World J Surg DOI 10.1007/s00268-013-2286-0
Patterns of Structural Recurrence in Papillary Thyroid Cancer Schelto Kruijff • Japke F. Petersen • Paul Chen • Ahmed M. Aniss • Roderick J. Clifton-Bligh • Stan B. Sidhu • Leigh W. Delbridge • Anthony J. Gill Diana Learoyd • Mark S. Sywak
•
Ó Socie´te´ Internationale de Chirurgie 2013
Abstract Background Papillary thyroid carcinoma (PTC) is uncommonly associated with tumor-related mortality, although local recurrence can be a frequent and difficult problem. This study was conducted to clarify the pattern of structural locoregional recurrence in PTC. Material and method A retrospective cohort study of patients undergoing surgical intervention for PTC was undertaken. Data were collected from a comprehensive thyroid cancer database maintained within a single tertiary referral center. The primary outcome measure was cancer recurrence requiring surgical intervention. Secondary outcome measures were site of recurrence, time to recurrence, and risk factors for recurrence. Results In the period 1980–2013, 1,183 patients with PTC were included in the study. The overall rate of structural recurrence requiring reoperative surgery was 7.9 %. The median time to reoperation was 31 months. Younger age, male gender, large primary tumor diameter,
This study has been accepted for oral presentation at the International Surgical Week ISW 2013, Helsinki, Finland. S. Kruijff J. F. Petersen P. Chen A. M. Aniss S. B. Sidhu L. W. Delbridge M. S. Sywak (&) University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Suite 202, 69 Christie St., St. Leonards, Sydney, NSW 2065, Australia e-mail: [email protected] R. J. Clifton-Bligh D. Learoyd Department of Endocrinology, Royal North Shore Hospital, St. Leonards, Sydney, NSW 2065, Australia A. J. Gill Department of Anatomical Pathology, Royal North Shore Hospital, St. Leonards, Sydney, NSW 2065, Australia
and number of positive lymph nodes at initial presentation were all significantly associated with disease recurrence. The lateral compartments (levels I, II, III, IV, V) were involved almost twice as frequently as the central compartment (level VI) (67 vs 32 %, P \ 0.01). The distribution of recurrences was level I (1 %), level II (12 %), level III (18 %), level IV (18 %), level V (17 %), level VI (32 %), level VII (2 %). Conclusions In a center with a liberal approach to central compartment lymph node dissection for PTC, the lateral neck compartment is the most common site of structural recurrence requiring reoperative surgery.
Introduction Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, with an increasing incidence of, now, approximately 8.7 cases/100,000 per year [1]. Overall, the 10-year disease-specific survival rate for PTC is [90 % [2]. Despite this excellent prognosis, cervical lymph node metastases are found in 40–90 % of cases, and up to 20 % of patients encounter recurrence of PTC after their primary operation [3–5]. Primary lymph node metastases are most commonly found in the central compartment, level VI, and most often involve the delphian, prelaryngeal, pretracheal, and paratracheal lymph nodes [6]. Skip metastases are uncommon, occurring in 7 % of cases [7]. While it was previously thought that lymph node metastases only increased local recurrence rates with no effect on survival, recent studies have reported that lymph node involvement does have a negative impact on survival [8–10]. A study by Young et al. [11] has shown that, after adjusting for all other variables, patients who require reoperation for recurrence
123
World J Surg
of PTC face a poorer prognosis than patients without recurrence, with increased morbidity and mortality rates. Factors that are generally associated with a higher risk of recurrence are tumor size, male gender, age younger than 45 years, extent of lymph node involvement, and presence of distant metastases at time of diagnosis [5, 12]. Because imaging of the central compartment by ultrasonography has a high rate of false-negative findings, an increasing number of institutions have incorporated central lymph node dissection (CLND) as a therapeutic procedure and also as a prophylactic procedure in some cases [13, 14]. In 2011 Popadich et al. [15] evaluated the impact of performing routine prophylactic CLND in the treatment of patients with PTC and showed that this was associated with lower levels of serum thyroglobulin postoperatively and reduced the need for reoperation in the central compartment. The reported benefits of CLND during total thyroidectomy are a more thorough clearance of thyroid tissue and subclinical metastases, avoidance of reoperation in the central compartment, and improved staging of the tumor, which informs decision making regarding ablative radioiodine treatment [7, 15, 16]. Potential harmful effects could be an increased morbidity, largely due to higher rates of permanent hypoparathyroidism, and injury to the recurrent laryngeal nerve (RLN) [7, 17]. Whereas the patterns of nodal spread in PTC from the primary tumor have been well described, the anatomical distribution of recurrent disease is less well understood and warrants further evaluation. A clearer understanding of the sites of persisting and recurrent disease may help to avoid repeated therapeutic interventions. Further interventions involving revision surgery or radioiodine ablation result in time away from work for the patient and are associated with a higher rate of treatment-related complications. The aim of this study, therefore, was to describe the anatomical distribution of locoregional recurrence in PTC and to identify the predisposing factors.
cell), as well as papillary microcarcinoma, were included. Cases of insular, follicular carcinoma, Hurthle cell carcinoma, and poorly differentiated carcinoma were excluded. Patients undergoing hemithyroidectomy only or partial thyroidectomy were excluded. Preoperative lymph node status was determined by physical examination and routine neck ultrasonography. Data collection was approved by the Northern Sydney Local Health District Human Research Ethics Committee. Treatment protocol
Materials and methods
All study patients underwent total thyroidectomy. Before 2003 only patients with clinically evident lymphadenopathy underwent central lymph node dissection (CLND) (level VI) and or lateral lymph node dissection (levels II– V). Central lymph node dissection was routinely performed after 2003 for patients in whom the diagnosis of PTC had been confirmed preoperatively. When necessary, autotransplantation of the ipsilateral inferior parathyroid gland into the sternocleidomastoid muscle was undertaken. Patients with incidentally discovered papillary microcarcinoma did not typically undergo CLND, and, similarly, patients in whom PTC was discovered only after diagnostic thyroid lobectomy mostly underwent completion thyroidectomy without CLND in the absence of overt cervical lymphadenopathy. After operation, patients were administered recombinant human thyrotropin (rhTSH; Thyrogen, Genzyme, Cambridge, MA) or underwent traditional L-thyroxine withdrawal. After this patients were treated with radioactive iodine (RAI) (dose range 1.1–6 GBq, 30–150 mCi). The ablative dose was individually tailored on the basis of tumor characteristics, generally giving low-risk patients a lower dose. All patients were routinely seen every 6–12 months in the first 5 years and either annual neck ultrasound or whole body RAI and stimulated thyroglobulin measurement was performed. Thereafter they were followed yearly and after 3 years referred to the general practitioner with the advice to perform a yearly ultrasound and thyroglobulin assessment.
Patient selection
Outcome measurements
A retrospective cohort study of patients undergoing surgical intervention for PTC at the University of Sydney Endocrine Unit from 1980 to 2013 was undertaken. Data were collected from a thyroid cancer database maintained within a single tertiary referral center. All patients were diagnosed with PTC on histopathology by a dedicated endocrine pathologist and fulfilled the 2004 WHO criteria for this diagnosis. Patients with PTC and its variants (follicular variant, solid, trabecular, tall cell, and columnar
Recurrence was defined as the development of new structural or anatomical abnormality on imaging (high-resolution neck ultrasound and/or whole-body radioactive iodine scan), that was confirmed by fine-needle aspiration cytology and histopathology only when a reoperation was considered. The primary outcome measure was recurrence requiring reoperative surgery. Patients requiring reoperative surgery had careful documentation of the involved lymph node basin according to
123
World J Surg Table 1 Patient demographics
Table 2 Recurrence demographics
Recurrence
Non-recurrence
P value
Number of patients (%)
94 (7.9)
1,089 (92.1)
Mean age at surgery, years
43
47
0.027
Number of males (%)
33 (35)
213 (20)
0.001
Mean tumor size, mm
26
19
\.001
T1
18 (19 %)
597 (55 %)
\.001
T2
10 (11 %)
159 (15 %)
0.29
T3
40 (43 %)
301 (28 %)
0.0022
T4
19 (20 %)
49 (4 %)
Multifocality
46 (49 %)
Extrathyroidal extension Vascular invasion
95 % CI Patients with recurrence (%)
94 (7.9)
Median time to recurrence in months (range)
31 (6–402)
Mean number of lymph nodes removed during first operation Mean number of involved nodes during first operation
8.8
(5.9–12.0)
4.3
(2.9–5.7)
Recurrence in lateral compartment
120 (67 %)
\.001
Level 1
2 (1 %)
489 (45 %)
0.279
Level 2
22 (12 %)
58 (62 %) 34 (36 %)
329 (30 %) 225 (21 %)
\.001 \.001
Level 3
33 (18 %)
Level 4
33 (18 %)
Distant metastases
14 (15 %)
21 (2 %)
\.001
Mean follow-up, months
85
57
\.001
30 (17 %) 57 (32 %)
Disease-specific mortality
3 (3 %)
10 (1 %)
0.151
Level 5 Recurrence in central compartment, level VI Recurrence in level VII
3 (2 %)
Lymph nodes removed during second operation
20
(14–26)
Involved nodes during second operation
3.1
(2.9–4.2)
Tumor stage
the classification of neck levels proposed by the Memorial Sloan-Kettering Cancer Center group [18]. The operative description was correlated with the final histopathological findings, and the location of recurrences was documented within the local Thyroid Cancer Database. Patient demographics and tumor characteristics were collected and analyzed. Tumor classification was performed according to the American Joint Cancer Commission/International Union Against Cancer (AJCC/UICC) 6th Edition tumor, node, and metastases (TNM) system [19]. Statistical analysis Continuous variables are expressed as mean (95 % confidence intervals), or as medians and were compared with Student’s t test. Categorical variables were compared with Fisher’s exact test. The disease-free survival (DFS) was calculated from Kaplan–Meier estimates and compared with the log rank test. Univariate and multivariate analysis was performed with a Cox proportional hazard model to identify factors significantly associated with disease recurrence. The alpha for significance was set at 0.05. Statistical analysis was performed using the Stata software package (version 12, Stata Corporation, College Station, TX).
Results Patient demographics Of the 1,183 patients included in this study, 94 patients (7.9 %) developed PTC recurrence requiring further surgery. The general patient demographics are listed in
Table 1. Of the 94 patients with recurrences, 3 patients did not undergo further surgery but instead had alcohol ablation. This treatment choice was based on personal preference. Patients having reoperative surgery tended to be younger (43 vs 47 years), were more likely to be male, and had a larger primary tumor diameter: 26 versus 19 mm (P \ 0.001). The mean follow-up was 85 months for the recurrence group and 57 months for the non-recurrence group. Patients requiring reoperative surgery had a smaller proportion of T1 tumors than the non-recurrence group (19 vs 55 %, P \ 0.001) and a greater proportion of T4 tumors (20 vs 4 %, P \ 0.001). Extrathyroidal extension, vascular invasion, and the presence of distant metastases all were significantly higher in the recurrence group (P \ 0.001). Recurrence characteristics Ninety-four patients in the study cohort required reoperation for recurrent disease, of which 16 % had two or more reoperations. Of those 94 patients, 90 patients had nodal recurrence and 4 patients had recurrence in the thyroid bed or tracheal wall. The median time to recurrence was 31 months (range 6–402 months). Table 2 summarizes the recurrence data. The average number of nodes removed at reoperation was 20, with a median of three lymph nodes per case positive for cancer. The mean number of neck levels dissected at reoperation was 2. Most recurrences were located in the lateral compartment (67 %), as opposed to the central compartment, which comprised 32 % of the
123
World J Surg
Fig. 1 Distribution of papillary thyroid cancer recurrences in central versus lateral neck compartments
recurrences (Fig. 1). The overall anatomical distribution of recurrences between central, lateral, and upper mediastinal compartments is illustrated in Fig. 2. In the lateral compartment, most recurrences occurred in levels III and IV, with each of these levels being involved in reoperation in 18 % of cases, respectively. Neck levels I and VII were the most infrequently involved, with recurrence requiring repeat surgery in 1 and 2 % of reoperative cases, respectively. Recurrence in the contralateral lymph node basin occurred in 17 % of patients, and 14 % had recurrence in the contralateral level VI zone. Within the study cohort 458 patients (39 %) underwent CLND with therapeutic or prophylactic intent in addition to total thyroidectomy at the time of initial surgery. These patients had a nonsignificantly lower rate of recurrence requiring surgery in the central compartment (4.4 vs 2.4 %, P = 0.07).
Fig. 2 Distribution of papillary thyroid cancer recurrences by cervical level
recurrence (P = 0.151; Table 1). Univariate analysis identified younger age, male gender, large tumor diameter, nodal positivity, vascular invasion, and extrathyroidal extension as being significantly associated with PTC recurrence. Multivariate analysis with the Cox proportional hazards model identified a number of factors significantly associated with structural recurrence (Table 3). Clinical factors included younger age and male gender, and histopathological factors included large primary tumor diameter, presence of vascular invasion and/or extrathyroidal extension, and number of positive lymph nodes at initial presentation. DFS curves constructed using the Kaplan– Meier method illustrate significantly reduced DFS in patients with lymph node positivity (N1a or N1b) at initial presentation (P \ 0.001, log rank test). DFS based on nodal staging is illustrated in Fig. 3.
Survival analysis and prognostic factors
Discussion
The 5-year and 10-year DFS for the study population were 95 and 92 %, respectively. The overall disease-specific mortality was 1.1 %. For the recurrence group, diseasespecific mortality was 3.2 %, which was not significantly different from the 1 % recorded for the group without
This study documents the structural recurrence rates in a large group of patients with PTC and illustrates the anatomical distribution of these locoregional recurrences. Overall the recurrence rate approached 8 %, with the majority occurring in the lateral neck compartments
123
World J Surg Table 3 Univariate and multivariate analysis of clinicopathological predictors associated with primary thyroid carcinoma (PTC) recurrence Predictor
Category
Univariate analysis Hazard ratio
P value 0.027
Age at presentation, years
\45
1
[45
0.91
Gender
Female
1
Male
3.1
\2
1
[2
1.9
Involved lymph nodes
No
1
Yes
2.1
Vascular invasion
No
1
Yes
2.4
Multifocality
No
1
Yes
1.2
No
1
Yes
3.1
Tumor size, cm
Extrathyroidal extension
Multivariate analysis Hazard ratio
P value
1
0.03
0.94 0.002 0.012
2.44
\0.001
1
0.02
1.2 0.002
1
\0.01
1.9 \0.001
1
0.004
2.18 0.28
1
0.32
1.54 \0.001
1
\0.001
4.4
Fig. 3 Kaplan–Meier curve for disease-free survival per lymph node stage
(67 %). While it is clearly understood that mortality rates attributable to papillary thyroid cancer are low, the problem of locoregional recurrence can represent a major challenge to treating physicians and surgeons and is an issue that consumes considerable medical resources in the follow-up period. Like our experience, authors of several other studies have found rates of recurrence ranging from 2.2 to 20 % [15, 20, 21]. The pattern of lymph node spread in PTC was documented by Machens et al. [22] in 2002. They showed that nodal metastasis occurred almost as often as in the ipsilateral central compartment as in the contralateral lateral compartment, in both primary presentations of PTC and in
the reoperative setting. The contralateral compartments were infrequently involved by PTC, with rates of 3 % described. However, the study population consisted of a small cohort and a heterogeneous group of cancers, including both papillary and medullary thyroid lesions. While the patterns of primary nodal disease have been well documented, less is known about the pattern of lymph node metastasis in reoperative surgery. In the present study we found that the majority of recurrences seem to appear in the lateral compartment (67 %), whereas only 32 % of recurrences were found in the central compartment. Our data show that the median time to recurrence is 31 months after initial surgery. This relatively short time frame suggests that at least some of the cohort, rather than experiencing a de novo recurrence, were likely to have had persisting disease that may have been subclinical at initial presentation. These cases may have avoided detection at initial sonographic and surgical evaluation and reflect the relatively high rate of falsenegative findings [13, 14]. The risk factors for recurrence in this study population were younger age, male gender, large tumor size, number of involved lymph nodes, vascular invasion, and extrathyroidal extension. These predictors are similar to those described elsewhere in the literature [5, 7, 8, 12]. Of interest, in this study the recurrence group were significantly younger at initial presentation, reflecting the higher rate of nodal involvement commonly seen when PTC presents in younger patients, although they still have lower reported mortality rates than patients [45 years [8, 23]. We were unable to demonstrate any influence of multifocality on the rate of tumor recurrence. The pattern of recurrence at reoperative surgery illustrates that in the lateral compartment, levels III and IV were most commonly involved (both 18 %), and that level V was involved in 17 % of cases. While levels III and IV are indeed reported to be most commonly involved, a study by Caron et al. [24] demonstrated that recurrences in level V were seen in only 1 % of cases if this level had not been previously resected, and in 5 % if the level had been resected. On the basis of our findings, we would recommend therefore that in the setting of lateral PTC recurrence surgeons should undertake selective lymph node dissection that incorporates levels II to Vb at a minimum. Because of the low rate of involvement in level I (1 %), dissection of this zone can be safely avoided in most cases. When treating patients with PTC, 40–90 % of patients appear to have regional lymph node metastases during primary surgery [3, 4]. The sensitivity to detect these positive lymph nodes in the central compartment by means of ultrasound is low [7, 13, 14]. Performing a prophylactic CLND at the first operation thus has two main advantages. The first is the opportunity for better staging, which aids in
123
World J Surg
the decision making in subsequent RAI treatment and follow-up with thyroglobulin. Second, a reoperation in the central compartment is associated with higher risks of permanent hypoparathyroidism and RLN injury [10]. In our center, we have performed routine ipsilateral CLND with both therapeutic and prophylactic intent in all patients with known PTC greater than 10 mm since 2003. Lateral neck dissection is generally undertaken only if there is clinical evidence of nodal involvement in these compartments. The discussion about prophylactic CLND has been an ongoing controversy, and various groups claim the benefits of performing CLND do not outweigh the burden of complications. Several studies have not been able to report improved DFS after CLND, and in fact have reported higher rates of permanent hypoparathyroidism and RLN palsy than after thyroidectomy alone [7, 20, 25]. Ultimately, the decision about how to approach central compartment nodal disease will depend on local preferences and expertise [15]. The concept of performing prophylactic CLND during the first procedure is thus based on an aggressive approach in the central compartment in order to prevent a riskier reoperation and potentially to reduce the rate of recurrence. Within our study cohort, at the time of initial surgery 458 patients (39 %) underwent CLND with therapeutic or prophylactic intent in addition to total thyroidectomy. These patients had a nonsignificantly lower rate of recurrence requiring surgery in the central compartment (4.4 vs 2.4 %, P = 0.07), and thus it seems that CLND does have an effect on lowering the amount of central recurrences. Another finding was that the percentage of recurrences in the contralateral level 6 (central neck) basin was 14 %. It has been our practice only to perform an ipsilateral CLND, but given this high percentage of bilateral central neck nodal disease, the new data could support a strategy of performing a bilateral CLND. Also, it is much safer to perform bilateral CLND at the initial operation. Many centers around the world support bilateral CLND in combination with total thyroidectomy; however, we believe that further research is warranted to further asses this clinical question. Some high-volume groups take this strategy even further by performing prophylactic lateral neck dissections during primary surgery. A study by Hartl et al. reported that 23 % of patients had metastases in the lateral compartment (level III and IV) during primary surgery. They therefore advocate performing both central and lateral nodal dissection in all patients to optimize staging of the neck. They report low morbidity rates, low complication rates, and an added operative time of only 20 min with a significant reduction in disease recurrence [7]. Lim et al. [26] found similar rates of involvement of the lateral compartment. On the basis of our data that the majority of recurrences occur in the lateral
123
compartment, incorporation of a prophylactic lateral nodal dissection warrants further evaluation [27, 28]. The benefits of a more extensive initial surgical approach may go beyond the traditional recurrence outcomes, and it is increasingly appreciated that the extra information provided by nodal status helps to guide decision making regarding the need and dose of radioiodine for remnant ablation [29, 30]. The aim of our report is to illustrate patterns of locoregional recurrence in papillary thyroid cancer. Although the retrospective nature of the analysis does introduce some selection biases, we argue that the large study population and the uniformity in operative approach make the observations robust. The mean overall follow-up of approximately 6 years might be considered relatively short in the setting of differentiated thyroid cancer; however, we believe that this interval is likely to capture the majority of recurrences. This opinion is supported by the fact that our median time to recurrence was relatively short at less than 3 years. In conclusion, in a center with a liberal approach to CLND, the majority of recurrences now occur in the lateral neck compartments. These recurrences typically become apparent within 3 years of presentation of the primary tumor.
References 1. Davies L, Welch HG (2006) Increasing incidence of thyroid cancer in the United States 1973–2002. JAMA 295:2164–2167 2. Malterling RR, Andersson RE, Falkmer S et al (2010) Differentiated thyroid cancer in a Swedish county-long-term results and quality of life. Acta Oncol 49:454–459 3. Grodski S, Cornford L, Sywak M et al (2007) Routine level VI lymph node dissection for papillary thyroid cancer: surgical technique. ANZ J Surg 77:203–208 4. Moo TA, McGill J, Allendorf J et al (2010) Impact of prophylactic central neck lymph node dissection on early recurrence in papillary thyroid carcinoma. World J Surg 34:1187–1191. doi:10. 1007/s00268-010-0418-3 5. Enyioha C, Roman SA, Sosa JA (2013) Central lymph node dissection in patients with papillary thyroid cancer: a population level analysis of 14,257 cases. Am J Surg 205(6):655–661 6. Sywak M, Cornford L, Roach P et al (2006) Routine ipsilateral level VI lymphadenectomy reduces postoperative thyroglobulin levels in papillary thyroid cancer. Surgery 140:1000–1005 7. Hartl DM, Leboulleux S, Al Ghuzlan A et al (2012) Optimization of staging of the neck with prophylactic central and lateral neck dissection for papillary thyroid carcinoma. Ann Surg 255:777–783 8. Scheumann GF, Gimm O, Wegener G et al (1994) Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surg 18:559–567. doi:10.1007/BF00353765 9. Lundgren CI, Hall P, Dickman PW et al (2006) Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case–control study. Cancer 106: 524–531
World J Surg 10. White ML, Gauger PG, Doherty GM (2007) Central lymph node dissection in differentiated thyroid cancer. World J Surg 31:895–904. doi:10.1007/s00268-006-0907-6 11. Young A, Harari A, Smooke-Praw S et al (2013) Effect of reoperation on outcomes in papillary thyroid cancer. Surgery (submitted) 12. Giles Senyurek Y, Tunca F, Boztepe H et al (2009) The long term outcome of papillary thyroid carcinoma patients without primary central lymph node dissection: expected improvement of routine dissection. Surgery 146:1188–1195 13. Kouvaraki MA, Shapiro SE, Fornage BD et al (2003) Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery 134:946–954 14. Choi JS, Kim J, Kwak JY et al (2009) Preoperative staging of papillary thyroid carcinoma: comparison of ultrasound imaging and CT. AJR Am J Roentgenol 193:871–878 15. Popadich A, Levin O, Lee JC et al (2011) A multicenter cohort study of total thyroidectomy and routine central lymph node dissection for cN0 papillary thyroid cancer. Surgery 150: 1048–1057 16. Pacini F, Castagna MG, Brilli L, The ESMO Guidelines Working Group et al (2009) Differentiated thyroid cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20(Suppl 4):143–146 17. Henry JF, Gramatica L, Denizot A et al (1998) Morbidity of prophylactic lymph node dissection in the central neck area in patients with papillary thyroid carcinoma. Langenbecks Arch Surg 383:167–169 18. Shaha AR (2007) TNM classification of thyroid carcinoma. World J Surg 31:879–887. doi:10.1007/s00268-006-0864-0 19. Cooper S, Doherty G, Huagen B et al (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19: 1167–1214 20. Zetoune T, Keutgen X, Buitrago D et al (2010) Prophylactic central neck dissection and local recurrence in papillary thyroid cancer: a meta-analysis. Ann Surg Oncol 17:3287–3293
21. Hartl DM, Mamelle E, Borget I et al (2013) Influence of prophylactic neck dissection on rate of retreatment for papillary thyroid carcinoma. World J Surg 37:1951–1958. doi:10.1007/ s00268-013-2089-3 22. Machens A, Hinze R, Thomusch O et al (2002) Patterns of nodal metastasis for primary and reoperative thyroid cancer. World J Surg 26:22–28. doi:10.1007/s00268-001-0176-3 23. Zaydfudim V, Feurer ID, Griffin MR et al (2008) The impact of lymph node involvement on survival in patients with papillary and follicular thryroid carcinoma. Surgery 144:1070–1077 24. Caron NR, Tan YY, Ogilvie JB et al (2006) Selective modified radical neck dissection for papillary thyroid cancer—is level I, II and IV dissection always neccesary? World J Surg 30:833–840. doi:10.1007/s00268-005-0358-5 25. Roh JL, Park JY, Park CI (2009) Prevention of postoperative hypocalcemia with routine oral calcium and vitamin D supplements in patients with differentiated papillary thryoid carcinoma undergoing total thyroidectomy plus central neck dissection. Cancer 115:251–258 26. Lim YS, Lee JC, Lee YS et al (2011) Lateral cervical lymph node metastases from papillary thyroid carcinoma: predictive factors of nodal metastasis. Surgery 150:116–121 27. Kim C, Bi X, Pan D et al (2013) The risk of second cancers after diagnosis of primary thyroid cancer is elevated in thyroid microcarcinomas. Thyroid 23:575–582 28. Brown AP, Chen J, Hitchcock YJ et al (2008) The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab 93:504–515 29. Kruijff S, Chen P, Aniss A et al (2013) Lowering doses of radioiodine for remnant ablation does not increase structural recurrence rates in papillary thyroid carcinoma. Surgery (accepted) 30. Schlumberger M, Catargi B, Borget I et al (2012) Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 366:1163–1673
123
Patterns of Structural Recurrence in Papillary Thyroid Cancer Schelto Kruijff • Japke F. Petersen • Paul Chen • Ahmed M. Aniss • Roderick J. Clifton-Bligh • Stan B. Sidhu • Leigh W. Delbridge • Anthony J. Gill Diana Learoyd • Mark S. Sywak
•
Ó Socie´te´ Internationale de Chirurgie 2013
Abstract Background Papillary thyroid carcinoma (PTC) is uncommonly associated with tumor-related mortality, although local recurrence can be a frequent and difficult problem. This study was conducted to clarify the pattern of structural locoregional recurrence in PTC. Material and method A retrospective cohort study of patients undergoing surgical intervention for PTC was undertaken. Data were collected from a comprehensive thyroid cancer database maintained within a single tertiary referral center. The primary outcome measure was cancer recurrence requiring surgical intervention. Secondary outcome measures were site of recurrence, time to recurrence, and risk factors for recurrence. Results In the period 1980–2013, 1,183 patients with PTC were included in the study. The overall rate of structural recurrence requiring reoperative surgery was 7.9 %. The median time to reoperation was 31 months. Younger age, male gender, large primary tumor diameter,
This study has been accepted for oral presentation at the International Surgical Week ISW 2013, Helsinki, Finland. S. Kruijff J. F. Petersen P. Chen A. M. Aniss S. B. Sidhu L. W. Delbridge M. S. Sywak (&) University of Sydney Endocrine Surgery Unit, Royal North Shore Hospital, Suite 202, 69 Christie St., St. Leonards, Sydney, NSW 2065, Australia e-mail: [email protected] R. J. Clifton-Bligh D. Learoyd Department of Endocrinology, Royal North Shore Hospital, St. Leonards, Sydney, NSW 2065, Australia A. J. Gill Department of Anatomical Pathology, Royal North Shore Hospital, St. Leonards, Sydney, NSW 2065, Australia
and number of positive lymph nodes at initial presentation were all significantly associated with disease recurrence. The lateral compartments (levels I, II, III, IV, V) were involved almost twice as frequently as the central compartment (level VI) (67 vs 32 %, P \ 0.01). The distribution of recurrences was level I (1 %), level II (12 %), level III (18 %), level IV (18 %), level V (17 %), level VI (32 %), level VII (2 %). Conclusions In a center with a liberal approach to central compartment lymph node dissection for PTC, the lateral neck compartment is the most common site of structural recurrence requiring reoperative surgery.
Introduction Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy, with an increasing incidence of, now, approximately 8.7 cases/100,000 per year [1]. Overall, the 10-year disease-specific survival rate for PTC is [90 % [2]. Despite this excellent prognosis, cervical lymph node metastases are found in 40–90 % of cases, and up to 20 % of patients encounter recurrence of PTC after their primary operation [3–5]. Primary lymph node metastases are most commonly found in the central compartment, level VI, and most often involve the delphian, prelaryngeal, pretracheal, and paratracheal lymph nodes [6]. Skip metastases are uncommon, occurring in 7 % of cases [7]. While it was previously thought that lymph node metastases only increased local recurrence rates with no effect on survival, recent studies have reported that lymph node involvement does have a negative impact on survival [8–10]. A study by Young et al. [11] has shown that, after adjusting for all other variables, patients who require reoperation for recurrence
123
World J Surg
of PTC face a poorer prognosis than patients without recurrence, with increased morbidity and mortality rates. Factors that are generally associated with a higher risk of recurrence are tumor size, male gender, age younger than 45 years, extent of lymph node involvement, and presence of distant metastases at time of diagnosis [5, 12]. Because imaging of the central compartment by ultrasonography has a high rate of false-negative findings, an increasing number of institutions have incorporated central lymph node dissection (CLND) as a therapeutic procedure and also as a prophylactic procedure in some cases [13, 14]. In 2011 Popadich et al. [15] evaluated the impact of performing routine prophylactic CLND in the treatment of patients with PTC and showed that this was associated with lower levels of serum thyroglobulin postoperatively and reduced the need for reoperation in the central compartment. The reported benefits of CLND during total thyroidectomy are a more thorough clearance of thyroid tissue and subclinical metastases, avoidance of reoperation in the central compartment, and improved staging of the tumor, which informs decision making regarding ablative radioiodine treatment [7, 15, 16]. Potential harmful effects could be an increased morbidity, largely due to higher rates of permanent hypoparathyroidism, and injury to the recurrent laryngeal nerve (RLN) [7, 17]. Whereas the patterns of nodal spread in PTC from the primary tumor have been well described, the anatomical distribution of recurrent disease is less well understood and warrants further evaluation. A clearer understanding of the sites of persisting and recurrent disease may help to avoid repeated therapeutic interventions. Further interventions involving revision surgery or radioiodine ablation result in time away from work for the patient and are associated with a higher rate of treatment-related complications. The aim of this study, therefore, was to describe the anatomical distribution of locoregional recurrence in PTC and to identify the predisposing factors.
cell), as well as papillary microcarcinoma, were included. Cases of insular, follicular carcinoma, Hurthle cell carcinoma, and poorly differentiated carcinoma were excluded. Patients undergoing hemithyroidectomy only or partial thyroidectomy were excluded. Preoperative lymph node status was determined by physical examination and routine neck ultrasonography. Data collection was approved by the Northern Sydney Local Health District Human Research Ethics Committee. Treatment protocol
Materials and methods
All study patients underwent total thyroidectomy. Before 2003 only patients with clinically evident lymphadenopathy underwent central lymph node dissection (CLND) (level VI) and or lateral lymph node dissection (levels II– V). Central lymph node dissection was routinely performed after 2003 for patients in whom the diagnosis of PTC had been confirmed preoperatively. When necessary, autotransplantation of the ipsilateral inferior parathyroid gland into the sternocleidomastoid muscle was undertaken. Patients with incidentally discovered papillary microcarcinoma did not typically undergo CLND, and, similarly, patients in whom PTC was discovered only after diagnostic thyroid lobectomy mostly underwent completion thyroidectomy without CLND in the absence of overt cervical lymphadenopathy. After operation, patients were administered recombinant human thyrotropin (rhTSH; Thyrogen, Genzyme, Cambridge, MA) or underwent traditional L-thyroxine withdrawal. After this patients were treated with radioactive iodine (RAI) (dose range 1.1–6 GBq, 30–150 mCi). The ablative dose was individually tailored on the basis of tumor characteristics, generally giving low-risk patients a lower dose. All patients were routinely seen every 6–12 months in the first 5 years and either annual neck ultrasound or whole body RAI and stimulated thyroglobulin measurement was performed. Thereafter they were followed yearly and after 3 years referred to the general practitioner with the advice to perform a yearly ultrasound and thyroglobulin assessment.
Patient selection
Outcome measurements
A retrospective cohort study of patients undergoing surgical intervention for PTC at the University of Sydney Endocrine Unit from 1980 to 2013 was undertaken. Data were collected from a thyroid cancer database maintained within a single tertiary referral center. All patients were diagnosed with PTC on histopathology by a dedicated endocrine pathologist and fulfilled the 2004 WHO criteria for this diagnosis. Patients with PTC and its variants (follicular variant, solid, trabecular, tall cell, and columnar
Recurrence was defined as the development of new structural or anatomical abnormality on imaging (high-resolution neck ultrasound and/or whole-body radioactive iodine scan), that was confirmed by fine-needle aspiration cytology and histopathology only when a reoperation was considered. The primary outcome measure was recurrence requiring reoperative surgery. Patients requiring reoperative surgery had careful documentation of the involved lymph node basin according to
123
World J Surg Table 1 Patient demographics
Table 2 Recurrence demographics
Recurrence
Non-recurrence
P value
Number of patients (%)
94 (7.9)
1,089 (92.1)
Mean age at surgery, years
43
47
0.027
Number of males (%)
33 (35)
213 (20)
0.001
Mean tumor size, mm
26
19
\.001
T1
18 (19 %)
597 (55 %)
\.001
T2
10 (11 %)
159 (15 %)
0.29
T3
40 (43 %)
301 (28 %)
0.0022
T4
19 (20 %)
49 (4 %)
Multifocality
46 (49 %)
Extrathyroidal extension Vascular invasion
95 % CI Patients with recurrence (%)
94 (7.9)
Median time to recurrence in months (range)
31 (6–402)
Mean number of lymph nodes removed during first operation Mean number of involved nodes during first operation
8.8
(5.9–12.0)
4.3
(2.9–5.7)
Recurrence in lateral compartment
120 (67 %)
\.001
Level 1
2 (1 %)
489 (45 %)
0.279
Level 2
22 (12 %)
58 (62 %) 34 (36 %)
329 (30 %) 225 (21 %)
\.001 \.001
Level 3
33 (18 %)
Level 4
33 (18 %)
Distant metastases
14 (15 %)
21 (2 %)
\.001
Mean follow-up, months
85
57
\.001
30 (17 %) 57 (32 %)
Disease-specific mortality
3 (3 %)
10 (1 %)
0.151
Level 5 Recurrence in central compartment, level VI Recurrence in level VII
3 (2 %)
Lymph nodes removed during second operation
20
(14–26)
Involved nodes during second operation
3.1
(2.9–4.2)
Tumor stage
the classification of neck levels proposed by the Memorial Sloan-Kettering Cancer Center group [18]. The operative description was correlated with the final histopathological findings, and the location of recurrences was documented within the local Thyroid Cancer Database. Patient demographics and tumor characteristics were collected and analyzed. Tumor classification was performed according to the American Joint Cancer Commission/International Union Against Cancer (AJCC/UICC) 6th Edition tumor, node, and metastases (TNM) system [19]. Statistical analysis Continuous variables are expressed as mean (95 % confidence intervals), or as medians and were compared with Student’s t test. Categorical variables were compared with Fisher’s exact test. The disease-free survival (DFS) was calculated from Kaplan–Meier estimates and compared with the log rank test. Univariate and multivariate analysis was performed with a Cox proportional hazard model to identify factors significantly associated with disease recurrence. The alpha for significance was set at 0.05. Statistical analysis was performed using the Stata software package (version 12, Stata Corporation, College Station, TX).
Results Patient demographics Of the 1,183 patients included in this study, 94 patients (7.9 %) developed PTC recurrence requiring further surgery. The general patient demographics are listed in
Table 1. Of the 94 patients with recurrences, 3 patients did not undergo further surgery but instead had alcohol ablation. This treatment choice was based on personal preference. Patients having reoperative surgery tended to be younger (43 vs 47 years), were more likely to be male, and had a larger primary tumor diameter: 26 versus 19 mm (P \ 0.001). The mean follow-up was 85 months for the recurrence group and 57 months for the non-recurrence group. Patients requiring reoperative surgery had a smaller proportion of T1 tumors than the non-recurrence group (19 vs 55 %, P \ 0.001) and a greater proportion of T4 tumors (20 vs 4 %, P \ 0.001). Extrathyroidal extension, vascular invasion, and the presence of distant metastases all were significantly higher in the recurrence group (P \ 0.001). Recurrence characteristics Ninety-four patients in the study cohort required reoperation for recurrent disease, of which 16 % had two or more reoperations. Of those 94 patients, 90 patients had nodal recurrence and 4 patients had recurrence in the thyroid bed or tracheal wall. The median time to recurrence was 31 months (range 6–402 months). Table 2 summarizes the recurrence data. The average number of nodes removed at reoperation was 20, with a median of three lymph nodes per case positive for cancer. The mean number of neck levels dissected at reoperation was 2. Most recurrences were located in the lateral compartment (67 %), as opposed to the central compartment, which comprised 32 % of the
123
World J Surg
Fig. 1 Distribution of papillary thyroid cancer recurrences in central versus lateral neck compartments
recurrences (Fig. 1). The overall anatomical distribution of recurrences between central, lateral, and upper mediastinal compartments is illustrated in Fig. 2. In the lateral compartment, most recurrences occurred in levels III and IV, with each of these levels being involved in reoperation in 18 % of cases, respectively. Neck levels I and VII were the most infrequently involved, with recurrence requiring repeat surgery in 1 and 2 % of reoperative cases, respectively. Recurrence in the contralateral lymph node basin occurred in 17 % of patients, and 14 % had recurrence in the contralateral level VI zone. Within the study cohort 458 patients (39 %) underwent CLND with therapeutic or prophylactic intent in addition to total thyroidectomy at the time of initial surgery. These patients had a nonsignificantly lower rate of recurrence requiring surgery in the central compartment (4.4 vs 2.4 %, P = 0.07).
Fig. 2 Distribution of papillary thyroid cancer recurrences by cervical level
recurrence (P = 0.151; Table 1). Univariate analysis identified younger age, male gender, large tumor diameter, nodal positivity, vascular invasion, and extrathyroidal extension as being significantly associated with PTC recurrence. Multivariate analysis with the Cox proportional hazards model identified a number of factors significantly associated with structural recurrence (Table 3). Clinical factors included younger age and male gender, and histopathological factors included large primary tumor diameter, presence of vascular invasion and/or extrathyroidal extension, and number of positive lymph nodes at initial presentation. DFS curves constructed using the Kaplan– Meier method illustrate significantly reduced DFS in patients with lymph node positivity (N1a or N1b) at initial presentation (P \ 0.001, log rank test). DFS based on nodal staging is illustrated in Fig. 3.
Survival analysis and prognostic factors
Discussion
The 5-year and 10-year DFS for the study population were 95 and 92 %, respectively. The overall disease-specific mortality was 1.1 %. For the recurrence group, diseasespecific mortality was 3.2 %, which was not significantly different from the 1 % recorded for the group without
This study documents the structural recurrence rates in a large group of patients with PTC and illustrates the anatomical distribution of these locoregional recurrences. Overall the recurrence rate approached 8 %, with the majority occurring in the lateral neck compartments
123
World J Surg Table 3 Univariate and multivariate analysis of clinicopathological predictors associated with primary thyroid carcinoma (PTC) recurrence Predictor
Category
Univariate analysis Hazard ratio
P value 0.027
Age at presentation, years
\45
1
[45
0.91
Gender
Female
1
Male
3.1
\2
1
[2
1.9
Involved lymph nodes
No
1
Yes
2.1
Vascular invasion
No
1
Yes
2.4
Multifocality
No
1
Yes
1.2
No
1
Yes
3.1
Tumor size, cm
Extrathyroidal extension
Multivariate analysis Hazard ratio
P value
1
0.03
0.94 0.002 0.012
2.44
\0.001
1
0.02
1.2 0.002
1
\0.01
1.9 \0.001
1
0.004
2.18 0.28
1
0.32
1.54 \0.001
1
\0.001
4.4
Fig. 3 Kaplan–Meier curve for disease-free survival per lymph node stage
(67 %). While it is clearly understood that mortality rates attributable to papillary thyroid cancer are low, the problem of locoregional recurrence can represent a major challenge to treating physicians and surgeons and is an issue that consumes considerable medical resources in the follow-up period. Like our experience, authors of several other studies have found rates of recurrence ranging from 2.2 to 20 % [15, 20, 21]. The pattern of lymph node spread in PTC was documented by Machens et al. [22] in 2002. They showed that nodal metastasis occurred almost as often as in the ipsilateral central compartment as in the contralateral lateral compartment, in both primary presentations of PTC and in
the reoperative setting. The contralateral compartments were infrequently involved by PTC, with rates of 3 % described. However, the study population consisted of a small cohort and a heterogeneous group of cancers, including both papillary and medullary thyroid lesions. While the patterns of primary nodal disease have been well documented, less is known about the pattern of lymph node metastasis in reoperative surgery. In the present study we found that the majority of recurrences seem to appear in the lateral compartment (67 %), whereas only 32 % of recurrences were found in the central compartment. Our data show that the median time to recurrence is 31 months after initial surgery. This relatively short time frame suggests that at least some of the cohort, rather than experiencing a de novo recurrence, were likely to have had persisting disease that may have been subclinical at initial presentation. These cases may have avoided detection at initial sonographic and surgical evaluation and reflect the relatively high rate of falsenegative findings [13, 14]. The risk factors for recurrence in this study population were younger age, male gender, large tumor size, number of involved lymph nodes, vascular invasion, and extrathyroidal extension. These predictors are similar to those described elsewhere in the literature [5, 7, 8, 12]. Of interest, in this study the recurrence group were significantly younger at initial presentation, reflecting the higher rate of nodal involvement commonly seen when PTC presents in younger patients, although they still have lower reported mortality rates than patients [45 years [8, 23]. We were unable to demonstrate any influence of multifocality on the rate of tumor recurrence. The pattern of recurrence at reoperative surgery illustrates that in the lateral compartment, levels III and IV were most commonly involved (both 18 %), and that level V was involved in 17 % of cases. While levels III and IV are indeed reported to be most commonly involved, a study by Caron et al. [24] demonstrated that recurrences in level V were seen in only 1 % of cases if this level had not been previously resected, and in 5 % if the level had been resected. On the basis of our findings, we would recommend therefore that in the setting of lateral PTC recurrence surgeons should undertake selective lymph node dissection that incorporates levels II to Vb at a minimum. Because of the low rate of involvement in level I (1 %), dissection of this zone can be safely avoided in most cases. When treating patients with PTC, 40–90 % of patients appear to have regional lymph node metastases during primary surgery [3, 4]. The sensitivity to detect these positive lymph nodes in the central compartment by means of ultrasound is low [7, 13, 14]. Performing a prophylactic CLND at the first operation thus has two main advantages. The first is the opportunity for better staging, which aids in
123
World J Surg
the decision making in subsequent RAI treatment and follow-up with thyroglobulin. Second, a reoperation in the central compartment is associated with higher risks of permanent hypoparathyroidism and RLN injury [10]. In our center, we have performed routine ipsilateral CLND with both therapeutic and prophylactic intent in all patients with known PTC greater than 10 mm since 2003. Lateral neck dissection is generally undertaken only if there is clinical evidence of nodal involvement in these compartments. The discussion about prophylactic CLND has been an ongoing controversy, and various groups claim the benefits of performing CLND do not outweigh the burden of complications. Several studies have not been able to report improved DFS after CLND, and in fact have reported higher rates of permanent hypoparathyroidism and RLN palsy than after thyroidectomy alone [7, 20, 25]. Ultimately, the decision about how to approach central compartment nodal disease will depend on local preferences and expertise [15]. The concept of performing prophylactic CLND during the first procedure is thus based on an aggressive approach in the central compartment in order to prevent a riskier reoperation and potentially to reduce the rate of recurrence. Within our study cohort, at the time of initial surgery 458 patients (39 %) underwent CLND with therapeutic or prophylactic intent in addition to total thyroidectomy. These patients had a nonsignificantly lower rate of recurrence requiring surgery in the central compartment (4.4 vs 2.4 %, P = 0.07), and thus it seems that CLND does have an effect on lowering the amount of central recurrences. Another finding was that the percentage of recurrences in the contralateral level 6 (central neck) basin was 14 %. It has been our practice only to perform an ipsilateral CLND, but given this high percentage of bilateral central neck nodal disease, the new data could support a strategy of performing a bilateral CLND. Also, it is much safer to perform bilateral CLND at the initial operation. Many centers around the world support bilateral CLND in combination with total thyroidectomy; however, we believe that further research is warranted to further asses this clinical question. Some high-volume groups take this strategy even further by performing prophylactic lateral neck dissections during primary surgery. A study by Hartl et al. reported that 23 % of patients had metastases in the lateral compartment (level III and IV) during primary surgery. They therefore advocate performing both central and lateral nodal dissection in all patients to optimize staging of the neck. They report low morbidity rates, low complication rates, and an added operative time of only 20 min with a significant reduction in disease recurrence [7]. Lim et al. [26] found similar rates of involvement of the lateral compartment. On the basis of our data that the majority of recurrences occur in the lateral
123
compartment, incorporation of a prophylactic lateral nodal dissection warrants further evaluation [27, 28]. The benefits of a more extensive initial surgical approach may go beyond the traditional recurrence outcomes, and it is increasingly appreciated that the extra information provided by nodal status helps to guide decision making regarding the need and dose of radioiodine for remnant ablation [29, 30]. The aim of our report is to illustrate patterns of locoregional recurrence in papillary thyroid cancer. Although the retrospective nature of the analysis does introduce some selection biases, we argue that the large study population and the uniformity in operative approach make the observations robust. The mean overall follow-up of approximately 6 years might be considered relatively short in the setting of differentiated thyroid cancer; however, we believe that this interval is likely to capture the majority of recurrences. This opinion is supported by the fact that our median time to recurrence was relatively short at less than 3 years. In conclusion, in a center with a liberal approach to CLND, the majority of recurrences now occur in the lateral neck compartments. These recurrences typically become apparent within 3 years of presentation of the primary tumor.
References 1. Davies L, Welch HG (2006) Increasing incidence of thyroid cancer in the United States 1973–2002. JAMA 295:2164–2167 2. Malterling RR, Andersson RE, Falkmer S et al (2010) Differentiated thyroid cancer in a Swedish county-long-term results and quality of life. Acta Oncol 49:454–459 3. Grodski S, Cornford L, Sywak M et al (2007) Routine level VI lymph node dissection for papillary thyroid cancer: surgical technique. ANZ J Surg 77:203–208 4. Moo TA, McGill J, Allendorf J et al (2010) Impact of prophylactic central neck lymph node dissection on early recurrence in papillary thyroid carcinoma. World J Surg 34:1187–1191. doi:10. 1007/s00268-010-0418-3 5. Enyioha C, Roman SA, Sosa JA (2013) Central lymph node dissection in patients with papillary thyroid cancer: a population level analysis of 14,257 cases. Am J Surg 205(6):655–661 6. Sywak M, Cornford L, Roach P et al (2006) Routine ipsilateral level VI lymphadenectomy reduces postoperative thyroglobulin levels in papillary thyroid cancer. Surgery 140:1000–1005 7. Hartl DM, Leboulleux S, Al Ghuzlan A et al (2012) Optimization of staging of the neck with prophylactic central and lateral neck dissection for papillary thyroid carcinoma. Ann Surg 255:777–783 8. Scheumann GF, Gimm O, Wegener G et al (1994) Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surg 18:559–567. doi:10.1007/BF00353765 9. Lundgren CI, Hall P, Dickman PW et al (2006) Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case–control study. Cancer 106: 524–531
World J Surg 10. White ML, Gauger PG, Doherty GM (2007) Central lymph node dissection in differentiated thyroid cancer. World J Surg 31:895–904. doi:10.1007/s00268-006-0907-6 11. Young A, Harari A, Smooke-Praw S et al (2013) Effect of reoperation on outcomes in papillary thyroid cancer. Surgery (submitted) 12. Giles Senyurek Y, Tunca F, Boztepe H et al (2009) The long term outcome of papillary thyroid carcinoma patients without primary central lymph node dissection: expected improvement of routine dissection. Surgery 146:1188–1195 13. Kouvaraki MA, Shapiro SE, Fornage BD et al (2003) Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery 134:946–954 14. Choi JS, Kim J, Kwak JY et al (2009) Preoperative staging of papillary thyroid carcinoma: comparison of ultrasound imaging and CT. AJR Am J Roentgenol 193:871–878 15. Popadich A, Levin O, Lee JC et al (2011) A multicenter cohort study of total thyroidectomy and routine central lymph node dissection for cN0 papillary thyroid cancer. Surgery 150: 1048–1057 16. Pacini F, Castagna MG, Brilli L, The ESMO Guidelines Working Group et al (2009) Differentiated thyroid cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 20(Suppl 4):143–146 17. Henry JF, Gramatica L, Denizot A et al (1998) Morbidity of prophylactic lymph node dissection in the central neck area in patients with papillary thyroid carcinoma. Langenbecks Arch Surg 383:167–169 18. Shaha AR (2007) TNM classification of thyroid carcinoma. World J Surg 31:879–887. doi:10.1007/s00268-006-0864-0 19. Cooper S, Doherty G, Huagen B et al (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19: 1167–1214 20. Zetoune T, Keutgen X, Buitrago D et al (2010) Prophylactic central neck dissection and local recurrence in papillary thyroid cancer: a meta-analysis. Ann Surg Oncol 17:3287–3293
21. Hartl DM, Mamelle E, Borget I et al (2013) Influence of prophylactic neck dissection on rate of retreatment for papillary thyroid carcinoma. World J Surg 37:1951–1958. doi:10.1007/ s00268-013-2089-3 22. Machens A, Hinze R, Thomusch O et al (2002) Patterns of nodal metastasis for primary and reoperative thyroid cancer. World J Surg 26:22–28. doi:10.1007/s00268-001-0176-3 23. Zaydfudim V, Feurer ID, Griffin MR et al (2008) The impact of lymph node involvement on survival in patients with papillary and follicular thryroid carcinoma. Surgery 144:1070–1077 24. Caron NR, Tan YY, Ogilvie JB et al (2006) Selective modified radical neck dissection for papillary thyroid cancer—is level I, II and IV dissection always neccesary? World J Surg 30:833–840. doi:10.1007/s00268-005-0358-5 25. Roh JL, Park JY, Park CI (2009) Prevention of postoperative hypocalcemia with routine oral calcium and vitamin D supplements in patients with differentiated papillary thryoid carcinoma undergoing total thyroidectomy plus central neck dissection. Cancer 115:251–258 26. Lim YS, Lee JC, Lee YS et al (2011) Lateral cervical lymph node metastases from papillary thyroid carcinoma: predictive factors of nodal metastasis. Surgery 150:116–121 27. Kim C, Bi X, Pan D et al (2013) The risk of second cancers after diagnosis of primary thyroid cancer is elevated in thyroid microcarcinomas. Thyroid 23:575–582 28. Brown AP, Chen J, Hitchcock YJ et al (2008) The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab 93:504–515 29. Kruijff S, Chen P, Aniss A et al (2013) Lowering doses of radioiodine for remnant ablation does not increase structural recurrence rates in papillary thyroid carcinoma. Surgery (accepted) 30. Schlumberger M, Catargi B, Borget I et al (2012) Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med 366:1163–1673
123
