Screening Hepatoblastoma in Beckwith-Wiedemann Syndrome: A Complex Issue.

To the Editor: Trobaugh-Lotrario et al1 are to be congratulated on their detailed review of cases of Beckwith-Wiedemann Syndrome (BWS) with hepatoblastoma. We think that details concerning genotype of such cases would add valuable information to the report. BWS is the most common overgrowth-cancer predisposition syndrome; after Wilms tumor, hepatoblastoma represents the second most common embryonal tumor associated with the syndrome, developing in B2% of patients. Actually, BWS is the major risk factor for hepatoblastoma, accounting for a risk 2280 times higher than that of the general population. There is accumulating evidence that BWS can be separated into 4 molecular subtypes with overlapping features and specific phenotypic profiles. The 4 subtypes—Imprinting Center 1 hypomethylation, chromosome 11 paternal uniparental disomy (UPD), Imprinting Center 2 hypermethylation, and CDKN1C loss-offunction mutation—are characterized by relevant differences in cancer incidence and histotypes.2 We found hepatoblastoma in 5.7% of our UPD patients and first reported a significant association between hepatoblastoma and this molecular defect.2 Literature data apparently confirm this association. Interestingly, it should be noted that Trobaugh-Lotrario reported hemihyperplasia in the vast majority of review cases; this feature is more common in the UPD subgroup. Consistent with the antecedent report reviewing BWS-related hepatoblastomas,3 Trobaugh-Lotrario observed a higher survival rate and lower staging at diagnosis in patients diagnosed through specific screening procedures, namely repeated serum alpha-fetoprotein (aFP) measurement in the first 5 years of life. Remarkably, 41 of 56 reviewed cases have no details concerning cancer screening procedures used or were not screened at all. Actually, aFP screening for hepatoblastoma in the BWS population is controversial as invasive and has a debated cost-effectiveness. Relevant compliance issues (likely connected to the frequent blood drawn in early infancy) complicate the follow-up of patients with BWS. The variability in the natural decrease of normal serum aFP levels (from 10 magnitude at birth to 10 ng/mL at 1 to 2 y of age) and its wide fluctuations dependent on premature birth (very frequent in BWS patients) account for further difficulties in the interpretation of aFP measurements.4 Because of these complex issues, many centers opt to waive aFP screening. By the way, all the 14 reported cases diagnosed by screening display clearly elevated aFP levels at diagnosis once reliable reference values were used.5 On the basis of these premises, we could debate whether screening all BWS patients for hepatoblastoma is worthwhile, but, in our opinion, screening the UPD ones is mandatory. Collaborative studies are needed to verify proficiency and costeffectiveness of aFP screening in this setting: meanwhile, the application of hepatoblastoma surveillance protocol is prudential and reasonable. However, clinical research should focus on alternative, more cost-effective, and less invasive methods for screening BWS children for hepatoblastoma.4