In contrast to syndromic Wilms tumors, the molecular abnormalities underlying sporadic (i.e., nonsyndromic) tumors, which account for 90% of cases overall in children, are only recently being elucidated. Some of them are associated with specific histologic features described later. For example, gain-of-function mutations of the gene encoding β-catenin (Chapter 6) have been demonstrated in approximately 10% of sporadic Wilms tumors. Other recurrent mutations occur in genes encoding proteins involved in microRNA processing (DROSHA, DGCR8, and DICER1); these are seen in 15% to 20% of Wilms tumors with predominantly blastemal histology (see later). It is postulated that aberrations in microRNA processing lead to reduced levels of many mature microRNAs, in particular in the miR-200 family, which is involved in “mesenchymal to epithelial transformation” during renal morphogenesis. The lack of mesenchymal to epithelial transformation likely leads to persistent blastemal “rests” in the kidney (see the following), which evolve into Wilms tumors. Finally, tumors with TP53 mutations are associated with an especially poor prognosis and often have a distinctive anaplastic histologic appearance, described later.
MORPHOLOGYWilmstumortypicallyisalarge,solitary,well-circumscribedmass,although10%areeitherbilateralormulticentricatthetimeofdiagnosis.Oncutsection,thetumorissoft,homogeneous,andtantogray,withoccasionalfociofhemorrhage,cysticdegeneration,andnecrosis(
Fig.7.36
Onmicroscopicexamination,Wilmstumorsarecharacterizedbyrecognizableattemptstorecapitulatedifferentstagesofnephrogenesis.Theclassictriphasic combination ofblastemal,stromal,andepithelialcelltypesisobservedinmostlesions,althoughthepercentageofeachcomponentisvariable(
Fig.
7.37A ).Sheetsofsmallbluecells,withfewdistinctivefeatures,characterizetheblastemal component.Epithelial“differentiation”usuallytakestheformofabortive tubules or glomeruli.Stromalcellsareusuallyfibrocyticormyxoidinnature,althoughskeletalmuscle“differentiation”isnotuncommon.Approximately5%oftumorscontainfociofanaplasia (cellswithlarge,hyperchromatic,pleomorphicnucleiandabnormalmitoses)(
Fig.
7.37B ).ThepresenceofanaplasiacorrelateswiththepresenceofacquiredTP53 mutationsandtheemergenceofresistancetochemotherapy.Thepatternofdistributionofanaplasticcellswithintheprimarytumor(focalversusdiffuse)hasimportantimplicationsforprognosis(seefurthertext).
Nephrogenic rests areputativeprecursorlesionsofWilmstumorsandaresometimespresentintherenalparenchymaadjacenttothetumor.Nephrogenicrestshaveaspectrumofhistologicappearances,fromexpansilemassesthatresembleWilmstumors(hyperplasticrests)toscleroticrestsconsistingpredominantlyoffibroustissuewithoccasionaladmixedimmaturetubulesorglomeruli.Itisimportanttodocumentthepresenceofnephrogenicrestsintheresectedspecimen,becausethesepatientsareatanincreasedriskforthedevelopmentofWilmstumorsinthecontralateralkidney.
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Fig. 7.36 Wilmstumorinthelowerpoleofthekidneywiththecharacteristictantograycolorandwell-circumscribedmargins.