SAT-368 - When Histopathology Says Benign and Molecular Genetics Says Malignant: Can the Thyroid Tumor Immune Microenvironment Reconcile Discordant Diagnoses?

When Histopathology Says Benign and Molecular Genetics Says Malignant:
Can the Thyroid Tumor Immune Microenvironment Reconcile Discordant Diagnoses?

Shafiya Imtiaz Rafiqi, Kostantina Angelopoulos, Ellil Krishnaraju, Julian Sebastian Jaume, Ambika Amblee and Juan Carlos Jaume

Abstract

Background: While fine needle aspiration (FNA) remains the primary diagnostic tool for thyroid malignancies, the utilization of molecular markers has become increasingly common in the workup of thyroid nodules. For equivocal cytology, molecular genetics is used for surgery decision making. Sometimes, post operative histopathology is discordant. Could investigating the Tumor Immune Microenvironment (TIME) reconcile diagnoses before surgery (1, 2)?

Case: A 73-year-old male with a history of left hemithyroidectomy for a benign 3.5-cm thyroid nodule presented six years later with midline, superficial nodules. Ultrasound showed well-circumscribed subcutaneous lesions separated from the left thyroid bed. Fine-needle aspiration demonstrated benign follicular cells. Excision revealed benign-appearing thyroid tissue within fibrotic stroma, lacking nuclear atypia or vascular invasion. Next-generation sequencing unexpectedly identified a TERT C228T, HRAS Q61R, and EIF1AX A113 splice mutation triad. Therefore, the patient underwent completion thyroidectomy that showed no histological malignancy. The final diagnosis was benign subcutaneous thyroid tissue “implantation.” Two years after, new thyroid “implants” developed. Cytology was again consistent with benign thyroid tissue, but molecular markers were again positive for malignancy. Experimental Flow-Cytometry Lymphocytic Profiling favored a malignant tumor immune microenvironment (TIME).

Conclusions: This case highlights the occurrence of molecular alterations typically associated with malignancy with discordant cytology and histopathology. It emphasizes the need for integrative interpretation of molecular findings within the broader clinicopathologic framework and the need for more accurate diagnostic tools for appropriate management which should include analysis of the tumor microenvironment.

References:
1. Imam S, Paparodis RD, Rafiqi SI, Ali S, Niaz A, Kanzy A, Tovar YE, Madkhali MA, Elsherif A, Khogeer F, Zahid ZA, Sarwar H, Karim T, Salim N, Jaume JC. Thyroid Cancer Screening Using Tumor-Associated DN T Cells as Immunogenomic Markers. Front Oncol. 2022 May 27;12:891002. doi: 10.3389/fonc.2022.891002. eCollection 2022.
2. Jaume JC. Thyroid Cancer-The Tumor Immune Microenvironment (TIME) over Time and Space. Cancers (Basel). 2025 Feb 26;17(5):794. doi: 10.3390/cancers17050794.

Acknowledgment: Robert Ladd, Research Technologist, Flow Cytometry.

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