & Cotran Pathologic Basis of Disease, Seventh Edition. 7th ed. Saunders; 2004:1552.