Summary

Background

Central lymph node dissection (CLND) in patients with papillary thyroid microcarcinoma (PTMC) is still controversial. The aim of this study was to examine the risk factors and the incidence of central lymph node metastases (CLNMs) in patients with PTMC who underwent thyroidectomy and CLND.

Patients and methods

Between 2002 and 2013, 613 patients were enrolled who underwent thyroidectomy with routine CLND for PTMC at the Korea University Medical Center, Ansan Hospital and risk factors and the incidence of CLNM were analyzed. In addition, we also evaluated the complications after thyroidectomy with CLND.

Results

Out of 613 patients, 239 (39.0%) were found to have CLNM. Male sex (p = 0.012), tumor size ≥ 0.5 cm (p = 0.001), capsular invasion or extrathyroidal extension (p = 0.029), and multifocality (p = 0.004) were independent risk factors for CLNM. Among the 69 patients who had PTMC without these risk factors, CLNM was identified in 12 (17.4%). In this study group, two (0.3%) had permanent recurrent laryngeal nerve injury, two (0.3%) had persistent hypocalcemia, and two (0.3%) developed postoperative hemorrhage.

Conclusion

CLNM in PTMC is highly prevalent in male sex, tumor size ≥ 0.5 cm, extrathyroidal extension, and multifocality. Even in PTMC patients without these risk factors, the incidence of CLNM is rather higher than expected, and the complication rate of thyroidectomy with CLND is acceptable. Thus, CLND should be considered in all patients with PTMC.

Keywords

central lymph node;papillary thyroid cancer;papillary thyroid microcarcinoma

1. Introduction

Papillary thyroid microcarcinoma (PTMC) is defined as a papillary thyroid carcinoma (PTC) measuring ≤ 1 cm in maximal diameter, and the overall 10-year survival rate associated with this malignancy is > 90%.1 ;  2 Because of the overall excellent prognosis of PTMC, many current guidelines and recommendations regarding the optimal treatment strategy for PTMC remain controversial.3 ;  4

Many arguments about PTMC treatments have focused on routine central lymph node dissection (CLND), because despite the excellent prognosis, central lymph node metastases (CLNMs) are common in patients with PTC. Several studies have reported that CLNM are associated with a significantly increased probability of locoregional disease recurrence, and routine CLND for PTC patients may decrease recurrence and improve disease-specific survival.5; 6; 7; 8 ;  9

However, Ito et al10 have insisted that prophylactic CLND may result in postoperative complications and provides no overall survival benefit. Moreover, the 2009 guidelines for the management of thyroid nodules and differentiated thyroid cancer issued by the American Thyroid Association Guidelines Taskforce state the following: “Prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors.”11

To investigate the efficacy and indication of CLND for PTMC patients, we examined the overall incidence and risk factors of CLNM in our cases. In addition, we also analyzed the complications and incidence of CLNM in PTMC patients without risk factors.

2. Patients and methods

A total of 613 patients who underwent thyroidectomy with routine CLND for PTMC at the Korea University Medical Center, Ansan Hospital, between January 2002 and December 2013 were enrolled in this study. Based on a review of our computerized database, the following data were collected: demographic information and pathological parameters, such as tumor size, extra thyroidal extension, multifocality, cervical lymph node metastasis, lymphovascular invasion, and thyroiditis. This study was approved by the Institutional Review Board of Korea University Medical Center, Ansan Hospital.

All 613 patients underwent hemithyroidectomy or total thyroidectomy with routine CLND. Hemithyroidectomy with ipsilateral CLND was performed in 205 patients because they had single lesions that were limited to the thyroid and clinically negative radiologic findings in the central lymph node, and four underwent subsequent completion thyroidectomy. Among the remaining 408 patients, 310 patients with clinically node negative findings underwent total thyroidectomy with ipsilateral CLND, and bilateral CLND was performed in 98 patients with clinically suspicious node metastasis or bilateral lesions. CLND was performed superiorly to the hyoid bone, laterally to the carotid sheath, inferiorly to the manubrium, and dorsally to the prevertebral fascia. The parathyroid glands were carefully preserved in situ, and the devascularized parathyroid glands were autotransplanted into the sternocleidomastoid muscle.

The incidence rates of recurrent laryngeal nerve injury, hypocalcemia, and postoperative hemorrhage were evaluated. Temporary recurrent laryngeal nerve injury was based on the surgeons assessment and the patients symptoms during the immediate postoperative day. Recurrent laryngeal nerve injury was considered permanent when paralysis of the vocal cords persisted > 6 months after the surgery. Transient hypocalcemia was defined as an ionized calcium level < 1.0 mg/dL postoperatively but recovered until 6 months, and permanent hypocalcemia was defined as persistent hypocalcemia requiring calcium carbonate and calcitriol supplementation > 6 months after the surgery. Performing an emergency evacuation of a hematoma after thyroidectomy was considered postoperative hemorrhage.

Categorical variables were compared using the Chi-square test or Fishers exact test to analyze the significance of differences. Logistic regression was used for multivariate analysis. Differences were considered statistically significant with p ≤ 0.05 using a two-tailed test. All statistical analyses were performed using SPSS Statistics version 20.0.0 for Macintosh (IBM, Armonk, NY, USA).

3. Results

3.1. Patient characteristics and pathology

The patient clinicopathological characteristics are summarized in Table 1. The study population included 558 women (91.0%) and 55 men (9.0%) with a mean age of 46.2 ± 10.5 years. The mean size of PTMCs was 0.8 ± 0.4 cm; 126 (20.6%) patients had PTMCs < 0.5 cm and 487 (79.4%) patients had PTMCs ≥ 0.5 cm in size. Of these patients, 264 (43.1%) patients had PTMC confined to the thyroid, and 349 (56.9%) patients had PTMC with extrathyroidal extension. Multifocality was observed in 152 (24.8%) patients, lymphovascular invasion was found in 16 (2.6%) patients, and thyroiditis was found in 293 (47.8%) patients. CLNMs were identified in 239 (39.0%) patients.

Table 1. Clinicopathological characteristics (n = 613).
Characteristic n (%)
Age (y) 46.2 (10.5)
Sex
 Female 558 (91.0)
 Male 55 (9.0)
Tumor size (cm)
 Mean 0.8 (0.4)
 < 0.5 126 (20.6)
 ≥ 0.5 487 (79.4)
Extrathyroidal extension
 No 264 (43.1)
 Yes 349 (56.9)
Multifocality
 No 461 (75.2)
 Yes 152 (24.8)
Central lymph node metastasis
 No 374 (61.0)
 Yes 239 (39.0)
Lymphovascular invasion
 No 597 (97.4)
 Yes 16 (2.6)
Thyroiditis
 No 320 (52.2)
 Yes 293 (47.8)

3.2. Risk factors associated with CLNMs

Male sex [odds ratio (OR), 2.17; 95% confidence interval (CI), 1.24–3.80; p = 0.006], tumor size ≥ 0.5 cm (OR, 2.83; 95% CI, 1.78–4.49; p < 0.001), extrathyroidal extension (OR, 1.93; 95% CI, 1.38–2.70; p < 0.001), and multifocality (OR, 2.11; 95% CI, 1.46–3.06; p < 0.001) were significantly associated with CLNM. Age, lymphovascular invasion, and thyroiditis were not significantly associated with CLNM. After all variables with p < 0.5 in the univariate analysis were input into the logistic regression model, male sex (OR, 2.10; 95% CI, 1.18–3.75; p = 0.012), tumor size ≥ 0.5 cm (OR, 2.29; 95% CI, 1.42–3.69; p = 0.001), extrathyroidal extension (OR, 1.49; 95% CI, 1.04–2.13; p = 0.029), and multifocality (OR, 1.76; 95% CI, 1.19–2.59; p = 0.004) remained as independent risk factors of CLNM ( Table 2).

Table 2. Risk factors associated with cervical lymph node metastasis.
Risk factor Cervical LN metastasis Univariate analysis Multivariate analysis
Negative Positive OR (95% CI) p OR (95% CI) p
Age (y) 0.96 (0.69–1.33) 0.817
 < 45 167 109
 ≥ 45 207 130
Sex 2.17 (1.24–3.80) 0.006 2.10 (1.18–3.75) 0.012
 Female 350 208
 Male 24 31
Tumor size (cm) 2.83 (1.78–4.49) < 0.001 2.29 (1.42–3.69) 0.001
 < 0.5 99 27
 ≥ 0.5 275 212
LV invasion 2.68 (0.96–7.47) 0.051
 No 368 229
 Yes 6 10
Extrathyroidal extension 1.93 (1.38–2.70) < 0.001 1.49 (1.04–2.13) 0.029
 No 184 80
 Yes 190 159
Multifocality 2.11 (1.46–3.06) < 0.001 1.76 (1.19–2.59) 0.004
 No 302 159
 Yes 72 80
Thyroiditis 1.02 (0.74–1.41) 0.899
 No 196 124
 Yes 178 115

CI = confidence interval; LN = lymph node; LV = lymphovascular; OR = odds ratio.

3.3. CLNM incidence and postoperative complications

Overall, 39% of PTMC patients (239 of 613) had pathologically metastatic lymph nodes in the central compartment. Among the 69 PTMC patients without all four risk factors shown in Table 2, 17.4% (12 of 69) had CLNM (Table 3).

Table 3. Incidence of central lymph node metastasis in patients with PTMC.
Central lymph node metastasis, n (%) Total
Negative Positive
Total 374 (61.0) 239 (39.0) 613 (100)
Without RFs 57 (82.6) 12 (17.4) 69 (100)

PTMC = papillary thyroid microcarcinoma; RF = risk factor.

Thirteen (2.1%) patients experienced temporary recurrent laryngeal nerve palsy, and two (0.3%) patients had permanent recurrent laryngeal nerve palsy. Transient hypocalcemia occurred in 74 (12.1%) patients, and hypocalcemia persisting > 6 months after the operation occurred in two (0.3%) patients. Emergency operations for postoperative hemorrhage were performed in two (0.3%) patients (Table 4).

Table 4. Postoperative complications.
Complication Number of patients (%)
Recurrent laryngeal nerve palsy
 Temporary 13 (2.1)
 Permanent 2 (0.3)
Hypocalcemia
 Transient 74 (12.1)
 Permanent 2 (0.3)
Postoperative hemorrhage 2 (0.3)

4. Discussion

Male sex, tumor size ≥ 0.5 cm, extrathyroidal extension, and multifocality were associated with a significantly increased risk of CLNM in our study. In general, smaller lesion size and female sex are considered good prognostic factors of PTC.12; 13 ;  14 Lim et al15 and Zhang et al16 have also demonstrated that larger tumor size (> 0.7 cm, > 0.6 cm) was associated with CLNM. Male sex and tumor size ≥ 0.5 cm were independent risk factors of CLNM in this study, and these results are compatible with those of other reports in PTMC patients.15 ;  16 In the present study, extrathyroidal extension and multifocality also correlated with CLNM. Similar studies in PTMC have shown that extrathyroidal extension is associated with CLNM (p < 0.001) and recurrence (p = 0.037), and multifocality has also been shown to be an independent risk factor of CLNM. 17; 18; 19 ;  20 According to Mazeh et al,21 multifocality may develop by intraglandular spread of the primary tumor, and this may be related to CLNM.

CLNMs are relatively common in PTMC patients. Several studies have demonstrated that CLNMs are observed in about 31–64.1% of patients with PTMC.15; 22 ;  23 In this study, the incidence of CLNMs in patients with PTMC was 39.0%. To analyze the feasibility of prophylactic CLND for PTMC patients with no clinical risk factors, we also evaluated the incidence of CLNM in PTMC patients without any of these four risk factors. Even after the elimination of risk factors, the incidence of CLNM in these patients was 17.4%. Hence, the prediction of CLNM using only these risk factors should be considered unsafe.

Appetecchia et al24 do not believe that CLND is necessary, because the reported mortality rates of PTMC range from 0% to 1%, and CLND provides no survival benefit despite the high incidence of CLNM. In addition, Wada et al23 have reported that CLND may increase the frequency of perioperative complications, such as recurrent laryngeal nerve injury, hypocalcemia, or immediate postoperative bleeding.23

However, Chow et al25 showed that the risk of locoregional recurrence (OR, 4.2; 95% CI, 1.3–13.6) and cervical lymph node recurrence (OR, 6.2; 95% CI, 1.6–24.4) significantly increased in PTMC patients with CLNM, and the presence of cervical lymph node metastasis also increased the incidence rate of distant metastasis (OR, 11.2; 95% CI, 1.3–100.7).25 Simon et al26 have also suggested that lymph node metastases are significantly associated with a higher risk of recurrence. Vini et al27 recommended routine CLND for patients aged ≥ 70 years. They indicated that radioactive iodine ablation may not be effective because the capacity of thyroid tumor cells for radioactive iodine uptake is reduced in elderly people.27 Furthermore, Levin et al28 have demonstrated that the operations for recurred lymph nodes in PTC increased the risk of postoperative complications. In addition, CLND is helpful to assess the accurate staging of lymph node.28

Currently, the diagnostic performance of ultrasonography (US) for determining the presence of CLNM in PTMC patients is not completely reliable. The sensitivity of US in predicting CLNM for PTMC patients has been reported to range from 21.6% to 38.0%.29; 30 ;  31 Kim et al31 also showed that the false negative rate of US at the central neck level was 30% (32/107). As described above, although US findings can indicate clinically negative nodes in the central neck compartment, this does not guarantee pathologically negative nodes.

The risk of postoperative complications is one concern about performing CLND in PTMC patients. According to a study by Henry et al32 that compared the complications after thyroidectomy only with thyroidectomy and CLND, CLND does not increase the incidence of recurrent laryngeal nerve injury. Gemsenjäger et al33 described that 1–2% of patients who underwent total thyroidectomy only experienced permanent hypocalcemia or permanent recurrent laryngeal nerve injury, and the rate of complications was not increased with the addition of CLND. In this study, 0.3% of patients had permanent recurrent laryngeal nerve injury, and another 0.3% of patients experienced permanent hypocalcemia. These results are compatible with those of another study.34 The postoperative complications appear to be related to surgical experiences, and experts can perform CLND safely.

In conclusion, the incidence of CLNM in PTMC patients (even with no risk factors) was not infrequent, whereas the rate of postoperative complications after CLND was acceptably low. Thus, CLND should be considered for even PTMC patients.

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