A Systematic Review and Meta-Analysis of Prophylactic Central Neck Dissection on Short-Term Locoregional Recurrence in Papillary Thyroid Carcinoma After Total Thyroidectomy

Abstract

Background:

Prophylactic central neck dissection (pCND) at the time of total thyroidectomy (TT) remains controversial in clinically node-negative (cN0) papillary thyroid carcinoma (PTC). Despite occult central lymph node metastases being common, it is unclear if removing these metastases initially would reduce future locoregional recurrence (LRR). This systematic review and meta-analysis aimed at comparing the short-term LRR between patients who underwent TT with pCND and those who underwent TT alone.

Methods:

A systematic review of the literature was performed to identify studies comparing LRR between patients with PTC who underwent TT+pCND (group A) and those who underwent TT alone (group B). Inclusion criteria were cN0 patients, with each comparative group containing >10 patients, and with the number of LRR and mean follow-up duration available. The pooled incidence rate ratio (IRR) was used for calculating the LRR rate between the two groups. Other parameters evaluated included postoperative radioiodine (RAI) ablation, surgically related complications, and overall morbidity. Meta-analysis was performed using a fixed-effects model.

Results:

Fourteen studies matched the selection criteria. Of the 3331 patients, 1592 (47.8%) belonged to group A, while 1739 (52.2%) belonged to group B. Relative to group B, group A was significantly more likely to have postoperative RAI ablation (71.7% vs. 53.1%; odds ratio [OR]=2.60 [95% confidence interval (CI)=2.12–3.18]), temporary hypocalcemia (26.0% vs. 10.8%; OR=2.56 [CI=2.04–3.21]), and overall morbidity (33.2% vs. 17.7%; OR=2.12 [CI=1.75–2.57]). When temporary hypocalcemia was excluded, overall morbidity was similar between the two groups (7.3% vs. 6.8%; OR=1.07 [CI=0.78–1.47]). Group A had a significantly lower risk of LRR than group B (4.7% vs. 8.6%; IRR=0.65 [CI=0.48–0.86]).

Conclusions:

Group A was more likely to have postoperative RAI ablation, temporary hypocalcemia, and overall morbidity than group B. Temporary hypocalcemia was the major surgical morbidity in pCND and, when excluded, the overall morbidity appeared similar between the two groups. Although our meta-analysis would suggest that those who undergo TT+pCND may have a 35% reduction in risk of LRR than those who undergo TT alone in the short term (<5 years), it remains unclear how much of this risk reduction is related to increased use of RAI ablation and potential selection bias in some of the studies examined.

Introduction

P apillary thyroid carcinoma (PTC) is the most common type of differentiated thyroid carcinoma, with its age-adjusted incidence doubling in the last 25 years (1). Despite its good prognosis, locoregional recurrence (LRR) is common (2). With recognition of the stepwise progression of lymph node metastasis (LNM) from the central (level VI) to lateral compartment (levels II–V), some surgeons have advocated routine prophylactic central neck dissection (pCND) at the time of total thyroidectomy for PTC (3). Although there is general agreement that formal lymph node dissection should be performed in the setting of imageable, biopsy-proven, or palpable nodal disease (cN1), it remains controversial in patients with no clinical evidence of nodal metastasis (cN0) (4). There is little evidence to suggest that patients with cN0 undergoing a total thyroidectomy (TT) and pCND (TT+pCND) would reduce the risk of future LRR when compared to patients undergoing TT alone. Although the incidence of occult or microscopic LNM in patients with cN0 is relatively common, it is unclear whether removing these occult or microscopic LNM at the time of the primary operation could prevent LRR (5,6). Analysis of short-term surrogates for recurrence (such as postsurgical thyroglobulin level) would suggest that pCND may improve short-term outcomes, but this has not been fully resolved (4,7,8). Furthermore, patients undergoing pCND are at increased risk of temporary hypocalcemia (9 –11).

One of the main reasons for the lack of evidence is that studies so far comparing TT+pCND with TT alone have not had the statistical power to detect a difference in LRR. A recent study estimated more than 5000 patients would be required to have sufficient statistical power to demonstrate a 25% reduction in LRR with pCND in patients with cN0 (12). To our knowledge, three meta-analyses have compared the outcomes between TT+pCND and TT alone. Two were not strictly relevant because one included patients with benign disease, while the other included patients who underwent therapeutic CND (9,10). Zetoune et al. pooled together five relevant studies and found a similar overall LRR rate between TT+pCND and TT alone (2.02% vs. 3.92%; odds ratio [OR]=1.05 [95% confidence interval (CI)=0.44–3.91]) (11). However, this study did not account for the difference in follow-up duration between the two groups. With an increasing number of new publications on this controversial subject in recent years, we conducted a systematic review and meta-analysis to compare the risk of LRR between TT+pCND and TT alone by reviewing the current literature.

Methods

This systematic review and meta-analysis was conducted in accordance with the PRISMA statement (13).

Search strategy

Studies comparing the rate of LRR between patients who underwent TT+pCND and TT alone were retrieved from the Scopus, Medline (PubMed), and Cochrane Library electronic databases on January 30, 2013. We used the following free-text search terms in “All fields”: (i) “central neck dissection” or “level VI neck dissection” or “neck dissection”; (ii) “papillary thyroid carcinoma”; (iii) i and ii.

There was no language restriction and no methodological filters. The bibliographies of three previous meta-analyses were searched for other additional relevant references (9 –11).

Study selection

All titles identified by the search strategy were independently screened by three authors (B.H.L., S.H.N., and K.P.W.). Search results were compared, and disagreements were resolved by consensus. Abstracts of potentially relevant titles were then reviewed for eligibility, and full-length articles were selected for closer examination if there was a specific description on CND in patients with PTC. The criteria for eligibility were as follows. First, any prospective or retrospective studies on patients with PTC only were included. Studies that analyzed differentiated thyroid carcinoma were considered if results of PTC were separately reported. Second, studies with two arms comparing LRR between TT+pCND and TT alone were included. Third, each study arm had to have >10 patients. Fourth, patients in either arm had to be cN0 by preoperative imaging and intraoperative examination; patients with cN1 or distant metastasis (M1) were not included. Finally, the number of LRR and the mean follow-up (in months) in each study arm had to be available. The reason for obtaining the mean follow-up period was because, in order to work out the pooled incidence rate ratio (IRR) for TT+pCND and TT alone groups, we had to first calculate the number of person-years in each respective arm. Studies that specifically reported the number of LRR and follow-up period in TT+pCND and TT alone as subgroups were included. Patients who underwent hemithyroidectomy with pCND or underwent simultaneous pCND and prophylactic lateral neck dissection were excluded. For studies that only provided the number of LRR without the mean follow-up duration or provided only the median and not the mean follow-up duration, the corresponding author of those studies was individually contacted for further information. Multiple reports of the same data set were assessed, and the most updated report of a study was included.

Data extraction

All data were extracted onto a standardized form. The primary data extracted from each article included type or design of study, first authorship, country of origin, year of publication, patient demographics, preoperative nodal assessment, method of selection for pCND, tumor characteristics, number of patients who underwent TT+pCND or TT alone, extent of pCND (unilateral vs. bilateral), number of normal and metastatic central LNs harvested, mean follow-up period, radioiodine (RAI) ablation given or not, number of LRR, operating time, volume of blood loss, and any surgically related morbidities. LRR was defined as a recurrence occurring in the thyroid bed, central and/or lateral compartments. A patient found to have distant recurrence only (i.e., without concomitant LRR) was not counted as a LRR, while a patient with concomitant LRR and distant recurrence was counted as a LRR. The percentage of recurrent laryngeal nerve (RLN) injury was calculated based on the number of patients. The overall morbidity rate was calculated by dividing the total number of patients who suffered one or more perioperative morbidity over the total number of patients. If a patient suffered from two or more morbidities, it was counted as one.

Statistical analysis

All the individual outcomes were integrated with the meta-analysis software Review Manager Software 5.0 (Cochrane Collaborative, Oxford, United Kingdom). LRR was assessed by IRR according to person-year of follow-up, and ORs were examined for the other surgical outcomes. All results were aggregated and analyzed using a fixed-effects model. A subgroup analysis of overall morbidity was performed excluding temporary postoperative hypocalcemia. Publication bias was estimated by Begg's rank correlation test and Egger's regression test (14,15). The meta-analyses in this study were conducted using R version 2.15.1 (R Foundation for Statistical Computing, Vienna, Austria) and the metafor package (16).

Results

Figure 1 shows the flowchart of studies retrieved and excluded. Of the 1822 titles initially identified from the database search, 41 full-length articles were assessed for inclusion, of which 27 were excluded and 14 studies were determined to be eligible and were included in this systematic review (7,17 –29). Appendix Table A1 lists these 27 articles (6,8,30 –54) and the reason for their exclusion. No additional study was found from our search of the three bibliographies in previous meta-analyses (9 –11). One study (8) was excluded, as it analyzed a subset of study subjects that were later recruited in a multicenter cohort study (25).

FIG. 1.

Flow diagram for study selection.

Baseline characteristics

Table 1 shows a comparison of the baseline characteristics between the 14 eligible studies. There was no randomized trial. Thirteen studies were retrospective, while one was prospective. Of the 3331 patients included, 1592 (47.8%) underwent TT+pCND (group A), while 1739 (52.2%) underwent TT only (group B). In terms of preoperative nodal assessment, ultrasonography (US) was used as the standard imaging modality in all studies, but only two studies specifically mentioned that both bilateral central and lateral neck compartments were examined (25,27).

Table 1.

Summary and Comparison of Baseline Characteristics Between Total Thyroidectomy+Prophylactic Central Neck Dissection (Group A) and Total Thyroidectomy Alone (Group B)

	No. of patients								No. of central LNs excised		Incidence of central LNM (%)
First author (country)	A	B	Mean age at operation (years)	Sex ratio (male:female)	Mean tumor size (mm)	ETE (%)	Multifocality (%)	No significant difference^a between A and B	A	B	A	B
Roh (Korea) (17)	40	73	A=na B=48.5	A=na B=9:64	A=na B=22	A=na B=30.1	A=na B=15.1	1,2,3,4,5	5.6	na	62.2	na
Choi (Korea) (18)	48	53	A=52 B=48	A=6:42 B=11:42	A=6.8 B=7.3	A=45.8 B=58.5	A=31.3 B=22.6	1,2,3,4,5	na	na	37.5	na
Bardet (France) (19)	36	161	na	na	na	na	na	na	na	na	23.5	na
Perrino (Italy) (20)	92	159	na	na	na	na	na	na	na	na	33–52	na
Costa (Italy) (21)	126	118	A=46 B=52	A=26:100 B=24:94	A=17 B=15	na	A=45.2 B=40.7	2,4,5	na	na	46.8	5.1
Zuniga (Columbia) (22)	136	130	A=42.9 B=41.5	A=10:126 B=13:117	na	A=44.8 B=27.3	A=38.2 B=13.1	1,2,3	na	na	82.4	na
Moo (United States) (23)	45	36	A=45.7 B=49.2	A=10:35 B=4:32	A=14 B=20	A=24.4 B=36.1	A=55.6 B=63.9	1,2,4,5	8.8	1.7	33.3	na
Hughes (United States) (24)	78	65	A=46.8 B=41.2	A=17:61 B=16:49	A=19 B=20	A=41.0 B=16.9	A=33.3 B=33.8	1,2,3,5	6.0	0.0	61.5	9.2
Popadich (Australia, United States, and United Kingdom) (25)	259	347	A=44 B=48	A=52:207 B=81:266	A=23 B=22	A=27.8 B=24.2	A=48.3 B=42.7	2,3,4,5	6.8	0.35	49.0	0.9
So (Korea) (26)	119	113	A=49.2 B=49.8	A=21:98 B=16:97	A=6.6 B=6.2	A=51.3 B=51.3	A=37.8 B=23.9	1,2,3,4	na	na	37.0	na
Lang (China) (7)	82	103	A=52.0 B=50.0	A=18:64 B=22:81	A=15 B=10	A=26.8 B=14.6	A=36.6 B=27.2	1,2,5	5	0	54.9	4.9
Wang (United States) (27)	49	37	na	na	s	na	na	na	9	na	40.8	na
Raffaelli (Italy) (28)	124	62	A=42.7 B=43.2	A=24:100 B=13:49	A=12.9 B=12.1	na	A=51.6 B=46.8	1,2,3,5	9.6	1.5	35.5	9.7
Barczynski (Poland) (29)	358	282	na	A=75:283 B=60:222	na	A=13.1 B=12.8	A=37.7 B=35.1	1,2,4,5	6.7	na	na	na

Matching: 1=age; 2=sex ratio; 3=tumor size; 4=extrathyroidal extension; 5=tumor multifocality.

s, significantly different (p<0.05) between groups A and B; ns, not significantly different between groups A and B; na, not available or specified; LN, lymph node; LNM, lymph node metastasis; ETE, extrathyroidal extension.

In terms of selection for pCND, seven studies were based on individual surgeon's preference (7,18,22,24,25,27,28), while four studies did not specify their method of selection (17,19,23,26). Three studies used historical controls (TT alone) for comparison (20,21,29). Only 11 of 14 studies statistically compared age, sex ratio, tumor size, extrathyroidal extension, and tumor multifocality between the two groups (7,17,18,21 –26,28,29). Of these, two studies found age to be significantly older in group B (21,25), and three studies found tumor size to be significantly different (7,21,23). Two studies found tumor size to be significantly larger in group A (7,21), while one study found tumor size to be significantly smaller in group A (23). Three of nine studies found the rate of extrathyroidal extension to be significantly higher in group A (7,22,24), and two of nine studies found the rate of tumor multifocality to be significantly higher in group A (22,26). Bilateral pCND was performed in eight studies (17,18,22 –24,26,28,29), while the other six studies performed either unilateral or a combination of unilateral and bilateral pCND (7,19,20,21,25,27). Among the eight studies reporting bilateral pCND (17,18,22 –24,26,28,29), the mean number of central lymph nodes harvested ranged between 5.6 and 9.6, while the one study reporting unilateral pCND harvested a median of five (7). The incidence of central LNM in group A ranged from 23.5% to 82.4%, while in group B it ranged from 0.9% to 9.7% with 9 of 14 studies not reporting the incidence of central LNM in group B.

Surgical outcomes

Table 2 shows a comparison of outcomes between the two groups. Only 9 of the 14 studies reported whether RAI ablation was given after surgery (7,18,21 –24,26,27,29). Their dose ranged from 2.78 to 5.55 GBq. One study empirically gave the same dose of RAI, irrespective of the extent of LNM (7). The mean frequency of postoperative RAI ablation in groups A and B were 746/1041 (71.7%) and 498/937 (53.1%). Group A was significantly more likely to receive RAI ablation than group B (OR=2.60 [CI=2.12–3.18]). This was expected because of the higher incidence of central LNM (or N1a) in group A leading to tumor group upstaging in patients older than 45 years (28). Only 1 of 14 studies compared operating time between the two groups and found group B to have a significantly shorter operating time than group A (28).

Table 2.

Comparison of Surgical Outcomes Between Total Thyroidectomy+Prophylactic Central Neck Dissection (Group A) and Total Thyroidectomy Alone (Group B)

		No. of postoperative hypocalcemia (%)		No. of recurrent laryngeal nerve injury (%)
First author	No. of postoperative RAI ablation (%)	Temporary	Permanent	Temporary	Permanent	No. of hematoma formation (%)	No. of wound infection/seroma (%)	Total morbidity^a (%)
Roh (17)	na	A=13 (32.5) B=7 (9.6)	na	A=0 (0.0) B=3 (4.1)	A=0 (0.0) B=2 (2.7)	A=1 (2.5) B=1 (1.4)	A=0 (0.0) B=0 (0.0)	A=14 (35.0) B=13 (17.8)
Choi (18)	A=48 (100) B=53 (100)	A=8 (16.7) B=6 (11.3)	A=0 (0.0) B=1 (1.9)	A=1 (2.1) B=0 (0.0)	na	A=0 (0.0) B=0 (0.0)	A=0 (0.0) B=0 (0.0)	A=9 (18.8) B=7 (13.2)
Bardet (19)	na	na	na	na	na	na	na	—
Perrino (20)	na	A=8 (8.7) B=11 (6.9)	A=3 (3.2) B=2 (1.3)	A=3 (3.3) B=5 (3.1)	A=1 (1.1) B=4 (2.5)	A=0 (0.0) B=0 (0.0)	A=0 (0.0) B=1 (0.6)	A=15 (16.3) B=23 (14.5)
Costa (21)	A=87 (69.0) B=62 (52.5)	na	na	na	na	na	na	—
Zuniga (22)	A=79 (58.1) B=55 (42.3)	na	na	na	na	na	na	—
Moo (23)	A=31 (68.9) B=26 (72.2)	A=14 (31.1) B=2 (5.6)	A=0 (0.0) B=2 (5.6)	A=2 (4.4) B=0 (0.0)	A=0 (0.0) B=0 (0.0)	na	na	A=16 (35.6) B=4 (11.1)
Hughes (24)	A=72 (92.3) B=56 (86.2)	A=21 (26.9) B=5 (7.7)	A=2 (2.6) B=0 (0.0)	A=0 (0.0) B=2 (3.1)	A=0 (0.0) B=na	A=1 (1.3) B=2 (3.1)	A=0 (0.0) B=1 (1.5)	A=24 (30.8) B=10 (15.4)
Popadich (25)	na	A=25 (9.7) B=14 (4.0)	A=2 (0.8) B=2 (0.6)	A=1 (0.4) B=8 (2.3)	A=1 (0.4) B=6 (1.7)	A=5 (1.9) B=3 (0.9)	A=3 (1.2) B=5 (1.4)	A=37 (14.3) B=38 (11.0)
So (26)	A=101 (84.9) B=92 (81.4)	A=49 (41.2) B=38 (33.6)	A=7 (5.9) B=2 (1.8)	A=4 (3.4) B=4 (3.5)	A=1 (0.8) B=2 (1.8)	A=1 (0.8) B=0 (0.0)	A=0 (0.0) B=0 (0.0)	A=64 (53.8)^b B=46 (40.7)
Lang (7)	A=62 (75.6) B=63 (61.2)	A=15 (18.3) B=9 (8.7)	A=2 (2.4) B=1 (1.2)	A=3 (3.7) B=0 (0.0)	A=1 (1.2) B=1 (1.0)	A=0 (0.0) B=1 (1.0)	A=0 (0.0) B=0 (0.0)	A=21 (25.6) B=12 (11.7)
Wang (27)	A=35 (71.4) B=12 (32.4)	A=21 (42.9) B=4 (10.8)	A=0 (0.0) B=3 (8.3)	A=1 (2.0) B=1 (2.7)	na	na	na	A=22 (44.9) B=8 (21.6)
Raffaelli (28)	na	A=53 (42.7) B=11 (17.7)	A=1 (0.8) B=0 (0.0)	A=1 (0.8) B=0 (0.0)	A=1 (0.8) B=0 (0.0)	A=0 (0.0) B=0 (0.0)	A=0 (0.0) B=0 (0.0)	A=56 (45.2) B=11 (17.7)
Barczynski (29)	A=231 (64.5) B=79 (28.0)	A=109 (30.4) B=37 (13.1)	A=8 (2.2) B=2 (0.7)	A=26 (7.3) B=18 (6.4)	A=9 (2.5) B=6 (2.1)	na	na	A=152 (42.5) B=63 (22.3)

The sum of all complications; same patient with more than two complications was counted as one.

Including two chyle leaks.

Figure 2 shows the forest plot for temporary hypocalcemia. Of the 14 studies, 11 studies compared temporary postoperative hypocalcemia between the two groups, while 10 studies compared permanent postoperative hypocalcemia in the two groups. In eight studies, permanent hypocalcemia was defined as persistent hypocalcemia and/or need for calcium supplements for more than six months (7,20,23 –28), while two studies defined it as more than 12 months (18,29). If one assumed all studies utilized a similar definition for temporary and permanent hypocalcemia, the overall temporary hypocalcaemia rate in group A was significantly higher than that in B (336/1294 (26.0%) and 144/1330 (10.8%), respectively; OR=2.56 [CI=2.04–3.21]) while the overall permanent hypocalcaemia was also similar between the group A and B (25/1254 (2.0%) and 15/1257 (1.2%), respectively; OR=1.74 [CI=0.87–3.50]).

FIG. 2.

Forest plot for temporary hypocalcemia (tph). OR, odds ratio; CI, confidence interval.

Similar to hypocalcemia, the definition for temporary and permanent RLN injury varied between studies. Routine perioperative DL was performed in five studies (7,25,26,28,29), and persistent impairment in vocal cord function for more than six months was defined as permanent RLN injury in seven studies (19,23 –27). The cumulative temporary RLN palsy was comparable between group A and B (42/1294 (3.2%) and 41/1330 (3.1%), respectively; OR=1.02 [CI=0.64–1.64]). The cumulative permanent RLN palsy was also comparable between groups A and B (14/1197 (1.2%) and 21/1240 (1.7%), respectively; OR=0.75 [CI=0.37–1.55]).

The rate of hematoma was reported in eight studies. The cumulative hematoma rate was comparable between groups A and B (8/842 (1.0%) and 7/975 (0.9%), respectively; OR=1.33 [CI=0.53–3.35]). The wound infection/seroma rate was also similar between groups A and B (3/842 (0.4%) and 7/975 (0.9%), respectively; OR=0.78 [CI=0.28–2.07]). Figure 3 shows the forest plot for overall morbidity. The overall morbidity rate ranged between 14.3% and 53.8% in group A, while in group B it ranged between 11.0% and 40.7%. The overall morbidity after thyroid surgery in group A was significantly higher than in group B (430/1294 (33.2%) vs. 235/1330 (17.7%); OR=2.12 [CI=1.75–2.57]). However, after excluding temporary hypocalcemia, the overall morbidity in group A was not significantly different from group B (94/1294 (7.3%) vs. 90/1330 (6.8%); OR=1.07 [CI=0.78–1.47]). Figure 4 shows the forest plot for overall morbidity after excluding temporary hypocalcemia. The potential publication bias did not appear significant, as confirmed by the Begg analysis (Kendall's tau=−0.1636, p=0.5423) and the Egger regression test (z=−0.8921, p=0.4167).

FIG. 3.

Forest plot for overall morbidity (morb).

FIG. 4.

Forest plot for overall morbidity after excluding temporary hypocalcemia.

LRR

Table 3 compares the LRR rate between the two groups. One study was excluded in the IRR calculation because the mean duration of follow-up was not available (19). Figure 5 shows the forest plot for LRR. The pooled mean follow-up in groups A and B were 45.2 and 50.8 months, respectively, while the pooled mean number of person-years in groups A and B were 598.9 and 662.3, respectively. Group A had significantly lower LRR than group B (75/1592 (4.7%) vs. 149/1739 (8.6%); IRR=0.65 [CI=0.48–0.86]). The potential publication bias was not significant, as confirmed by Begg analysis (Kendall's tau=−0.1677, p=0.4268) and the Egger regression test (z=0.0984, p=0.9216).

FIG. 5.

Forest plot for locoregional recurrence (LRR).

Table 3.

Comparison of Locoregional Recurrence Rate Between Total Thyroidectomy+Prophylactic Central Neck Dissection (Group A) and Total Thyroidectomy Alone (Group B)

	Number of LRR (%)		Mean follow-up (months)		Number of person-years
First author	A	B	A	B	A	B	Incidence rate ratio [CI]
Roh (17)	0 (0.0)	3 (4.1)	51	53	170	322	0.27 [0.01–5.25]
Choi (18)	1 (2.1)	2 (3.8)	24.4	24.4	98	108	0.55 [0.05–6.09]
Bardet (19)	4 (11.1)	6 (3.7)	na^a	na^a	—	—	—
Perrino (20)	5 (5.4)	22 (13.8)	69.2	69.2	531	917	0.39 [0.15–1.04]
Costa (21)	8 (6.3)	9 (7.6)	47	62	494	629	1.13 [0.44–2.94]
Zuniga (22)	19 (14.0)	26 (20.0)	73.44	95.52	832	1035	0.91 [0.50–1.64]
Moo (23)	2 (4.4)	6 (16.7)	37.2	37.2	140	112	0.27 [0.05–1.32]
Hughes (24)	2 (2.6)	2 (3.1)	19.1	27.5	124	149	1.20 [0.17–8.52]
Popadich (25)	13 (5.0)	29 (8.4)	32	50	691	1446	0.94 [0.49–1.81]
So (26)	2 (1.7)	4 (3.5)	44.7	45.4	443	428	0.48 [0.09–2.63]
Lang (7)	3 (3.7)	3 (2.9)	28.2	31.9	193	274	1.42 [0.29–7.04]
Wang (27)	0 (0.0)	0 (0.0)	10	10	41	31	0.76 [0.01–38.06]
Raffaelli (28)	1 (0.8)	0 (0.0)	25.0	25.5	258	132	1.53 [0.06–37.56]
Barczynski (29)	15 (5.8)	37 (13.1)	126.4	128.8	3771	3027	0.33 [0.18–0.59]
Overall	75	149	45.2	50.8	598.9	662.3	0.65 [0.18–0.86]

Only medians were provided and therefore incidence rate ratio could not be calculated.

LRR, locoregional recurrence.

Discussion

To our knowledge, this is to date one of the largest meta-analyses evaluating the impact of pCND on LRR in patients with clinically nodal negative PTC or cN0. With significantly more patients being included than in previous meta-analyses, our data suggest that those who undergo TT+pCND have a 35% reduction in risk of LRR than those who undergo TT alone. Although no significant publication bias was found in our meta-analysis, as shown by the Begg's rank correlation test and Egger's regression test, it is worth nothing that there was one particular large recent study that could have had a profound impact on the overall IRR (29). In fact, its number of person-years in groups A and B were almost two to three times of that of the next largest study (25). Nevertheless, on the funnel plot (data not shown), this particular study was just on the margin of the funnel, and therefore it was not excluded from the final meta-analysis.

Despite this important positive finding, we remain cautious in our conclusions, as there are a number of potential limitations. First, the mean follow-up period was relatively short in one study, having a mean follow-up period of only 10 months. In fact, the overall mean follow-up duration for groups A and B was only 45.2 and 50.8 months, respectively, and hence both groups had a mean follow-up of less than five years. Given the fact that PTC is a relatively slow-growing, indolent tumor, patients may not develop detectable LRR until many years after the initial operation. Therefore, a significant longer follow-up duration would be necessary to assess fully whether pCND could significantly reduce LRR at least in the medium to long term (12). Apart from this, 13 of 14 studies were retrospective analyses, and so they were subject to selection bias. Surgeon's preference or discretion was mentioned in 7 of 14 studies as their method of selecting pCND, while four studies did not clearly describe their method of selection. Three studies actually used historical controls for outcome comparison (20,21,29). These selection biases were evident by the fact that only one of the five baseline characteristics (i.e., sex ratio) was consistently comparable in all studies. The other baseline characteristics such as age, tumor size, presence of extrathyroidal extension, and tumor multifocality were not consistently comparable, and since some of these could also potentially influence the risk of LRR, it was difficult to assess the real impact of pCND on LRR. Accounting for these factors in the multivariate analysis may help, but not all these characteristics were readily available for analysis. Perhaps the best way to resolve this would be to conduct a prospective randomized trial in the future. Although all studies did mention using US as a method for preoperative nodal assessment, it was difficult to assess the quality and the comprehensiveness of the assessment. This issue was particularly relevant in the three studies where historical controls were analyzed because quality of imaging tended to change with time. Furthermore, it was unclear from these studies what US criteria were used for deciding on fine needle aspiration or surgery.

In terms of other outcomes, similar to previous studies (7,24,27), we found the rate of postoperative RAI ablation was significantly higher in group A than B (71.7% vs. 53.1%, respectively; OR=2.60 [CI=2.12–3.18]). This can likely be attributed to the higher incidence of central LNM in group A relative to B. However, it is interesting to note that the incidence of central LNM varied widely from 23.5% to 82.4% between studies. Perhaps this is also a reflection of the quality of preoperative US assessment, and might also be a result of differences in the extent of the pCND and quality of the histological examination between studies (5,55,56). Moreover, similar to previous meta-analyses (9 –11), we found temporary hypocalcemia to be significantly higher in group A than B (26.0% vs. 10.8%, respectively; OR=2.56 [CI=2.04–3.21]). This would suggest that patients undergoing pCND during TT are 2.6 times more likely to develop temporary hypocalcemia than those undergoing TT alone. This is undoubtedly related to increased extent of surgical dissection leading to devascularization of parathyroid glands and/or inadvertent removal of parathyroid glands (7,17 –27). However, it is worth noting that the rate of permanent hypocalcemia, temporary and permanent RLN injury, hematoma, and wound infection/seroma were not similar between the two groups. In addition, even though the overall morbidity was significantly higher in group A than B (OR=2.12 [CI=1.75–2.57]), when this analysis was repeated with temporary hypocalcemia excluded, the overall morbidity was similar between group A and B (OR=1.07 [CI=0.78–1.47]). This finding implied that the majority of morbidity arising from pCND was actually related to temporary hypocalcemia rather than other surgically related complications.

Conclusion

The addition of pCND to TT resulted in a greater likelihood of administering postoperative RAI ablation, temporary hypocalcemia, and overall morbidity. However, since temporary hypocalcemia accounted for the majority of overall morbidity in patients undergoing pCND, when temporary hypocalcemia was excluded from overall morbidity, it was similar between the two groups. Although our meta-analysis would suggest that those who undergo TT+pCND may have a 35% reduction in risk of LRR than those who undergo TT alone in the short term (<5 years), it remains unclear how much of this risk reduction is related to increased use of RAI ablation and potential selection bias in some of the studies examined.

Footnotes

Author Disclosure Statement

All authors had nothing to disclose. No competing financial interests exist.

Appendix Table A1.

Articles That Were Excluded After Reviewing the Full-Length Text

First author	Journal	Year, country	Title	Main reason(s) for excluding from analysis
Henry (32)	Langenbeck's Archives of Surgery	1998, France	Morbidity of prophylactic lymph node dissection in the central neck area in patients with papillary thyroid carcinoma	The TT alone group had patients with benign thyroid disease
Steinmuller (33)	Langenbeck's Archives of Surgery	1999, Germany	Complications associated with different surgical approaches to differentiated thyroid carcinoma	Unable to separate some patients with follicular thyroid carcinoma and some who had therapeutic LND
Wada (34)	Annals of Surgery	2003, Japan	Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection	Unable to separate some patients who underwent therapeutic CND
Gemsenjäger (35)	Journal of the American College of Surgeons	2003, Switzerland	Lymph node surgery in papillary thyroid carcinoma	Unable to separate patients with therapeutic LND and lobectomy
Sywak (8)	Surgery	2006, Australia	Routine ipsilateral level VI lymphadenectomy reduces postoperative thyroglobulin levels in papillary thyroid cancer	Data from this study were included in a later study (25)
Palestini (36)	Langenbeck's Archives of Surgery	2008, Italy	Is central neck dissection a safe procedure in the treatment of papillary thyroid cancer? Our experience	Unable to exclude some patients with cN1; also no follow-up and recurrence data were available
Davidson (37)	Laryngoscope	2008, United States	Papillary thyroid cancer: controversies in the management of neck metastasis	Unable to separate patients who had nodal plucking, therapeutic CND, LND, or combination
Hu (38)	Chinese Journal of Cancer	2008, China	Application of central lymph node dissection to surgical operation for clinical stage N0 papillary thyroid carcinoma	No follow-up or recurrence data were reported
Sadowski (39)	Surgery	2009, United States	Routine bilateral central lymph node clearance for papillary thyroid cancer	All patients who underwent CND had cN1
Besic (40)	Annals of Surgical Oncology	2009, Slovenia	Extent of thyroidectomy and lymphadenectomy in 254 patients with papillary thyroid microcarcinoma: a single institution experience	Too few (i.e., <10) patients in the prophylactic arm
Rosenbaum (41)	Archives of Otorhinolaryngology Head Neck Surgery	2009, United States	Central neck dissection for papillary thyroid cancer	Unable to exclude patients with cN1
Giles (42)	Surgery	2009, Turkey	The long term outcome of papillary thyroid carcinoma patients without primary central lymph node dissection: expected improvement of routine dissection	Only included patients who underwent TT without CND
Bonnet (43)	Journal of Clinical and Endocrinology Metabolism	2009, France	Prophylactic lymph node dissection for papillary thyroid cancer less than 2cm: implications for radioiodine treatment	Prophylactic LND were included; also no TT alone group was available for comparison
Lim (44)	British Journal of Surgery	2009, Korea	Central lymph node metastases in unilateral papillary thyroid microcarcinoma	No TT alone group was available for comparison
Shen (45)	Surgery	2010, United States	Central neck lymph node dissection for papillary thyroid cancer: the reliability of surgeon judgment in predicting which patients will benefit	All patients had therapeutic CND
Chung (46)	Journal of the Korean Surgical Society	2010, Korea	Is central lymph node dissection mandatory in 2 cm or less sized papillary thyroid cancer?	All patients had lobectomy
Shindo (47)	Archives of Otorhinolaryngology Head Neck Surgery	2010, United States	Total thyroidectomy with and without selective central compartment dissection	The TT alone group had benign thyroid disease
Bozec (48)	European Archives of Otorhinolaryngology	2011, France	Clinical impact of cervical lymph node involvement and central neck dissection in patients with papillary thyroid carcinoma: a retrospective analysis of 368 cases	TT alone group was not available; also some patients had therapeutic CND or LND
Forest (49)	Annals of Surgery	2011, Australia	Central compartment dissection in thyroid papillary carcinoma	No TT alone group was available for comparison
Mitra (50)	Journal of Laryngology and Otology	2011, United Kingdom	Effect of central compartment neck dissection on hypocalcaemia incidence after total thyroidectomy for carcinoma	No follow-up or recurrence data reported
Teixeira (6)	Surgery	2011, Brazil	The incidence of central neck micrometastatic disease in patients with papillary thyroid cancer staged preoperatively and intraoperatively as N0	No TT alone group for comparison
Kutler (51)	Head and Neck	2012, United States	Routine central compartment lymph node dissection for patients with papillary thyroid carcinoma	Unable to exclude patients who had hemithyroidectomy and CND; also some therapeutic LND were included
Hyun (52)	Annals of Surgical Oncology	2012, Korea	Impact of combined prophylactic unilateral central neck dissection and hemithyroidectomy in patients with papillary thyroid microcarcinoma	All patients underwent hemithyroidectomy
Zhang (53)	Journal of Clinical Endocrinology and Metabolism	2012, China	Risk factors for neck nodal metastasis in papillary thyroid microcarcinoma: a study of 1066 patients	All patients underwent hemithyroidectomy
Hartl (54)	Annals of Surgery	2012, France	Optimization of staging of the neck with prophylactic central and lateral neck dissection for papillary thyroid carcinoma	All patients routinely underwent prophylactic CND and ipsilateral LND
Yoo (55)	World Journal of Surgery	2012, United States	Level VI lymph node dissection does not decrease radioiodine uptake in patients undergoing radioiodine ablation for differentiated thyroid cancer	Unable to separate some patients who underwent therapeutic CND
Giordano (56)	Thyroid	2012, Italy	Complications of central neck dissection in patents with papillary thyroid carcinoma: results of a study on 1087 patients and review of the literature	No follow-up or recurrence data reported

TT, total thyroidectomy; cN1, clinically involved lymph node metastases; LND, lateral neck dissection; CND, central neck dissection.

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