To the Editor:
Ossifying renal tumor of infancy (ORTI) is a rare pediatric benign renal
neoplasm first described in 1980.1 In the latest
review of 28 cases, whose diagnostic age was
described,2 the median age of diagnosis was 4.3 months
old, and 23 cases (82.1%) were diagnosed within the first year of life.
These observations suggest in utero development of ORTI but no
direct confirmation has been made. Here, we reported a newborn girl with
ORTI whose cystic lesion was first noticed at 25 weeks of gestation by
ultrasonography. Furthermore, we identified the CTNNB1 mutation
in her tumor sample by whole exome sequencing (WES). To our knowledge,
this is the first identification of CTNNB1 mutation as a genetic
alteration involved in ORTI tumorigenesis.
The patient was transferred to our hospital 10 days after birth due to
intermittent gross hematuria that appeared on the second day of life. In
ultrasonography at 25 weeks of gestation, a cystic lesion was first
noticed in her right kidney, and it was continuously enlarged in
proportion to fetal growth and multiloculated in the follow-up
evaluations (Figure 1A). She was born by scheduled cesarean section at
38 weeks of gestation with a birth weight of 2,672 g. There was no
significant family history. Her general condition was fair, but a soft
mass was palpable on her right abdomen. On admission, ultrasonography
showed a mass lesion with multiple cystic components at the lower pole
of the right kidney (Figure S1). An abdominal computed tomography image
performed 5 days after birth revealed a 4.5 x 4 cm multi-cystic mass
with a small linear calcification in the middle of the solid part
(Figure S2) without any sign of metastasis. Considering the gradually
increased tumor size and continuous hematuria, right nephrectomy was
performed at 23 days old. In the resected kidney, the tumor was
consisted of cystic and solid lesions and was well-demarcated from the
adjacent kidney. Histopathologically, the tumor consisted of three main
components, an osteoid core, osteoblast-like cells, and spindle cells
(Figure 1B), without typical nephrogenic rest. Immunohistochemically,
osteoblast-like cells were positive for cytoplasmic WT1 and epithelial
membrane antigen (EMA) while spindle cells were positive for nuclear WT1
but not EMA (Figure S3). Based on these findings, a final diagnosis of
ORTI was made. She had a good postoperative course and no local
recurrence or metastasis was observed at 9 months of age.
Since genetic alterations involved in the ORTI tumorigenesis have not
been fully elucidated, we conducted WES of the patient’s tumor sample
and her peripheral blood mononuclear cells (PBMC) after written informed
consent was obtained from her parents. In copy number variation (CNV)
analysis, several tumor-specific CNVs were identified (Table S1)
including a gain of 7q34 locus containing the EPHB6 gene that was
reportedly overexpressed in thyroid and breast
cancers,3 and a loss of 19p13.3 locus containingTLE2 and TLE6 , which was previously reported in one
sporadic Wilms tumor case.4 However, trisomy 4, which
was previously observed in some ORTI cases with a relatively low
prevalence,5,6 was undetectable with +1.20 of
threshold. In mutational analysis, c.121A>G (p.T41A)
mutation of the CTNNB1 gene was confirmed in the tumor tissue
with 0.38 of variant allele frequency (Figures 2A, S4 and Table S1) but
not in her PBSC, suggesting the heterozygous somatic mutation in the
tumor. Threonine 41 is one of the targets for GSK-3β-dependent
phosphorylation and is one of the hotspot mutation sites in diverse
tumors.7 Consistently, nuclear accumulations of
β-catenin protein, encoded by CTNNB1 , were confirmed in both
osteoblast-like and spindle cells of the tumor by immunohistochemistry
(Figure 2B). No further mutations were detected in the tumor sample
including the WT1 and WTX genes, which are frequently
mutated in Wilms tumors.8 Loss of heterozygosity ofWT1 was also unlikely since heterozygous genotypes were observed
in the same single nucleotide polymorphisms in the tumor sample and her
PBSC (Table S2).
Hyperplastic intralobar nephrogenic rest (ILNR), which is known as a
precursor lesion of Wilms tumors, is also considered as possible origin
of ORTI.9 In the ILNR-associated Wilms tumors,
co-clustering of WT1 and CTNNB1 mutations has been
identified.10 In the Wilms tumors with these two
mutations, ILNR lesions had WT1 mutations but no CTNNB1mutations, indicating that CTNNB1 mutation is a later event in
tumorigenesis.11 These observations suggest that
preceding CTNNB1 mutation might induce ORTI instead of Wilms
tumor. Of note, the CTNNB1 mutations in the
GSK-3β-phosphorylation sites have been previously identified in at least
two types of childhood benign tumors characterized by nested
proliferation of spindled and epithelioid cells with calcification or
ossification (Figure 2C). In almost all cases of pilomatricoma, a skin
adnexal tumor in children,12 the CTNNB1mutations including threonine 41 were identified.13Moreover, in all sequenced cases of calcifying nested stromal-epithelial
tumor (CNSET), a rare hepatic tumor in children and young adults, theCTNNB1 mutations including threonine 41 were identified in
combination with the TERT promoter mutations,14which were undetectable in our case (Figure S5).
In summary, our case indicates in utero development of ORTI and
involvement of CTNNB1 mutation in its tumorigenesis. Our
observations warrant further investigation of pathobiological
similarities and differences among pediatric CTNNB1 -mutated
tumors.