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Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?
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Asian Journal of Surgery (2015) xx, 1e5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.e-asianjournalsurgery.com
ORIGINAL ARTICLE
Should central lymph node dissection be considered for all papillary thyroid microcarcinoma? Young Woo Chang a,b, Hwan Soo Kim a,b, Hoon Yub Kim a,b, Jae Bok Lee a,b, Jeoung Won Bae a,b, Gil Soo Son a,b,* a b
Department of Breast Endocrine Surgery, Korea University Medical Center, Seoul, Republic of Korea Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
Received 12 January 2015; received in revised form 13 February 2015; accepted 24 February 2015
KEYWORDS central lymph node; papillary thyroid cancer; papillary thyroid microcarcinoma
Summary Background: Central lymph node dissection (CLND) in patients with papillary thyroid microcarcinoma (PTMC) is still controversial. The aim of this study was to examine the risk factors and the incidence of central lymph node metastases (CLNMs) in patients with PTMC who underwent thyroidectomy and CLND. Patients and methods: Between 2002 and 2013, 613 patients were enrolled who underwent thyroidectomy with routine CLND for PTMC at the Korea University Medical Center, Ansan Hospital and risk factors and the incidence of CLNM were analyzed. In addition, we also evaluated the complications after thyroidectomy with CLND. Results: Out of 613 patients, 239 (39.0%) were found to have CLNM. Male sex (p Z 0.012), tumor size 0.5 cm (p Z 0.001), capsular invasion or extrathyroidal extension (p Z 0.029), and multifocality (p Z 0.004) were independent risk factors for CLNM. Among the 69 patients who had PTMC without these risk factors, CLNM was identified in 12 (17.4%). In this study group, two (0.3%) had permanent recurrent laryngeal nerve injury, two (0.3%) had persistent hypocalcemia, and two (0.3%) developed postoperative hemorrhage. Conclusion: CLNM in PTMC is highly prevalent in male sex, tumor size 0.5 cm, extrathyroidal extension, and multifocality. Even in PTMC patients without these risk factors, the incidence of CLNM is rather higher than expected, and the complication rate of thyroidectomy with CLND is acceptable. Thus, CLND should be considered in all patients with PTMC. Copyright ª 2015, Asian Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.
Conflicts of interest: This study was supported by Korea University Grant (K1032401). * Corresponding author. Department of Breast Endocrine Surgery, Korea University Medical Center, 123, Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do 425-707, Republic of Korea. E-mail address: [email protected] (G.S. Son). http://dx.doi.org/10.1016/j.asjsur.2015.02.006 1015-9584/Copyright ª 2015, Asian Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006
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1. Introduction Papillary thyroid microcarcinoma (PTMC) is defined as a papillary thyroid carcinoma (PTC) measuring 1 cm in maximal diameter, and the overall 10-year survival rate associated with this malignancy is > 90%.1,2 Because of the overall excellent prognosis of PTMC, many current guidelines and recommendations regarding the optimal treatment strategy for PTMC remain controversial.3,4 Many arguments about PTMC treatments have focused on routine central lymph node dissection (CLND), because despite the excellent prognosis, central lymph node metastases (CLNMs) are common in patients with PTC. Several studies have reported that CLNM are associated with a significantly increased probability of locoregional disease recurrence, and routine CLND for PTC patients may decrease recurrence and improve disease-specific survival.5e9 However, Ito et al10 have insisted that prophylactic CLND may result in postoperative complications and provides no overall survival benefit. Moreover, the 2009 guidelines for the management of thyroid nodules and differentiated thyroid cancer issued by the American Thyroid Association Guidelines Taskforce state the following: “Prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors.”11 To investigate the efficacy and indication of CLND for PTMC patients, we examined the overall incidence and risk factors of CLNM in our cases. In addition, we also analyzed the complications and incidence of CLNM in PTMC patients without risk factors.
Y.W. Chang et al. were autotransplanted into the sternocleidomastoid muscle. The incidence rates of recurrent laryngeal nerve injury, hypocalcemia, and postoperative hemorrhage were evaluated. Temporary recurrent laryngeal nerve injury was based on the surgeon’s assessment and the patient’s symptoms during the immediate postoperative day. Recurrent laryngeal nerve injury was considered permanent when paralysis of the vocal cords persisted > 6 months after the surgery. Transient hypocalcemia was defined as an ionized calcium level < 1.0 mg/dL postoperatively but recovered until 6 months, and permanent hypocalcemia was defined as persistent hypocalcemia requiring calcium carbonate and calcitriol supplementation > 6 months after the surgery. Performing an emergency evacuation of a hematoma after thyroidectomy was considered postoperative hemorrhage. Categorical variables were compared using the Chisquare test or Fisher’s exact test to analyze the significance of differences. Logistic regression was used for multivariate analysis. Differences were considered statistically significant with p 0.05 using a two-tailed test. All statistical analyses were performed using SPSS Statistics version 20.0.0 for Macintosh (IBM, Armonk, NY, USA).
3. Results 3.1. Patient characteristics and pathology The patient clinicopathological characteristics are summarized in Table 1. The study population included 558 women (91.0%) and 55 men (9.0%) with a mean age of
2. Patients and methods A total of 613 patients who underwent thyroidectomy with routine CLND for PTMC at the Korea University Medical Center, Ansan Hospital, between January 2002 and December 2013 were enrolled in this study. Based on a review of our computerized database, the following data were collected: demographic information and pathological parameters, such as tumor size, extra thyroidal extension, multifocality, cervical lymph node metastasis, lymphovascular invasion, and thyroiditis. This study was approved by the Institutional Review Board of Korea University Medical Center, Ansan Hospital. All 613 patients underwent hemithyroidectomy or total thyroidectomy with routine CLND. Hemithyroidectomy with ipsilateral CLND was performed in 205 patients because they had single lesions that were limited to the thyroid and clinically negative radiologic findings in the central lymph node, and four underwent subsequent completion thyroidectomy. Among the remaining 408 patients, 310 patients with clinically node negative findings underwent total thyroidectomy with ipsilateral CLND, and bilateral CLND was performed in 98 patients with clinically suspicious node metastasis or bilateral lesions. CLND was performed superiorly to the hyoid bone, laterally to the carotid sheath, inferiorly to the manubrium, and dorsally to the prevertebral fascia. The parathyroid glands were carefully preserved in situ, and the devascularized parathyroid glands
Table 1
Clinicopathological characteristics (n Z 613).
Characteristic
n (%)
Age (y) Sex Female Male Tumor size (cm) Mean < 0.5 0.5 Extrathyroidal extension No Yes Multifocality No Yes Central lymph node metastasis No Yes Lymphovascular invasion No Yes Thyroiditis No Yes
46.2 (10.5) 558 (91.0) 55 (9.0) 0.8 (0.4) 126 (20.6) 487 (79.4) 264 (43.1) 349 (56.9) 461 (75.2) 152 (24.8) 374 (61.0) 239 (39.0) 597 (97.4) 16 (2.6) 320 (52.2) 293 (47.8)
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006
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Central lymph node dissection for papillary thyroid microcarcinoma 46.2 10.5 years. The mean size of PTMCs was 0.8 0.4 cm; 126 (20.6%) patients had PTMCs < 0.5 cm and 487 (79.4%) patients had PTMCs 0.5 cm in size. Of these patients, 264 (43.1%) patients had PTMC confined to the thyroid, and 349 (56.9%) patients had PTMC with extrathyroidal extension. Multifocality was observed in 152 (24.8%) patients, lymphovascular invasion was found in 16 (2.6%) patients, and thyroiditis was found in 293 (47.8%) patients. CLNMs were identified in 239 (39.0%) patients.
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Table 3 Incidence of central lymph node metastasis in patients with PTMC. Central lymph node metastasis, n (%)
Total Without RFs
Negative
Positive
374 (61.0) 57 (82.6)
239 (39.0) 12 (17.4)
Total
613 (100) 69 (100)
PTMC Z papillary thyroid microcarcinoma; RF Z risk factor.
3.2. Risk factors associated with CLNMs Male sex [odds ratio (OR), 2.17; 95% confidence interval (CI), 1.24e3.80; p Z 0.006], tumor size 0.5 cm (OR, 2.83; 95% CI, 1.78e4.49; p < 0.001), extrathyroidal extension (OR, 1.93; 95% CI, 1.38e2.70; p < 0.001), and multifocality (OR, 2.11; 95% CI, 1.46e3.06; p < 0.001) were significantly associated with CLNM. Age, lymphovascular invasion, and thyroiditis were not significantly associated with CLNM. After all variables with p < 0.5 in the univariate analysis were input into the logistic regression model, male sex (OR, 2.10; 95% CI, 1.18e3.75; p Z 0.012), tumor size 0.5 cm (OR, 2.29; 95% CI, 1.42e3.69; p Z 0.001), extrathyroidal extension (OR, 1.49; 95% CI, 1.04e2.13; p Z 0.029), and multifocality (OR, 1.76; 95% CI, 1.19e2.59; p Z 0.004) remained as independent risk factors of CLNM (Table 2).
3.3. CLNM incidence and postoperative complications Overall, 39% of PTMC patients (239 of 613) had pathologically metastatic lymph nodes in the central compartment.
Table 2
Among the 69 PTMC patients without all four risk factors shown in Table 2, 17.4% (12 of 69) had CLNM (Table 3). Thirteen (2.1%) patients experienced temporary recurrent laryngeal nerve palsy, and two (0.3%) patients had permanent recurrent laryngeal nerve palsy. Transient hypocalcemia occurred in 74 (12.1%) patients, and hypocalcemia persisting > 6 months after the operation occurred in two (0.3%) patients. Emergency operations for postoperative hemorrhage were performed in two (0.3%) patients (Table 4).
4. Discussion Male sex, tumor size 0.5 cm, extrathyroidal extension, and multifocality were associated with a significantly increased risk of CLNM in our study. In general, smaller lesion size and female sex are considered good prognostic factors of PTC.12e14 Lim et al15 and Zhang et al16 have also demonstrated that larger tumor size (> 0.7 cm, > 0.6 cm) was associated with CLNM. Male sex and tumor size
Risk factors associated with cervical lymph node metastasis.
Risk factor
Cervical LN metastasis Negative
Age (y) < 45 45 Sex Female Male Tumor size (cm) < 0.5 0.5 LV invasion No Yes Extrathyroidal extension No Yes Multifocality No Yes Thyroiditis No Yes
Positive
167 207
109 130
350 24
208 31
99 275
27 212
368 6
229 10
184 190
80 159
302 72
159 80
196 178
124 115
Univariate analysis OR (95% CI)
Multivariate analysis
p
OR (95% CI)
p
0.006
2.10 (1.18e3.75)
0.012
2.83 (1.78e4.49)
< 0.001
2.29 (1.42e3.69)
0.001
2.68 (0.96e7.47)
0.051
1.93 (1.38e2.70)
< 0.001
1.49 (1.04e2.13)
0.029
2.11 (1.46e3.06)
< 0.001
1.76 (1.19e2.59)
0.004
1.02 (0.74e1.41)
0.899
0.96 (0.69e1.33)
0.817
2.17 (1.24e3.80)
CI Z confidence interval; LN Z lymph node; LV Z lymphovascular; OR Z odds ratio.
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006
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Y.W. Chang et al. Table 4
Postoperative complications.
Complication Recurrent laryngeal nerve palsy Temporary Permanent Hypocalcemia Transient Permanent Postoperative hemorrhage
Number of patients (%) 13 (2.1) 2 (0.3) 74 (12.1) 2 (0.3) 2 (0.3)
0.5 cm were independent risk factors of CLNM in this study, and these results are compatible with those of other reports in PTMC patients.15,16 In the present study, extrathyroidal extension and multifocality also correlated with CLNM. Similar studies in PTMC have shown that extrathyroidal extension is associated with CLNM (p < 0.001) and recurrence (p Z 0.037), and multifocality has also been shown to be an independent risk factor of CLNM.17e20 According to Mazeh et al,21 multifocality may develop by intraglandular spread of the primary tumor, and this may be related to CLNM. CLNMs are relatively common in PTMC patients. Several studies have demonstrated that CLNMs are observed in about 31e64.1% of patients with PTMC.15,22,23 In this study, the incidence of CLNMs in patients with PTMC was 39.0%. To analyze the feasibility of prophylactic CLND for PTMC patients with no clinical risk factors, we also evaluated the incidence of CLNM in PTMC patients without any of these four risk factors. Even after the elimination of risk factors, the incidence of CLNM in these patients was 17.4%. Hence, the prediction of CLNM using only these risk factors should be considered unsafe. Appetecchia et al24 do not believe that CLND is necessary, because the reported mortality rates of PTMC range from 0% to 1%, and CLND provides no survival benefit despite the high incidence of CLNM. In addition, Wada et al23 have reported that CLND may increase the frequency of perioperative complications, such as recurrent laryngeal nerve injury, hypocalcemia, or immediate postoperative bleeding.23 However, Chow et al25 showed that the risk of locoregional recurrence (OR, 4.2; 95% CI, 1.3e13.6) and cervical lymph node recurrence (OR, 6.2; 95% CI, 1.6e24.4) significantly increased in PTMC patients with CLNM, and the presence of cervical lymph node metastasis also increased the incidence rate of distant metastasis (OR, 11.2; 95% CI, 1.3e100.7).25 Simon et al26 have also suggested that lymph node metastases are significantly associated with a higher risk of recurrence. Vini et al27 recommended routine CLND for patients aged 70 years. They indicated that radioactive iodine ablation may not be effective because the capacity of thyroid tumor cells for radioactive iodine uptake is reduced in elderly people.27 Furthermore, Levin et al28 have demonstrated that the operations for recurred lymph nodes in PTC increased the risk of postoperative complications. In addition, CLND is helpful to assess the accurate staging of lymph node.28 Currently, the diagnostic performance of ultrasonography (US) for determining the presence of CLNM in PTMC
patients is not completely reliable. The sensitivity of US in predicting CLNM for PTMC patients has been reported to range from 21.6% to 38.0%.29e31 Kim et al31 also showed that the false negative rate of US at the central neck level was 30% (32/107). As described above, although US findings can indicate clinically negative nodes in the central neck compartment, this does not guarantee pathologically negative nodes. The risk of postoperative complications is one concern about performing CLND in PTMC patients. According to a study by Henry et al32 that compared the complications after thyroidectomy only with thyroidectomy and CLND, CLND does not increase the incidence of recurrent laryngeal nerve injury. Gemsenja ¨ger et al33 described that 1e2% of patients who underwent total thyroidectomy only experienced permanent hypocalcemia or permanent recurrent laryngeal nerve injury, and the rate of complications was not increased with the addition of CLND. In this study, 0.3% of patients had permanent recurrent laryngeal nerve injury, and another 0.3% of patients experienced permanent hypocalcemia. These results are compatible with those of another study.34 The postoperative complications appear to be related to surgical experiences, and experts can perform CLND safely. In conclusion, the incidence of CLNM in PTMC patients (even with no risk factors) was not infrequent, whereas the rate of postoperative complications after CLND was acceptably low. Thus, CLND should be considered for even PTMC patients.
References 1. Hedinger CE, Williams ED, Sobin LH. Histological Typing of Thyroid Tumours. World Health Organization. International Histological Classification of Tumours. Berlin: Springer-Verlag Berlin; 1988. 2. Wang TS, Goffredo P, Sosa JA, Roman SA. Papillary thyroid microcarcinoma: an over-treated malignancy? World J Surg. 2014;38:2297e2303. 3. Udelsman R, Lakatos E, Ladenson P. Optimal surgery for papillary thyroid carcinoma. World J Surg. 1996;20:88e93. 4. Byar DP, Green SB, Dor P, et al. A prognostic index for thyroid carcinoma. A study of the E.O.R.T.C. Thyroid Cancer Cooperative Group. Eur J Cancer. 1979;15:1033e1041. 5. Sakorafas GH, Sampanis D, Safioleas M. Cervical lymph node dissection in papillary thyroid cancer: current trends, persisting controversies, and unclarified uncertainties. Surg Oncol. 2010;19:e57ee70. 6. White ML, Doherty GM. Level VI lymph node dissection for papillary thyroid cancer. Minerva Chir. 2007;62:383e393. 7. Shindo M, Wu JC, Park EE, Tanzella F. The importance of central compartment elective lymph node excision in the staging and treatment of papillary thyroid cancer. Arch Otolaryngol Head Neck Surg. 2006;132:650e654. 8. Sadowski BM, Snyder SK, Lairmore TC. Routine bilateral central lymph node clearance for papillary thyroid cancer. Surgery. 2009;146:696e703. 9. Moo TA, McGill J, Allendorf J, Lee J, Fahey T, Zarnegar R. Impact of prophylactic central neck lymph node dissection on early recurrence in papillary thyroid carcinoma. World J Surg. 2010;34:1187e1191. 10. Ito Y, Tomoda C, Uruno T, et al. Clinical significance of metastasis to the central compartment from papillary microcarcinoma of the thyroid. World J Surg. 2006;30:91e99.
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006
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Central lymph node dissection for papillary thyroid microcarcinoma 11. American Thyroid Association 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;19:1167e1214. 12. Tubiana M, Schlumberger M, Rougier P, et al. Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer. 1985;55:794e804. 13. Shaha AR, Jaffe BM. Parathyroid preservation during thyroid surgery. Am J Otolaryngol. 1998;19:113e117. 14. McHenry CR, Speroff T, Wentworth D, Murphy T. Risk factors for postthyroidectomy hypocalcemia. Surgery. 1994;116: 641e647. discussion 7e8. 15. Lim YC, Choi EC, Yoon YH, Kim EH, Koo BS. Central lymph node metastases in unilateral papillary thyroid microcarcinoma. Br J Surg. 2009;96:253e257. 16. Zhang L, Wei WJ, Ji QH, et al. Risk factors for neck nodal metastasis in papillary thyroid microcarcinoma: a study of 1066 patients. J Clin Endocrinol Metab. 2012;97:1250e1257. 17. Kim WY, Kim HY, Son GS, Bae JW, Lee JB. Clinicopathological, immunohistochemical factors and recurrence associated with extrathyroidal extension in papillary thyroid microcarcinoma. J Cancer Res Ther. 2014;10:50e55. 18. Park JP, Roh JL, Lee JH, et al. Risk factors for central neck lymph node metastasis of clinically noninvasive, node-negative papillary thyroid microcarcinoma. Am J Surg. 2014;208: 412e418. 19. So YK, Son YI, Hong SD, et al. Subclinical lymph node metastasis in papillary thyroid microcarcinoma: a study of 551 resections. Surgery. 2010;148:526e531. 20. Kim KE, Kim EK, Yoon JH, Han KH, Moon HJ, Kwak JY. Preoperative prediction of central lymph node metastasis in thyroid papillary microcarcinoma using clinicopathologic and sonographic features. World J Surg. 2013;37:385e391. 21. Mazeh H, Samet Y, Hochstein D, et al. Multifocality in welldifferentiated thyroid carcinomas calls for total thyroidectomy. Am J Surg. 2011;201:770e775. 22. Roh JL, Kim JM, Park CI. Central cervical nodal metastasis from papillary thyroid microcarcinoma: pattern and factors predictive of nodal metastasis. Ann Surg Oncol. 2008;15:2482e2486.
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23. Wada N, Duh QY, Sugino K, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg. 2003;237:399e407. 24. Appetecchia M, Scarcello G, Pucci E, Procaccini A. Outcome after treatment of papillary thyroid microcarcinoma. J Exp Clin Cancer Res. 2002;21:159e164. 25. Chow SM, Law SCK, Chan JKC, Au SK, Yau S, Lau WH. Papillary microcarcinoma of the thyroiddprognostic significance of lymph node metastasis and multifocality. Cancer. 2003;98:31e40. 26. Simon D, Goretzki PE, Witte J, Roher HD. Incidence of regional recurrence guiding radicality in differentiated thyroid carcinoma. World J Surg. 1996;20:860e866. discussion 6. 27. Vini L, Hyer SL, Marshall J, A’Hern R, Harmer C. Long-term results in elderly patients with differentiated thyroid carcinoma. Cancer. 2003;97:2736e2742. 28. Levin KE, Clark AH, Duh QY, Demeure M, Siperstein AE, Clark OH. Reoperative thyroid surgery. Surgery. 1992;111: 604e609. 29. Ito Y, Jikuzono T, Higashiyama T, et al. Clinical significance of lymph node metastasis of thyroid papillary carcinoma located in one lobe. World J Surg. 2006;30:1821e1828. 30. Hwang HS, Orloff LA. Efficacy of preoperative neck ultrasound in the detection of cervical lymph node metastasis from thyroid cancer. Laryngoscope. 2011;121:487e491. 31. Kim E, Park JS, Son KR, Kim JH, Jeon SJ, Na DG. Preoperative diagnosis of cervical metastatic lymph nodes in papillary thyroid carcinoma: comparison of ultrasound, computed tomography, and combined ultrasound with computed tomography. Thyroid. 2008;18:411e418. 32. Henry JF, Gramatica L, Denizot A, Kvachenyuk A, Puccini M, Defechereux T. Morbidity of prophylactic lymph node dissection in the central neck area in patients with papillary thyroid carcinoma. Langenbecks Arch Surg. 1998;383:167e169. 33. Gemsenja ¨ger E, Perren A, Seifert B, Schu ¨ler G, Schweizer I, Heitz PU. Lymph node surgery in papillary thyroid carcinoma. J Am Coll Surg. 2003;197:182e190. 34. Noguchi M, Katev N, Miwa K. Therapeutic strategies and longterm results in differentiated thyroid cancer. J Surg Oncol. 1998;67:52e59.
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006
MODEL
Asian Journal of Surgery (2015) xx, 1e5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.e-asianjournalsurgery.com
ORIGINAL ARTICLE
Should central lymph node dissection be considered for all papillary thyroid microcarcinoma? Young Woo Chang a,b, Hwan Soo Kim a,b, Hoon Yub Kim a,b, Jae Bok Lee a,b, Jeoung Won Bae a,b, Gil Soo Son a,b,* a b
Department of Breast Endocrine Surgery, Korea University Medical Center, Seoul, Republic of Korea Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
Received 12 January 2015; received in revised form 13 February 2015; accepted 24 February 2015
KEYWORDS central lymph node; papillary thyroid cancer; papillary thyroid microcarcinoma
Summary Background: Central lymph node dissection (CLND) in patients with papillary thyroid microcarcinoma (PTMC) is still controversial. The aim of this study was to examine the risk factors and the incidence of central lymph node metastases (CLNMs) in patients with PTMC who underwent thyroidectomy and CLND. Patients and methods: Between 2002 and 2013, 613 patients were enrolled who underwent thyroidectomy with routine CLND for PTMC at the Korea University Medical Center, Ansan Hospital and risk factors and the incidence of CLNM were analyzed. In addition, we also evaluated the complications after thyroidectomy with CLND. Results: Out of 613 patients, 239 (39.0%) were found to have CLNM. Male sex (p Z 0.012), tumor size 0.5 cm (p Z 0.001), capsular invasion or extrathyroidal extension (p Z 0.029), and multifocality (p Z 0.004) were independent risk factors for CLNM. Among the 69 patients who had PTMC without these risk factors, CLNM was identified in 12 (17.4%). In this study group, two (0.3%) had permanent recurrent laryngeal nerve injury, two (0.3%) had persistent hypocalcemia, and two (0.3%) developed postoperative hemorrhage. Conclusion: CLNM in PTMC is highly prevalent in male sex, tumor size 0.5 cm, extrathyroidal extension, and multifocality. Even in PTMC patients without these risk factors, the incidence of CLNM is rather higher than expected, and the complication rate of thyroidectomy with CLND is acceptable. Thus, CLND should be considered in all patients with PTMC. Copyright ª 2015, Asian Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.
Conflicts of interest: This study was supported by Korea University Grant (K1032401). * Corresponding author. Department of Breast Endocrine Surgery, Korea University Medical Center, 123, Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do 425-707, Republic of Korea. E-mail address: [email protected] (G.S. Son). http://dx.doi.org/10.1016/j.asjsur.2015.02.006 1015-9584/Copyright ª 2015, Asian Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006
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1. Introduction Papillary thyroid microcarcinoma (PTMC) is defined as a papillary thyroid carcinoma (PTC) measuring 1 cm in maximal diameter, and the overall 10-year survival rate associated with this malignancy is > 90%.1,2 Because of the overall excellent prognosis of PTMC, many current guidelines and recommendations regarding the optimal treatment strategy for PTMC remain controversial.3,4 Many arguments about PTMC treatments have focused on routine central lymph node dissection (CLND), because despite the excellent prognosis, central lymph node metastases (CLNMs) are common in patients with PTC. Several studies have reported that CLNM are associated with a significantly increased probability of locoregional disease recurrence, and routine CLND for PTC patients may decrease recurrence and improve disease-specific survival.5e9 However, Ito et al10 have insisted that prophylactic CLND may result in postoperative complications and provides no overall survival benefit. Moreover, the 2009 guidelines for the management of thyroid nodules and differentiated thyroid cancer issued by the American Thyroid Association Guidelines Taskforce state the following: “Prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors.”11 To investigate the efficacy and indication of CLND for PTMC patients, we examined the overall incidence and risk factors of CLNM in our cases. In addition, we also analyzed the complications and incidence of CLNM in PTMC patients without risk factors.
Y.W. Chang et al. were autotransplanted into the sternocleidomastoid muscle. The incidence rates of recurrent laryngeal nerve injury, hypocalcemia, and postoperative hemorrhage were evaluated. Temporary recurrent laryngeal nerve injury was based on the surgeon’s assessment and the patient’s symptoms during the immediate postoperative day. Recurrent laryngeal nerve injury was considered permanent when paralysis of the vocal cords persisted > 6 months after the surgery. Transient hypocalcemia was defined as an ionized calcium level < 1.0 mg/dL postoperatively but recovered until 6 months, and permanent hypocalcemia was defined as persistent hypocalcemia requiring calcium carbonate and calcitriol supplementation > 6 months after the surgery. Performing an emergency evacuation of a hematoma after thyroidectomy was considered postoperative hemorrhage. Categorical variables were compared using the Chisquare test or Fisher’s exact test to analyze the significance of differences. Logistic regression was used for multivariate analysis. Differences were considered statistically significant with p 0.05 using a two-tailed test. All statistical analyses were performed using SPSS Statistics version 20.0.0 for Macintosh (IBM, Armonk, NY, USA).
3. Results 3.1. Patient characteristics and pathology The patient clinicopathological characteristics are summarized in Table 1. The study population included 558 women (91.0%) and 55 men (9.0%) with a mean age of
2. Patients and methods A total of 613 patients who underwent thyroidectomy with routine CLND for PTMC at the Korea University Medical Center, Ansan Hospital, between January 2002 and December 2013 were enrolled in this study. Based on a review of our computerized database, the following data were collected: demographic information and pathological parameters, such as tumor size, extra thyroidal extension, multifocality, cervical lymph node metastasis, lymphovascular invasion, and thyroiditis. This study was approved by the Institutional Review Board of Korea University Medical Center, Ansan Hospital. All 613 patients underwent hemithyroidectomy or total thyroidectomy with routine CLND. Hemithyroidectomy with ipsilateral CLND was performed in 205 patients because they had single lesions that were limited to the thyroid and clinically negative radiologic findings in the central lymph node, and four underwent subsequent completion thyroidectomy. Among the remaining 408 patients, 310 patients with clinically node negative findings underwent total thyroidectomy with ipsilateral CLND, and bilateral CLND was performed in 98 patients with clinically suspicious node metastasis or bilateral lesions. CLND was performed superiorly to the hyoid bone, laterally to the carotid sheath, inferiorly to the manubrium, and dorsally to the prevertebral fascia. The parathyroid glands were carefully preserved in situ, and the devascularized parathyroid glands
Table 1
Clinicopathological characteristics (n Z 613).
Characteristic
n (%)
Age (y) Sex Female Male Tumor size (cm) Mean < 0.5 0.5 Extrathyroidal extension No Yes Multifocality No Yes Central lymph node metastasis No Yes Lymphovascular invasion No Yes Thyroiditis No Yes
46.2 (10.5) 558 (91.0) 55 (9.0) 0.8 (0.4) 126 (20.6) 487 (79.4) 264 (43.1) 349 (56.9) 461 (75.2) 152 (24.8) 374 (61.0) 239 (39.0) 597 (97.4) 16 (2.6) 320 (52.2) 293 (47.8)
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006
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Central lymph node dissection for papillary thyroid microcarcinoma 46.2 10.5 years. The mean size of PTMCs was 0.8 0.4 cm; 126 (20.6%) patients had PTMCs < 0.5 cm and 487 (79.4%) patients had PTMCs 0.5 cm in size. Of these patients, 264 (43.1%) patients had PTMC confined to the thyroid, and 349 (56.9%) patients had PTMC with extrathyroidal extension. Multifocality was observed in 152 (24.8%) patients, lymphovascular invasion was found in 16 (2.6%) patients, and thyroiditis was found in 293 (47.8%) patients. CLNMs were identified in 239 (39.0%) patients.
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Table 3 Incidence of central lymph node metastasis in patients with PTMC. Central lymph node metastasis, n (%)
Total Without RFs
Negative
Positive
374 (61.0) 57 (82.6)
239 (39.0) 12 (17.4)
Total
613 (100) 69 (100)
PTMC Z papillary thyroid microcarcinoma; RF Z risk factor.
3.2. Risk factors associated with CLNMs Male sex [odds ratio (OR), 2.17; 95% confidence interval (CI), 1.24e3.80; p Z 0.006], tumor size 0.5 cm (OR, 2.83; 95% CI, 1.78e4.49; p < 0.001), extrathyroidal extension (OR, 1.93; 95% CI, 1.38e2.70; p < 0.001), and multifocality (OR, 2.11; 95% CI, 1.46e3.06; p < 0.001) were significantly associated with CLNM. Age, lymphovascular invasion, and thyroiditis were not significantly associated with CLNM. After all variables with p < 0.5 in the univariate analysis were input into the logistic regression model, male sex (OR, 2.10; 95% CI, 1.18e3.75; p Z 0.012), tumor size 0.5 cm (OR, 2.29; 95% CI, 1.42e3.69; p Z 0.001), extrathyroidal extension (OR, 1.49; 95% CI, 1.04e2.13; p Z 0.029), and multifocality (OR, 1.76; 95% CI, 1.19e2.59; p Z 0.004) remained as independent risk factors of CLNM (Table 2).
3.3. CLNM incidence and postoperative complications Overall, 39% of PTMC patients (239 of 613) had pathologically metastatic lymph nodes in the central compartment.
Table 2
Among the 69 PTMC patients without all four risk factors shown in Table 2, 17.4% (12 of 69) had CLNM (Table 3). Thirteen (2.1%) patients experienced temporary recurrent laryngeal nerve palsy, and two (0.3%) patients had permanent recurrent laryngeal nerve palsy. Transient hypocalcemia occurred in 74 (12.1%) patients, and hypocalcemia persisting > 6 months after the operation occurred in two (0.3%) patients. Emergency operations for postoperative hemorrhage were performed in two (0.3%) patients (Table 4).
4. Discussion Male sex, tumor size 0.5 cm, extrathyroidal extension, and multifocality were associated with a significantly increased risk of CLNM in our study. In general, smaller lesion size and female sex are considered good prognostic factors of PTC.12e14 Lim et al15 and Zhang et al16 have also demonstrated that larger tumor size (> 0.7 cm, > 0.6 cm) was associated with CLNM. Male sex and tumor size
Risk factors associated with cervical lymph node metastasis.
Risk factor
Cervical LN metastasis Negative
Age (y) < 45 45 Sex Female Male Tumor size (cm) < 0.5 0.5 LV invasion No Yes Extrathyroidal extension No Yes Multifocality No Yes Thyroiditis No Yes
Positive
167 207
109 130
350 24
208 31
99 275
27 212
368 6
229 10
184 190
80 159
302 72
159 80
196 178
124 115
Univariate analysis OR (95% CI)
Multivariate analysis
p
OR (95% CI)
p
0.006
2.10 (1.18e3.75)
0.012
2.83 (1.78e4.49)
< 0.001
2.29 (1.42e3.69)
0.001
2.68 (0.96e7.47)
0.051
1.93 (1.38e2.70)
< 0.001
1.49 (1.04e2.13)
0.029
2.11 (1.46e3.06)
< 0.001
1.76 (1.19e2.59)
0.004
1.02 (0.74e1.41)
0.899
0.96 (0.69e1.33)
0.817
2.17 (1.24e3.80)
CI Z confidence interval; LN Z lymph node; LV Z lymphovascular; OR Z odds ratio.
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006
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Y.W. Chang et al. Table 4
Postoperative complications.
Complication Recurrent laryngeal nerve palsy Temporary Permanent Hypocalcemia Transient Permanent Postoperative hemorrhage
Number of patients (%) 13 (2.1) 2 (0.3) 74 (12.1) 2 (0.3) 2 (0.3)
0.5 cm were independent risk factors of CLNM in this study, and these results are compatible with those of other reports in PTMC patients.15,16 In the present study, extrathyroidal extension and multifocality also correlated with CLNM. Similar studies in PTMC have shown that extrathyroidal extension is associated with CLNM (p < 0.001) and recurrence (p Z 0.037), and multifocality has also been shown to be an independent risk factor of CLNM.17e20 According to Mazeh et al,21 multifocality may develop by intraglandular spread of the primary tumor, and this may be related to CLNM. CLNMs are relatively common in PTMC patients. Several studies have demonstrated that CLNMs are observed in about 31e64.1% of patients with PTMC.15,22,23 In this study, the incidence of CLNMs in patients with PTMC was 39.0%. To analyze the feasibility of prophylactic CLND for PTMC patients with no clinical risk factors, we also evaluated the incidence of CLNM in PTMC patients without any of these four risk factors. Even after the elimination of risk factors, the incidence of CLNM in these patients was 17.4%. Hence, the prediction of CLNM using only these risk factors should be considered unsafe. Appetecchia et al24 do not believe that CLND is necessary, because the reported mortality rates of PTMC range from 0% to 1%, and CLND provides no survival benefit despite the high incidence of CLNM. In addition, Wada et al23 have reported that CLND may increase the frequency of perioperative complications, such as recurrent laryngeal nerve injury, hypocalcemia, or immediate postoperative bleeding.23 However, Chow et al25 showed that the risk of locoregional recurrence (OR, 4.2; 95% CI, 1.3e13.6) and cervical lymph node recurrence (OR, 6.2; 95% CI, 1.6e24.4) significantly increased in PTMC patients with CLNM, and the presence of cervical lymph node metastasis also increased the incidence rate of distant metastasis (OR, 11.2; 95% CI, 1.3e100.7).25 Simon et al26 have also suggested that lymph node metastases are significantly associated with a higher risk of recurrence. Vini et al27 recommended routine CLND for patients aged 70 years. They indicated that radioactive iodine ablation may not be effective because the capacity of thyroid tumor cells for radioactive iodine uptake is reduced in elderly people.27 Furthermore, Levin et al28 have demonstrated that the operations for recurred lymph nodes in PTC increased the risk of postoperative complications. In addition, CLND is helpful to assess the accurate staging of lymph node.28 Currently, the diagnostic performance of ultrasonography (US) for determining the presence of CLNM in PTMC
patients is not completely reliable. The sensitivity of US in predicting CLNM for PTMC patients has been reported to range from 21.6% to 38.0%.29e31 Kim et al31 also showed that the false negative rate of US at the central neck level was 30% (32/107). As described above, although US findings can indicate clinically negative nodes in the central neck compartment, this does not guarantee pathologically negative nodes. The risk of postoperative complications is one concern about performing CLND in PTMC patients. According to a study by Henry et al32 that compared the complications after thyroidectomy only with thyroidectomy and CLND, CLND does not increase the incidence of recurrent laryngeal nerve injury. Gemsenja ¨ger et al33 described that 1e2% of patients who underwent total thyroidectomy only experienced permanent hypocalcemia or permanent recurrent laryngeal nerve injury, and the rate of complications was not increased with the addition of CLND. In this study, 0.3% of patients had permanent recurrent laryngeal nerve injury, and another 0.3% of patients experienced permanent hypocalcemia. These results are compatible with those of another study.34 The postoperative complications appear to be related to surgical experiences, and experts can perform CLND safely. In conclusion, the incidence of CLNM in PTMC patients (even with no risk factors) was not infrequent, whereas the rate of postoperative complications after CLND was acceptably low. Thus, CLND should be considered for even PTMC patients.
References 1. Hedinger CE, Williams ED, Sobin LH. Histological Typing of Thyroid Tumours. World Health Organization. International Histological Classification of Tumours. Berlin: Springer-Verlag Berlin; 1988. 2. Wang TS, Goffredo P, Sosa JA, Roman SA. Papillary thyroid microcarcinoma: an over-treated malignancy? World J Surg. 2014;38:2297e2303. 3. Udelsman R, Lakatos E, Ladenson P. Optimal surgery for papillary thyroid carcinoma. World J Surg. 1996;20:88e93. 4. Byar DP, Green SB, Dor P, et al. A prognostic index for thyroid carcinoma. A study of the E.O.R.T.C. Thyroid Cancer Cooperative Group. Eur J Cancer. 1979;15:1033e1041. 5. Sakorafas GH, Sampanis D, Safioleas M. Cervical lymph node dissection in papillary thyroid cancer: current trends, persisting controversies, and unclarified uncertainties. Surg Oncol. 2010;19:e57ee70. 6. White ML, Doherty GM. Level VI lymph node dissection for papillary thyroid cancer. Minerva Chir. 2007;62:383e393. 7. Shindo M, Wu JC, Park EE, Tanzella F. The importance of central compartment elective lymph node excision in the staging and treatment of papillary thyroid cancer. Arch Otolaryngol Head Neck Surg. 2006;132:650e654. 8. Sadowski BM, Snyder SK, Lairmore TC. Routine bilateral central lymph node clearance for papillary thyroid cancer. Surgery. 2009;146:696e703. 9. Moo TA, McGill J, Allendorf J, Lee J, Fahey T, Zarnegar R. Impact of prophylactic central neck lymph node dissection on early recurrence in papillary thyroid carcinoma. World J Surg. 2010;34:1187e1191. 10. Ito Y, Tomoda C, Uruno T, et al. Clinical significance of metastasis to the central compartment from papillary microcarcinoma of the thyroid. World J Surg. 2006;30:91e99.
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006
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MODEL
Central lymph node dissection for papillary thyroid microcarcinoma 11. American Thyroid Association 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;19:1167e1214. 12. Tubiana M, Schlumberger M, Rougier P, et al. Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer. 1985;55:794e804. 13. Shaha AR, Jaffe BM. Parathyroid preservation during thyroid surgery. Am J Otolaryngol. 1998;19:113e117. 14. McHenry CR, Speroff T, Wentworth D, Murphy T. Risk factors for postthyroidectomy hypocalcemia. Surgery. 1994;116: 641e647. discussion 7e8. 15. Lim YC, Choi EC, Yoon YH, Kim EH, Koo BS. Central lymph node metastases in unilateral papillary thyroid microcarcinoma. Br J Surg. 2009;96:253e257. 16. Zhang L, Wei WJ, Ji QH, et al. Risk factors for neck nodal metastasis in papillary thyroid microcarcinoma: a study of 1066 patients. J Clin Endocrinol Metab. 2012;97:1250e1257. 17. Kim WY, Kim HY, Son GS, Bae JW, Lee JB. Clinicopathological, immunohistochemical factors and recurrence associated with extrathyroidal extension in papillary thyroid microcarcinoma. J Cancer Res Ther. 2014;10:50e55. 18. Park JP, Roh JL, Lee JH, et al. Risk factors for central neck lymph node metastasis of clinically noninvasive, node-negative papillary thyroid microcarcinoma. Am J Surg. 2014;208: 412e418. 19. So YK, Son YI, Hong SD, et al. Subclinical lymph node metastasis in papillary thyroid microcarcinoma: a study of 551 resections. Surgery. 2010;148:526e531. 20. Kim KE, Kim EK, Yoon JH, Han KH, Moon HJ, Kwak JY. Preoperative prediction of central lymph node metastasis in thyroid papillary microcarcinoma using clinicopathologic and sonographic features. World J Surg. 2013;37:385e391. 21. Mazeh H, Samet Y, Hochstein D, et al. Multifocality in welldifferentiated thyroid carcinomas calls for total thyroidectomy. Am J Surg. 2011;201:770e775. 22. Roh JL, Kim JM, Park CI. Central cervical nodal metastasis from papillary thyroid microcarcinoma: pattern and factors predictive of nodal metastasis. Ann Surg Oncol. 2008;15:2482e2486.
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23. Wada N, Duh QY, Sugino K, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg. 2003;237:399e407. 24. Appetecchia M, Scarcello G, Pucci E, Procaccini A. Outcome after treatment of papillary thyroid microcarcinoma. J Exp Clin Cancer Res. 2002;21:159e164. 25. Chow SM, Law SCK, Chan JKC, Au SK, Yau S, Lau WH. Papillary microcarcinoma of the thyroiddprognostic significance of lymph node metastasis and multifocality. Cancer. 2003;98:31e40. 26. Simon D, Goretzki PE, Witte J, Roher HD. Incidence of regional recurrence guiding radicality in differentiated thyroid carcinoma. World J Surg. 1996;20:860e866. discussion 6. 27. Vini L, Hyer SL, Marshall J, A’Hern R, Harmer C. Long-term results in elderly patients with differentiated thyroid carcinoma. Cancer. 2003;97:2736e2742. 28. Levin KE, Clark AH, Duh QY, Demeure M, Siperstein AE, Clark OH. Reoperative thyroid surgery. Surgery. 1992;111: 604e609. 29. Ito Y, Jikuzono T, Higashiyama T, et al. Clinical significance of lymph node metastasis of thyroid papillary carcinoma located in one lobe. World J Surg. 2006;30:1821e1828. 30. Hwang HS, Orloff LA. Efficacy of preoperative neck ultrasound in the detection of cervical lymph node metastasis from thyroid cancer. Laryngoscope. 2011;121:487e491. 31. Kim E, Park JS, Son KR, Kim JH, Jeon SJ, Na DG. Preoperative diagnosis of cervical metastatic lymph nodes in papillary thyroid carcinoma: comparison of ultrasound, computed tomography, and combined ultrasound with computed tomography. Thyroid. 2008;18:411e418. 32. Henry JF, Gramatica L, Denizot A, Kvachenyuk A, Puccini M, Defechereux T. Morbidity of prophylactic lymph node dissection in the central neck area in patients with papillary thyroid carcinoma. Langenbecks Arch Surg. 1998;383:167e169. 33. Gemsenja ¨ger E, Perren A, Seifert B, Schu ¨ler G, Schweizer I, Heitz PU. Lymph node surgery in papillary thyroid carcinoma. J Am Coll Surg. 2003;197:182e190. 34. Noguchi M, Katev N, Miwa K. Therapeutic strategies and longterm results in differentiated thyroid cancer. J Surg Oncol. 1998;67:52e59.
Please cite this article in press as: Chang YW, et al., Should central lymph node dissection be considered for all papillary thyroid microcarcinoma?, Asian Journal of Surgery (2015), http://dx.doi.org/10.1016/j.asjsur.2015.02.006