Thyroglobulin mRNA ectopic expression was an excellent marker to detect lymph node metastasis for patients with papillary thyroid cancer

Abstract

Objective: To investigate whether the mRNA expression of thyroglobulin (TG) and TSH receptor (TSHR) in lymph node could be used to diagnose lymph node metastasis in patients with papillary thyroid cancer (PTC).

Subjects and methods: Around 156 paraffin samples of lymph nodes from 89 patients with PTC after surgery were collected, and the expressions of TG and TSHR mRNA were detected by nested qPCR.

Results: Compared with the results of confirmed histopathology, 86 out of 87 tissues of lymph nodes metastasis ectopically expressed TG mRNA, while 66 out of 69 tissues of non-metastasis lymph nodes did not express the TG mRNA. The specificity and sensitivity of TG mRNA measurement for detecting the lymph node metastasis were 95.65% and 98.85%, as effective as the first postoperative histopathology. However, the specificity and sensitivity of TSHR mRNA measurement were 92.75% and 85.06%, respectively. The accuracy of TG, TSHR mRNA measurement and the first postoperative histopathology were 97.44%, 88.46% and 95.51%, with the positive predictive rate (PPR) 96.63%, 93.67%, and 98.78%, respectively, negative predictive rate (NPR) 98.51%, 83.12% and 91.89%, respectively, as well as Youden’s index 0.95, 0.78 and 0.92.

Conclusions: TG mRNA ectopic expression in the lymph node might be an excellent marker to diagnose the lymph node metastasis for patients with PTCs.

Keywords

mRNA expression / nested qPCR / papillary thyroid cancer / thyroglobulin / TSH receptor

References

[1] HuangJ, NgaiCH, DengY, et al. Incidence and mortality of thyroid cancer in 50 countries: a joinpoint regression analysis of global trends. Endocrine. 2023;80:355-365.

[2] DuranteC, GraniG, LamartinaL, Filetti S, MandelSJ, CooperDS. The diagnosis and management of thyroid nodules: a review. JAMA. 2018;319:914-924.

[3] JangJY, KimDS, ParkHY, et al. Preoperative serum VEGF-C but not VEGF-A level is correlated with lateral neck metastasis in papillary thyroid carcinoma. Head Neck. 2019;41:2602-2609.

[4] GronlundMP, JensenJS, HahnCH, Gronhoj C, BuchwaldCV. Risk factors for recurrence of follicular thyroid cancer: a systematic review. Thyroid. 2021;31:1523-1530.

[5] ZouM, BaiteiEY, AlzahraniAS, et al. Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma. Thyroid. 2014;24:1256-1266.

[6] LiuW, ZhuJ, WuZ, et al. Insight of novel biomarkers for papillary thyroid carcinoma through multiomics. Front Oncol. 2023;13:1269751.

[7] OrtizI, Barros-Filho MC, Dos ReisMB, et al. Loss of DNA methylation is related to increased expression of miR-21 and miR-146b in papillary thyroid carcinoma. Clin Epigenetics. 2018;10:144.

[8] DiaoY, FuH, WangQ. MiR-221 exacerbate cell proliferation and invasion by targeting TIMP3 in papillary thyroid carcinoma. Am J Ther. 2017;24:e317-e328.

[9] ZhangC, ChangQ, HuY, et al. MiR-222-3p promotes the proliferation, migration and invasion of papillary thyroid carcinoma cells through targeting SLC4A4. Histol Histopathol. 2021;36:1199-1207.

[10] BrownLM, HelmkeSM, HunsuckerSW, et al. Quantitative and qualitative differences in protein expression between papillary thyroid carcinoma and normal thyroid tissue. Mol Carcinog. 2006;45:613-626.

[11] AbdullahMI, LeeCC, Mat JunitS, Ng KL, HashimOH. Tissue and serum samples of patients with papillary thyroid cancer with and without benign background demonstrate different altered expression of proteins. PeerJ. 2016;4:e2450.

[12] YuanX, YuanH, ZhangN, Liu T, XuD. Thyroid carcinoma-featured telomerase activation and telomere maintenance: biology and translational/clinical significance. Clin Transl Med. 2022;12:e1111.

[13] DunnLA, Sherman EJ, BaxiSS, et al. Vemurafenib redifferentiation of BRAF mutant, RAI-refractory thyroid cancers. J Clin Endocrinol Metab. 2019;104:1417-1428.

[14] IesatoA, LiS, RotiG, Hacker MR, FischerAH, NuceraC. Lenvatinib targets PDGFR-beta pericytes and inhibits synergy with thyroid carcinoma cells: novel translational insights. J Clin Endocrinol Metab. 2021;106:3569-3590.

[15] MengL, ZhaoP, HuZ, et al. Nilotinib, a tyrosine kinase inhibitor, suppresses the cell growth and triggers autophagy in papillary thyroid cancer. Anticancer Agents Med Chem. 2022;22:596-602.

[16] Borson-ChazotF, Dantony E, IllouzF, et al. Effect of buparlisib, a Pan-Class I PI3K inhibitor, in refractory follicular and poorly differentiated thyroid cancer. Thyroid. 2018;28:1174-1179.

[17] JamaiyarA, YogeshK. How accurate is fine-needle aspiration cytology (FNAC) for thyroid lesion: a correlation of FNAC with histopathology. J Family Med Prim Care. 2023;12:15-20.

[18] CibasES, AliSZ. The 2017 Bethesda system for reporting thyroid cytopathology. Thyroid. 2017;27:1341-1346.

[19] BadulescuIC, BarbusE, PiciuD. Circulating tumor cells in thyroid carcinoma—the prognostic role of this biomarker. Review of the literature. Clujul Med. 2017;90:256-261.

[20] WangSF, ZhaoWH, WangWB, Teng XD, TengLS, MaZM. Clinical features and prognosis of patients with benign thyroid disease accompanied by an incidental papillary carcinoma. Asian Pac J Cancer Prev. 2013;14:707-711.

[21] SmithJJ, ChenX, SchneiderDF, et al. Cancer after thyroidectomy: a multi-institutional experience with 1, 523 patients. J Am Coll Surg. 2013;216:571-577. discussion 577–579.

[22] BombilI, Bentley A, KrugerD, LuvhengoTE. Incidental cancer in multinodular goitre post thyroidectomy. S Afr J Surg. 2014;52:5-9.

[23] LuoJ, McManus C, ChenH, SippelRS. Are there predictors of malignancy in patients with multinodular goiter? J Surg Res. 2012;174:207-210.

[24] MirkatouliNB, HirotaS, YoshinagaS. Thyroid cancer risk after radiation exposure in adults-systematic review and meta-analysis. J Radiat Res. 2023;64:893-903.

[25] IglesiasML, Schmidt A, GhuzlanAA, et al. Radiation exposure and thyroid cancer: a review. Arch Endocrinol Metab. 2017;61:180-187.

[26] VerburgFA, MaderU, LusterM, Reiners C. The effects of the Union for International Cancer Control/American Joint Committee on cancer tumour, node, metastasis system version 8 on staging of differentiated thyroid cancer: a comparison to version 7. Clin Endocrinol. 2018;88:950-956.

[27] RobinsonTJ, ThomasS, DinanMA, Roman S, SosaJA, HyslopT. How many lymph nodes are enough? assessing the adequacy of lymph node yield for papillary thyroid cancer? J Clin Oncol. 2016;34:3434-3439.

[28] HaugenBR, Alexander EK, BibleKC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:1-133.

[29] LiuQ, MaoL, ZhangZ, Li G, SongH. Diagnostic efficacy of FNA-Tg in DTC cervical LN metastasis and its impact factors: a large retrospective study. J Clin Endocrinol Metab. 2023;108:3311-3319.

[30] Broecker-PreussM, Mehnert I, GilmanE, HerrmannK, WeberM, GorgesR. Evaluation of a new automated assay for high-sensitivity thyroglobulin measurement and comparison with two established high-sensitivity thyroglobulin assays. Pract Lab Med. 2021;26:e00250.

[31] NishiharaE, AminoN, KudoT, et al. Comparison of thyroglobulin and thyroid peroxidase antibodies measured by five different kits in autoimmune thyroid diseases. Endocr J. 2017;64:955-961.

[32] BarbesinoG, Algeciras-Schimnich A, BornhorstJA. False positives in thyroglobulin determinations due to the presence of heterophile antibodies: an underrecognized and consequential clinical problem. Endocr Pract. 2021;27:396-400.

[33] BlazekovicI, RomicM, Bosak ButkovicM, et al. Thyroglobulin measurement in needle aspiration for detection of recurrences and neck metastases in patients with differentiated thyroid carcinoma: significance of anti-Tg antibodies. Acta Clin Croat. 2020;59:9-17.

[34] SuhI, VriensMR, GuerreroMA, et al. Serum thyroglobulin is a poor diagnostic biomarker of malignancy in follicular and Hurthle-cell neoplasms of the thyroid. Am J Surg. 2010;200:41-46.

[35] KimK, BaeJS, KimJS. Measurement of thyroglobulin level in lateral neck lymph node fine needle aspiration washout fluid in papillary thyroid cancer. Gland Surg; 2021:2686-2694.

[36] ZhangJ, ChengX, ShenL, et al. The association between lymph node stage and clinical prognosis in thyroid cancer. Front Endocrinol. 2020;11:90.

[37] RandolphGW, DuhQY, HellerKS, et al, American Thyroid Association Surgical Affairs Committee’s Taskforce on Thyroid Cancer Nodal, S. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid. 2012;22:1144-1152.

[38] DongS, PanJ, DuXL, XieXJ, XiaQ, WuYJ. Prediction of bilateral thyroid carcinoma and lateral cervical lymph node metastasis in PTC patients with suspicious thyroid nodules. Endocrine. 2024;85:803-810.

[39] WuLM, GuHY, QuXH, et al. The accuracy of ultrasonography in the preoperative diagnosis of cervical lymph node metastasis in patients with papillary thyroid carcinoma: a meta-analysis. Eur J Radiol. 2012;81:1798-1805.

[40] WangJ, JiangX, XiaoG, Zhou W, HuY. Excellent diagnostic performance of FNA-Tg in detecting lymph nodes metastases from papillary thyroid cancer. Future Oncol. 2020;16:2735-2746.

[41] CignarelliM, Ambrosi A, MarinoA, et al. Diagnostic utility of thyroglobulin detection in fine-needle aspiration of cervical cystic metastatic lymph nodes from papillary thyroid cancer with negative cytology. Thyroid. 2003;13:1163-1167.

[42] CunhaN, Rodrigues F, CuradoF, et al. Thyroglobulin detection in fine-needle aspirates of cervical lymph nodes: a technique for the diagnosis of metastatic differentiated thyroid cancer. Eur J Endocrinol. 2007;157:101-107.

[43] PaciniF, Fugazzola L, LippiF, et al. 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.

[44] GraniG, 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.

[45] MoonJH, KimYI, LimJA, et al. 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.

[46] JeonMJ, ParkJW, HanJM, et al. Serum antithyroglobulin antibodies interfere with thyroglobulin detection in fine-needle aspirates of metastatic neck nodes in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2013;98:153-160.

[47] WeaverDL. The prognostic importance of isolated tumor cell clusters and micrometastases in sentinel lymph nodes. Cancer Invest. 2009;27:121-128.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.