分子标记可以作为诊断工具，支持甲状腺肿瘤的病理学分析。然而，由于相同的标记在一些良性甲状腺病变中也可观察到，需要采用其他方法来区分甲状腺肿瘤的亚型，以避免过度治疗并进行个体化的临床管理。这尤其适用于最近描述的一种甲状腺癌变异型，被称为非侵袭性滤泡样甲状腺肿瘤（NIFTP）。这种变异型在全球乳头状甲状腺癌中的估计患病率为4.4％至9.1％。我们研究了60例甲状腺病变：20例经典乳头状甲状腺癌（CPTC），20例乳头状癌的滤泡变异型（FVPTC）和20例NIFTP。我们检查了形态学和分子特征，以确定可以区分NIFTP与其他PTC亚型的参数。在对甲状腺肿瘤的核结构进行盲测时，我们观察到NIFTP的端粒显著较长，而CPTC和FVPTC则不是这样。超分辨率的三维结构照明显微镜显示，NIFTP是异质性的，并且其细胞核含有比CPTC和FVPTC更密集的DNA和更小的染色质间空间，这种模式类似于正常甲状腺组织。这些数据与我们观察到的与NIFTP相关的慢性生物学行为和良好预后一致，NIFTP缺乏BRAFV600E突变。值得注意的是，下一代甲状腺肿瘤基因组检测在我们的研究队列中无法区分甲状腺癌组织类型。总之，我们的数据表明，三维核结构可以成为诊断和指导NIFTP临床管理的有力分析工具。© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Molecular markers can serve as diagnostic tools to support pathological analysis in thyroid neoplasms. However, because the same markers can be observed in some benign thyroid lesions, additional approaches are necessary to differentiate thyroid tumor subtypes, prevent overtreatment and tailor specific clinical management. This applies particularly to the recently described variant of thyroid cancer referred to as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This variant has an estimated prevalence of 4.4% to 9.1% of all papillary thyroid carcinomas worldwide. We studied 60 thyroid lesions: 20 classical papillary thyroid carcinoma (CPTC), 20 follicular variant of PTC (FVPTC) and 20 NIFTP. We examined morphological and molecular features to identify parameters that can differentiate NIFTP from the other PTC subtypes. When blindly investigating the nuclear architecture of thyroid neoplasms, we observed that NIFTP has significantly longer telomeres than CPTC and FVPTC. Super-resolved 3D-structured illumination microscopy demonstrated that NIFTP is heterogeneous and that its nuclei contain more densely packed DNA and smaller interchromatin spaces than CPTC and FVPTC, a pattern that resembles normal thyroid tissue. These data are consistent with the observed indolent biological behavior and favorable prognosis associated with NIFTP, which lacks BRAFV600E mutations. Of note, next-generation thyroid oncopanel sequencing was unable to distinguish the thyroid cancer histotypes in our study cohort. In summary, our data suggest that 3D nuclear architecture can be a powerful analytical tool to diagnose and guide clinical management of NIFTP.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.