Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, Austria.
Department of Clinical Pathology, Ordensklinikum/Hospital of the Sisters of Charity, Linz, Austria.
J Pathol Clin Res. 2022 Mar;8(2):155-168. doi: 10.1002/cjp2.247. Epub 2021 Nov 17.
Papillary thyroid carcinoma tall cell variant (PTC-TCV), a form of PTC regarded as an aggressive subtype, shares several morphologic features with oncocytic tumors. Pathogenic homoplasmic/highly heteroplasmic somatic mitochondrial DNA (mtDNA) mutations, usually affecting oxidative phosphorylation (OXPHOS) complex I subunits, are hallmarks of oncocytic cells. To clarify the relationship between PTC-TCV and oncocytic thyroid tumors, 17 PTC-TCV and 16 PTC non-TCV controls (cPTC) were subjected to: (1) transmission electron microscopy (TEM) to assess mitochondria accumulation, (2) next-generation sequencing to analyze mtDNA and nuclear genes frequently mutated in thyroid carcinoma, and (3) immunohistochemistry (IHC) for prohibitin and complex I subunit NDUFS4 to evaluate OXPHOS integrity. TEM showed replacement of cytoplasm by mitochondria in PTC-TCV but not in cPTC cells. All 17 PTC-TCV had at least one mtDNA mutation, totaling 21 mutations; 3/16 cPTC (19%) had mtDNA mutations (p < 0.001). PTC-TCV mtDNA mutations were homoplasmic/highly heteroplasmic, 16/21 (76%) mapping within mtDNA-encoded complex I subunits. MtDNA mutations in cPTC were homoplasmic in 2 cases and at low heteroplasmy in the third case, 2/3 mapping to mtDNA-encoded complex I subunits; 2/3 cPTC with mtDNA mutations had small tall cell subpopulations. PTC-TCV showed strong prohibitin expression and cPTC low-level expression, consistent with massive and limited mitochondrial content, respectively. All 17 PTC-TCV showed NDUFS4 loss (partial or complete) and 3 of 16 cPTC (19%) had (partial) NDUFS4 loss, consistent with lack of complex I integrity in PTC-TCV (p < 0.001). IHC loss of NDUFS4 was associated with mtDNA mutations (p < 0.001). Four BRAF V600E mutated PTCs had loss of NDUSF4 expression limited to neoplastic cell subpopulations with tall cell features, indicating that PTCs first acquire BRAF V600E and then mtDNA mutations. Similar to oncocytic thyroid tumors, PTC-TCV is characterized by mtDNA mutations, massive accumulation of mitochondria, and loss of OXPHOS integrity. IHC loss of NDUFS-4 can be used as a surrogate marker for OXPHOS disruption and to reliably diagnose PTC-TCV.
甲状腺乳头状癌高细胞变异型（PTC-TCV）是一种被认为具有侵袭性的 PTC 亚型，与嗜酸细胞瘤具有一些形态学特征。致病性同质性/高度异质性体细胞线粒体 DNA（mtDNA）突变，通常影响氧化磷酸化（OXPHOS）复合物 I 亚基，是嗜酸细胞瘤的标志。为了阐明 PTC-TCV 与嗜酸细胞性甲状腺肿瘤之间的关系，对 17 例 PTC-TCV 和 16 例 PTC 非 TCV 对照（cPTC）进行了以下研究：（1）透射电子显微镜（TEM）评估线粒体积累，（2）下一代测序分析甲状腺癌中经常发生突变的 mtDNA 和核基因，（3）免疫组织化学（IHC）检测抑制素和复合物 I 亚基 NDUFS4，以评估 OXPHOS 完整性。TEM 显示 PTC-TCV 细胞的细胞质被线粒体取代，但 cPTC 细胞没有。17 例 PTC-TCV 中均至少存在 1 种 mtDNA 突变，总计 21 种突变；16 例 cPTC（19%）中有 mtDNA 突变（p<0.001）。PTC-TCV mtDNA 突变是同质性/高度异质性的，16/21（76%）突变位于 mtDNA 编码的复合物 I 亚基内。cPTC 中的 mtDNA 突变在 2 例中为同质性，在第 3 例中为低异质性，2/3 例突变位于 mtDNA 编码的复合物 I 亚基中；2/3 例有 mtDNA 突变的 cPTC 具有小的高细胞亚群。PTC-TCV 表现出强烈的抑制素表达和 cPTC 低水平表达，分别与大量和有限的线粒体含量相对应。17 例 PTC-TCV 均显示 NDUFS4 缺失（部分或完全），16 例 cPTC 中有 3 例（部分）存在 NDUFS4 缺失，与 PTC-TCV 中复合物 I 完整性缺失一致（p<0.001）。IHC 中 NDUFS4 的缺失与 mtDNA 突变相关（p<0.001）。4 例 BRAF V600E 突变的 PTC 中，NDUSF4 表达缺失仅限于具有高细胞特征的肿瘤细胞亚群，表明 PTC 首先获得 BRAF V600E，然后是 mtDNA 突变。与嗜酸细胞性甲状腺肿瘤类似，PTC-TCV 的特征是 mtDNA 突变、线粒体大量堆积和 OXPHOS 完整性缺失。IHC 中 NDUFS-4 的缺失可用作 OXPHOS 破坏的替代标志物，并可可靠地诊断 PTC-TCV。
