Clinical outcome, role of BRAFV600E, and molecular pathways in papillary thyroid microcarcinoma: Is it an indolent cancer or an early stage of papillary thyroid cancer?

Frontiers in Endocrinology

Volumn 3, Issue FEB, 2012, Pages

  Nucera, Carmelo ^a   Pontecorvi, Alfredo ^b  

^a BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^b CATHOLIC UNIVERSITY   (Italy)

Author keywords

Angiogenesis; BRAFV600E mutation; Clinical outcome; Extracellular matrix; Genetics; Neck lymph node metastasis; Papillary thyroid microcarcinoma; Tumor microenvironment

Indexed keywords

EID: 84870798372     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2012.00033     Document Type: Review

References (80)

1. Arem, R., Padayatty, S. J., Saliby, A. H., and Sherman, S. I. (1999). Thyroid microcarcinoma: prevalence, prognosis, and management. Endocr. Pract. 5, 148-156.
2. Barbaro, D., Simi, U., Meucci, G., Lapi, P.,Orsini,P.,and Pasquini,C. (2005). Thyroid papillary cancers: microcarcinoma and carcinoma, incidental cancers and non-incidental cancers - are they different diseases? Clin. Endocrinol. (Oxf.) 63, 577-581.
3. Baudin, E., Travagli, J. P., Ropers, J., Mancusi, F., Bruno-Bossio, G., Caillou, B., Cailleux, A. F., Lumbroso, J. D., Parmentier, C., and Schlumberger, M. (1998). Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience. Cancer 83, 553-559.
4. Biscolla, R. P., Ugolini, C., Sculli, M., Bottici, V., Castagna, M. G., Romei, C., Cosci, B., Molinaro, E., Faviana, P., Basolo, F., Miccoli, P., Pacini, F., Pinchera, A., and Elisei, R. (2004). Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior. Thyroid 14, 946-952.
5. Bollag, G., Hirth, P., Tsai, J., Zhang, J., Ibrahim, P. N., Cho, H., Spevak, W., Zhang, C., Zhang, Y., Habets, G., Burton, E. A., Wong, B., Tsang, G., West, B. L., Powell, B., Shellooe, R., Marimuthu, A., Nguyen, H., Zhang, K. Y., Artis, D. R., Schlessinger, J., Su, F., Higgins, B., Iyer, R., D'Andrea, K., Koehler, A., Stumm, M., Lin, P. S., Lee, R. J., Grippo, J., Puzanov, I., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. A., Chapman, P. B., Flaherty, K. T., Xu, X., Nathanson, K. L., and Nolop, K. (2010). Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596-599.
6. Bramley, M. D., and Harrison, B. J. (1996). Papillary microcarcinoma of the thyroid gland. Br. J. Surg. 83, 1674-1683.
7. Caronia, L. M., Phay, J. E., and Shah, M. H. (2011). Role of BRAF in thyroid oncogenesis. Clin. Cancer Res. 17, 7511-7517.
8. Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., Hogg, D., Lorigan, P., Lebbe, C., Jouary, T., Schadendorf, D., Ribas, A., O'Day, S. J., Sosman, J. A., Kirkwood, J. M., Eggermont, A. M., Dreno, B., Nolop, K., Li, J., Nelson, B., Hou, J., Lee, R. J., Flaherty, K. T., McArthur, G. A., and BRIM-3 Study Group. (2011). Improved survival with vemurafenib in melanoma with BRAFV600E mutation. N. Engl. J. Med. 364, 2507-2516.
9. Chow, S. M., Law, S. C., Chan, J. K., Au, S. K., Yau, S., and Lau, W. H. (2003a). Papillary microcarcinoma of the thyroid-Prognostic significance of lymph node metastasis and multifocality. Cancer 98, 31-40.
10. Chow, S. M., Law, S. C., Au, S. K., Mang, O., Yau, S., Yuen, K. T., and Lau, W. H. (2003b). Changes in clinical presentation, management and outcome in 1348 patients with differentiated thyroid carcinoma: experience in a single institute in Hong Kong, 1960-2000. Clin. Oncol. (R. Coll. Radiol.) 15, 329-336.
11. Cooper, D. S., Doherty, G. M., Haugen, B. R., Kloos, R. T., Lee, S. L., Mandel, S. J., Mazzaferri, E. L., McIver, B., Pacini, F., Schlumberger, M., Sherman, S. I., Steward, D. L., and Tuttle, R. M. (2009). Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19, 1167-1214.
12. Corvi, R., Martinez-Alfaro, M., Harach, H. R., Zini, M., Papotti, M., and Romeo, G. (2001). Frequent RET rearrangements in thyroid papillary microcarcinoma detected by interphase fluorescence in situ hybridization. Lab. Invest. 81, 1639-1645.
13. David, J. M., Ruaux, C., Bachaud, J. M., Bonnet, F., Lucot, H., Boneu, A., Suc, E., and Cabarrot, E. (1992). Multiple localization and lymphatic involvement of papillary microcarcinoma of the thyroid. Results of total thyroidectomy with bilateral lymph node excision. Apropos of 38 patients. Ann. Otolaryngol. Chir. Cervicofac. 109, 183-187.
14. Davies, L., and Welch, H. G. (2006). Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 295, 2164-2167.
15. Ezzat, S., Sarti, D. A., Cain, D. R., and Braunstein, G. D. (1994). Thyroid incidentalomas. Prevalence by palpation and ultrasonography. Arch. Intern. Med. 154, 1838-1840.
16. Falvo, L., D'Ercole, C., Sorrenti, S., D'Andrea, V., Catania, A., Berni, A., Grilli, P., and De Antoni, E. (2003). Papillary microcarcinoma of the thyroid gland: analysis of prognostic factors including histological subtype. Eur. J. Surg. Suppl. 588, 28-32.
17. Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. A., O'Dwyer, P. J., Lee, R. J., Grippo, J. F., Nolop, K., and Chapman, P. B. (2010). Inhibition of mutated,activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809-819.
18. Frasca, F., Nucera, C., Pellegriti, G., Gangemi, P., Attard, M., Stella, M., Loda, M., Vella, V., Giordano, C., Trimarchi, F., Mazzon, E., Belfiore, A., and Vigneri, R. (2008). BRAF(V600E) mutation and the biology of papillary thyroid cancer. Endocr. Relat. Cancer 15, 191-205.
19. Garrett, S. C., Varney, K. M., Weber, D. J., and Bresnick, A. R. (2006). S100A4, a mediator of metastasis. J. Biol. Chem. 281, 677-680.
20. Gild,M. L.,Bullock,M.,Robinson,B. G., and Clifton-Bligh, R. (2011). Multikinase inhibitors: a new option for the treatment of thyroid cancer. Nat Rev Endocrinol 7, 617-624.
21. Hauschild, A., Agarwala, S. S., Trefzer, U.,Hogg,D.,Robert,C.,Hersey,P., Eggermont, A., Grabbe, S., Gonzalez, R., Gille, J., Peschel, C., Schadendorf, D., Garbe, C., O'Day, S., Daud, A., White, J. M., Xia, C., Patel, K., Kirkwood, J. M., and Keilholz, U. (2009). Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J. Clin. Oncol. 27, 2823-2830.
22. Hay, I. D., Grant, C. S., van Heerden, J. A., Goellner, J. R., Ebersold, J. R., and Bergstralh, E. J. (1992). Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery 112, 1139-1146; discussion 1146-1137.
23. Hori, Y., Kashima, K., Daa, T., Yokoyama, S., Nakayama, I., and Noguchi, S. (1995). Relationship between cell proliferation activity and morphological characteristics of papillary microcarcinoma in the thyroid of Graves' disease. Pathol. Int. 45, 846-853.
24. Ito, Y., Tomoda, C., Uruno, T., Takamura, Y., Miya, A., Kobayashi, K., Matsuzuka, F., Kuma, K., and Miyauchi, A. (2004). Papillary microcarcinoma of the thyroid: how should it be treated? WorldJ.Surg. 28, 1115-1121.
25. Ito, Y., Uruno, T., Nakano, K., Takamura, Y., Miya, A., Kobayashi, K., Yokozawa, T., Matsuzuka, F., Kuma, S., Kuma, K., and Miyauchi, A. (2003). An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid 13, 381-387.
26. Jonklaas, J., Sarlis, N. J., Litofsky, D., Ain, K. B., Bigos, S. T., Brierley, J. D., Cooper, D. S., Haugen, B. R., Ladenson, P. W., Magner, J., Robbins, J., Ross, D. S., Skarulis, M., Maxon, H. R., and Sherman, S. I. (2006). Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 16, 1229-1242.
27. Kim, H. Y., Park, W. Y., Lee, K. E., Park, W. S., Chung, Y. S., Cho, S. J., and Youn,Y. K. (2010). Comparative analysis of gene expression profiles of papillary thyroid microcarcinoma and papillary thyroid carcinoma. J. Cancer. Res. Ther. 6, 452-457.
28. Kloos, R. T., Ringel, M. D., Knopp, M. V., Hall, N. C., King, M., Stevens, R., Liang, J., Wakely, P. E. Jr., Vasko, V. V., Saji, M., Rittenberry, J., Wei, L., Arbogast, D., Collamore, M.,Wright, J. J., Grever, M., and Shah, M. H. (2009). Phase II trial of sorafenib in metastatic thyroid cancer. J. Clin. Oncol. 27, 1675-1684.
29. Knauf, J. A., Sartor, M. A., Medvedovic, M., Lundsmith, E., Ryder, M., Salzano, M., Nikiforov, Y. E., Giordano, T. J., Ghossein, R. A., and Fagin, J. A. (2011). Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFbeta signaling. Oncogene 30, 3153-3162.
30. Lee, X., Gao, M., Ji, Y., Yu, Y., Feng, Y., Li, Y., Zhang, Y., Cheng, W., and Zhao, W. (2009). Analysis of differential BRAF(V600E) mutational status in high aggressive papillary thyroid microcarcinoma. Ann. Surg. Oncol. 16, 240-245.
31. Leenhardt, L., Grosclaude, P., and Cherie-Challine, L. (2004). Increased incidence of thyroid carcinoma in france: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee. Thyroid 14, 1056-1060.
32. Leenhardt, L., Hejblum, G., Franc, B., Fediaevsky, L. D., Delbot, T., Le Guillouzic, D., Menegaux, F., Guillausseau, C., Hoang, C., Turpin, G., and Aurengo, A. (1999). Indications and limits of ultrasoundguided cytology in the management of nonpalpable thyroid nodules. J. Clin. Endocrinol. Metab. 84, 24-28.
33. Lin, K. D., Lin, J. D., Huang, H. S., Jeng, L. B., and Ho, Y. S. (1997). Skull metastasis with brain invasion from thyroid papillary microcarcinoma. J. Formos. Med. Assoc. 96, 280-282.
34. Lin, X., Finkelstein, S. D., Zhu, B., and Silverman, J. F. (2008). Molecular analysis of multifocal papillary thyroid carcinoma. J. Mol. Endocrinol. 41, 195-203.
35. Lloyd, R., De Lellis, R., Heitz, P., and Eng, C. (2004). World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Endocrine Organs. Lyon: IARC Press.
36. Lo, C. Y., Chan, W. F., Lang, B. H., Lam, K. Y., and Wan, K. Y. (2006). Papillary microcarcinoma: is there any difference between clinically overt and occult tumors? WorldJ.Surg.30, 759-766.
37. Lupi, C., Giannini, R., Ugolini, C., Proietti, A., Berti, P., Minuto, M., Materazzi, G., Elisei, R., Santoro, M., Miccoli, P., and Basolo, F. (2007). Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J. Clin. Endocrinol. Metab. 92, 4085-4090.
38. Marotta, V., Guerra, A., Sapio, M. R., and Vitale, M. (2011). RET/PTC rearrangement in benign and malignant thyroid diseases: a clinical standpoint. Eur. J. Endocrinol. 165, 499-507.
39. Mazzaferri, E. L. (1990). Thyroid cancer and Graves' disease. J. Clin. Endocrinol. Metab. 70, 826-829.
40. McCarthy, R. P., Wang, M., Jones, T. D., Strate, R. W., and Cheng, L. (2006). Molecular evidence for the same clonal origin of multifocal papillary thyroid carcinomas. Clin. Cancer Res. 12, 2414-2418.
41. McDougall, I. R., and Camargo, C. A. (2007). Treatment of micropapillary carcinoma of the thyroid: where do we draw the line? Thyroid 17, 1093-1096.
42. Melillo, R. M., Castellone, M. D., Guarino, V., De Falco, V., Cirafici, A. M., Salvatore, G., Caiazzo, F., Basolo, F., Giannini, R., Kruhoffer, M., Orntoft, T., Fusco, A., and Santoro, M. (2005). The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells. J. Clin. Invest. 115, 1068-1081.
43. Merchant, F. H., Hirschowitz, S. L., Cohan, P., Van Herle, A. J., and Natarajan, S. (2002). Simultaneous occurrence of medullary and papillary carcinoma of the thyroid gland identified by fine needle aspiration. A case report. Acta Cytol. 46, 762-766.
44. Min, H. S., Choe, G., Kim, S. W., Park, Y. J., Park do, J., Youn, Y. K., Park, S. H., Cho, B. Y., and Park, S. Y. (2008). S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid. Mod. Pathol. 21, 748-755.
45. Motti, M. L., De Marco, C., Califano, D., De Gisi, S., Malanga, D., Troncone, G., Persico, A., Losito, S., Fabiani, F., Santoro, M., Chiappetta, G., Fusco, A., and Viglietto, G. (2007). Loss of p27 expression through RAS→BRAF→MAP kinase-dependent pathway in human thyroid carcinomas. Cell Cycle 6, 2817-2825.
46. Nasir, A., Chaudhry, A. Z., Gillespie, J., and Kaiser, H. E. (2000). Papillary microcarcinoma of the thyroid: a clinico-pathologic and prognostic review. In vivo 14, 367-376.
47. Niemeier, L. A., Kuffner Akatsu, H., Song, C., Carty, S. E., Hodak, S. P., Yip, L., Ferris, R. L., Tseng, G. C., Seethala, R. R., Lebeau, S. O., Stang, M. T.,Coyne, C., Johnson, J. T., Stewart, A. F., and Nikiforov, Y. E. (2011). A combined molecular-pathologic score improves risk stratification of thyroid papillary microcarcinoma. Cancer. doi: 10.1002/cncr.26425. [Epub ahead of print].
48. Nikiforova, M. N., Kimura, E. T., Gandhi, M., Biddinger, P. W., Knauf, J. A., Basolo, F., Zhu, Z., Giannini, R., Salvatore, G., Fusco, A., Santoro, M., Fagin, J. A., and Nikiforov, Y. E. (2003). BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J. Clin. Endocrinol. Metab. 88, 5399-5404.
49. Noguchi, S., Yamashita, H., Murakami, N., Nakayama, I., Toda, M., and Kawamoto, H. (1996). Small carcinomas of the thyroid. A longterm follow-up of 867 patients. Arch. Surg. 131, 187-191.
50. Nucera, C., Goldfarb, M., Hodin, R., and Parangi, S. (2009). Role of B-Raf(V600E) in differentiated thyroid cancer and preclinical validation of compounds against B-Raf(V600E). Biochim. Biophys. Acta 1795, 152-161.
51. Nucera, C., Lawler, J., and Parangi, S. (2011a). BRAFV600E and microenvironment in thyroid cancer: a functional link to drive cancer progression. Cancer Res. 71, 2417-2422.
52. Nucera, C., Nehs, M. A., Nagarkatti, S. S., Sadow, P. M., Mekel, M., Fischer, A. H., Lin, P. S., Bollag, G. E., Lawler, J., Hodin, R. A., and Parangi, S. (2011b). Targeting BRAFV600E with PLX4720 displays potent antimigratory and antiinvasive activity in preclinical models of human thyroid cancer. Oncologist 16, 296-309.
53. Nucera, C., Porrello, A., Antonello, Z. A., Mekel, M., Nehs, M. A., Giordano, T. J., Gerald, D., Benjamin, L. E., Priolo, C., Puxeddu, E., Finn, S., Jarzab, B., Hodin, R. A., Pontecorvi, A., Nose, V., Lawler, J., and Parangi, S. (2010). B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression. Proc. Natl. Acad. Sci. U.S.A. 107, 10649-10654.
54. Ott, P. A., Hamilton, A., Min, C., Safarzadeh-Amiri, S., Goldberg, L., Yoon, J., Yee, H., Buckley, M., Christos, P. J., Wright, J. J., Polsky, D., Osman, I., Liebes, L., and Pavlick, A. C. (2010). A phase II trial of sorafenib in metastatic melanoma with tissue correlates. PLoS ONE 5, e15588. doi:10.1371/journal.pone.0015588
55. Pacini, F., Schlumberger, M., Dralle, H., Elisei, R., Smit, J. W., and Wiersinga, W. (2006). European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur. J. Endocrinol. 154, 787-803.
56. Papini, E., Guglielmi, R., Bianchini, A., Crescenzi, A., Taccogna, S., Nardi, F., Panunzi, C., Rinaldi, R., Toscano, V., and Pacella, C. M. (2002). Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features. J. Clin. Endocrinol. Metab. 87, 1941-1946.
57. Papini, E., Guglielmi, R., Hosseim, G., Misischi, I., Graziano, F., Chianelli, M., Crescenzi, A., Bianchini, A., Valle, D., and Bizzarri, G. (2011). Ultrasound-guided laser ablation of incidental papillary thyroid microcarcinoma: a potential therapeutic approach in patients at surgical risk. Thyroid 21, 917-920.
58. Pazaitou-Panayiotou, K., Capezzone, M., and Pacini, F. (2007). Clinical features and therapeutic implication of papillary thyroid microcarcinoma. Thyroid 17, 1085-1092.
59. Pelizzo, M. R., Bernante, P., Toniato, A., and Fassina, A. (1997). Frequency of thyroid carcinoma in a recent series of 539 consecutive thyroidectomies for multinodular goiter. Tumori 83, 653-655.
60. Pelizzo, M. R., Boschin, I. M., Toniato, A., Pagetta, C., Piotto, A., Bernante, P., Casara, D., Pennelli, G., and Rubello, D. (2004). Natural history, diagnosis, treatment and outcome of papillary thyroid microcarcinoma (PTMC): a mono-institutional 12-year experience. Nucl.Med.Commun. 25, 547-552.
61. Pellegriti, G., Scollo, C., Lumera, G., Regalbuto, C., Vigneri, R., and Belfiore, A. (2004). Clinical behavior and outcome of papillary thyroid cancers smaller than 1.5 cm in diameter: study of 299 cases. J. Clin. Endocrinol. Metab. 89, 3713-3720.
62. Ringel, M. D. (2011). Metastatic dormancy and progression in thyroid cancer: targeting cells in the metastatic frontier. Thyroid 21, 487-492.
63. Rodriguez, J. M., Moreno, A., Parrilla, P., Sola, J., Soria, T., Tebar, F. J., and Aranda, F. (1997). Papillary thyroid microcarcinoma: clinical study and prognosis. Eur. J. Surg. 163, 255-259.
64. Roti, E., Rossi, R., Trasforini, G., Bertelli, F., Ambrosio, M. R., Busutti, L., Pearce, E. N., Braverman, L. E., and Degli Uberti, E. C. (2006). Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. J. Clin. Endocrinol. Metab. 91, 2171-2178.
65. Sakorafas, G. H., Stafyla, V., Kolettis, T., Tolumis, G., Kassaras, G., and Peros, G. (2007). Microscopic papillary thyroid cancer as an incidental finding in patients treated surgically for presumably benign thyroid disease. J. Postgrad. Med. 53, 23-26.
66. Salerno, P., De Falco, V., Tamburrino, A., Nappi, T. C., Vecchio, G., Schweppe, R. E., Bollag, G., Santoro, M., and Salvatore, G. (2010). Cytostatic activity of adenosine triphosphatecompetitive kinase inhibitors in BRAF mutant thyroid carcinoma cells. J. Clin. Endocrinol. Metab. 95, 450-455.
67. Schwartz, R. W., Kenady, D. E.,Bensema, M., McGrath, P. C., and Flueck, J. (1989). Medullary thyroid cancer and Graves' disease. Surgery 105, 804-807.
68. Sedliarou, I., Saenko, V., Lantsov, D., Rogounovitch, T., Namba, H., Abrosimov, A., Lushnikov, E., Kumagai, A., Nakashima, M., Meirmanov, S., Mine, M., Hayashi, T., and Yamashita, S. (2004). The BRAFT1796A transversion is a prevalent mutational event in human thyroid microcarcinoma. Int. J. Oncol. 25, 1729-1735.
69. Shaha, A. R., Tuttle, R. M., and Shah, J. P. (2007). Papillary microcarcinoma of the thyroid. J. Surg. Oncol. 95, 532-533.
70. Shattuck, T. M., Westra, W. H., Ladenson, P. W., and Arnold, A. (2005). Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma. N. Engl. J. Med. 352, 2406-2412.
71. Soares, P., and Sobrinho-Simoes, M. (2011). Cancer: small papillary thyroid cancers - is BRAF of prognostic value? Nat. Rev. Endocrinol. 7, 9-10.
72. Sugitani, I., and Fujimoto, Y. (1999). Symptomatic versus asymptomatic papillary thyroid microcarcinoma: a retrospective analysis of surgical outcome and prognostic factors. Endocr. J. 46, 209-216.
73. Sugitani, I., Yanagisawa, A., Shimizu, A., Kato, M., and Fujimoto, Y. (1998). Clinicopathologic and immuno histochemical studies of papillary thyroid microcarcinoma presenting with cervical lymphadenopathy. WorldJ.Surg.22, 731-737.
74. Tallini,G.,Santoro,M.,Helie,M.,Carlomagno, F., Salvatore, G., Chiappetta, G., Carcangiu, M. L., and Fusco, A. (1998). 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. 4, 287-294.
75. Tsai, J., Lee, J. T., Wang, W., Zhang, J., Cho, H., Mamo, S., Bremer, R., Gillette, S., Kong, J., Haass, N. K., Sproesser, K., Li, L., Smalley, K. S., Fong, D., Zhu, Y. L., Marimuthu, A., Nguyen, H., Lam, B., Liu, J., Cheung, I., Rice, J., Suzuki, Y., Luu, C., Settachatgul, C., Shellooe, R., Cantwell, J., Kim, S. H., Schlessinger, J., Zhang, K. Y., West, B. L., Powell, B., Habets, G., Zhang, C., Ibrahim, P. N., Hirth, P., Artis, D. R., Herlyn, M., and Bollag, G. (2008). Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. U.S.A. 105, 3041-3046.
76. Ugolini, C., Giannini, R., Lupi, C., Salvatore, G., Miccoli, P., Proietti, A., Elisei, R., Santoro, M., and Basolo, F. (2007). Presence of BRAF V600E in very early stages of papillary thyroid carcinoma. Thyroid 17, 381-388.
77. Xing, M. (2007). BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr. Rev. 28, 742-762.
78. Xing, M. (2009). BRAF mutation in papillary thyroid microcarcinoma: the promise of better risk management. Ann. Surg. Oncol. 16, 801-803.
79. Yamashita, H., Noguchi, S., Murakami, N., Toda, M., Uchino, S., Watanabe, S., and Kawamoto, H. (1999). Extracapsular invasion of lymph node metastasis. A good indicator of disease recurrence and poor prognosis in patients with thyroid microcarcinoma. Cancer 86, 842-849.
80. Yun, M., Noh, T. W., Cho, A., Choi, Y. J., Hong, S. W., Park, C. S., Lee, J. D., and Kim, C. K. (2010). Visually discernible [18F]fluorodeoxyglucose uptake in papillary thyroid microcarcinoma: a potential new risk factor. J. Clin. Endocrinol. Metab. 95, 3182-3188.