- 4 例男婴 ORTI（0.5–10 月，中位 2.5 月），均以肉眼血尿就诊；临床上需与 Wilms 瘤、细胞性先天性中胚叶肾瘤等恶性拟诊鉴别。
- 组织学双相：富骨样/成骨细胞成分 + 温和梭形细胞，可伴钙化、局灶 blastema 样灶与分叶状生长。
- IHC：两成分均弥漫核 β-catenin、核 WT1 与 SATB2，灶性 cyclin D1；Ki-67 在梭形区高于骨样区；pan-TRK / ALK / CD34 / S100 / PAX8 均阴；FISH 无 ETV6::NTRK3。
- WGS/WES：4/4 检出 CTNNB1 外显子 3 热点激活突变（c.A121G, p.T41A），与核 β-catenin 完美对应；可伴 Wnt 通路次级改变。完整切除后随访最长 10 年无病——作者提出 CTNNB1 / 核 β-catenin 为诊断标志。
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摘要
婴儿骨化性肾肿瘤（ossifying renal tumor of infancy, ORTI）是一种极为罕见的小儿肾肿瘤，临床过程本质上良性。尽管形态学描述较充分，其分子发病机制大体未知，与 Wilms 瘤及细胞性先天性中胚叶肾瘤等恶性拟诊鉴别时常有陷阱。本文系统评估 4 例小儿 ORTI 的临床病理、免疫组化与基因组谱：均为男婴，年龄 0.5–10 个月（中位 2.5 月），均表现为肉眼血尿。组织学上，全部肿瘤呈特征性双相结构，由富含骨样/成骨细胞的成分与温和梭形细胞成分交织组成，可伴不同程度钙化、局灶 blastema 样灶及分叶状生长。免疫组化：全部病例（4/4，100%）在两成分中均见强而弥漫的核 β-catenin 积聚，同时弥漫核阳性 WT1 与 SATB2，并见灶性 cyclin D1；Ki-67 增殖指数呈梯度，梭形细胞成分（5%–30%）始终高于骨样区（2%–15%）。全部肿瘤 pan-TRK、ALK、CD34、S100 与 PAX8 阴性。新一代测序（WGS/WES）在 100% 病例（4/4）检出 CTNNB1 外显子 3 复发性体细胞激活热点突变（c.A121G, p.T41A），与核 β-catenin 定位完全对应。亦检出 Wnt 通路调节分子（APC、AXIN1/AXIN2）及 BMPR1A 的次级改变；FISH 证实无 ETV6::NTRK3 基因重排。全部患者完整手术切除后获长期无病生存（随访最长达 10 年）。总之，ORTI 是一种由 CTNNB1 驱动的独特小儿肾肿瘤，以复发性外显子 3 热点突变及异常核 β-catenin 表达为特征。认识这些具有诊断特征性的 分子与免疫表型标志，有助于建立稳健诊断标准，将其与恶性小儿肾拟诊明确区分。
- 4 male-infant ORTI cases (0.5–10 mo, median 2.5 mo), all with gross hematuria; differential includes Wilms tumor and cellular congenital mesoblastic nephroma.
- Biphasic histology: osteoid/osteoblast-rich + bland spindle cells ± calcification, blastema-like foci, lobulated growth.
- IHC: diffuse nuclear β-catenin, WT1, SATB2 in both components; focal cyclin D1; higher Ki-67 in spindle vs osteoid areas; negative pan-TRK/ALK/CD34/S100/PAX8; no ETV6::NTRK3 by FISH.
- WGS/WES: CTNNB1 exon 3 hotspot (c.A121G, p.T41A) in 4/4, correlating with nuclear β-catenin; long-term DFS after complete resection (up to 10 y) — proposed diagnostic hallmarks.
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Abstract
Ossifying renal tumor of infancy (ORTI) is an exceedingly rare pediatric renal neoplasm with an inherently benign clinical course. Although histomorphologically well-described, its underlying molecular pathogenesis remains largely unknown, often posing diagnostic pitfalls when distinguishing it from malignant mimics such as Wilms tumor and cellular congenital mesoblastic nephroma. Here, we systematically evaluated the clinicopathologic, immunohistochemical, and genomic spectrum of 4 pediatric ORTI cases from male infants aged 0.5 to 10 months (median: 2.5 mo), all presenting with gross hematuria. Histologically, all tumors exhibited a characteristic biphasic architecture composed of an osteoid/osteoblast-rich component intermixed with a bland spindle cell component, accompanied by variable calcification, localized blastema-like foci, and a lobulated growth pattern. By immunohistochemistry, all cases (4/4, 100%) demonstrated strong, diffuse nuclear β-catenin accumulation in both components, alongside diffuse nuclear positivity for WT1 and SATB2, and focal cyclin D1 expression. The Ki-67 proliferation index revealed a distinct gradient, being consistently higher in the spindle cell component (5% to 30%) than in the osteoid areas (2% to 15%). All tumors were negative for pan-TRK, ALK, CD34, S100, and PAX8. Next-generation sequencing (NGS) (WGS/WES) identified a recurrent, somatic activating hotspot mutation in exon 3 of CTNNB1 (c.A121G, p.T41A) in 100% of cases (4/4), perfectly correlating with nuclear β-catenin localization. Secondary alterations in Wnt pathway regulators (APC, AXIN1/AXIN2) and BMPR1A were also detected, while FISH confirmed the absence of ETV6::NTRK3 gene rearrangements. All patients achieved long-term disease-free survival following complete surgical resection (follow-up up to 10 y). In summary, ORTI is a distinct, CTNNB1-driven pediatric renal neoplasm defined by recurrent exon 3 hotspot mutations and aberrant nuclear β-catenin expression. Recognition of these pathognomonic molecular and immunophenotypic hallmarks establishes robust diagnostic criteria to definitively distinguish ORTI from its malignant pediatric renal mimics.