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Quantitative second harmonic generation microscopy for characterizing collagen remodeling in papillary thyroid
Wesley Poon1,2, Lin Wang1,3, Orhun Davarci1,4
1Houston Methodist Neal Cancer Center, Department of Systems Medicine and Bioengineering, Houston, Texas, United States.
Journal of Biomedical Optics
|May 28, 2026
Summary
Second Harmonic Generation (SHG) microscopy analyzes collagen structure to differentiate normal and cancerous thyroid tissue. This approach shows promise for improving thyroid cancer diagnosis and reducing unnecessary procedures.
Area of Science:
- Biomedical Optics
- Cancer Diagnostics
- Materials Science
Background:
- Thyroid cancer is the most common endocrine malignancy, with indeterminate fine needle aspiration (FNA) cytology posing diagnostic challenges.
- Current diagnostic methods offer limited information on the extracellular matrix, particularly collagen remodeling, a key feature of malignancy.
- Diagnostic uncertainty from indeterminate FNAs leads to increased healthcare costs, patient distress, and unnecessary interventions.
Purpose of the Study:
- To develop and validate a quantitative framework using Second Harmonic Generation (SHG) microscopy to distinguish between normal and papillary thyroid carcinoma (PTC) tissues based on collagen architecture.
- To assess the potential of label-free, architecture-based imaging for improving real-time diagnostic decision-making in thyroid cancer.
Main Methods:
- Utilized formalin-fixed paraffin-embedded human thyroid tissue sections (normal and PTC).
- Employed multiphoton microscopy with SHG imaging (803 nm excitation, 400 nm emission) to capture collagen structural information.
- Quantified 35 metrics related to collagen intensity, geometry, texture, and frequency domain features.
- Applied a linear mixed-effects model for statistical comparison between normal and cancerous tissues, accounting for data structure and assessing metric significance.
Main Results:
- 19 out of 35 quantified collagen metrics were statistically significant after FDR adjustment, demonstrating substantial differences between normal and cancerous thyroid tissue.
- Effect sizes for significant metrics ranged from moderate to large, indicating robust discriminatory power.
- Consistent directional changes in collagen organization were observed, including increased spectral power and heterogeneity in cancer tissues, even with a small cohort size.
Conclusions:
- SHG-derived collagen architecture signatures hold significant potential for accurate thyroid cancer diagnosis.
- Integrating these quantitative features into an automated platform could enable rapid, objective optical biopsies.
- This approach may reduce indeterminate FNAs, aid intraoperative decisions, and enhance routine thyroid cancer care.
