Clinical Implications of Lymph Node Thyroglobulin in Papillary Thyroid Carcinoma Metastases: Independent from Thyroglobulin Antibody Interference
Abstract
1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Measurement Methods and Biochemical Analysis
4.3. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Miranda-Filho, A.; Lortet-Tieulent, J.; Bray, F.; Cao, B.; Franceschi, S.; Vaccarella, S.; Dal Maso, L. Thyroid cancer incidence trends by histology in 25 countries: A population-based study. Lancet Diabetes Endocrinol. 2021, 9, 225–234. [Google Scholar] [CrossRef] [PubMed]
- Fiorentino, V.; Dell’Aquila, M.; Musarra, T.; Martini, M.; Capodimonti, S.; Fadda, G.; Curatolo, M.; Traini, E.; Raffaelli, M.; Lombardi, C.P. The role of cytology in the diagnosis of subcentimeter thyroid lesions. Diagnostics 2021, 11, 1043. [Google Scholar] [CrossRef] [PubMed]
- Lam, A.K. Papillary thyroid carcinoma: Current position in epidemiology, genomics, and classification. In Papillary Thyroid Carcinoma: Methods and Protocols; Springer: Berlin/Heidelberg, Germany, 2022; pp. 1–15. [Google Scholar]
- Kitahara, C.M.; Schneider, A.B. Epidemiology of thyroid cancer. Cancer Epidemiol. Biomark. Prev. 2022, 31, 1284–1297. [Google Scholar] [CrossRef]
- Liu, F.H.; Kuo, S.F.; Hsueh, C.; Chao, T.C.; Lin, J.D. Postoperative recurrence of papillary thyroid carcinoma with lymph node metastasis. J. Surg. Oncol. 2015, 112, 149–154. [Google Scholar] [CrossRef]
- Podnos, Y.D.; Smith, D.; Wagman, L.D.; Ellenhorn, J.D. The implication of lymph node metastasis on survival in patients with well-differentiated thyroid cancer. Am. Surg. 2005, 71, 731–734. [Google Scholar] [CrossRef]
- Hay, I.D.; Johnson, T.R.; Kaggal, S.; Reinalda, M.S.; Iniguez-Ariza, N.M.; Grant, C.S.; Pittock, S.T.; Thompson, G.B. Papillary thyroid carcinoma (PTC) in children and adults: Comparison of initial presentation and long-term postoperative outcome in 4432 patients consecutively treated at the Mayo Clinic during eight decades (1936–2015). World J. Surg. 2018, 42, 329–342. [Google Scholar] [CrossRef]
- Roti, E.; degli Uberti, E.C.; Bondanelli, M.; Braverman, L.E. Thyroid papillary microcarcinoma: A descriptive and meta-analysis study. Eur. J. Endocrinol. 2008, 159, 659–673. [Google Scholar] [CrossRef]
- Durante, C.; Montesano, T.; Torlontano, M.; Attard, M.; Monzani, F.; Tumino, S.; Costante, G.; Meringolo, D.; Bruno, R.; Trulli, F. Papillary thyroid cancer: Time course of recurrences during postsurgery surveillance. J. Clin. Endocrinol. Metab. 2013, 98, 636–642. [Google Scholar] [CrossRef] [PubMed]
- Leenhardt, L.; Erdogan, M.; Hegedus, L.; Mandel, S.; Paschke, R.; Rago, T.; Russ, G. 2013 European thyroid association guidelines for cervical ultrasound scan and ultrasound-guided techniques in the postoperative management of patients with thyroid cancer. Eur. Thyroid J. 2013, 2, 147–159. [Google Scholar] [CrossRef]
- Frasoldati, A.; Toschi, E.; Zini, M.; Flora, M.; Caroggio, A.; Dotti, C.; Valcavi, R. Role of thyroglobulin measurement in fine-needle aspiration biopsies of cervical lymph nodes in patients with differentiated thyroid cancer. Thyroid 1999, 9, 105–111. [Google Scholar] [CrossRef]
- Hasukic, B.; Jakubovic-Cickusic, A.; Sehanovic, E.; Osmic, H. Fine needle aspiration cytology and thyroglobulin antibodies in preoperative diagnosis of thyroid malignancy. Med. Arch. 2019, 73, 382. [Google Scholar] [CrossRef] [PubMed]
- Al-Hilli, Z.; Strajina, V.; McKenzie, T.J.; Thompson, G.B.; Farley, D.R.; Regina Castro, M.; Algeciras-Schimnich, A.; Richards, M.L. Thyroglobulin measurement in fine-needle aspiration improves the diagnosis of cervical lymph node metastases in papillary thyroid carcinoma. Ann. Surg. Oncol. 2017, 24, 739–744. [Google Scholar] [CrossRef] [PubMed]
- Hall, T.L.; Layfield, L.J.; Philippe, A.; Rosenthal, D.L. Sources of diagnostic error in fine needle aspiration of the thyroid. Cancer 1989, 63, 718–725. [Google Scholar] [CrossRef]
- Pacini, F.; Fugazzola, L.; Lippi, F.; Ceccarelli, C.; Centoni, R.; Miccoli, P.; Elisei, R.; Pinchera, A. Detection of thyroglobulin in fine needle aspirates of nonthyroidal neck masses: A clue to the diagnosis of metastatic differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 1992, 74, 1401–1404. [Google Scholar]
- Trimboli, P.; D’Aurizio, F.; Tozzoli, R.; Giovanella, L. Measurement of thyroglobulin, calcitonin, and PTH in FNA washout fluids. Clin. Chem. Lab. Med. (CCLM) 2017, 55, 914–925. [Google Scholar] [CrossRef]
- Moon, J.H.; Kim, Y.I.; Lim, J.A.; Choi, H.S.; Cho, S.W.; Kim, K.W.; Park, H.J.; Paeng, J.C.; Park, Y.J.; Yi, K.H. Thyroglobulin in washout fluid from lymph node fine-needle aspiration biopsy in papillary thyroid cancer: Large-scale validation of the cutoff value to determine malignancy and evaluation of discrepant results. J. Clin. Endocrinol. Metab. 2013, 98, 1061–1068. [Google Scholar] [CrossRef] [PubMed]
- Xiao, J.; Meng, S.; Zhang, M.; Li, Y.; Yan, L.; Li, X.; Yang, Z.; Zhang, Y.; Luo, Y. Optimal method for detecting cervical lymph node metastasis from papillary thyroid cancer. Endocrine 2023, 79, 342–348. [Google Scholar] [CrossRef]
- Torres, M.R.d.S.; Nóbrega Neto, S.H.; Rosas, R.J.; Martins, A.L.B.; Ramos, A.L.C.; da Cruz, T.R.P. Thyroglobulin in the washout fluid of lymph-node biopsy: What is its role in the follow-up of differentiated thyroid carcinoma? Thyroid 2014, 24, 7–18. [Google Scholar] [CrossRef]
- Grani, G.; Fumarola, A. Thyroglobulin in lymph node fine-needle aspiration washout: A systematic review and meta-analysis of diagnostic accuracy. J. Clin. Endocrinol. Metab. 2014, 99, 1970–1982. [Google Scholar] [CrossRef]
- Zhao, H.; Wang, Y.; Wang, M.J.; Zhang, Z.H.; Wang, H.R.; Zhang, B.; Guo, H.Q. Influence of presence/absence of thyroid gland on the cutoff value for thyroglobulin in lymph-node aspiration to detect metastatic papillary thyroid carcinoma. BMC Cancer 2017, 17, 296. [Google Scholar] [CrossRef]
- Jiang, H.J.; Hsiao, P.J. Clinical application of the ultrasound-guided fine needle aspiration for thyroglobulin measurement to diagnose lymph node metastasis from differentiated thyroid carcinoma-literature review. Kaohsiung J. Med. Sci. 2020, 36, 236–243. [Google Scholar] [CrossRef] [PubMed]
- Haugen, B.R.; Alexander, E.K.; Bible, K.C.; Doherty, G.M.; Mandel, S.J.; Nikiforov, Y.E.; Pacini, F.; Randolph, G.W.; Sawka, A.M.; Schlumberger, M. 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. Thyroid 2016, 26, 1–133. [Google Scholar] [CrossRef]
- Jiang, H.J.; Wu, C.W.; Chiang, F.Y.; Chiou, H.Y.; Chen, I.J.; Hsiao, P.J. Reliable sonographic features for nodal thyroglobulin to diagnose recurrent lymph node metastasis from papillary thyroid carcinoma. Clin. Otolaryngol. 2018, 43, 1065–1072. [Google Scholar] [CrossRef] [PubMed]
- Xu, Y.; Xu, L.; Wang, J. Clinical predictors of lymph node metastasis and survival rate in papillary thyroid microcarcinoma: Analysis of 3607 patients at a single institution. J. Surg. Res. 2018, 221, 128–134. [Google Scholar] [CrossRef]
- Yao, R.; Chiu, C.G.; Strugnell, S.S.; Gill, S.; Wiseman, S.M. Gender differences in thyroid cancer: A critical review. Expert Rev. Endocrinol. Metab. 2011, 6, 215–243. [Google Scholar] [CrossRef] [PubMed]
- Lee, S.; Lee, J.Y.; Yoon, R.G.; Kim, J.-h.; Hong, H.S. The value of microvascular imaging for triaging indeterminate cervical lymph nodes in patients with papillary thyroid carcinoma. Cancers 2020, 12, 2839. [Google Scholar] [CrossRef]
- Li, Q.L.; Ma, T.; Wang, Z.J.; Huang, L.; Liu, W.; Chen, M.; Sang, T.; Ren, X.G.; Tong, J.; Cao, C.L. The value of contrast-enhanced ultrasound for the diagnosis of metastatic cervical lymph nodes of papillary thyroid carcinoma: A systematic review and meta-analysis. J. Clin. Ultrasound 2022, 50, 60–69. [Google Scholar] [CrossRef]
- Zhang, M.-B.; Meng, Z.-L.; Mao, Y.; Jiang, X.; Xu, N.; Xu, Q.-H.; Tian, J.; Luo, Y.-K.; Wang, K. Cervical lymph node metastasis prediction from papillary thyroid carcinoma US videos: A prospective multicenter study. BMC Med. 2024, 22, 153. [Google Scholar] [CrossRef]
- David, E.; Grazhdani, H.; Tattaresu, G.; Pittari, A.; Foti, P.V.; Palmucci, S.; Spatola, C.; Greco, M.C.L.; Inì, C.; Tiralongo, F. Thyroid nodule characterization: Overview and state of the art of diagnosis with recent developments, from imaging to molecular diagnosis and artificial intelligence. Biomedicines 2024, 12, 1676. [Google Scholar] [CrossRef]
- Demers, L.M.; Spencer, C.A. Laboratory medicine practice guidelines: Laboratory support for the diagnosis and monitoring of thyroid disease. Clin. Endocrinol. 2003, 58, 138. [Google Scholar] [CrossRef]
- Spencer, C.; Bergoglio, L.; Kazarosyan, M.; Fatemi, S.; LoPresti, J. Clinical impact of thyroglobulin (Tg) and Tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas. J. Clin. Endocrinol. Metab. 2005, 90, 5566–5575. [Google Scholar] [CrossRef] [PubMed]
- Borel, A.-L.; Boizel, R.; Faure, P.; Barbe, G.; Boutonnat, J.; Sturm, N.; Seigneurin, D.; Bricault, I.; Caravel, J.-P.; Chaffanjon, P. Significance of low levels of thyroglobulin in fine needle aspirates from cervical lymph nodes of patients with a history of differentiated thyroid cancer. Eur. J. Endocrinol. 2008, 158, 691–698. [Google Scholar] [CrossRef] [PubMed]
- Jack Baskin, H. Detection of recurrent papillary thyroid carcinoma by thyroglobulin assessment in the needle washout after fine-needle aspiration of suspicious lymph nodes. Thyroid 2004, 14, 959–963. [Google Scholar] [CrossRef]
- Snozek, C.L.; Chambers, E.P.; Reading, C.C.; Sebo, T.J.; Sistrunk, J.W.; Singh, R.J.; Grebe, S.K. Serum thyroglobulin, high-resolution ultrasound, and lymph node thyroglobulin in diagnosis of differentiated thyroid carcinoma nodal metastases. J. Clin. Endocrinol. Metab. 2007, 92, 4278–4281. [Google Scholar] [CrossRef]
- Bournaud, C.; Charrié, A.; Nozières, C.; Chikh, K.; Lapras, V.; Denier, M.-L.; Paulin, C.; Decaussin-Petrucci, M.; Peix, J.-L.; Lifante, J.-C. Thyroglobulin measurement in fine-needle aspirates of lymph nodes in patients with differentiated thyroid cancer: A simple definition of the threshold value, with emphasis on potential pitfalls of the method. Clin. Chem. Lab. Med. 2010, 48, 1171–1177. [Google Scholar] [CrossRef]
- Kim, D.-W.; Jeon, S.J.; Kim, C.G. Usefulness of thyroglobulin measurement in needle washouts of fine-needle aspiration biopsy for the diagnosis of cervical lymph node metastases from papillary thyroid cancer before thyroidectomy. Endocrine 2012, 42, 399–403. [Google Scholar] [CrossRef]
- Uruno, T.; Miyauchi, A.; Shimizu, K.; Tomoda, C.; Takamura, Y.; Ito, Y.; Miya, A.; Kobayashi, K.; Matsuzuka, F.; Amino, N. Usefulness of thyroglobulin measurement in fine-needle aspiration biopsy specimens for diagnosing cervical lymph node metastasis in patients with papillary thyroid cancer. World J. Surg. 2005, 29, 483–485. [Google Scholar] [CrossRef] [PubMed]
- D’angeli, S.; Paladino, N.C.; Fargette, C.; Archange, C.; Essamet, W.; Hamidou, Z.; Palazzo, F.; Baumstarck, K.; Sebag, F.; Taïeb, D. Lymph node thyroglobulin in the diagnosis of metastases of thyroid carcinoma with the thyroid in situ: A prospective intraoperative study. Eur. J. Surg. Oncol. 2023, 49, 760–763. [Google Scholar] [CrossRef]
- Boi, F.; Baghino, G.; Atzeni, F.; Lai, M.; Faa, G.; Mariotti, S. The diagnostic value for differentiated thyroid carcinoma metastases of thyroglobulin (Tg) measurement in washout fluid from fine-needle aspiration biopsy of neck lymph nodes is maintained in the presence of circulating anti-Tg antibodies. J. Clin. Endocrinol. Metab. 2006, 91, 1364–1369. [Google Scholar] [CrossRef]
- Sigstad, E.; Heilo, A.; Paus, E.; Holgersen, K.; Grøholt, K.; Jørgensen, L.; Bogsrud, T.; Berner, A.; Bjøro, T. The usefulness of detecting thyroglobulin in fine-needle aspirates from patients with neck lesions using a sensitive thyroglobulin assay. Diagn. Cytopathol. 2007, 35, 761–767. [Google Scholar] [CrossRef]
- Cappelli, C.; Pirola, I.; De Martino, E.; Gandossi, E.; Cimino, E.; Samoni, F.; Agosti, B.; Rosei, E.A.; Casella, C.; Castellano, M. Thyroglobulin measurement in fine-needle aspiration biopsy of metastatic lymph nodes after rhTSH stimulation. Head Neck 2013, 35, E21–E23. [Google Scholar] [CrossRef] [PubMed]
- Zanella, A.B.; Meyer, E.L.S.; Balzan, L.; Silva, A.C.; Camargo, J.; Migliavacca, A.; Guimarães, J.R.; Maia, A.L. Thyroglobulin measurements in washout of fine needle aspirates in cervical lymph nodes for detection of papillary thyroid cancer metastases. Arq. Bras. Endocrinol. Metabol. 2010, 54, 550–554. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.-h.; Baek, J.H.; Lim, H.K.; Ahn, H.S.; Baek, S.M.; Choi, Y.J.; Choi, Y.J.; Chung, S.R.; Ha, E.J.; Hahn, S.Y. 2017 thyroid radiofrequency ablation guideline: Korean Society of Thyroid Radiology. Korean J. Radiol. 2018, 19, 632–655. [Google Scholar] [CrossRef] [PubMed]
- San Lim, L.; Lin, W.-C.; Chiang, P.-L.; Huang, S.C.; Chen, Y.-S.; Chang, Y.-H.; Chen, W.-C.; Chi, S.-Y.; Chou, C.-K. One year follow-up of US-Guided radiofrequency ablation for low-risk papillary thyroid microcarcinoma: The first experience in Taiwan. J. Formos. Med. Assoc. 2022, 121, 1406–1413. [Google Scholar]
- Cibas, E.S.; Ali, S.Z. The 2017 Bethesda system for reporting thyroid cytopathology. Thyroid 2017, 27, 1341–1346. [Google Scholar] [CrossRef]
All Patients (n = 63) | Final Diagnosis | |||
---|---|---|---|---|
Malignancy (n = 22) | Benign (n = 41) | p Value | ||
Patients’ characteristics | ||||
Sex (males/females) | [15/48] | [4/18] | [11/30] | 0.442 |
Age, y | 50 ± 13.1 | 50.5 ± 14.9 | 50 ± 12.1 | 0.990 |
Primary tumor | ||||
Size, mm | 15 (18) | 18 (14.2) | 16 (19) | 0.266 |
LN metastasis, % [yes/no] | 41.2% [26/37] | 54.5% [12/10] | 34.1% [14/27] | 0.179 |
Distant metastasis, % [yes/no] | 3.2% [2/61] | 9% [2/20] | 0% [0/41] | 0.118 |
Follow-up LNs | ||||
Size, mm | 8 (4) | 7.5 (3.7) | 8 (4) | 0.873 |
Calcification (yes/no) | [3/60] | [3/19] | [0/41] | 0.039 |
Cystic content (yes/no) | [7/56] | [4/18] | [3/38] | 0.281 |
Hyperechoic content (yes/no) | [14/49] | [6/16] | [8/33] | 0.534 |
Absence of hilum (yes/no) | [38/25] | [17/5] | [21/20] | 0.060 |
Lab data | ||||
Serum Tg, ng/mL | 1.67 (12.7) | 4.8 (20.4) | 0.7 (10.8) | 0.021 |
Serum Tg antibody (yes/no) | [9/54] | [4/18] | [5/36] | 0.133 |
Serum TSH, µIU/mL | 0.4 (1.9) | 0.24 (1.47) | 0.50 (2.04) | 0.065 |
FNA-Tg, ng/mL | 0.4 (976) | 5000 (4447) | 0.04 (0.26) | <0.001 |
Sensitivity | Specificity | PPV | NPV | Accuracy | |
---|---|---|---|---|---|
FNA-Tg > 4.23 ng/mL | 100% | 90.2% | 84.6% | 100% | 93.6% |
FNA-Tg > 1 ng/mL [17,23] | 100% | 80.5% | 73.3% | 100% | 87.3% |
FNA-Tg-Serum Tg > 1 ng/mL [24] | 95.5% | 90.2% | 84.4% | 97.4% | 92% |
Serum Tg Antibody (+) | FNA-Tg, ng/mL | Serum Tg, ng/mL | LN Size, mm |
---|---|---|---|
Malignancy-Case 1 | 535 | 0.8 | 8 |
Malignancy-Case 2 | 5000 | 0.5 | 13 |
Malignancy-Case 3 | 5021 | 0.04 | 6 |
Malignancy-Case 4 | 508 | 0.04 | 5 |
Benign-Case 1 | 0.04 | 0.1 | 8 |
Benign-Case 2 | 0.3 | 0.1 | 7 |
Benign-Case 3 | 0.48 | 0.03 | 5 |
Benign-Case 4 | 0.04 | 0.04 | 11 |
Benign-Case 5 | 3.93 | 14.2 | 8 |
Benign Group | Thyroid Preserved | Total Thyroid Removed | p Value |
---|---|---|---|
Cases, n | 11 | 30 | |
FNA-Tg, ng/mL | 0.05 (0.18) | 0.04 (0.14) | 0.607 |
Serum Tg, ng/mL | 9.22 (19.2) | 0.2 (5.57) | 0.027 |
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Kuo, P.-C.; Chen, W.-C.; Lin, W.-C.; Chi, S.-Y.; Chiu, Y.-H.; Yang, Y.-C.; Chou, C.-K. Clinical Implications of Lymph Node Thyroglobulin in Papillary Thyroid Carcinoma Metastases: Independent from Thyroglobulin Antibody Interference. Int. J. Mol. Sci. 2025, 26, 5340. https://doi.org/10.3390/ijms26115340
Kuo P-C, Chen W-C, Lin W-C, Chi S-Y, Chiu Y-H, Yang Y-C, Chou C-K. Clinical Implications of Lymph Node Thyroglobulin in Papillary Thyroid Carcinoma Metastases: Independent from Thyroglobulin Antibody Interference. International Journal of Molecular Sciences. 2025; 26(11):5340. https://doi.org/10.3390/ijms26115340
Chicago/Turabian StyleKuo, Ping-Chen, Wen-Chieh Chen, Wei-Che Lin, Shun-Yu Chi, Yi-Hsiang Chiu, Ya-Chen Yang, and Chen-Kai Chou. 2025. "Clinical Implications of Lymph Node Thyroglobulin in Papillary Thyroid Carcinoma Metastases: Independent from Thyroglobulin Antibody Interference" International Journal of Molecular Sciences 26, no. 11: 5340. https://doi.org/10.3390/ijms26115340
APA StyleKuo, P.-C., Chen, W.-C., Lin, W.-C., Chi, S.-Y., Chiu, Y.-H., Yang, Y.-C., & Chou, C.-K. (2025). Clinical Implications of Lymph Node Thyroglobulin in Papillary Thyroid Carcinoma Metastases: Independent from Thyroglobulin Antibody Interference. International Journal of Molecular Sciences, 26(11), 5340. https://doi.org/10.3390/ijms26115340