Extra-thyroidal malignancy history and postoperative malignancy in Bethesda category III thyroid nodules

Year 2026, Volume: 7 Issue: 1, 20 - 25, 20.02.2026

Sena Akça , Merve Çatak

https://izlik.org/JA82SM65TH

Abstract

Aims: Management of Bethesda category III (atypia of undetermined significance/follicular lesion of undetermined significance, AUS/FLUS) thyroid nodules remains challenging due to their heterogeneous malignancy risk. Patients with a history of extrathyroidal malignancy represent a clinically distinct subgroup, yet data regarding malignancy outcomes in this population are limited.
Methods: This retrospective study included 336 patients who underwent thyroid surgery between 2013 and 2023 with preoperative Bethesda category III cytology. Among them, 23 patients (6.7%) had a documented history of extra-thyroidal primary malignancy. Demographic characteristics, thyroid functional status, laboratory parameters, ultrasonographic findings, and history of extra-thyroidal malignancy were recorded. Suspicious ultrasound features were evaluated. Postoperative histopathology was used as the reference standard.
Results: Overall, malignant pathology was identified in 101 patients (30.1%), while 235 patients (69.9%) had benign pathology. A history of extra-thyroidal malignancy was significantly more frequent in patients with malignant postoperative pathology compared with benign cases (10.0% vs 5.5%, p=0.008). Malignant cases were younger than benign cases (p<0.001), and suspicious ultrasonographic features were significantly associated with malignancy (p=0.003). Nodules ≤1 cm were more common in the malignant group (p=0.016). Thyroid hormone levels did not differ significantly between benign and malignant pathology groups. Within the subgroup of patients with extra-thyroidal malignancy, further comparisons between benign and malignant thyroid pathology did not reach statistical significance, likely due to limited sample size, and were therefore considered descriptive.
Conclusion: In patients with Bethesda category III thyroid cytology, a history of extra-thyroidal malignancy was associated with a higher likelihood of malignant postoperative pathology. These findings suggest that patients with prior malignancy constitute a higher-risk subgroup and may benefit from a more individualized management strategy, including consideration of earlier surgical intervention after a single indeterminate cytology result.

Keywords

Bethesda category III , extra-thyroidal malignancy , AUS/FLUS , thyroid nodules , malignancy risk

References

• Kaya C, Bozkurt E, Türkyılmaz Mut D, Mihmanli M, Uludağ M. Which factors are associated with malignancy in thyroid nodules classified as Bethesda category 3 (aus/flus) and how do they influence the patient's management? Acta Endocrinol (Buchar). 2019;15(4):491-496. doi:10. 4183/aeb.2019.491
• Kocer D, Karakukcu C, Karaman H, Gokay F, Bayram F. May the neutrophil/lymphocyte ratio be a predictor in the differentiation of different thyroid disorders? Asian Pac J Cancer Prev. 2015;16(9):3875-3879. doi:10.7314/apjcp.2015.16.9.3875
• Bostan H, Sencar ME, Calapkulu M, et al. The predictive value of hematologic parameters in the risk of thyroid malignancy in cases with atypia/follicular lesion of undetermined significance. Eur Arch Otorhinolaryngol. 2022;279(8):4077-4084. doi:10.1007/s00405-021-07248-9
• Słowińska-Klencka D, Popowicz B, Duda-Szymańska J, Klencki M. Thyroid nodules with nuclear atypia of undetermined significance (AUS-Nuclear) hold a two-times-higher risk of malignancy than AUS-other nodules regardless of EU-TIRADS class of the nodule or borderline tumor interpretation. Cancers (Basel). 2025;17(8):1365. doi: 10.3390/cancers17081365
• Cibas ES, Ali SZ. The 2017 Bethesda system for reporting thyroid cytopathology. Thyroid. 2017;27(11):1341-1346. doi:10.1089/thy.2017.0500
• Kaliszewski K, Diakowska D, Rzeszutko M, Nowak Ł, Tokarczyk U, Rudnicki J. Atypia and follicular lesions of undetermined significance in subsequent biopsy result: what clinicians need to know. J Clin Med. 2021;10(14):3082. doi:10.3390/jcm10143082
• Altın F, Paksoy M. What should be considered in Bethesda III thyroid nodules when prefering hemitioidectomy or total thyroidectomy. Med Bull Haseki. 2020;58(3):293-300. doi:10.4274/haseki.galenos.2020.6185
• Zahnreich S, Schmidberger H. Childhood cancer: occurrence, treatment and risk of second primary malignancies. Cancers (Basel). 2021;13(11): 2607. doi:10.3390/cancers13112607
• Pan SY, Huang CP, Chen WC. Synchronous/metachronous multiple primary malignancies: review of associated risk factors. Diagnostics (Basel). 2022;12(8):1940. doi:10.3390/diagnostics12081940
• Demoor-Goldschmidt C, de Vathaire F. Review of risk factors of secondary cancers among cancer survivors. Br J Radiol. 2019;92(1093): 20180390. doi:10.1259/bjr.20180390
• Krzentowska A, Gołkowski F, Broniatowska E, Konturek A, Barczyński M. Risk factors for malignancy of thyroid nodules in patients undergoing thyroid resection. J Clin Med. 2024;13(24):7559. doi:10.3390/jcm13247559
• Paulus YM, Riedel ER, Sabra MM, Tuttle RM, Kalin MF. Prevalence of diabetes mellitus in patients with newly evaluated papillary thyroid cancer. Thyroid Res. 2014;7:7. doi:10.1186/1756-6614-7-7
• Delman AM, Turner KM, Ammann AM, Sisak S, Farooqui Z, Holm TM. The national rate of malignancy among Bethesda III, IV, and V thyroid nodules is higher than expected: a NSQIP analysis. Surgery. 2023;173(3):645-652. doi:10.1016/j.surg.2022.06.049
• Iskandar ME, Bonomo G, Avadhani V, et al. Evidence for overestimation of the prevalence of malignancy in indeterminate thyroid nodules classified as Bethesda category III. Surgery. 2015;157(3):510-517. doi:10. 1016/j.surg.2014.10.004
• Hassan I, Hassan L, Balalaa N, Askar M, Alshehhi H, Almarzooqi M. The incidence of thyroid cancer in Bethesda III thyroid nodules: a retrospective analysis at a single endocrine surgery center. Diagnostics (Basel). 2024;14(10):1026. doi:10.3390/diagnostics14101026
• Liu X, Wang J, Du W, Dai L, Fang Q. Predictors of malignancy in thyroid nodules classified as Bethesda category III. Front Endocrinol (Lausanne). 2022;13:806028. doi:10.3389/fendo.2022.806028
• Kant R, Davis A, Verma V. Thyroid nodules: advances in evaluation and management. Am Fam Physician. 2020;102(5):298-304.
• Yuan Y, Sun P, Xiao H, Li L, Li J, Ai X. Risk of second primary thyroid cancer in cancer survivors. Sci Rep. 2024;14(1):12478. doi:10.1038/s 41598-024-63155-z
• Trinh LN, Crawford AR, Hussein MH, et al. Deciphering the risk of developing second primary thyroid cancer following a primary malignancy-who is at the greatest risk? Cancers (Basel). 2021;13(6):1402. doi:10.3390/cancers13061402
• Crocetti E, Mattioli V, Buzzoni C, et al. Risk of thyroid as a first or second primary cancer. A population-based study in Italy, 1998-2012. Cancer Med. 2021;10(19):6855-6867. doi:10.1002/cam4.4193
• Cohen A, Rovelli A, Merlo DF, et al. Risk for secondary thyroid carcinoma after hematopoietic stem-cell transplantation: an EBMT Late Effects Working Party Study. J Clin Oncol. 2007;25(17):2449-2454. doi: 10.1200/JCO.2006.08.9276
• Yildirim UM, Kebudi R, İribaş Çelik A, Zülfikar B, Kebudi A. Thyroid cancer in childhood cancer survivors: demographic, clinical, germline genetic characteristics, treatment, and outcome. J Clin Med. 2025;14(2): 589. doi:10.3390/jcm14020589
• Al-Ibraheem A, Abdlkadir AS, Al-Adhami DA, et al. Comparative analysis through propensity score matching in thyroid cancer: unveiling the impact of multiple malignancies. Front Endocrinol (Lausanne). 2024;15:1366935. doi:10.3389/fendo.2024.1366935
• Cieszyńska M, Kluźniak W, Wokołorczyk D, et al. Risk of second primary thyroid cancer in women with breast cancer. Cancers (Basel). 2022;14(4):957. doi:10.3390/cancers14040957
• Ko WS, Kim SJ. Prediction of malignant thyroid nodules using 18 F-FDG PET/CT-based radiomics features in thyroid incidentalomas. Clin Nucl Med. 2023;48(6):497-504. doi:10.1097/RLU.0000000000004637
• Kostek M, Kostek H, Unlu MT, et al. Deciding on fine needle aspiration biopsy in thyroid incidentalomas in FDG-PET/CT: should ultrasonographic evaluation or FDG uptake be in the foreground? Sisli Etfal Hastan Tip Bul. 2025;59(1):20-27. doi:10.14744/SEMB.2025.49140
• Topaloglu O, Baser H, Cuhaci FN, et al. Malignancy is associated with microcalcification and higher AP/T ratio in ultrasonography, but not with Hashimoto's thyroiditis in histopathology in patients with thyroid nodules evaluated as Bethesda Category III (AUS/FLUS) in cytology. Endocrine. 2016;54(1):156-168. doi:10.1007/s12020-016-0982-x
• Li F, Pan D, Wu Y, et al. Ultrasound characteristics of thyroid nodules facilitate interpretation of the malignant risk of Bethesda system III/IV thyroid nodules and inform therapeutic schedule. Diagn Cytopathol. 2019;47(9):881-889. doi:10.1002/dc.24248
• Alshahrani AS, Alamri AS, Balkhoyor AH, Mahzari MM, Alshieban SS, Majed PM. The prediction of malignancy risk in thyroid nodules classified as Bethesda system category III (AUS/FLUS) and the role of ultrasound finding for prediction of malignancy risk. Cureus. 2021; 13(9):e17924. doi:10.7759/cureus.17924
• Kaliszewski K, Diakowska D, Rzeszutko M, et al. Assessment of preoperative TSH serum level and thyroid cancer occurrence in patients with AUS/FLUS thyroid nodule diagnosis. Biomedicines. 2022;10(8): 1916. doi:10.3390/biomedicines10081916
• Fan XY, You W, Chen Y, et al. A meta-analysis of the value of serum TSH concentration in the diagnosis of differentiated thyroid cancer in patients with thyroid nodules. Heliyon. 2024;10(2):e24391. doi:10.1016/j.heliyon.2024.e24391