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Lateral cervical lymph node metastases from papillary thyroid carcinoma: Predictive factors of nodal metastasis
Lateral cervical lymph node metastases from papillary thyroid carcinoma: Predictive factors of nodal metastasis Yun-Sung Lim, MD,a Jin-Choon Lee, MD,a Yoon Se Lee, MD,a Byung-Joo Lee, MD,a Soo-Geun Wang, MD,a Seok-Man Son, MD,b and In-Ju Kim, MD,b Busan, Korea
Background. Papillary thyroid carcinoma (PTC) frequently metastasizes to the regional neck; skip metastasis (metastasis to the lateral compartment in the absence of central disease) is uncommon. This prospective study was to evaluate the incidence of occult lateral neck metastasis (LNM) and elucidated the factors that predict LNM in PTC with central neck metastasis (CNM) by performing prophylactic selective lateral neck dissection (SND). Methods. Sixty-two patients with PTC without clinical LNM underwent total thyroidectomy with central compartment neck dissection and prophylactic SND consecutively after ipsilateral CNM was confirmed by intraoperative frozen biopsy. Results. The incidence of occult LNM in PTC was 55%. Patients with LNM had a larger primary tumor and more positive ipsilateral and bilateral central lymph nodes than patients without LNM. There were no differences between patients with and without LNM with regard to age and extrathyroidal extension. The incidence of occult LNM increased significantly as the number of metastatic ipsilateral and bilateral lymph nodes increased. Independent risk factors for occult LNM were tumor size and the number of positive bilateral lymph nodes (odds ratio [OR] = 1.449; OR = 1.110, respectively). The most common metastatic site was level III (68%: 23/34), followed by level IV (59%: 20/34) and level II (21%: 7/34). Conclusion. The important risk factors for LNM in PTC are primary tumor size and the number of positive bilateral central lymph nodes. Prophylactic SND may be considered in selected patients with a large number of positive central lymph nodes and large tumors. (Surgery 2011;150:116-21.) From the Departments of Otorhinolaryngology-Head and Neck Surgerya and Internal Medicine,b Pusan National University School of Medicine and Medical Research Institute, Busan, Korea
INTRODUCTION PAPILLARY THYROID CARCINOMA (PTC) is the most common histologic type of thyroid malignancy. These tumors generally grow slowly, resulting in a good prognosis; however, they frequently metastasize to the regional lymph nodes,1-3 with recurrence in the cervical lymph nodes occurring in 5.4–13% of patients after initial surgery.4 Although lymph node metastasis does not have a major effect on prognosis,5,6 it is associated with an increased recurrence rate and overall mortality rate in selected patient populations.4,7 As a result, controlling locoregional recurrence has become a major concern for most clinicians.8 Accepted for publication February 10, 2011. Reprint requests: Byung-Joo Lee, MD, Department of Otorhinolaryngology-Head and Neck Surgery, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, Korea. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2011 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2011.02.003
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The lymphatic drainage pattern of the thyroid is uniform and consistent; therefore, metastatic patterns are relatively predictable. Initial nodal metastasis in PTC usually occurs in the paratracheal and pretracheal nodes in level VI of the central compartment of the ipsilateral neck and spreads to the lateral cervical lymph nodes. Macroscopic skip metastases to the lateral compartment of the neck in the absence of central disease are uncommon.9 Although the stepwise nodal involvement of the central and lateral neck compartments in PTC is clear, the optimal extent of neck dissection remains controversial. Furthermore, the discussion of lymph node metastasis in PTC is limited because of the lack of prospective clinical trials.10 On the basis of a careful review of the lymphatic metastasis pattern in PTC,11,12 we hypothesized that lateral neck metastasis (LNM) in patients with no preoperative evidence of LNM can be predicted by the nodal status of central compartment. Hence, we performed systematic node dissection of the ipsilateral and bilateral central
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compartments as well as the lateral neck consecutively after confirmation of central neck metastasis (CNM) by intraoperative frozen biopsy. This prospective study determined the incidence of occult LNM after prophylactic selective lateral neck dissection (SND) in PTC patients with CNM. More important, this study evaluated the clinicopathologic factors for the intraoperative prediction of LNM in patients in whom CNM was confirmed by frozen biopsy. METHODS From April 2008 to May 2009, a total of 310 patients diagnosed with PTC underwent total thyroidectomy with central compartment neck dissection (CND) and with or without lateral neck dissection as an initial operation. Among them, 46 patients (14.8%) presented with either palpable or preoperatively imaged lateral neck nodes that required elective lateral neck dissection. Twohundred sixty-four patients (85.2%), diagnosed as having PTC without LNM based on the findings from preoperative high-resolution neck ultrasonography and computed tomography, underwent total thyroidectomy with bilateral central CND. Among them, 134 patients (51% [134/262]) had CNM, of whom 62 patients with PTC underwent total thyroidectomy with bilateral central CND, which was followed by consecutive prophylactic ipsilateral SND in cases where ipsilateral CNM was confirmed by intraoperative frozen biopsy. We obtained approval from the ethical committee and informed consent from all patients for consecutive prophylactic ipsilateral SND. Patients with clinical evidence of LNM (as determined by highresolution neck ultrasonography and computed tomography), history of thyroid operation, and isthmic lesion were excluded from the study. We used the following protocol. After ipsilateral thyroid lobectomy, ipsilateral CND was performed. A sample was analyzed by frozen biopsy for confirmation of CNM and for quantitative evaluation of the lymphatic status of positive nodes in the ipsilateral central compartment (Fig 1). Pathologists examined the specimens grossly and dissected all visible lymph nodes from the fat tissue. All isolated lymph nodes and remaining fat tissue were frozen, sectioned, and then stained with hematoxylin and eosin. The specimen was bisected if the size of lymph node was <5 mm and sectioned at 2-mm intervals if the size of lymph node was $5 mm. All of the harvested and the metastatic lymph nodes in the ipsilateral compartment were identified quantitatively and reported intraoperatively. These frozen sectional diagnosis require
Fig 1. Flowchart depicting the protocol used in this prospective study. CND, central neck dissection; CNM, central neck metastasis; LNM, lateral neck metastasis; SND, selective lateral neck dissection.
<30 minutes. Successive contralateral thyroid lobectomy and CND were performed while waiting for the biopsy results. The sensitivity, specificity, and diagnostic accuracy of frozen biopsy were investigated for the detection of CNM and the number of positive ipsilateral central lymph nodes. If CNM in the ipsilateral compartment was confirmed by frozen biopsy, then ipsilateral prophylactic SND (levels II, III, and IV) was performed via an additional, small, transverse incision. Central node clearance was performed cranially to the superior thyroid arteries and the pyramidal lobe, caudally to the innominate vein, laterally to the carotid sheaths, and dorsally to the prevertebral fascia.13 Ipsilateral CND was defined as lymph node dissection confined to the ipsilateral, paratracheal, pretracheal, and prelaryngeal lymph nodes. SND consisted of the en bloc removal of all lymph node–bearing tissues in nodal lesions II, III, and IV, with preservation of sternocleidomastoid muscle, jugular vein, and phrenic and spinal accessory nerves. We also tried to preserve sensory branches of the cervical plexus as much as possible. If multiple thyroid tumors were observed on preoperative ultrasonography, paratracheal lymph node dissection was performed on the side where the largest tumor was located.
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Table I. Demographic data Occult lateral neck metastasis
No. of patients (%) Age, yrs Gender, male (%) Mean tumor diameter* (mm) No. of patients with multifocalities (%) No. of patients with extrathyroidal extensions (%) No. of patients with positive margins (%) Mean no. of positive ipsilateral nodes* Mean no. of positive bilateral nodes*
Positive
Negative
P value
34 (55) 47.7 9 (26) 14.2 (3–33) 14 (41) 22 (65) 4 (12) 4.1 (1–12) 5.3 (1–19)
28 (45) 46.5 4 (14) 10.2 (3–22) 11 (39) 17 (61) 2 (7) 2.8 (1–9) 3.2 (1–9)
>.05 >.05 .013 >.05 >.05 >.05 .034 .004
*Mean ± standard deviation (range).
Descriptive statistics were represented as the mean and range, where appropriate. The t-test and chi-square tests were used for analyzing categorical data, and relationships between continuous variables were tested using Pearson’s correlation coefficient. Logistic regression analysis was performed to model dichotomous variables. All analyses were carried out using SPSS (release 15; SPSS, Chicago, IL). RESULTS First, the sensitivity and specificity of frozen biopsy for the detection of CNM were 100% and 99.2%, respectively, among 264 patients who underwent total thyroidectomy with bilateral CND. The diagnostic accuracy for the number of metastatic ipsilateral central lymph nodes was 85.8% compared with permanent biopsy in 134 patients who had CNM. The undercount was 9.7% and the overcount was 4.5%, respectively. This means that the probability that the number of metastatic lymph nodes in frozen biopsy will be greater than or equal to the actual number of metastatic lymph nodes in permanent biopsy is 95.5% in consideration of underdiagnosis of frozen biopsy. This study group consisted of 62 patients (49 women, 13 men; mean age, 47.1 years). All histologic types of tumor consisted of PTC without other aggressive subtype of PTC, such as tall cell variant. The mean postoperative follow-up period was 18.2 months (range, 12–26). Thirty-four (55%) of the 62 patients had occult LNM. The primary tumor was larger in patients with LNM (mean diameter, 14.2 mm) than in patients without LNM (mean diameter, 10.2 mm; P = .013; Table I). The tumor size correlated with the number of positive ipsilateral central lymph nodes (g = 0.385; P = .002) and the number of positive bilateral central lymph nodes (g = 0.449; P = .0002).
There was no difference between patients with and without LNM with regard to age, gender, multifocality, extrathyroidal extension, and surgical margin. The mean number of positive lateral neck nodes was 3 (range, 1–8), and the most commonly involved site was level III (68% [23/ 34]), followed by level IV (59% [20/34]) and level II (21% [7/34]). The mean number of positive ipsilateral central lymph nodes was greater in patients with LNM than in patients without LNM (4.1 vs 2.8; range, 1–12 vs 1–9; P = .034). In addition, the mean number of positive bilateral central lymph nodes was greater in patients with LNM than in patients without LNM (5.3 vs 3.2; range, 1–19 vs 1–9; P = .004). In terms of metastatic ratio (the ratio of the number of positive central lymph nodes to the number of total acquired lymph nodes), patients with LNM had a higher bilateral metastatic ratio than patients without LNM, and the difference achieved borderline significance (mean, 49% vs 37%; P = .052). Furthermore, the incidence of LNM increased with an increase in the number of positive ipsilateral and bilateral central lymph nodes (P = .035 and P = .007, respectively; Fig 2, A and B) and with an increase in tumor size (P = .043). The individual numbers of positive ipsilateral and bilateral central lymph nodes were risk factors for LNM (P = .046; odds ratio [OR], 1.312 [P = .010] and OR, 1.428, respectively; Table II). Multivariate analysis revealed that the number of positive bilateral central lymph nodes was an independent risk factor for LNM (P = .015; OR, 1.449); however, the number of positive ipsilateral central lymph nodes was not significant (P = .113; OR, 1.259). A statistical relationship was also observed between the primary tumor with the largest diameter and LNM (P = .026; OR, 1.110; Table III).
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Table II. Univariate analysis of LNM factors as determined by frozen biopsy P value No. of positive ipsilateral central nodes No. of positive bilateral central nodes Metastatic ratio of ipsilateral central nodes Metastatic ratio of bilateral central nodes Tumor size
Odds ratio
95% Confidence limits
.046 1.312
1.004–1.715
.010 1.428
1.089–1.873
>.05
1.015
0.998–1.033
.057 1.023
0.999–1.046
.025 1.094
1.012–1.183
Table III. Multivariate regression analysis of LNM factors as determined by frozen biopsy
Fig 2. As the number of positive ipsilateral (A) and bilateral (B) central lymph nodes increased, the incidence of occult LNM significantly increased (P = .035; P = .007).
DISCUSSION Up until now, performing a prophylactic lateral neck dissection in PTC with clinically negative lateral neck disease has been highly debatable, especially if patients are scheduled to be treated with postoperative radioactive iodine therapy (RAI). Actually, the historical recurrence rate is less than the incidence of occult LNM found in this study, suggesting that this treatment may be excessive. The purpose of this study was to evaluate the incidence of occult LNM and the clinicopathologic factors to predict LNM in PTC by performing prophylactic SND. Cervical metastasis occurs first to the nodes in the central compartment and subsequently to those in the lateral neck14,15; and skip metastasis, that is, metastasis to the lateral compartment but not to the central lymph nodes, is rare.1,3,9,16 The reported incidence of central lymph node metastasis is 50–60%, even in patients with clinically nodenegative PTCs.12,13 To the best of our knowledge, this is the first prospective trial to quantitatively evaluate the relationship between central and LNM in patients with PTC without preoperative evidence of LNM. The incidence of occult LNM was considerably high (55%) in patients with metastasis in the central compartment. This finding
No. of positive ipsilateral central nodes No. of positive bilateral central nodes Metastatic ratio of ipsilateral central nodes Metastatic ratio of bilateral central nodes Tumor size
P value
Odds ratio
95% Confidence limits
>.05
1.259
0.947–1.672
.015 1.449
1.076–1.949
>.05
1.010
0.99–1.03
>.05
1.019
0.991–1.047
.026 1.110
1.012–1.216
suggests that the initial operative treatment without prophylactic SND would not effectively eliminate the residual disease. Therefore, emphasis may be placed on the need for appropriate initial therapy for lymph node metastasis in PTC, especially taking into account the risks and benefits of surgery and radioiodine remnant ablation.17 Locoregional residual disease and recurrences in the neck require high-dose RAI. Additionally, patients who have a markedly fluorodeoxyglucose-avid metastatic disease are unresponsive to high-dose RAI, have poor outcomes, and their disease-free survival rates are often <2–3 years.18,19 Lateral lymph node metastasis of PTC may reflects the aggressiveness of the carcinoma. According to the American Joint Committee on Cancer staging system, tumors that show only central node metastasis are classified as N1a, whereas those that also show lateral node
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metastasis are classified as N1b. If the patient is $45 years old, the N1a tumor would be staged as III and the N1b tumor would be upstaged to IVA. Despite the fact that the second most common compartment to which thyroid carcinomas metastasize is the lateral neck, few studies have reported prophylactic lateral neck dissection for patients without gross LNM and the indication for lateral node dissection remains controversial.20-22 The following factors have previously been suggested as important indicators for prophylactic SND: Age of $55 years, male gender, and a maximal tumor diameter of >30 mm.23 Although this study included a large number of cases and long-term follow-up, patients with a heterogeneous subtypes of PTC were analyzed and different treatment modalities were used for the primary tumor, including isthmectomy, subtotal thyroidectomy, near-total thyroidectomy, and total thyroidectomy. In addition, massive extrathyroidal extension was considered to be a risk factor for lymph node metastasis and an indicator for prophylactic lateral neck dissection.23 However, extrathyroidal extension was not significant in the present study. It might be assumed that the meaning of extrathyroidal extension for neck metastasis had been already implicit, because PTC patients who already had CNM confirmed by frozen biopsy were included. This prospective study showed a significant difference in the number of positive ipsilateral and bilateral central lymph nodes and primary tumor size between patients with LNM and without LNM. Occult LNM in PTC patients with CNM correlated with the number of ipsilateral and bilateral positive lymph nodes and the primary tumor size. More important, multivariate analysis showed that the number of positive bilateral central lymph nodes and tumor size were independent risk factors for occult LNM in PTC patients with CNM; the OR values were 1.449 and 1.110, respectively. It is notable that the OR of the number of positive central lymph nodes is very high. These data suggest that, as the number of positive bilateral central lymph nodes and tumor size increases, the risk of occult LNM increases by 45% and 11%, respectively. As shown in Fig 2, it is also expected that if >4 positive lymph nodes are present in the ipsilateral or bilateral central compartment, the probability of occult LNM is approximately >70%. The significance of radioactive iodine possessed a restricted effect on invisible nodal metastasis; for some patients >45 years of age, radioactive iodine uptake capacity is low, which can suggest the limit of postoperative RAI.24 Prophylactic lateral neck dissection may provide accurate tumor staging
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regarding the nodal status of the lateral compartment and may reduce the risk of lymph node recurrences in elderly patients. However, this procedure necessitates wound extension and increases the chances of postoperative complications. Before consideration of prophylactic lateral neck dissection, surgeons should weigh the possible benefits of dissection against the potential risks. It should also be interpreted in light of the available surgical environment and expertise. Apart from 1 case of chyle leakage, the incidence of SND-related complications in this study was minimal. Given the high rate of occult LNM (55%) in PTC with CNM, prophylactic SND may be performed in selected elderly patients with multiple positive central lymph nodes and large tumors by skilled surgeons. Moreover, quantitative analysis of central lymphatic status may be helpful to predict the lymphatic status of the lateral neck compartment. The present study has important limitations, such as small sample size and short-term postoperative follow-up. Further large-scale studies with long-term follow-up data are needed to determine the cutoff value for the number of positive central lymph nodes, the prognosis of occult LNM, and the efficacy of prophylactic SND. Actually, we are collecting clinical data, for example, postoperative radioiodine studies, thyroglobulin levels, disease status to date, and recurrence for a consecutive report about the efficacy of prophylactic SND compared with the control group. This study suggests that tumor size and the number of positive bilateral central lymph nodes are the important predictive factors for LNM in PTC with CNM. It seems that prophylactic SND may be considered as one of treatment options in selected patients with a large number of positive central lymph nodes and large primary tumors. The authors thank Dr. Dong-Hoon Shin for kind advice for pathologic data and Dr. Sang-Gil Lee for statistical analysis. REFERENCES 1. Sivanandan R, Soo KC. Pattern of cervical lymph node metastases from papillary carcinoma of the thyroid. Br J Surg 2001;88:1241-4. 2. Caron NR, Tan YY, Ogilvie JB, Triponez F, Reiff ES, Kebebew E, et al. Selective modified radical neck dissection for papillary thyroid cancer-is level I, II and V dissection always necessary? World J Surg 2006;30:833-40. 3. Kupferman ME, Patterson M, Mandel SJ, LiVolsi V, Weber RS. Patterns of lateral neck metastasis in papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg 2004;130: 857-60. 4. Grant CS, Hay ID, Gough IR, Bergstralh EJ, Goellner JR, McConahey WM. Local recurrence in papillary thyroid
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5.
6.
7.
8.
9. 10.
11.
12.
13.
14.
carcinoma: is extent of surgical resection important? Surgery 1988;104:954-62. Lundgren CI, Hall P, Dickman PW, Zedenius J. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study. Cancer 2006;106:524-31. McConahey WM, Hay ID, Woolner LB, van Heerden JA, Taylor WF. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 1986;61:978-96. Hughes CJ, Shaha AR, Shah JP, Loree TR. Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis. Head Neck 1996;18:127-32. Roh JL, Park JY, Rha KS, Park CI. Is central neck dissection necessary for the treatment of lateral cervical nodal recurrence of papillary thyroid carcinoma? Head Neck 2007;29:901-6. Gimm O, Rath FW, Dralle H. Pattern of lymph node metastases in papillary thyroid carcinoma. Br J Surg 1998;85:252-4. Rotstein L. The role of lymphadenectomy in the management of papillary carcinoma of the thyroid. J Surg Oncol 2009;99:186-8. Pereira JA, Jimeno J, Miquel J, Iglesias M, Munne A, Sancho JJ, et al. Nodal yield, morbidity, and recurrence after central neck dissection for papillary thyroid carcinoma. Surgery 2005;138:1095-100. Wada N, Duh QY, Sugino K, Iwasaki H, Kameyama K, Mimura T, 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;237:399-407. Lee BJ, Lee JC, Wang SG, Kim YK, Kim IJ, Son SM. Metastasis of right upper para-esophageal lymph nodes in central compartment lymph node dissection of papillary thyroid cancer. World J Surg 2009;33:2094-8. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid. I. Developing pattern of metastasis. Cancer 1970;26:1053-60.
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15. Shaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin North Am 1998;31:823-31. 16. Mirallie E, Visset J, Sagan C, Hamy A, Le Bodic MF, Paineau J. Localization of cervical node metastasis of papillary thyroid carcinoma. World J Surg 1999;23:970-3. 17. Mazzaferri EL. A vision for the surgical management of papillary thyroid carcinoma: extensive lymph node compartmental dissections and selective use of radioiodine. J Clin Endocrinol Metab 2009;94:1086-8. 18. Wang W, Larson SM, Tuttle RM, Kalaigian H, Lolbert K, Sonenberg M, et al. Resistance of [18f]-fluorodeoxyglucoseavid metastatic thyroid cancer lesions to treatment with high-dose radioactive iodine. Thyroid 2001;11:1169-75. 19. Robbins RJ, Wan Q, Grewal RK, Reibke R, Gonen M, Strauss HW, et al. Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab 2006;91:498-505. 20. Simon D, Goretzki PE, Witte J, Roher HD. Incidence of regional recurrence guiding radicality in differentiated thyroid carcinoma. World J Surg 1996;20:860-6. 21. Marchesi M, Biffoni M, Biancari F, Berni A, Campana FP. Predictors of outcome for patients with differentiated and aggressive thyroid carcinoma. Eur J Surg Suppl 2003: 46-50. 22. Machens A, Hinze R, Thomusch O, Dralle H. Pattern of nodal metastasis for primary and reoperative thyroid cancer. World J Surg 2002;26:22-8. 23. Ito Y, Higashiyama T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, et al. Risk factors for recurrence to the lymph node in papillary thyroid carcinoma patients without preoperatively detectable lateral node metastasis: validity of prophylactic modified radical neck dissection. World J Surg 2007;31:2085-91. 24. Vini L, Hyer SL, Marshall J, A’Hern R, Harmer C. Longterm results in elderly patients with differentiated thyroid carcinoma. Cancer 2003;97:2736-42.
Background. Papillary thyroid carcinoma (PTC) frequently metastasizes to the regional neck; skip metastasis (metastasis to the lateral compartment in the absence of central disease) is uncommon. This prospective study was to evaluate the incidence of occult lateral neck metastasis (LNM) and elucidated the factors that predict LNM in PTC with central neck metastasis (CNM) by performing prophylactic selective lateral neck dissection (SND). Methods. Sixty-two patients with PTC without clinical LNM underwent total thyroidectomy with central compartment neck dissection and prophylactic SND consecutively after ipsilateral CNM was confirmed by intraoperative frozen biopsy. Results. The incidence of occult LNM in PTC was 55%. Patients with LNM had a larger primary tumor and more positive ipsilateral and bilateral central lymph nodes than patients without LNM. There were no differences between patients with and without LNM with regard to age and extrathyroidal extension. The incidence of occult LNM increased significantly as the number of metastatic ipsilateral and bilateral lymph nodes increased. Independent risk factors for occult LNM were tumor size and the number of positive bilateral lymph nodes (odds ratio [OR] = 1.449; OR = 1.110, respectively). The most common metastatic site was level III (68%: 23/34), followed by level IV (59%: 20/34) and level II (21%: 7/34). Conclusion. The important risk factors for LNM in PTC are primary tumor size and the number of positive bilateral central lymph nodes. Prophylactic SND may be considered in selected patients with a large number of positive central lymph nodes and large tumors. (Surgery 2011;150:116-21.) From the Departments of Otorhinolaryngology-Head and Neck Surgerya and Internal Medicine,b Pusan National University School of Medicine and Medical Research Institute, Busan, Korea
INTRODUCTION PAPILLARY THYROID CARCINOMA (PTC) is the most common histologic type of thyroid malignancy. These tumors generally grow slowly, resulting in a good prognosis; however, they frequently metastasize to the regional lymph nodes,1-3 with recurrence in the cervical lymph nodes occurring in 5.4–13% of patients after initial surgery.4 Although lymph node metastasis does not have a major effect on prognosis,5,6 it is associated with an increased recurrence rate and overall mortality rate in selected patient populations.4,7 As a result, controlling locoregional recurrence has become a major concern for most clinicians.8 Accepted for publication February 10, 2011. Reprint requests: Byung-Joo Lee, MD, Department of Otorhinolaryngology-Head and Neck Surgery, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, Korea. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2011 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2011.02.003
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The lymphatic drainage pattern of the thyroid is uniform and consistent; therefore, metastatic patterns are relatively predictable. Initial nodal metastasis in PTC usually occurs in the paratracheal and pretracheal nodes in level VI of the central compartment of the ipsilateral neck and spreads to the lateral cervical lymph nodes. Macroscopic skip metastases to the lateral compartment of the neck in the absence of central disease are uncommon.9 Although the stepwise nodal involvement of the central and lateral neck compartments in PTC is clear, the optimal extent of neck dissection remains controversial. Furthermore, the discussion of lymph node metastasis in PTC is limited because of the lack of prospective clinical trials.10 On the basis of a careful review of the lymphatic metastasis pattern in PTC,11,12 we hypothesized that lateral neck metastasis (LNM) in patients with no preoperative evidence of LNM can be predicted by the nodal status of central compartment. Hence, we performed systematic node dissection of the ipsilateral and bilateral central
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compartments as well as the lateral neck consecutively after confirmation of central neck metastasis (CNM) by intraoperative frozen biopsy. This prospective study determined the incidence of occult LNM after prophylactic selective lateral neck dissection (SND) in PTC patients with CNM. More important, this study evaluated the clinicopathologic factors for the intraoperative prediction of LNM in patients in whom CNM was confirmed by frozen biopsy. METHODS From April 2008 to May 2009, a total of 310 patients diagnosed with PTC underwent total thyroidectomy with central compartment neck dissection (CND) and with or without lateral neck dissection as an initial operation. Among them, 46 patients (14.8%) presented with either palpable or preoperatively imaged lateral neck nodes that required elective lateral neck dissection. Twohundred sixty-four patients (85.2%), diagnosed as having PTC without LNM based on the findings from preoperative high-resolution neck ultrasonography and computed tomography, underwent total thyroidectomy with bilateral central CND. Among them, 134 patients (51% [134/262]) had CNM, of whom 62 patients with PTC underwent total thyroidectomy with bilateral central CND, which was followed by consecutive prophylactic ipsilateral SND in cases where ipsilateral CNM was confirmed by intraoperative frozen biopsy. We obtained approval from the ethical committee and informed consent from all patients for consecutive prophylactic ipsilateral SND. Patients with clinical evidence of LNM (as determined by highresolution neck ultrasonography and computed tomography), history of thyroid operation, and isthmic lesion were excluded from the study. We used the following protocol. After ipsilateral thyroid lobectomy, ipsilateral CND was performed. A sample was analyzed by frozen biopsy for confirmation of CNM and for quantitative evaluation of the lymphatic status of positive nodes in the ipsilateral central compartment (Fig 1). Pathologists examined the specimens grossly and dissected all visible lymph nodes from the fat tissue. All isolated lymph nodes and remaining fat tissue were frozen, sectioned, and then stained with hematoxylin and eosin. The specimen was bisected if the size of lymph node was <5 mm and sectioned at 2-mm intervals if the size of lymph node was $5 mm. All of the harvested and the metastatic lymph nodes in the ipsilateral compartment were identified quantitatively and reported intraoperatively. These frozen sectional diagnosis require
Fig 1. Flowchart depicting the protocol used in this prospective study. CND, central neck dissection; CNM, central neck metastasis; LNM, lateral neck metastasis; SND, selective lateral neck dissection.
<30 minutes. Successive contralateral thyroid lobectomy and CND were performed while waiting for the biopsy results. The sensitivity, specificity, and diagnostic accuracy of frozen biopsy were investigated for the detection of CNM and the number of positive ipsilateral central lymph nodes. If CNM in the ipsilateral compartment was confirmed by frozen biopsy, then ipsilateral prophylactic SND (levels II, III, and IV) was performed via an additional, small, transverse incision. Central node clearance was performed cranially to the superior thyroid arteries and the pyramidal lobe, caudally to the innominate vein, laterally to the carotid sheaths, and dorsally to the prevertebral fascia.13 Ipsilateral CND was defined as lymph node dissection confined to the ipsilateral, paratracheal, pretracheal, and prelaryngeal lymph nodes. SND consisted of the en bloc removal of all lymph node–bearing tissues in nodal lesions II, III, and IV, with preservation of sternocleidomastoid muscle, jugular vein, and phrenic and spinal accessory nerves. We also tried to preserve sensory branches of the cervical plexus as much as possible. If multiple thyroid tumors were observed on preoperative ultrasonography, paratracheal lymph node dissection was performed on the side where the largest tumor was located.
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Table I. Demographic data Occult lateral neck metastasis
No. of patients (%) Age, yrs Gender, male (%) Mean tumor diameter* (mm) No. of patients with multifocalities (%) No. of patients with extrathyroidal extensions (%) No. of patients with positive margins (%) Mean no. of positive ipsilateral nodes* Mean no. of positive bilateral nodes*
Positive
Negative
P value
34 (55) 47.7 9 (26) 14.2 (3–33) 14 (41) 22 (65) 4 (12) 4.1 (1–12) 5.3 (1–19)
28 (45) 46.5 4 (14) 10.2 (3–22) 11 (39) 17 (61) 2 (7) 2.8 (1–9) 3.2 (1–9)
>.05 >.05 .013 >.05 >.05 >.05 .034 .004
*Mean ± standard deviation (range).
Descriptive statistics were represented as the mean and range, where appropriate. The t-test and chi-square tests were used for analyzing categorical data, and relationships between continuous variables were tested using Pearson’s correlation coefficient. Logistic regression analysis was performed to model dichotomous variables. All analyses were carried out using SPSS (release 15; SPSS, Chicago, IL). RESULTS First, the sensitivity and specificity of frozen biopsy for the detection of CNM were 100% and 99.2%, respectively, among 264 patients who underwent total thyroidectomy with bilateral CND. The diagnostic accuracy for the number of metastatic ipsilateral central lymph nodes was 85.8% compared with permanent biopsy in 134 patients who had CNM. The undercount was 9.7% and the overcount was 4.5%, respectively. This means that the probability that the number of metastatic lymph nodes in frozen biopsy will be greater than or equal to the actual number of metastatic lymph nodes in permanent biopsy is 95.5% in consideration of underdiagnosis of frozen biopsy. This study group consisted of 62 patients (49 women, 13 men; mean age, 47.1 years). All histologic types of tumor consisted of PTC without other aggressive subtype of PTC, such as tall cell variant. The mean postoperative follow-up period was 18.2 months (range, 12–26). Thirty-four (55%) of the 62 patients had occult LNM. The primary tumor was larger in patients with LNM (mean diameter, 14.2 mm) than in patients without LNM (mean diameter, 10.2 mm; P = .013; Table I). The tumor size correlated with the number of positive ipsilateral central lymph nodes (g = 0.385; P = .002) and the number of positive bilateral central lymph nodes (g = 0.449; P = .0002).
There was no difference between patients with and without LNM with regard to age, gender, multifocality, extrathyroidal extension, and surgical margin. The mean number of positive lateral neck nodes was 3 (range, 1–8), and the most commonly involved site was level III (68% [23/ 34]), followed by level IV (59% [20/34]) and level II (21% [7/34]). The mean number of positive ipsilateral central lymph nodes was greater in patients with LNM than in patients without LNM (4.1 vs 2.8; range, 1–12 vs 1–9; P = .034). In addition, the mean number of positive bilateral central lymph nodes was greater in patients with LNM than in patients without LNM (5.3 vs 3.2; range, 1–19 vs 1–9; P = .004). In terms of metastatic ratio (the ratio of the number of positive central lymph nodes to the number of total acquired lymph nodes), patients with LNM had a higher bilateral metastatic ratio than patients without LNM, and the difference achieved borderline significance (mean, 49% vs 37%; P = .052). Furthermore, the incidence of LNM increased with an increase in the number of positive ipsilateral and bilateral central lymph nodes (P = .035 and P = .007, respectively; Fig 2, A and B) and with an increase in tumor size (P = .043). The individual numbers of positive ipsilateral and bilateral central lymph nodes were risk factors for LNM (P = .046; odds ratio [OR], 1.312 [P = .010] and OR, 1.428, respectively; Table II). Multivariate analysis revealed that the number of positive bilateral central lymph nodes was an independent risk factor for LNM (P = .015; OR, 1.449); however, the number of positive ipsilateral central lymph nodes was not significant (P = .113; OR, 1.259). A statistical relationship was also observed between the primary tumor with the largest diameter and LNM (P = .026; OR, 1.110; Table III).
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Table II. Univariate analysis of LNM factors as determined by frozen biopsy P value No. of positive ipsilateral central nodes No. of positive bilateral central nodes Metastatic ratio of ipsilateral central nodes Metastatic ratio of bilateral central nodes Tumor size
Odds ratio
95% Confidence limits
.046 1.312
1.004–1.715
.010 1.428
1.089–1.873
>.05
1.015
0.998–1.033
.057 1.023
0.999–1.046
.025 1.094
1.012–1.183
Table III. Multivariate regression analysis of LNM factors as determined by frozen biopsy
Fig 2. As the number of positive ipsilateral (A) and bilateral (B) central lymph nodes increased, the incidence of occult LNM significantly increased (P = .035; P = .007).
DISCUSSION Up until now, performing a prophylactic lateral neck dissection in PTC with clinically negative lateral neck disease has been highly debatable, especially if patients are scheduled to be treated with postoperative radioactive iodine therapy (RAI). Actually, the historical recurrence rate is less than the incidence of occult LNM found in this study, suggesting that this treatment may be excessive. The purpose of this study was to evaluate the incidence of occult LNM and the clinicopathologic factors to predict LNM in PTC by performing prophylactic SND. Cervical metastasis occurs first to the nodes in the central compartment and subsequently to those in the lateral neck14,15; and skip metastasis, that is, metastasis to the lateral compartment but not to the central lymph nodes, is rare.1,3,9,16 The reported incidence of central lymph node metastasis is 50–60%, even in patients with clinically nodenegative PTCs.12,13 To the best of our knowledge, this is the first prospective trial to quantitatively evaluate the relationship between central and LNM in patients with PTC without preoperative evidence of LNM. The incidence of occult LNM was considerably high (55%) in patients with metastasis in the central compartment. This finding
No. of positive ipsilateral central nodes No. of positive bilateral central nodes Metastatic ratio of ipsilateral central nodes Metastatic ratio of bilateral central nodes Tumor size
P value
Odds ratio
95% Confidence limits
>.05
1.259
0.947–1.672
.015 1.449
1.076–1.949
>.05
1.010
0.99–1.03
>.05
1.019
0.991–1.047
.026 1.110
1.012–1.216
suggests that the initial operative treatment without prophylactic SND would not effectively eliminate the residual disease. Therefore, emphasis may be placed on the need for appropriate initial therapy for lymph node metastasis in PTC, especially taking into account the risks and benefits of surgery and radioiodine remnant ablation.17 Locoregional residual disease and recurrences in the neck require high-dose RAI. Additionally, patients who have a markedly fluorodeoxyglucose-avid metastatic disease are unresponsive to high-dose RAI, have poor outcomes, and their disease-free survival rates are often <2–3 years.18,19 Lateral lymph node metastasis of PTC may reflects the aggressiveness of the carcinoma. According to the American Joint Committee on Cancer staging system, tumors that show only central node metastasis are classified as N1a, whereas those that also show lateral node
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metastasis are classified as N1b. If the patient is $45 years old, the N1a tumor would be staged as III and the N1b tumor would be upstaged to IVA. Despite the fact that the second most common compartment to which thyroid carcinomas metastasize is the lateral neck, few studies have reported prophylactic lateral neck dissection for patients without gross LNM and the indication for lateral node dissection remains controversial.20-22 The following factors have previously been suggested as important indicators for prophylactic SND: Age of $55 years, male gender, and a maximal tumor diameter of >30 mm.23 Although this study included a large number of cases and long-term follow-up, patients with a heterogeneous subtypes of PTC were analyzed and different treatment modalities were used for the primary tumor, including isthmectomy, subtotal thyroidectomy, near-total thyroidectomy, and total thyroidectomy. In addition, massive extrathyroidal extension was considered to be a risk factor for lymph node metastasis and an indicator for prophylactic lateral neck dissection.23 However, extrathyroidal extension was not significant in the present study. It might be assumed that the meaning of extrathyroidal extension for neck metastasis had been already implicit, because PTC patients who already had CNM confirmed by frozen biopsy were included. This prospective study showed a significant difference in the number of positive ipsilateral and bilateral central lymph nodes and primary tumor size between patients with LNM and without LNM. Occult LNM in PTC patients with CNM correlated with the number of ipsilateral and bilateral positive lymph nodes and the primary tumor size. More important, multivariate analysis showed that the number of positive bilateral central lymph nodes and tumor size were independent risk factors for occult LNM in PTC patients with CNM; the OR values were 1.449 and 1.110, respectively. It is notable that the OR of the number of positive central lymph nodes is very high. These data suggest that, as the number of positive bilateral central lymph nodes and tumor size increases, the risk of occult LNM increases by 45% and 11%, respectively. As shown in Fig 2, it is also expected that if >4 positive lymph nodes are present in the ipsilateral or bilateral central compartment, the probability of occult LNM is approximately >70%. The significance of radioactive iodine possessed a restricted effect on invisible nodal metastasis; for some patients >45 years of age, radioactive iodine uptake capacity is low, which can suggest the limit of postoperative RAI.24 Prophylactic lateral neck dissection may provide accurate tumor staging
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regarding the nodal status of the lateral compartment and may reduce the risk of lymph node recurrences in elderly patients. However, this procedure necessitates wound extension and increases the chances of postoperative complications. Before consideration of prophylactic lateral neck dissection, surgeons should weigh the possible benefits of dissection against the potential risks. It should also be interpreted in light of the available surgical environment and expertise. Apart from 1 case of chyle leakage, the incidence of SND-related complications in this study was minimal. Given the high rate of occult LNM (55%) in PTC with CNM, prophylactic SND may be performed in selected elderly patients with multiple positive central lymph nodes and large tumors by skilled surgeons. Moreover, quantitative analysis of central lymphatic status may be helpful to predict the lymphatic status of the lateral neck compartment. The present study has important limitations, such as small sample size and short-term postoperative follow-up. Further large-scale studies with long-term follow-up data are needed to determine the cutoff value for the number of positive central lymph nodes, the prognosis of occult LNM, and the efficacy of prophylactic SND. Actually, we are collecting clinical data, for example, postoperative radioiodine studies, thyroglobulin levels, disease status to date, and recurrence for a consecutive report about the efficacy of prophylactic SND compared with the control group. This study suggests that tumor size and the number of positive bilateral central lymph nodes are the important predictive factors for LNM in PTC with CNM. It seems that prophylactic SND may be considered as one of treatment options in selected patients with a large number of positive central lymph nodes and large primary tumors. The authors thank Dr. Dong-Hoon Shin for kind advice for pathologic data and Dr. Sang-Gil Lee for statistical analysis. REFERENCES 1. Sivanandan R, Soo KC. Pattern of cervical lymph node metastases from papillary carcinoma of the thyroid. Br J Surg 2001;88:1241-4. 2. Caron NR, Tan YY, Ogilvie JB, Triponez F, Reiff ES, Kebebew E, et al. Selective modified radical neck dissection for papillary thyroid cancer-is level I, II and V dissection always necessary? World J Surg 2006;30:833-40. 3. Kupferman ME, Patterson M, Mandel SJ, LiVolsi V, Weber RS. Patterns of lateral neck metastasis in papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg 2004;130: 857-60. 4. Grant CS, Hay ID, Gough IR, Bergstralh EJ, Goellner JR, McConahey WM. Local recurrence in papillary thyroid
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5.
6.
7.
8.
9. 10.
11.
12.
13.
14.
carcinoma: is extent of surgical resection important? Surgery 1988;104:954-62. Lundgren CI, Hall P, Dickman PW, Zedenius J. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study. Cancer 2006;106:524-31. McConahey WM, Hay ID, Woolner LB, van Heerden JA, Taylor WF. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc 1986;61:978-96. Hughes CJ, Shaha AR, Shah JP, Loree TR. Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis. Head Neck 1996;18:127-32. Roh JL, Park JY, Rha KS, Park CI. Is central neck dissection necessary for the treatment of lateral cervical nodal recurrence of papillary thyroid carcinoma? Head Neck 2007;29:901-6. Gimm O, Rath FW, Dralle H. Pattern of lymph node metastases in papillary thyroid carcinoma. Br J Surg 1998;85:252-4. Rotstein L. The role of lymphadenectomy in the management of papillary carcinoma of the thyroid. J Surg Oncol 2009;99:186-8. Pereira JA, Jimeno J, Miquel J, Iglesias M, Munne A, Sancho JJ, et al. Nodal yield, morbidity, and recurrence after central neck dissection for papillary thyroid carcinoma. Surgery 2005;138:1095-100. Wada N, Duh QY, Sugino K, Iwasaki H, Kameyama K, Mimura T, 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;237:399-407. Lee BJ, Lee JC, Wang SG, Kim YK, Kim IJ, Son SM. Metastasis of right upper para-esophageal lymph nodes in central compartment lymph node dissection of papillary thyroid cancer. World J Surg 2009;33:2094-8. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid. I. Developing pattern of metastasis. Cancer 1970;26:1053-60.
Lim et al 121
15. Shaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin North Am 1998;31:823-31. 16. Mirallie E, Visset J, Sagan C, Hamy A, Le Bodic MF, Paineau J. Localization of cervical node metastasis of papillary thyroid carcinoma. World J Surg 1999;23:970-3. 17. Mazzaferri EL. A vision for the surgical management of papillary thyroid carcinoma: extensive lymph node compartmental dissections and selective use of radioiodine. J Clin Endocrinol Metab 2009;94:1086-8. 18. Wang W, Larson SM, Tuttle RM, Kalaigian H, Lolbert K, Sonenberg M, et al. Resistance of [18f]-fluorodeoxyglucoseavid metastatic thyroid cancer lesions to treatment with high-dose radioactive iodine. Thyroid 2001;11:1169-75. 19. Robbins RJ, Wan Q, Grewal RK, Reibke R, Gonen M, Strauss HW, et al. Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab 2006;91:498-505. 20. Simon D, Goretzki PE, Witte J, Roher HD. Incidence of regional recurrence guiding radicality in differentiated thyroid carcinoma. World J Surg 1996;20:860-6. 21. Marchesi M, Biffoni M, Biancari F, Berni A, Campana FP. Predictors of outcome for patients with differentiated and aggressive thyroid carcinoma. Eur J Surg Suppl 2003: 46-50. 22. Machens A, Hinze R, Thomusch O, Dralle H. Pattern of nodal metastasis for primary and reoperative thyroid cancer. World J Surg 2002;26:22-8. 23. Ito Y, Higashiyama T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, et al. Risk factors for recurrence to the lymph node in papillary thyroid carcinoma patients without preoperatively detectable lateral node metastasis: validity of prophylactic modified radical neck dissection. World J Surg 2007;31:2085-91. 24. Vini L, Hyer SL, Marshall J, A’Hern R, Harmer C. Longterm results in elderly patients with differentiated thyroid carcinoma. Cancer 2003;97:2736-42.