Cómo mejorar la precisión de los diagnósticos I y III del Sistema Bethesda

  1. Rodríguez González, Marta 1
  2. González Velasco, Cristina
  3. Gómez Muñoz, María Asunción
  4. Sayagués Manzano, José María
  5. Ludeña de la Cruz, María Dolores
  1. 1 Doctora, Licenciada Especialista
Revista ORL

ISSN: 2444-7986 2444-7986

Year of publication: 2021

Volume: 12

Volume: 4

Pages: 313-323

Type: Article

DOI: 10.14201/ORL.25005 DIALNET GOOGLE SCHOLAR lock_openDialnet editor

More publications in: Revista ORL


Fine-needle aspiration (FNA) has a primary role in the diagnosis of thyroid nodules. FNA allows us to differentiate benign lesions from malignant ones in most of the cases. However, management of Bethesda System diagnostic categories I (Nondiagnostic or Unsatisfactory) and III (Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance) are a clinical challenge. The aim of this work is to expose the options we have to improve the diagnosis of those categories using a multidisciplinary approach, an active follow-up, repeating FNA, applying immunohistochemical and/or molecular technics or even perform a core needle biopsy. Some or all of these choices are especially useful to identify category III, but active follow-up or additional FNA are preferred to detect category I.

Bibliographic References

  • Nikiforov YE. Role of molecular markers in thyroid nodule management: Then and now. Endocr Pract. 2017;23(8):979–88.
  • Partyka KL, Trevino K, Randolph ML, Cramer H, Wu HH. Risk of malignancy and neoplasia predicted by three molecular testing platforms in indeterminate thyroid nodules on fineneedle aspiration. Diagn Cytopathol. 2019;47(9):853–62.
  • Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide Increasing Incidence of Thyroid Cancer: Update on Epidemiology and Risk Factors. J Cancer Epidemiol [Internet]. 2013 [cited 2020 Oct 4];2013. Available from: http://dx.doi.org/10.1155/2013/965212
  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin [Internet]. 2018 Nov 1 [cited 2020 Oct 28];68(6):394–424. Available from: http://doi.wiley.com/10.3322/caac.21492
  • Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, et al. American association of Clinical Endocrinologists, American college of endocrinology, and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules - 2016 update. Endocr Pract. 2016;22(May):1–60.
  • Baloch ZW, Cibas ES, Clark DP, Layfield LJ, Ljung BM, Pitman MB, et al. The National Cancer Institute Thyroid fine needle aspiration state of the science conference: A summation. Cytojournal. 2008;5:1–17.
  • Nguyen GK, Lee MW, Ginsberg J, Wragg T, Bilodeau D. Fineneedle aspiration of the thyroid: An overview. Cytojournal. 2005;2:1–13.
  • Cha YJ, Pyo JY, Hong SW, Seok JY, Kim KJ, Han JY, et al. Thyroid fineneedle aspiration cytology practice in Korea. J Pathol Transl Med. 2017;51(6):521–7.
  • Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Am J Clin Pathol. 2009; 132:658–665.
  • Lloyd RV, Osamura RY, Klöppel G, Rosai J, World Health Organization., International Agency for Research on Cancer. WHO classification of tumours of endocrine organs [Internet]. [cited 2020 Oct 28]. 355 p. Available from: https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-Endocrine-Organs-2017
  • Cibas ES, Ali SZ. The 2017 Bethesda System for Reporting Thyroid Cytopathology. Thyroid [Internet]. 2017 [cited 2020 Oct 28];27(11):1341–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29091573
  • Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda System for Reporting Thyroid Cytopathology: a meta-analysis. Acta Cytol [Internet]. 2012 [cited 2020 Oct 28];56(4):333–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22846422
  • Coorough N, Hudak K, Jaume JC, Buehler D, Selvaggi S, Rivas J, et al. Nondiagnostic fineneedle aspirations of the thyroid: Is the risk of malignancy higher? J Surg Res [Internet]. 2013;184(2):746–50. Available from: http://dx.doi.org/10.1016/j.jss.2013.02.018
  • Hong S-H, Lee H, Cho M-S, Lee JE, Sung Y-A, Hong YS. Malignancy Risk and Related Factors of Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance in Thyroid Fine Needle Aspiration. 2018 [cited 2020 Oct 29]; Available from: https://doi.org/10.1155/2018/4521984
  • Nishino M, Wang HH. Should the thyroid AUS/FLUS category be further stratified by malignancy risk? Cancer Cytopathol. 2014;122(7):481–3.
  • Olson MT, Clark DP, Erozan YS, Ali SZ. Spectrum of risk of malignancy in subcategories of «atypia of undetermined significance.» Acta Cytol. 2011;55(6):518–25.
  • Jae Ryu Y, Seung Jung Y, Chul Yoon H, Jung Hwang M, Hyoung Shin S, Seong Cho J, et al. Atypia of undetermined significance on thyroid fine needle aspiration: surgical outcome and risk factors for malignancy. Ann Surg Treat Res [Internet]. [cited 2020 Oct 29];109. Available from: http://dx.doi.org/10.4174/astr
  • Gopalakrishna Iyer N, Shaha AR. Management of Thyroid Nodules and Surgery for Differentiated Thyroid Cancer. [cited 2020 Oct 29]; Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806860/pdf/nihms508330.pdf
  • Dincer N, Balci S, Yazgan A, Guney G, Ersoy R, Cakir B, et al. Follow-up of atypia and follicular lesions of undetermined significance in thyroid fine needle aspiration cytology. Cytopathology. 2013;24(6):385–90.
  • Sosa JA, Hanna JW, Robinson KA, Lanman RB. Increases in thyroid nodule fine-needle aspirations, operations, and diagnoses of thyroid cancer in the United States. Surg (United States) [Internet]. 2013;154(6):1420–7. Available from: http://dx.doi.org/10.1016/j.surg.2013.07.006
  • Saieg MA, Barbosa B, Nishi J, Ferrari A, Costa F. The impact of repeat FNA in non-diagnostic and indeterminate thyroid nodules: A 5-year single-centre experience. Cytopathology. 2018;29(2):196–200.
  • Lubitz CC, Nagarkatti SS, Faquin WC, Samir AE, Hassan MC, Barbesino G, et al. Diagnostic yield of nondiagnostic thyroid nodules is not altered by timing of repeat biopsy. Thyroid. 2012;22(6):590–4.
  • Deniwar A, Hammad ARY, Ali DB, Alsaleh N, Lahlouh M, Sholl AB, et al. Optimal timing for a repeat fine-needle aspiration biopsy of thyroid nodule following an initial nondiagnostic fine-needle aspiration. Am J Surg [Internet]. 2017;213(2):433–7. Available from: http://dx.doi.org/10.1016/j.amjsurg.2016.04.010
  • Yang J, Recavarren RA, Houser PM. Potential pitfalls of needle tract effects on repeat thyroid fine-needle aspiration. Cancer Cytopathol. 2013;121(3):155–61.
  • Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 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):1–133.
  • Renshaw AA. Does a repeated benign aspirate change the risk of malignancy after an initial atypical thyroid fine-needle aspiration? Am J Clin Pathol. 2010;134(5):788–92.
  • Vanderlaan PA, Marqusee E, Krane JF. Clinical outcome for atypia of undetermined significance in thyroid fine-needle aspirations: Should repeated FNA be the preferred initial approach? Am J Clin Pathol. 2011;135(5):770–5.
  • He Y, Franco OE, Jiang M, Williams K, Love HD, Coleman IM, et al. Tissue-specific consequences of cyclin D1 overexpression in prostate cancer progression. Cancer Res. 2007;67(17):8188–97.
  • Tong R, Yang Q, Wang C, Bi F, Jiang B. OVCA1 expression and its correlation with the expression levels of cyclin D1 and p16 in cervical cancer and intraepithelial neoplasia. Oncol Lett [Internet]. 2017 May [cited 2020 Oct 2];13(5):2929–36. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28521400
  • Smalley KSM, Lioni M, Dalla Palma M, Xiao M, Desai B, Egyhazi S, et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol Cancer Ther [Internet]. 2008 Sep [cited 2020 Oct 2];7(9):2876–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18790768
  • Temmim L, Ebraheem AK, Baker H, Sinowatz F. Cyclin D1 protein expression in human thyroid gland and thyroid cancer. Anat Histol Embryol [Internet]. 2006 Apr [cited 2020 Oct 2];35(2):125–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16542178
  • Lantsov D, Meirmanov S, Nakashima M, Kondo H, Saenko V, Naruke Y, et al. Cyclin D1 overexpression in thyroid papillary microcarcinoma: its association with tumour size and aberrant beta-catenin expression. Histopathology [Internet]. 2005 Sep [cited 2020 Oct 2];47(3):248–56. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16115225
  • Teshima M, Tokita K, Ryo E, Matsumoto F, Kondo M, Ikegami Y, et al. Clinical impact of a cytological screening system using cyclin D1 immunostaining and genomic analysis for the diagnosis of thyroid nodules. BMC Cancer. 2019;19(1):1–10.
  • Agrawal N, Akbani R, Aksoy A, Ally A, Arachchi H, Asa SL, et al. NIH Public Access Integrated Genomic Characterization of Papillary Thyroid. Cell. 2015;159(3):676–90.
  • Bullock M, O’Neill C, Chou A, Clarkson A, Dodds T, Toon C, et al. Utilization of a MAB for BRAFV600E detection in papillary thyroid carcinoma. Endocr Relat Cancer. 2012;19(6):779–84.
  • Capper D, Preusser M, Habel A, Sahm F, Ackermann U, Schindler G, et al. Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol. 2011;122(1):11–9.
  • Capper D, Berghoff AS, Magerle M, Ilhan A, Wöhrer A, Hackl M, et al. Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. Acta Neuropathol [Internet]. 2012 Feb [cited 2020 Oct 2];123(2):223–33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22012135
  • Koperek O, Kornauth C, Capper D, Berghoff AS, Asari R, Niederle B, et al. Immunohistochemical detection of the BRAF V600E-mutated protein in papillary thyroid carcinoma. Am J Surg Pathol [Internet]. 2012 Jun [cited 2020 Oct 2];36(6):844–50. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22592144
  • Zimmermann AK, Camenisch U, Rechsteiner MP, Bode-Lesniewska B, Rössle M. Value of immunohistochemistry in the detection of BRAFV600E mutations in fine-needle aspiration biopsies of papillary thyroid carcinoma. Cancer Cytopathol. 2014;122(1):48–58.
  • Rossi ED, Martini M, Capodimonti S, Cenci T, Straccia P, Angrisani B, et al. Analysis of immunocytochemical and molecular BRAF expression in thyroid carcinomas: a cytohistologic institutional experience. Cancer Cytopathol [Internet]. 2014 Jul [cited 2020 Oct 2];122(7):527–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24639117
  • Lee S-R, Yim H, Han JH, Lee KB, Lee J, Soh EY, et al. VE1 antibody is not highly specific for the BRAF V600E mutation in thyroid cytology categories with the exception of malignant cases. Am J Clin Pathol [Internet]. 2015 Mar [cited 2020 Oct 2];143(3):437–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25696803
  • Saggiorato E, De Pompa R, Volante M, Cappia S, Arecco F, Dei Tos AP, et al. Characterization of thyroid «follicular neoplasms» in fine-needle aspiration cytological specimens using a panel of immunohistochemical markers: A proposal for clinical application. Endocr Relat Cancer. 2005;12(2):305–17.
  • Yang RY, Liu FT. Galectins in cell growth and apoptosis. Cell Mol Life Sci. 2003;60(2):267–76.
  • Trimboli P, Guidobaldi L, Amendola S, Nasrollah N, Romanelli F, Attanasio D, et al. Galectin-3 and HBME-1 improve the accuracy of core biopsy in indeterminate thyroid nodules. Endocrine. 2016;52(1):39–45.
  • Asa SL. The role of immunohistochemical markers in the diagnosis of follicular-patterned lesions of the thyroid. Endocr Pathol [Internet]. 2005 [cited 2020 Oct 2];16(4):295–309. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16627917
  • Schröder S, Wodzynski A, Padberg B. [Cytokeratin expression of benign and malignant epithelial thyroid gland tumors. An immunohistologic study of 154 neoplasms using 8 different monoclonal cytokeratin antibodies]. Pathologe [Internet]. 1996 Nov [cited 2020 Oct 29];17(6):425–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9082363
  • Fonseca E, Nesland JM, Höie J, Sobrinho-Simões M. Pattern of expression of intermediate cytokeratin filaments in the thyroid gland: an immunohistochemical study of simple and stratified epithelial-type cytokeratins. Virchows Arch [Internet]. 1997 Mar [cited 2020 Oct 29];430(3):239. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9099982
  • Bose D, Das RN, Chatterjee U, Banerjee U. Cytokeratin 19 immunoreactivity in the diagnosis of papillary thyroid carcinoma. Indian J Med Paediatr Oncol [Internet]. 2012 Apr [cited 2020 Oct 29];33(2):107–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22988353
  • Saleh H, Feng J, Tabassum F, Al-Zohaili O, Husain M, Giorgadze T. Differential expression of galectin-3, CK19, HBME1, and Ret oncoprotein in the diagnosis of thyroid neoplasms by fine needle aspiration biopsy. Cytojournal. 2009;6:1–10.
  • Muthusamy S, Azhar Shah S, Abdullah Suhaimi SN, Kassim N, Mahasin M, Mohd Saleh MF, et al. CD56 expression in benign and malignant thyroid lesions. Malays J Pathol. 2018;40(2):111–9.
  • Yang A-H, Chen J-Y, Lee C-H, Chen J-Y. Expression of NCAM and OCIAD1 in well-differentiated thyroid carcinoma: correlation with the risk of distant metastasis. J Clin Pathol [Internet]. 2012 Mar 1 [cited 2020 Oct 2];65(3):206–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22081784
  • Song S, Kim H, Ahn SH. Role of immunohistochemistry in fine needle aspiration and core needle biopsy of thyroid nodules. Clin Exp Otorhinolaryngol. 2019;12(2):224–30.
  • Bizzarro T, Martini M, Marrocco C, D’Amato D, Traini E, Lombardi CP, et al. The role of CD56 in thyroid fine needle aspiration cytology: A pilot study performed on liquid based cytology. PLoS One [Internet]. 2015;10(7):1–13. Available from: http://dx.doi.org/10.1371/journal.pone.0132939
  • Cattoretti G, Becker MH, Key G, Duchrow M, Schlüter C, Galle J, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol [Internet]. 1992 Dec [cited 2020 Oct 2];168(4):357–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1484317
  • Mu N, Juhlin CC, Tani E, Sofiadis A, Reihnér E, Zedenius J, et al. High Ki-67 index in fine needle aspiration cytology of follicular thyroid tumors is associated with increased risk of carcinoma. Endocrine [Internet]. 2018 Aug 23 [cited 2020 Oct 2];61(2):293–302. Available from: http://link.springer.com/10.1007/s12020-018-1627-z
  • Sofiadis. Diagnostic and prognostic potential of MIB-1 proliferation index in thyroid fine needle aspiration biopsy. Int J Oncol [Internet]. 2009 Jun 26 [cited 2020 Oct 29]; Available from: http://www.spandidos-publications.com/ijo/35/2/369
  • Agrawal N, Akbani R, Aksoy BA, Ally A, Arachchi H, Asa SL, et al. Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell [Internet]. 2014 Oct 23 [cited 2020 Oct 3];159(3):676–90. Available from: https://www.sciencedirect.com/science/article/pii/S0092867414012380
  • Nikiforov YE, Steward DL, Carty SE, Sippel RS, Yang SP, Sosa JA, et al. Performance of a Multigene Genomic Classifier in Thyroid Nodules with Indeterminate Cytology: A Prospective Blinded Multicenter Study. JAMA Oncol. 2019;5(2):204–12.
  • Macerola E, Basolo F. Current methodologies for molecular screening of thyroid nodules. Gland Surg. 2018;7(I):S1–7.
  • Baca SC, Wong KS, Strickland KC, Heller HT, Kim MI, Barletta JA, et al. Qualifiers of atypia in the cytologic diagnosis of thyroid nodules are associated with different Afirma gene expression classifier results and clinical outcomes. Cancer Cytopathol. 2017;125(5):313–22.
  • Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367(8):705–15.
  • Yang SE, Sullivan PS, Zhang J, Govind R, Levin MR, Rao JY, et al. Has Afirma gene expression classifier testing refined the indeterminate thyroid category in cytology? Cancer Cytopathol. 2016;124(2):100–9.
  • Steward DL, Carty SE, Sippel RS, Yang SP, Sosa JA, Sipos JA, et al. Performance of a Multigene Genomic Classifier in Thyroid Nodules With Indeterminate Cytology. JAMA Oncol [Internet]. 2019 Feb 1 [cited 2020 Oct 4];5(2):204. Available from: http://oncology.jamanetwork.com/article.aspx?doi=10.1001/jamaoncol.2018.4616
  • Nikiforova MN, Mercurio S, Wald AI, Barbi de Moura M, Callenberg K, Santana-Santos L, et al. Analytical performance of the ThyroSeq v3 genomic classifier for cancer diagnosis in thyroid nodules. Cancer. 2018;124(8):1682–90.
  • Yip L, Wharry LI, Armstrong MJ, Silbermann A, McCoy KL, Stang MT, et al. A clinical algorithm for fine-needle aspiration molecular testing effectively guides the appropriate extent of initial thyroidectomy. Ann Surg. 2014;260(1):163–8.
  • Na DG, Baek JH, Jung SL, Kim JH, Sung JY, Kim KS, et al. Core needle biopsy of the thyroid: 2016 consensus statement and recommendations from Korean society of thyroid radiology. Korean J Radiol. 2017;18(1):217–37.
  • Novoa E, Gürtler N, Arnoux A, Kraft M. Role of ultrasound-guided core-needle biopsy in the assessment of head and neck lesions: A meta-analysis and systematic review of the literature. Eisele DW, editor. Head Neck [Internet]. 2012 Oct [cited 2020 Oct 29];34(10):1497–503. Available from: http://doi.wiley.com/10.1002/hed.21821
  • Yim Y, Baek JH. Core needle biopsy in the management of thyroid nodules with an indeterminate fine-needle aspiration report. Gland Surg. 2019;8(Suppl 2):S77–85.
  • Perros P, Boelaert K, Colley S, Evans C, Evans RM, Gerrard Ba G, Gilbert J, Harrison B, Johnson SJ, Giles TE, Moss L, Lewington V, Newbold K, Taylor J, Thakker RV, Watkinson J, Williams GR; British Thyroid Association. Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf). 2014 Jul;81 Suppl 1:1-122. doi: 10.1111/cen.12515. PMID: 24989897.
  • Baek JH. Current status of core needle biopsy of the thyroid. Ultrasonography. 2017;36(2):83–5.
  • Park VY, Kim EK, Kwak JY, Yoon JH, Moon HJ. Malignancy risk and characteristics of thyroid nodules with two consecutive results of atypia of undetermined significance or follicular lesion of undetermined significance on cytology. Eur Radiol. 2015;25(9):2601–7.