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Papillary thyroid carcinoma (PTC) is one of the most common, well-differentiated carcinomas of the thyroid gland. PTC nodules are often surrounded by a collagen capsule that prevents the spread of cancer cells. However, as the malignant tumor progresses, the integrity of this protective barrier is compromised, and cancer cells invade the surroundings. The detection of capsular invasion is, therefore, crucial for the diagnosis and the choice of treatment and the development of new approaches aimed at the increase of diagnostic performance are of great importance. In the present study, we exploited the wide-field second harmonic generation (SHG) microscopy in combination with texture analysis and unsupervised machine learning (ML) to explore the possibility of quantitative characterization of collagen structure in the capsule and designation of different capsule areas as either intact, disrupted by invasion, or apt to invasion. Two-step k-means clustering showed that the collagen capsules in all analyzed tissue sections were highly heterogeneous and exhibited distinct segments described by characteristic ML parameter sets. The latter allowed a structural interpretation of the collagen fibers at the sites of overt invasion as fragmented and curled fibers with rarely formed distributed networks. Clustering analysis also distinguished areas in the PTC capsule that were not categorized as invasion sites by the initial histopathological analysis but could be recognized as prospective micro-invasions after additional inspection. The characteristic features of suspicious and invasive sites identified by the proposed unsupervised ML approach can become a reliable complement to existing methods for diagnosing encapsulated PTC, increase the reliability of diagnosis, simplify decision making, and prevent human-related diagnostic errors. In addition, the proposed automated ML-based selection of collagen capsule images and exclusion of non-informative regions can greatly accelerate and simplify the development of reliable methods for fully automated ML diagnosis that can be integrated into clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Microscopic evaluation of tissue sections stained with hematoxylin and eosin is the current gold standard for diagnosing thyroid pathology. Digital pathology is gaining momentum providing the pathologist with additional cues to traditional routes when placing a diagnosis, therefore it is extremely important to develop new image analysis methods that can extract image features with diagnostic potential. In this work, we use histogram and texture analysis to extract features from microscopic images acquired on thin thyroid nodule capsules sections and demonstrate how they enable the differential diagnosis of thyroid nodules. Targeted thyroid nodules are benign (i.e., follicular adenoma) and malignant (i.e., papillary thyroid carcinoma and its sub-type arising within a follicular adenoma). Our results show that the considered image features can enable the quantitative characterization of the collagen capsule surrounding thyroid nodules and provide an accurate classification of the latter's type using random forest., (© 2022. The Author(s).)

Papillary carcinoma is the most prevalent type of thyroid cancer. Its diagnosis requires accurate and subjective analyses from expert pathologists. Here we propose a method based on the Hough transform (HT) to detect and objectively quantify local structural differences in collagen thyroid nodule capsules. Second harmonic generation (SHG) microscopy images were acquired on non-stained histological sections of capsule fragments surrounding the healthy thyroid gland and benign and tumoral/malignant nodules. The HT was applied to each SHG image to extract numerical information on the organization of the collagen architecture in the tissues under analysis. Results show that control thyroid capsule samples present a non-organized structure composed of wavy collagen distribution with local orientations. On the opposite, in capsules surrounding malignant nodules, a remodeling of the collagen network takes place and local undulations disappear, resulting in an aligned pattern with a global preferential orientation. The HT procedure was able to quantitatively differentiate thyroid capsules from capsules surrounding papillary thyroid carcinoma (PTC) nodules. Moreover, the algorithm also reveals that the collagen arrangement of the capsules surrounding benign nodules significantly differs from both the thyroid control and PTC nodule capsules. Combining SHG imaging with the HT results thus in an automatic and objective tool to discriminate between the pathological modifications that affect the capsules of thyroid nodules across the progressions of PTC, with potential to be used in clinical settings to complement current state-of-the-art diagnostic methods.