{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:59:59Z","timestamp":1790848799363,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Atypia of undetermined significance (AUS; Bethesda category III) remains a challenging thyroid cytological diagnosis because of its heterogeneous malignancy risk and limited preoperative certainty. Molecular testing can improve risk stratification but is not universally available. This study evaluated the diagnostic and incremental predictive value of preoperative complete blood count-derived systemic inflammatory indices in surgically treated Bethesda III thyroid nodules. Methods: This retrospective cohort included 352 patients who underwent thyroidectomy for Bethesda III thyroid nodules. Preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) were evaluated. Postoperative histopathology served as the reference standard. Receiver operating characteristic analysis and multivariable logistic regression were performed, followed by incremental model assessment, bootstrap internal validation, Hashimoto thyroiditis interaction analysis, and exploratory molecular subgroup analysis. Results: Among 352 patients, 197 (56.0%) had malignant histopathology. Malignant nodules showed higher NLR, PLR, SII, SIRI, and AISI and lower LMR. All six indices remained independently associated with malignancy after multivariable adjustment, with the strongest positive associations observed for SII (adjusted OR, 2.09; 95% CI, 1.60\u20132.72) and NLR (adjusted OR, 1.96; 95% CI, 1.51\u20132.54). SII demonstrated the numerically highest individual discrimination (AUC 0.687; 95% CI, 0.631\u20130.740), followed by NLR (AUC 0.661) and AISI (AUC 0.659); SII and NLR did not differ significantly (DeLong p = 0.182). Addition of SII increased the AUC of the clinico-ultrasonographic model from 0.695 to 0.761, with an optimism-corrected AUC of 0.721. Hashimoto thyroiditis did not significantly modify these associations. In the molecular subgroup, mutation status increased model discrimination from 0.765 to 0.824, whereas no statistically significant additional improvement with SII was detected in the exploratory molecular subgroup. Conclusions: Preoperative systemic inflammatory indices, particularly SII, provide modest but incremental predictive information beyond conventional clinical and ultrasonographic variables in surgically treated Bethesda III thyroid nodules. Their role appears complementary rather than diagnostic when used in isolation, particularly when comprehensive molecular testing is unavailable. Prospective external validation is required before clinical implementation.<\/jats:p>","DOI":"10.3390\/cancers18193170","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:38:16Z","timestamp":1790847496000},"page":"3170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preoperative Systemic Inflammatory Indices as Adjunctive Biomarkers for Malignancy Prediction in Bethesda III (AUS) Thyroid Nodules"],"prefix":"10.3390","volume":"18","author":[{"given":"G\u00f6khan R\u0131za","family":"Baykal","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Ankara Bilkent City Hospital, Ankara 06800, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"M\u00fcge","family":"Keskin","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Ankara Bilkent City Hospital, Health Sciences University, Ankara 06800, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"K\u00fcbra","family":"Katipo\u011flu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Ankara Bilkent City Hospital, Ankara 06800, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Ersin G\u00fcrkan","family":"Dumlu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara 06800, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Didem","family":"\u00d6zdemir","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara 06800, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Oya","family":"Topalo\u011flu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara 06800, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Reyhan","family":"Ersoy","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara 06800, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Bekir","family":"\u00c7ak\u0131r","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Faculty of Medicine, Ankara Yildirim Beyazit University, Ankara 06800, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/j.1365-2362.2009.02162.x","article-title":"Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination","volume":"39","author":"Guth","year":"2009","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.4103\/jmu.jmu_62_24","article-title":"Ultrasonography of incidental thyroid nodules: A systematic review and meta-analysis of prevalence","volume":"33","author":"Liao","year":"2025","journal-title":"J. Med. Ultrasound"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/thy.2015.0020","article-title":"2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer","volume":"26","author":"Haugen","year":"2016","journal-title":"Thyroid"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.jacr.2017.01.046","article-title":"ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White paper of the ACR TI-RADS Committee","volume":"14","author":"Tessler","year":"2017","journal-title":"J. Am. Coll. Radiol."},{"key":"ref_5","first-page":"1039","article-title":"The 2023 Bethesda System for Reporting Thyroid Cytopathology","volume":"33","author":"Ali","year":"2023","journal-title":"Thyroid"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1002\/cncy.21605","article-title":"A meta-analytic review of the Bethesda System for Reporting Thyroid Cytopathology: Has the rate of malignancy in indeterminate lesions been underestimated?","volume":"123","author":"Straccia","year":"2015","journal-title":"Cancer Cytopathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1002\/hed.24768","article-title":"Comparison of risk of malignancy in a subgroup with atypia of undetermined significance\/follicular lesion of undetermined significance: A meta-analysis","volume":"39","author":"Ahn","year":"2017","journal-title":"Head Neck"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e221","DOI":"10.1055\/s-0039-1698784","article-title":"Malignancy rate in thyroid nodules with atypia or follicular lesion of undetermined significance","volume":"24","author":"Pasha","year":"2020","journal-title":"Int. Arch. Otorhinolaryngol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1210\/jc.2011-1469","article-title":"Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: A prospective analysis of 1056 FNA samples","volume":"96","author":"Nikiforov","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1001\/jamaoncol.2018.4616","article-title":"Performance of a multigene genomic classifier in thyroid nodules with indeterminate cytology: A prospective blinded multicenter study","volume":"5","author":"Steward","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_11","unstructured":"Ontario Health (Quality) (2022). Molecular testing for thyroid nodules of indeterminate cytology: A health technology assessment. Ont. Health Technol. Assess. Ser., 22, 1\u2013111."},{"key":"ref_12","first-page":"286","article-title":"Inflammation in thyroid oncogenesis","volume":"2","author":"Liotti","year":"2012","journal-title":"Am. J. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R85","DOI":"10.1530\/ERC-13-0431","article-title":"The role of the inflammatory microenvironment in thyroid carcinogenesis","volume":"21","author":"Cunha","year":"2014","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e19686","DOI":"10.1097\/MD.0000000000019686","article-title":"Clinical and prognostic value of neutrophil-lymphocyte ratio for patients with thyroid cancer: A meta-analysis","volume":"99","author":"Feng","year":"2020","journal-title":"Medicine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6212","DOI":"10.1158\/1078-0432.CCR-14-0442","article-title":"Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma","volume":"20","author":"Hu","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e822","DOI":"10.4317\/medoral.26779","article-title":"Prognostic value of systemic immune-inflammation index and systemic inflammation response index for oral cancers: A systematic review and meta-analysis","volume":"29","author":"Yang","year":"2024","journal-title":"Med. Oral Patol. Oral Cir. Bucal"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15593258211064744","DOI":"10.1177\/15593258211064744","article-title":"Systemic inflammation response index as a prognostic marker in cancer patients: A systematic review and meta-analysis of 38 cohorts","volume":"19","author":"Zhou","year":"2021","journal-title":"Dose Response"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1007\/s11154-023-09845-x","article-title":"Preoperative systemic inflammatory markers as prognostic factors in differentiated thyroid cancer: A systematic review and meta-analysis","volume":"24","author":"Russo","year":"2023","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.21037\/gs-24-72","article-title":"Association between blood inflammatory indicators and prognosis of papillary thyroid carcinoma: A narrative review","volume":"13","author":"Cai","year":"2024","journal-title":"Gland Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8471235","DOI":"10.1155\/2017\/8471235","article-title":"Association of baseline neutrophil-to-lymphocyte ratio with clinicopathological characteristics of papillary thyroid carcinoma","volume":"2017","author":"Manatakis","year":"2017","journal-title":"Int. J. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2887","DOI":"10.2147\/IJGM.S461708","article-title":"The association of pretreatment systemic immune inflammatory response index (SII) and neutrophil-to-lymphocyte ratio (NLR) with lymph node metastasis in patients with papillary thyroid carcinoma","volume":"17","author":"Gu","year":"2024","journal-title":"Int. J. Gen. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2319660","DOI":"10.1155\/2022\/2319660","article-title":"Peripheral blood inflammatory markers can predict benign and malignant thyroid nodules","volume":"2022","author":"Deng","year":"2022","journal-title":"Int. J. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"131","DOI":"10.20492\/aeahtd.1342736","article-title":"The role of inflammatory parameters in the management of cases with atypia of undetermined significance\/follicular lesions of undetermined significance","volume":"56","author":"Bezirci","year":"2023","journal-title":"Ank. E\u011fitim Ve Ara\u015ft\u0131rma Hastan. T\u0131p Derg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.1007\/s00405-021-07248-9","article-title":"The predictive value of hematologic parameters in the risk of thyroid malignancy in cases with atypia\/follicular lesion of undetermined significance","volume":"279","author":"Bostan","year":"2022","journal-title":"Eur. Arch. Otorhinolaryngol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.5455\/annalsmedres.2020.03.198","article-title":"The predictors of malignancy in thyroid nodules with atypia of undetermined significance or follicular lesions of undetermined significance","volume":"27","author":"Simsek","year":"2020","journal-title":"Ann. Med. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1177\/0003489417719472","article-title":"Risk stratification of thyroid nodules with atypia of undetermined significance\/follicular lesion of undetermined significance cytology using ultrasonography patterns defined by the 2015 ATA guidelines","volume":"126","author":"Lee","year":"2017","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12022-022-09707-3","article-title":"Overview of the 2022 WHO Classification of Thyroid Neoplasms","volume":"33","author":"Baloch","year":"2022","journal-title":"Endocr. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Galdiero, M.R., Varricchi, G., Loffredo, S., Bellevicine, C., Lansione, T., Ferrara, A.L., Iannone, R., Di Somma, S., Borriello, F., and Clery, E. (2018). Potential involvement of neutrophils in human thyroid cancer. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199740"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ferrari, S.M., Fallahi, P., Galdiero, M.R., Ruffilli, I., Elia, G., Ragusa, F., Paparo, S.R., Patrizio, A., Mazzi, V., and Varricchi, G. (2019). Immune and inflammatory cells in thyroid cancer microenvironment. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184413"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1186\/s40001-023-01342-w","article-title":"The critical role of platelet in cancer progression and metastasis","volume":"28","author":"Zhou","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s12307-012-0123-x","article-title":"Monocytes and macrophages in cancer: Development and functions","volume":"6","author":"Richards","year":"2013","journal-title":"Cancer Microenviron."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3895","DOI":"10.1007\/s00262-023-03549-6","article-title":"Tumor-associated macrophages as a potential therapeutic target in thyroid cancers","volume":"72","author":"Zhu","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e37967","DOI":"10.1097\/MD.0000000000037967","article-title":"Advances in systemic immune inflammatory indices in non-small cell lung cancer: A review","volume":"103","author":"Mao","year":"2024","journal-title":"Medicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1002\/cncr.30057","article-title":"A novel systemic inflammation response index (SIRI) for predicting the survival of patients with pancreatic cancer after chemotherapy","volume":"122","author":"Qi","year":"2016","journal-title":"Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zinellu, A., Collu, C., Nasser, M., Paliogiannis, P., Mellino, S., Zinellu, E., Traclet, J., Ahmad, K., Mangoni, A.A., and Carru, C. (2021). The aggregate index of systemic inflammation (AISI): A novel prognostic biomarker in idiopathic pulmonary fibrosis. J. Clin. Med., 10.","DOI":"10.3390\/jcm10184134"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Van Calster, B., McLernon, D.J., van Smeden, M., Wynants, L., Steyerberg, E.W., and Topic Group \u201cEvaluating Diagnostic Tests and Prediction Models\u201d of the STRATOS Initiative (2019). Calibration: The Achilles heel of predictive analytics. BMC Med., 17.","DOI":"10.1186\/s12916-019-1466-7"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.eururo.2018.08.038","article-title":"Reporting and Interpreting Decision Curve Analysis: A Guide for Investigators","volume":"74","author":"Wynants","year":"2018","journal-title":"Eur. Urol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1089\/thy.2014.0353","article-title":"Thyroid ultrasound features and risk of carcinoma: A systematic review and meta-analysis of observational studies","volume":"25","author":"Remonti","year":"2015","journal-title":"Thyroid"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"R203","DOI":"10.1530\/EJE-13-0995","article-title":"Quantification of cancer risk of each clinical and ultrasonographic suspicious feature of thyroid nodules: A systematic review and meta-analysis","volume":"170","author":"Campanella","year":"2014","journal-title":"Eur. J. Endocrinol."},{"key":"ref_40","first-page":"435","article-title":"A comprehensive evaluation of hemogram-derived inflammatory indices in Hashimoto thyroiditis and non-immunogenic hypothyroidism","volume":"19","author":"Erinc","year":"2023","journal-title":"Acta Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/cncy.22112","article-title":"Clinical validation of the ThyroSeq v3 genomic classifier in thyroid nodules with indeterminate FNA cytology","volume":"127","author":"Nikiforov","year":"2019","journal-title":"Cancer Cytopathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/cncy.22796","article-title":"Performance of a multigene genomic classifier and clinical parameters in predicting malignancy in a Southeast Asian cohort of patients with cytologically indeterminate thyroid nodules","volume":"132","author":"Yang","year":"2024","journal-title":"Cancer Cytopathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"E1210","DOI":"10.1002\/hed.24193","article-title":"Institution-specific risk of papillary thyroid carcinoma in atypia\/follicular lesion of undetermined significance","volume":"38","author":"Bernstein","year":"2016","journal-title":"Head Neck"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e698","DOI":"10.1210\/clinem\/dgad181","article-title":"Bethesda III and IV thyroid nodules managed nonoperatively after molecular testing with Afirma GSC or ThyroSeq v3","volume":"108","author":"Kim","year":"2023","journal-title":"J. Clin. Endocrinol. Metab."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3170\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:47:11Z","timestamp":1790848031000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3170"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":44,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cancers18193170"],"URL":"https:\/\/doi.org\/10.3390\/cancers18193170","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]}}}