Research on BRAF Gene, Expression of VEGF-C, and Clinicopathologic Factors for Central Lymph Node Metastasis in Papillary Thyroid Carcinoma_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 ZHANGMing ^1,2 ,  ZHUJing-qiang ¹ , WEITao ¹

1. Center of Thyroid Disease Diagnosis and Treatment, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China;
2. PLA Nany General Hospital, Beijing 100048, China;

Corresponding author：

ZHUJing-qiang, Email: zjq-wkys@163.com

Keywords：

Papillary thyroid carcinoma; Central lymph nodes; Cervical lymph node dissection; Vascular endothe-lial growth factor C; BRAF gene

DOI：

10.7507/1007-9424.20150206

Video：

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Objective To identify the risk factors of central lymph nodal (CLN) metastasis in papillary thyroid carcinoma (PTC) and indicate central neck dissection. Methods Fifty cases were analyzed retrospectively. The BRAF^V600E gene mutation was analyzed by sequencing and expression of VEGF-C was analyzed by using immunohistochemically. The clinicopathologic and molecular marker factors relating to CLN metastasis were analyzed. Results The BRAF^V600E gene mutation was found in 30 of 50 (60.0%) patients of PTC. Univariate analysis showed that BRAF^V600E gene mutation of PTC patients was significantly correlated with high expression of VEGF-C (87.5% vs. 34.6%,P=0.000), not with clinicopathologic factors. High expression of VEGF-C was significantly correlated with CLN metastasis in PTC (87.5% vs. 57.7%, P=0.019). Multivariate analysis showed that invasion of the surrounding tissues (P=0.009,OR=9.082,95% CI:1.748-47.185) and the high expression of VEGF-C (P=0.009,OR=9.082,95% CI:1.748-47.185) were independent risk factors for the presence of CLN metastases. Conclusions ①The BRAF^V600E gene mutation for PTC patients is significantly correlated with high expression of VEGF-C, not with CLN metastasis in PTC. ②High expression of VEGF-C is significantly correlated with CLN metastasis in PTC. ③Tumor extrathyroidal extension, especially invasion of the surrounding tissues is significantly correlated with CLN metastasis in PTC.

Citation： ZHANGMing, ZHUJing-qiang, WEITao. Research on BRAF Gene, Expression of VEGF-C, and Clinicopathologic Factors for Central Lymph Node Metastasis in Papillary Thyroid Carcinoma. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2015, 22(7): 788-794. doi: 10.7507/1007-9424.20150206 Copy

1.	Trimboli P, Ulisse S, Graziano FM, et al. Trend in thyroid carcinoma size, age at diagnosis and histology in a retrospective study of 500 cases diagnosed over 20 years. Thyroid, 2006, 16(11):1151-1155.
2.	Grebe SK, Hay ID. Thyroid cancer nodal metastases:biologic significance and therapeutic considerations. Surg Oncol Clin N Am, 1996, 5(1):43-63.
3.	Scheumann GF, Gimm O, Wegener G, et al. Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surgery, 1994, 18(4):559-568.
4.	Hay ID, Thompson GB, Grant CS, et al. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999):temporal trends in initial therapy and long-term outcome in 2 444 consecutively treated patients. World J Surg, 2002, 26(8):879-885.
5.	Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53 856 cases of thyroid carcinoma treated in the U.S,1985-1995. Cancer, 1998, 83(12):2638-2648.
6.	Shaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin North Am, 1998, 31(5):823-831.
7.	Qubain SW, Nakano S, Baba M, et al. Distribution of lymph node micrometastasis in pN0 well-differentiated thyroid carcinoma. Surgery, 2002, 131(3):249-256.
8.	Gimm O, Rath FW, Dralle H. Pattern of lymph node metastases in papillary thyroid carcinoma. Br J Surg, 1998, 85(2):252-254.
9.	Lupi C, Giannini R, Ugolini C, et al. Association of BRAF^V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab, 2007, 92(11):4085-4090.
10.	Elisei R, Ugolini C, Viola D, et al. BRAF^V600E mutation and outcome of patients with papillary thyroid carcinoma:a 15-year median follow-up study. J Clin Endocrinol Metab, 2008, 93(10):3943-3949.
11.	Akagi K, Ikeda Y, Miyazaki M, et al. Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br J Cancer, 2000, 83(7):887-891.
12.	Yonemura Y, Endo Y, Fujita H, et al. Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. Clin Cancer Res, 1999, 5(7):1823-1829.
13.	Ueda M, Terai Y, Yamashita Y, et al. Correlation between vascular endothelial growth factor-C expression and invasion phenotype in cervical carcinomas. Int J Cancer, 2002, 98(3):335-343.
14.	Tsutsui S, Matsuyama A, Yamamoto M, et al. The Akt expression correlates with the VEGF-A and -C expression as well as the microvessel and lymphatic vessel density in breast cancer. Oncol Rep, 2010, 23(3):621-630.
15.	Robbins KT, Shaha AR, Medina JE, et al. Consensus statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg, 2008, 134(5):536-538.
16.	American Joint Committee on Cancer (AJC), Edge SB, Byrd DR, et al. AJCC Cancer Staging Manual, 7^th ed. New York:Springer,2010:87-96.
17.	Soslow RA, Dannenberg AJ, Rush D, et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer, 2000, 89(12):2637-2645.
18.	Cohen Y, Rosenbaum R, Clark DP, et al. Mutational analysis of BRAF in fine needle aspiration biopsies of the thyroid:a potential application for the preoperative assessment of thyroid nodules. Clin Cancer Res, 2004, 10(8):2761-2765.
19.	Sapio MR, Posca D, Troncone G, et al. Detection of BRAF mutation in thyoid papillary carcinomas by mutant allele-specific PCR amplification (MASA). Eur J Endocrinol, 2006, 154(2):341-348.
20.	Xing M, Vasko V, Tallini G, et al. BRAF T1796A transversion mutation in various thyroid neoplasms. J Clin Endocrinol Metab, 2004, 89(3):1365-1368.
21.	Trovisco V, Vieira de Castro I, Soares P, et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol, 2004, 202(2):247-251.
22.	Kim KH, Kang DW, Kim SH, et al. Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J, 2004, 45(5):818-821.
23.	Namba H, Nakashima M, Hayashi T, et al. Clinical implication of hot spot BRAF mutation,V599E, in papillary thyroid cancers. J Clin Endocrineol Metab, 2003, 88(9):4393-4397.
24.	Ito Y, Yoshida H, Maruo R, et al. BRAF mutation in papillary thyroid carcinoma in a Japanese population:its lack of correlation with high-risk clinicopathological features and disease-free survival of patients. Endocr J, 2009, 56(1):89-97.
25.	Duff SE, Jeziorska M, Kumar S, et al. Lymphatic vessel density, microvessel density and lymphangiogenic growth factor expression in colorectal cancer. Colorectal Dis, 2007, 9(9):793-800.
26.	Padera TP, Kadambi A, Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science, 2002, 296(5574):1882-1886.
27.	Krishnan J, Kirkin V, Stefen A, et al. Diferential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. Cancer Res, 2003, 63(3):713-722.
28.	Shushanov S, Bronstein M, Adelaide J, et al. VEGFc and VEGFR3 expression in human thyroid pathologies. Int J Cancer, 2000, 86(1):47-52.
29.	Bunone G, Vigneri P, Mariani L, et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol, 1999.155(6).1967-1976.
30.	Fellmer PT, Sato K, Tanaka R, et al. Vascular endothelial growth factor-C gene expression in papillary and follicular thyroid carcinomas. Surgery, 1999, 126(6):1056-1061.
31.	Hung CJ, Ginzinger DG, Zarnegar R, et al. Expression of vascular endothelial growth factor-C in benign and malignant thyroid tumors. J Clin Endocrinol Metab, 2003, 88(8):3694-3699.
32.	Yu XM, Lo CY, Chan WF, et al. Increased expression of vascular endothelial growth factor C in papillary thyroid carcinoma correlates with cervical lymph node metastases. Clin Cancer Res, 2005, 11(22):8063-8069.
33.	Shen WT, Ogawa L, Ruan D et al. Central neck lymph node dissection for papillary thyroid cancer:comparison of complication and recurrence rates in 295 initial dissections and reoperations. Arch Surg, 2010, 145(3):272-275.
34.	Roh JL, Kim JM, Park CI. Central lymph node metastasis of unilateral papillary thyroid carcinoma:patterns and factors predictive of nodal metastasis, morbidity, and recurrence. Ann Surg Oncol, 2011, 18(8):2245-50.
35.	Zuniga S, Sanabria A. Prophylactic central neck dissection in stage N0 papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg, 2009, 135(11):1087-1091.
36.	林益凯, 盛建明, 赵文和, 等. 多灶性甲状腺乳头状癌168例临床研究. 中华外科杂志, 2009, 47(6):450-453.
37.	Moo TA, Umunna B, Kato M, et al. Ipsilateral versus bilateral central neck lymph node dissection in papillary thyroid carcinoma. Ann Surg, 2009, 250(3):403-408.
38.	American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 2009, 19(11):1167-1214.

1. Trimboli P, Ulisse S, Graziano FM, et al. Trend in thyroid carcinoma size, age at diagnosis and histology in a retrospective study of 500 cases diagnosed over 20 years. Thyroid, 2006, 16(11):1151-1155.
2. Grebe SK, Hay ID. Thyroid cancer nodal metastases:biologic significance and therapeutic considerations. Surg Oncol Clin N Am, 1996, 5(1):43-63.
3. Scheumann GF, Gimm O, Wegener G, et al. Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surgery, 1994, 18(4):559-568.
4. Hay ID, Thompson GB, Grant CS, et al. Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999):temporal trends in initial therapy and long-term outcome in 2 444 consecutively treated patients. World J Surg, 2002, 26(8):879-885.
5. Hundahl SA, Fleming ID, Fremgen AM, et al. A National Cancer Data Base report on 53 856 cases of thyroid carcinoma treated in the U.S,1985-1995. Cancer, 1998, 83(12):2638-2648.
6. Shaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin North Am, 1998, 31(5):823-831.
7. Qubain SW, Nakano S, Baba M, et al. Distribution of lymph node micrometastasis in pN0 well-differentiated thyroid carcinoma. Surgery, 2002, 131(3):249-256.
8. Gimm O, Rath FW, Dralle H. Pattern of lymph node metastases in papillary thyroid carcinoma. Br J Surg, 1998, 85(2):252-254.
9. Lupi C, Giannini R, Ugolini C, et al. Association of BRAF^V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab, 2007, 92(11):4085-4090.
10. Elisei R, Ugolini C, Viola D, et al. BRAF^V600E mutation and outcome of patients with papillary thyroid carcinoma:a 15-year median follow-up study. J Clin Endocrinol Metab, 2008, 93(10):3943-3949.
11. Akagi K, Ikeda Y, Miyazaki M, et al. Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br J Cancer, 2000, 83(7):887-891.
12. Yonemura Y, Endo Y, Fujita H, et al. Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. Clin Cancer Res, 1999, 5(7):1823-1829.
13. Ueda M, Terai Y, Yamashita Y, et al. Correlation between vascular endothelial growth factor-C expression and invasion phenotype in cervical carcinomas. Int J Cancer, 2002, 98(3):335-343.
14. Tsutsui S, Matsuyama A, Yamamoto M, et al. The Akt expression correlates with the VEGF-A and -C expression as well as the microvessel and lymphatic vessel density in breast cancer. Oncol Rep, 2010, 23(3):621-630.
15. Robbins KT, Shaha AR, Medina JE, et al. Consensus statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg, 2008, 134(5):536-538.
16. American Joint Committee on Cancer (AJC), Edge SB, Byrd DR, et al. AJCC Cancer Staging Manual, 7^th ed. New York:Springer,2010:87-96.
17. Soslow RA, Dannenberg AJ, Rush D, et al. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer, 2000, 89(12):2637-2645.
18. Cohen Y, Rosenbaum R, Clark DP, et al. Mutational analysis of BRAF in fine needle aspiration biopsies of the thyroid:a potential application for the preoperative assessment of thyroid nodules. Clin Cancer Res, 2004, 10(8):2761-2765.
19. Sapio MR, Posca D, Troncone G, et al. Detection of BRAF mutation in thyoid papillary carcinomas by mutant allele-specific PCR amplification (MASA). Eur J Endocrinol, 2006, 154(2):341-348.
20. Xing M, Vasko V, Tallini G, et al. BRAF T1796A transversion mutation in various thyroid neoplasms. J Clin Endocrinol Metab, 2004, 89(3):1365-1368.
21. Trovisco V, Vieira de Castro I, Soares P, et al. BRAF mutations are associated with some histological types of papillary thyroid carcinoma. J Pathol, 2004, 202(2):247-251.
22. Kim KH, Kang DW, Kim SH, et al. Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J, 2004, 45(5):818-821.
23. Namba H, Nakashima M, Hayashi T, et al. Clinical implication of hot spot BRAF mutation,V599E, in papillary thyroid cancers. J Clin Endocrineol Metab, 2003, 88(9):4393-4397.
24. Ito Y, Yoshida H, Maruo R, et al. BRAF mutation in papillary thyroid carcinoma in a Japanese population:its lack of correlation with high-risk clinicopathological features and disease-free survival of patients. Endocr J, 2009, 56(1):89-97.
25. Duff SE, Jeziorska M, Kumar S, et al. Lymphatic vessel density, microvessel density and lymphangiogenic growth factor expression in colorectal cancer. Colorectal Dis, 2007, 9(9):793-800.
26. Padera TP, Kadambi A, Tomaso E, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science, 2002, 296(5574):1882-1886.
27. Krishnan J, Kirkin V, Stefen A, et al. Diferential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. Cancer Res, 2003, 63(3):713-722.
28. Shushanov S, Bronstein M, Adelaide J, et al. VEGFc and VEGFR3 expression in human thyroid pathologies. Int J Cancer, 2000, 86(1):47-52.
29. Bunone G, Vigneri P, Mariani L, et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol, 1999.155(6).1967-1976.
30. Fellmer PT, Sato K, Tanaka R, et al. Vascular endothelial growth factor-C gene expression in papillary and follicular thyroid carcinomas. Surgery, 1999, 126(6):1056-1061.
31. Hung CJ, Ginzinger DG, Zarnegar R, et al. Expression of vascular endothelial growth factor-C in benign and malignant thyroid tumors. J Clin Endocrinol Metab, 2003, 88(8):3694-3699.
32. Yu XM, Lo CY, Chan WF, et al. Increased expression of vascular endothelial growth factor C in papillary thyroid carcinoma correlates with cervical lymph node metastases. Clin Cancer Res, 2005, 11(22):8063-8069.
33. Shen WT, Ogawa L, Ruan D et al. Central neck lymph node dissection for papillary thyroid cancer:comparison of complication and recurrence rates in 295 initial dissections and reoperations. Arch Surg, 2010, 145(3):272-275.
34. Roh JL, Kim JM, Park CI. Central lymph node metastasis of unilateral papillary thyroid carcinoma:patterns and factors predictive of nodal metastasis, morbidity, and recurrence. Ann Surg Oncol, 2011, 18(8):2245-50.
35. Zuniga S, Sanabria A. Prophylactic central neck dissection in stage N0 papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg, 2009, 135(11):1087-1091.
36. 林益凯, 盛建明, 赵文和, 等. 多灶性甲状腺乳头状癌168例临床研究. 中华外科杂志, 2009, 47(6):450-453.
37. Moo TA, Umunna B, Kato M, et al. Ipsilateral versus bilateral central neck lymph node dissection in papillary thyroid carcinoma. Ann Surg, 2009, 250(3):403-408.
38. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 2009, 19(11):1167-1214.

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Research on BRAF Gene, Expression of VEGF-C, and Clinicopathologic Factors for Central Lymph Node Metastasis in Papillary Thyroid Carcinoma

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