Three-dimensional nuclear architecture distinguishes thyroid cancer histotypes

Area of Science:

• Oncology
• Pathology
• Molecular Biology

Background:

• Distinguishing noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) from other papillary thyroid carcinoma (PTC) subtypes is crucial for appropriate clinical management and avoiding overtreatment.
• Current molecular markers often lack specificity, necessitating alternative diagnostic approaches for thyroid tumor classification.

Purpose of the Study:

• To identify morphological and molecular parameters, specifically focusing on nuclear architecture, that can differentiate NIFTP from classical PTC (CPTC) and follicular variant of PTC (FVPTC).
• To evaluate the utility of 3D nuclear architecture analysis as a diagnostic tool for NIFTP.

Main Methods:

• Comparative analysis of 60 thyroid lesions: 20 CPTC, 20 FVPTC, and 20 NIFTP.
• Examination of morphological and molecular features, including telomere length and 3D-structured illumination microscopy of nuclear architecture.
• Assessment of next-generation thyroid oncopanel sequencing for histotype differentiation.

Main Results:

• NIFTP demonstrated significantly longer telomeres compared to CPTC and FVPTC.
• 3D nuclear architecture analysis revealed that NIFTP nuclei are heterogeneous, with more densely packed DNA and smaller interchromatin spaces, resembling normal thyroid tissue.
• Next-generation sequencing failed to distinguish between the studied thyroid cancer histotypes.

Conclusions:

• 3D nuclear architecture, characterized by longer telomeres and specific DNA packing patterns, serves as a reliable differentiator for NIFTP.
• These findings support the indolent behavior and favorable prognosis of NIFTP, which is also characterized by the absence of BRAF^V600E mutations.
• 3D nuclear architecture analysis is a promising tool for the diagnosis and clinical management guidance of NIFTP.