Stratifying the risk of malignancy in indeterminate thyroid nodules

Project ID D2019-45

Background
Thyroid cancer is the most common endocrine cancer globally, and accounts for 3.4% of all new cancer cases in the US. Although several clinical guidelines to detect/manage thyroid nodules are available, a great deal of controversy still exists around the optimal approach for diagnosis. Approximately 20-30% of cytology results from thyroid fine-needle aspiration (FNA) fall into one of three indeterminate diagnostic categories. In recent years, a number of molecular and gene mutation diagnostic tests have been developed to diagnose the indeterminate thyroid nodules in FNA specimens. However, nearly half of patients recommended for surgery based on these tests are still found to have a benign nodule. Therefore, there is a need for a more accurate predictive and prognostic test for thyroid cancer.

Description
Researchers at the University of Toledo have found that thyroid nodule microenvironment cell-profiling analysis can be used as a diagnostic and prognostic marker for thyroid cancer. This approach uniquely focuses on the phenotype, rather than the genotype, of the tumor microenvironment.

Recently described Double Negative (DN) T-cells were significantly more abundant in lymphocytic infiltrates of thyroid cancer. They were shown to downregulate proliferation and cytokine production of cytotoxic T cells present in the tumor microenvironment and contribute to tumor tolerance and active avoidance of tumor immunity. If the quantity of DN T cells exceeds a defined threshold, it indicates a higher likelihood of the presence of cancer.  Aside from immune cell profiling flowcytometric analysis, this approach integrates information derived from transcriptome/meta-analysis of the genome and cytokine/chemokine signal analysis all from the tumor microenvironment of thyroid FNAs. 

Application 

• Diagnosis of thyroid cancer from FNA samples
• Predictive tool of severity of disease

Advantages

• Microenvironment profiling can provide a unique way to diagnose and assess disease severity/progression
• Sheds light on cellular cross-talk; more accurate diagnosing and preventing unnecessary surgeries

IP Status:                           Patent Pending

Publications:                    

1. Imam S, Paparodis R, Sharma D, Jaume JC. Lymphocytic profiling in thyroid cancer provides clues for the failure of tumor immunity. Endocr Relat Cancer. 2014 Jun;21(3):505-16. doi: 10.1530/ERC-13-0436. Epub 2014 Mar 12. PMID: 24623740; PMCID: PMC4038677. (Impact Factor- 4.1)
2. Paparodis R, Imam S, Todorova-Koteva K, Staii A, Jaume JC. Hashimoto's thyroiditis pathology and risk for thyroid cancer. Thyroid. 2014 Jul;24(7):1107-14. doi: 10.1089/thy.2013.0588. Epub 2014 Jun 5. PMID: 24708347; PMCID: PMC4080848. (Impact Factor- 6.0)
3. Imam S*., R Paparodis., Rafiqi, S.I., et al. Thyroid Cancer Screening using Tumor-Associated DN T cells as Immunogenomic Markers. Front Oncol. 2022:12:891002. Published 2022 May 27. PMID: 35692772, PMCID: PMC9186057. * Corresponding author (Impact Factor- 3.5) 
4. Imam S, Dar P, Paparodis R, Almotah K, Al-Khudhair A, Hasan SA, Salim N, Jaume JC. Nature of coexisting thyroid autoimmune disease determines success or failure of tumor immunity in thyroid cancer. J Immunother Cancer. 2019 Jan 7;7(1):3. doi: 10.1186/s40425-018-0483-y. PMID: 30616690; PMCID: PMC6323721. (Impact Factor- 10.3)
5. Paparodis RD, Karvounis E, Bantouna D, Chourpiliadis C, Hourpiliadi H, Livadas S, Imam S, Jaume JC. Large, slowly growing, benign thyroid nodules frequently coexist with synchronous thyroid cancers. J Clin Endocrinol Metab. 2022 Apr 18:dgac242. doi: 10.1210/clinem/dgac242. PMID: 35436327. (Impact Factor- 5.0)
6. Paparodis RD, Bantouna D, Karvounis E, Imam S, Jaume JC. Higher TSH Is Not Associated With Thyroid Cancer Risk in the Presence of Thyroid Autoimmunity. J Clin Endocrinol Metab. 2020 Jul 1;105(7):dgaa237. doi: 10.1210/clinem/dgaa237. PMID: 32391913. (Impact Factor- 5.0)
7. Paparodis RD, Karvounis E, Bantouna D, Chourpiliadis C, Chourpiliadi H, Livadas S, Imam S, Jaume JC. Incidentally Discovered Papillary Thyroid Microcarcinomas Are More Frequently Found in Patients with Chronic Lymphocytic Thyroiditis Than with Multinodular Goiter or Graves' Disease. Thyroid. 2020 Apr;30(4):531-535. doi: 10.1089/thy.2019.0347. Epub 2020 Feb 20. PMID: 31950881. (Impact Factor- 6.0)
8. Paparodis RD, Bantouna D, Imam S, Jaume JC. The non-interventional approach to papillary thyroid microcarcinomas. An "active surveillance" dilemma. Surg Oncol. 2019 Jun;29:113-117. doi: 10.1016/j.suronc.2019.04.001. Epub 2019 Apr 10. PMID: 31196473. (Impact Factor- 2.35)
9. Paparodis, R., Livadas, S., Karvounis, E., Bantouna, D., Zoupas, I., Angelopoulos, N., Imam, S., & Jaume, J. C. Elevated Preoperative TPO Ab Titers Decrease Risk for DTC in a Linear Fashion: A Retrospective Analysis of 1635 Cases. J Clin Endocrinol Metab. 2024 109(1), e347–e355. https://doi.org/10.1210/clinem/dgad408 (Impact Factor- 5.0)
10. Zoupas I, Livadas S, Karvounis E, Bantouna D, Angelopoulos N, Imam S, Jaume JC, Paparodis RD. Thyroid Cancer in Thyroglossal Duct Remnants: Case Series and Extensive Review of the Literature. J Endocr Surg. 2024 Sep;24(3):61-71. https://doi.org/10.16956/jes.2024.24.3.61 (Impact Factor- 3.0)
11. Imam, S., Jaume, J.C. Stratifying risk of malignancy in indeterminate thyroid nodules and immuno-genomic markers for early detection of thyroid cancer. International Application No. PCT/US2021/012057, (2023), Publication of US20230105011A1. https://patents.google.com/patent/US20230105011A1/en