Odate Toru, Kondo Tetsuo, Katoh Ryohei, Ito Koichi, Ueno Toshihide, Yatabe Yasushi, Mori Taisuke
Department of Pathology, University of Yamanashi, Yamanashi, Japan.
Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
Endocr Pathol. 2025 Sep 1;36(1):30. doi: 10.1007/s12022-025-09875-y.
Although anaplastic thyroid carcinomas (ATCs) typically arise from papillary thyroid carcinomas (PTCs), follicular thyroid carcinomas (FTCs) can also progress to ATCs; however, histologically confirmed FTC-derived ATCs are relatively uncommon and remain poorly characterized. To clarify this phenomenon, we analyzed eight FTC-derived ATCs and compared them with 11 PTC-derived ATCs. Whole-exome sequencing (WES) was conducted on the differentiated thyroid carcinoma (DTC) and ATC components within the same tumors to examine mutational profiles; three additional cases underwent FoundationOne® testing. The demographic features were similar between FTC- and PTC-derived ATCs. Histologically, spindle-cell morphology was more common in FTC-derived ATCs (3/8), whereas PTC-derived ATCs exhibited squamoid (5/11) and giant cell features (5/11), including osteoclast-like cells. WES was successfully performed on both the ATC and FTC components in seven of the eight FTC-derived ATCs. Common alterations included TERT promoter (5/7), NRAS (4/7), and HRAS (2/7) mutations in both components. TP53 mutations were observed only in the ATC component (5/7). EIF1AX mutations co-occurred with TERT and HRAS mutations in two cases. PTEN mutations were found in two FTCs with solid/trabecular patterns but were absent in the corresponding ATC components. One tumor harbored a DGCR8 p.E518K mutation that was retained during progression. By contrast, PTC-derived ATCs consistently showed concurrent BRAF and TERT promoter mutations (11/11). Immunohistochemistry for BRAF V600E, RAS Q61R, p53, PTEN, and MTAP showed high concordance with the corresponding mutation status. These findings revealed significant histological and genetic differences between FTC- and PTC-derived ATCs, providing new insights into the molecular basis of FTC dedifferentiation into ATC.
虽然间变性甲状腺癌（ATC）通常起源于乳头状甲状腺癌（PTC），但滤泡状甲状腺癌（FTC）也可进展为ATC；然而，经组织学证实源自FTC的ATC相对少见，其特征仍不清楚。为阐明这一现象，我们分析了8例源自FTC的ATC，并将其与11例源自PTC的ATC进行比较。对同一肿瘤内的分化型甲状腺癌（DTC）和ATC成分进行全外显子测序（WES）以检测突变谱；另外3例进行了FoundationOne®检测。源自FTC和PTC的ATC的人口统计学特征相似。在组织学上，梭形细胞形态在源自FTC的ATC中更常见（3/8），而源自PTC的ATC表现为鳞状（5/11）和巨细胞特征（5/11），包括破骨细胞样细胞。在8例源自FTC的ATC中的7例中，成功地对ATC和FTC成分进行了WES。常见的改变包括两个成分中均存在TERT启动子突变（5/7）、NRAS突变（4/7）和HRAS突变（2/7）。TP53突变仅在ATC成分中观察到（5/7）。在两例中，EIF1AX突变与TERT和HRAS突变同时出现。在两例具有实性/小梁状模式的FTC中发现了PTEN突变，但在相应的ATC成分中未发现。一个肿瘤存在DGCR8 p.E518K突变，该突变在进展过程中保留。相比之下，源自PTC的ATC始终显示BRAF和TERT启动子同时突变（11/11）。BRAF V600E、RAS Q61R、p53、PTEN和MTAP的免疫组化显示与相应的突变状态高度一致。这些发现揭示了源自FTC和PTC的ATC在组织学和遗传学上的显著差异，为FTC去分化为ATC的分子基础提供了新的见解。
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