![[PDF]](/pb-assets/Icons/adobe-pdf-icon-1498649896243.png){kind=icon}
Abstract
The incidence of papillary thyroid microcarcinoma (PTmC) has been increasing everywhere due to the improvement of imaging and morphological diagnoses and probably also due to environmental alterations. Despite this, the mortality caused by thyroid cancer has not increased, reflecting the low clinical aggressiveness of most papillary thyroid carcinomas (PTCs) and the quality of the available treatment. The criteria used to classify PTmC remain questionable, making the clinical risk evaluation of these lesions very difficult. There is no solid basis for establishing the most appropriate tumor size (currently <10 mm) to distinguish PTmC from PTC. Moreover, PTmCs encompass all sorts of PTC histotypes, thus turning the whole group of PTmC genetically and biologically heterogeneous. In this review, we address the 2 most interesting issues from a practical standpoint: Are there any specific morphological or molecular features distinguishing PTmC from PTC? Is it possible to predict the clinical behavior of PTmC in fine needle aspiration biopsy and in surgical specimens, using morphological and/or molecular markers?
References
| 1. |
DeLellis, RA, Lloyd, RV, Heitz, PU, Eng, C. WHO Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press; 2004. Google Scholar |
| 2. |
Rosai, J, Carcangiu, ML, DeLellis, R. Tumors of the Thyroid Gland: Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1992. Google Scholar |
| 3. |
Basolo, F, Torregrossa, L, Giannini, R. Correlation between the BRAF V600E mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 millimeters: analysis of 1060 cases. J Clin Endocrinol Metab. 2010;95:4197-4205. Google Scholar | Crossref | Medline | ISI |
| 4. |
Chen, AY, Jemal, A, Ward, EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988-2005. Cancer. 2009;115:3801-3807. Google Scholar | Crossref | Medline | ISI |
| 5. |
Davies, L, Welch, HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006;295:2164-2167. Google Scholar | Crossref | Medline | ISI |
| 6. |
Sambade, MC, Goncalves, VS, Dias, M, Sobrinho-Simoes, MA. High relative frequency of thyroid papillary carcinoma in northern Portugal. Cancer. 1983;51:1754-1759. Google Scholar | Crossref | Medline | ISI |
| 7. |
Sobrinho-Simoes, MA, Sambade, MC, Goncalves, V. Latent thyroid carcinoma at autopsy: a study from Oporto, Portugal. Cancer. 1979;43:1702-1706. Google Scholar | Crossref | Medline | ISI |
| 8. |
Hayward, R . VOMIT (victims of modern imaging technology)—an acronym for our times. BMJ. 2003;326:1273. Google Scholar | Crossref |
| 9. |
Nikiforov, YE . Is ionizing radiation responsible for the increasing incidence of thyroid cancer? Cancer. 2010;116:1626-1628. Google Scholar | Crossref | Medline | ISI |
| 10. |
Kondo, T, Ezzat, S, Asa, SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6:292-306. Google Scholar | Crossref | Medline | ISI |
| 11. |
Sobrinho-Simoes, M, Maximo, V, Rocha, AS. Intragenic mutations in thyroid cancer. Endocrinol Metab Clin North Am. 2008;37:333-362. Google Scholar | Crossref | Medline | ISI |
| 12. |
Ezzat, S, Sarti, DA, Cain, DR, Braunstein, GD. Thyroid incidentalomas. Prevalence by palpation and ultrasonography. Arch Intern Med. 1994;154:1838-1840. Google Scholar | Crossref | Medline |
| 13. |
Papini, E, Guglielmi, R, Gharib, H. Ultrasound-guided laser ablation of incidental papillary thyroid microcarcinoma: a potential therapeutic approach in patients at surgical risk. Thyroid. 2011;21:917-920. Google Scholar | Crossref | Medline | ISI |
| 14. |
Nucera, C, Pontecorvi, A. Clinical outcome, role of BRAF(V600E), and molecular pathways in papillary thyroid microcarcinoma: is it an indolent cancer or an early stage of papillary thyroid cancer? Front Endocrinol. 2012;3:33. Google Scholar | Crossref | Medline |
| 15. |
Harach, HR, Franssila, KO, Wasenius, VM. Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study. Cancer. 1985;56:531-538. Google Scholar | Crossref | Medline | ISI |
| 16. |
Barbaro, D, Simi, U, Meucci, G, Lapi, P, Orsini, P, Pasquini, C. Thyroid papillary cancers: microcarcinoma and carcinoma, incidental cancers and non-incidental cancers—are they different diseases? Clin Endocrinol (Oxf). 2005;63:577-581. Google Scholar | Crossref | Medline | ISI |
| 17. |
Sugitani, I, Fujimoto, Y. Symptomatic versus asymptomatic papillary thyroid microcarcinoma: a retrospective analysis of surgical outcome and prognostic factors. Endocrine J. 1999;46:209-216. Google Scholar | Crossref | Medline | ISI |
| 18. |
Karatzas, T, Vasileiadis, I, Kapetanakis, S, Karakostas, E, Chrousos, G, Kouraklis, G. Risk factors contributing to the difference in prognosis for papillary versus micropapillary thyroid carcinoma. Am J Surg. 2013;206:586-593. Google Scholar | Crossref | Medline | ISI |
| 19. |
Pazaitou-Panayiotou, K, Capezzone, M, Pacini, F. Clinical features and therapeutic implication of papillary thyroid microcarcinoma. Thyroid. 2007;17:1085-1092. Google Scholar | Crossref | Medline | ISI |
| 20. |
Wartofsky, L . Management of papillary microcarcinoma: primum non nocere? J Clin Endocrinol Metab. 2012;97:1169-1172. Google Scholar | Crossref | Medline | ISI |
| 21. |
Vinagre, J, Almeida, A, Populo, H. Frequency of TERT promoter mutations in human cancers. Nat Commun. 2013;4:2185. Google Scholar | Crossref | Medline | ISI |
| 22. |
Ito, Y, Miyauchi, A, Inoue, H. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg. 2010;34:28-35. Google Scholar | Crossref | Medline | ISI |
| 23. |
Xing, M . BRAF mutation in papillary thyroid microcarcinoma: the promise of better risk management. Ann Surg Oncol. 2009;16:801-803. Google Scholar | Crossref | Medline | ISI |
| 24. |
Niemeier, LA, Kuffner Akatsu, H, Song, C. A combined molecular-pathologic score improves risk stratification of thyroid papillary microcarcinoma. Cancer. 2012;118:2069-2077. Google Scholar | Crossref | Medline | ISI |
| 25. |
Populo, H, Soares, P, Lopes, JM. Insights into melanoma: targeting the mTOR pathway for therapeutics. Expert Opin Ther Targets. 2012;16:689-705. Google Scholar | Crossref | Medline | ISI |
| 26. |
Dhomen, N, Reis-Filho, JS, da Rocha Dias, S. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009;15:294-303. Google Scholar | Crossref | Medline | ISI |
| 27. |
Guerra, A, Sapio, MR, Marotta, V. The primary occurrence of BRAF(V600E) is a rare clonal event in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2012;97:517-524. Google Scholar | Crossref | Medline | ISI |
| 28. |
Hall, A, Meyle, KD, Lange, MK. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E)BRAF oncogene. Oncotarget. 2013;4:584-599. Google Scholar | Crossref | Medline |
| 29. |
Kaplon, J, Zheng, L, Meissl, K. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature. 2013;498:109-112. Google Scholar | Crossref | Medline | ISI |
| 30. |
Jhiang, SM, Caruso, DR, Gilmore, E. Detection of the PTC/retTPC oncogene in human thyroid cancers. Oncogene. 1992;7:1331-1337. Google Scholar | Medline | ISI |
| 31. |
Tallini, G, Santoro, M, Helie, M. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res. 1998;4:287-294. Google Scholar | Medline | ISI |
| 32. |
Soares, P, Fonseca, E, Wynford-Thomas, D, Sobrinho-Simoes, M. Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset of slow growing, less aggressive thyroid neoplasms? J Pathol. 1998;185:71-78. Google Scholar | Crossref | Medline | ISI |
| 33. |
Soares, P, Sobrinho-Simoes, M. Cancer: small papillary thyroid cancers—is BRAF of prognostic value? Nat Rev Endocrinol. 2011;7:9-10. Google Scholar | Crossref | Medline | ISI |
| 34. |
Eloy, C, Santos, J, Cameselle-Teijeiro, J, Soares, P, Sobrinho-Simoes, M. TGF-beta/Smad pathway and BRAF mutation play different roles in circumscribed and infiltrative papillary thyroid carcinoma. Virchows Arch. 2012;460:587-600. Google Scholar | Crossref | Medline | ISI |
| 35. |
Mazzaferri, EL . Managing thyroid microcarcinomas. Yonsei Med J. 2012;53:1-14. Google Scholar | Crossref | Medline | ISI |
| 36. |
Rosai, J, LiVolsi, VA, Sobrinho-Simoes, M, Williams, ED. Renaming papillary microcarcinoma of the thyroid gland: the Porto proposal. Int J Surg Pathol. 2003;11:249-251. Google Scholar | SAGE Journals | ISI |
| 37. |
Colonna, M, Guizard, AV, Schvartz, C. A time trend analysis of papillary and follicular cancers as a function of tumour size: a study of data from six cancer registries in France (1983-2000). Eur J Cancer. 2007;43:891-900. Google Scholar | Crossref | Medline | ISI |
| 38. |
Cramer, JD, Fu, P, Harth, KC, Margevicius, S, Wilhelm, SM. Analysis of the rising incidence of thyroid cancer using the Surveillance, Epidemiology and End Results national cancer data registry. Surgery. 2010;148:1147-1152; discussion 1152-1143. Google Scholar | Crossref | Medline | ISI |
| 39. |
de Matos, PS, Ferreira, AP, Ward, LS. Prevalence of papillary microcarcinoma of the thyroid in Brazilian autopsy and surgical series. Endocr Pathol. 2006;17:165-173. Google Scholar | Crossref | Medline | ISI |
| 40. |
Elisei, R, Molinaro, E, Agate, L. Are the clinical and pathological features of differentiated thyroid carcinoma really changed over the last 35 years? Study on 4187 patients from a single Italian institution to answer this question. J Clin Endocrinol Metab. 2010;95:1516-1527. Google Scholar | Crossref | Medline | ISI |
| 41. |
Rego-Iraeta, A, Perez-Mendez, LF, Mantinan, B, Garcia-Mayor, RV. Time trends for thyroid cancer in northwestern Spain: true rise in the incidence of micro and larger forms of papillary thyroid carcinoma. Thyroid. 2009;19:333-340. Google Scholar | Crossref | Medline | ISI |
| 42. |
Sakorafas, GH, Stafyla, V, Kolettis, T, Tolumis, G, Kassaras, G, Peros, G. Microscopic papillary thyroid cancer as an incidental finding in patients treated surgically for presumably benign thyroid disease. J Postgrad Med. 2007;53:23-26. Google Scholar | Crossref | Medline | ISI |
| 43. |
Sugg, SL, Ezzat, S, Rosen, IB, Freeman, JL, Asa, SL. Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia. J Clin Endocrinol Metab. 1998;83:4116-4122. Google Scholar | Medline | ISI |
| 44. |
Corvi, R, Martinez-Alfaro, M, Harach, HR, Zini, M, Papotti, M, Romeo, G. Frequent RET rearrangements in thyroid papillary microcarcinoma detected by interphase fluorescence in situ hybridization. Lab Invest. 2001;81:1639-1645. Google Scholar | Crossref | Medline | ISI |
| 45. |
Sedliarou, I, Saenko, V, Lantsov, D. The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma. Int J Oncol. 2004;25:1729-1735. Google Scholar | Medline | ISI |
| 46. |
Kim, TY, Kim, WB, Song, JY. The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin Endocrinol (Oxf). 2005;63:588-593. Google Scholar | Crossref | Medline | ISI |
| 47. |
Trovisco, V, Soares, P, Preto, A. Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients’ age but not with tumour aggressiveness. Virchows Arch. 2005;446:589-595. Google Scholar | Crossref | Medline | ISI |
| 48. |
Lin, X, Finkelstein, SD, Zhu, B, Silverman, JF. Molecular analysis of multifocal papillary thyroid carcinoma. J Mol Endocrinol. 2008;41:195-203. Google Scholar | Crossref | Medline | ISI |
| 49. |
Min, HS, Choe, G, Kim, SW. S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid. Mod Pathol. 2008;21:748-755. Google Scholar | Crossref | Medline | ISI |
| 50. |
Kwak, JY, Kim, EK, Chung, WY, Moon, HJ, Kim, MJ, Choi, JR. Association of BRAFV600E mutation with poor clinical prognostic factors and US features in Korean patients with papillary thyroid microcarcinoma. Radiology. 2009;253:854-860. Google Scholar | Crossref | Medline | ISI |
| 51. |
Lee, X, Gao, M, Ji, Y. Analysis of differential BRAF(V600E) mutational status in high aggressive papillary thyroid microcarcinoma. Ann Surg Oncol. 2009;16:240-245. Google Scholar | Crossref | Medline | ISI |
| 52. |
Nasr, MR, Mukhopadhyay, S, Zhang, S, Katzenstein, AL. Absence of the BRAF mutation in HBME1+ and CK19+ atypical cell clusters in Hashimoto thyroiditis: supportive evidence against preneoplastic change. Am J Clin Pathol. 2009;132:906-912. Google Scholar | Crossref | Medline | ISI |
| 53. |
Lin, KL, Wang, OC, Zhang, XH, Dai, XX, Hu, XQ, Qu, JM. The BRAF mutation is predictive of aggressive clinicopathological characteristics in papillary thyroid microcarcinoma. Ann Surg Oncol. 2010;17:3294-3300. Google Scholar | Crossref | Medline | ISI |
| 54. |
Park, YJ, Kim, YA, Lee, YJ. Papillary microcarcinoma in comparison with larger papillary thyroid carcinoma in BRAF(V600E) mutation, clinicopathological features, and immunohistochemical findings. Head & Neck. 2010;32:38-45. Google Scholar | Medline | ISI |
| 55. |
Jung, CK, Im, SY, Kang, YJ. Mutational patterns and novel mutations of the BRAF gene in a large cohort of Korean patients with papillary thyroid carcinoma. Thyroid. 2012;22:791-797. Google Scholar | Crossref | Medline | ISI |
| 56. |
Lee, ST, Kim, SW, Ki, CS. Clinical implication of highly sensitive detection of the BRAF V600E mutation in fine-needle aspirations of thyroid nodules: a comparative analysis of three molecular assays in 4585 consecutive cases in a BRAF V600E mutation-prevalent area. J Clin Endocrinol Metab. 2012;97:2299-2306. Google Scholar | Crossref | Medline | ISI |
| 57. |
Marchetti, I, Iervasi, G, Mazzanti, CM. Detection of the BRAF(V600E) mutation in fine needle aspiration cytology of thyroid papillary microcarcinoma cells selected by manual macrodissection: an easy tool to improve the preoperative diagnosis. Thyroid. 2012;22:292-298. Google Scholar | Crossref | Medline | ISI |
| 58. |
Zhou, YL, Zhang, W, Gao, EL. Preoperative BRAF mutation is predictive of occult contralateral carcinoma in patients with unilateral papillary thyroid microcarcinoma. Asian Pac J Cancer Prev. 2012;13:1267-1272. Google Scholar | Crossref | Medline |
| 59. |
Bernstein, JI, Virk, R, Hui, P. Tall Cell Variant of Papillary Thyroid Microcarcinoma: Clinicopathological Features with BRAFV600E Mutational Analysis. Thyroid. 2013. Google Scholar | Crossref | Medline | ISI |
| 60. |
Piana, S, Ragazzi, M, Tallini, G. Papillary thyroid microcarcinoma with fatal outcome: evidence of tumor progression in lymph node metastases: Report of 3 cases, with morphological and molecular analysis. Hum Pathol. 2013;44:556-565. Google Scholar | Crossref | Medline | ISI |
| 61. |
Rossi, ED, Martini, M, Capodimonti, S. BRAF (V600E) mutation analysis on liquid-based cytology-processed aspiration biopsies predicts bilaterality and lymph node involvement in papillary thyroid microcarcinoma. Cancer Cytopathol. 2013;121:291-297. Google Scholar | Crossref | Medline | ISI |
| 62. |
Virk, RK, Van Dyke, AL, Finkelstein, A. BRAFV600E mutation in papillary thyroid microcarcinoma: a genotype-phenotype correlation. Modern pathology. 2013;26:62-70. Google Scholar | Crossref | Medline | ISI |
| 63. |
Zheng, X, Wei, S, Han, Y. Papillary Microcarcinoma of the Thyroid: Clinical Characteristics and BRAF(V600E) Mutational Status of 977 Cases. Ann Surg Oncol. 2013;20:2266-2273. Google Scholar | Crossref | Medline | ISI |
