Surgery xxx (2021) 1e8

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A prospective randomized controlled trial to assess the efficacy and

safety of prophylactic central compartment lymph node dissection in
papillary thyroid carcinoma
Jong-hyuk Ahn, MDa, Jung Hak Kwak, MDa, Sang Gab Yoon, MDb, Jin Wook Yi, MDc,
Hyeong Won Yu, MD, PhDd, Hyungju Kwon, MD, PhDe, Su-jin Kim, MD, PhDa,f,
Kyu Eun Lee, MD, PhDa,f,*
a
Department of Surgery, Seoul National University Hospital, Seoul, Korea
b
Department of Surgery, Young Do Hospital, Busan, Korea
c
Department of Surgery, Inha University Hospital, Inha University College of Medicine, Incheon, Korea
d
Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
e
Department of Surgery, Ewha Womans University Medical Center, Seoul, Korea
f
Department of Surgery, Seoul National University College of Medicine, Seoul, Korea

a r t i c l e i n f o a b s t r a c t

Article history: Background: The efficacy of prophylactic central compartment lymph node dissection for papillary
Accepted 29 March 2021 thyroid carcinoma remains controversial. We performed a randomized controlled trial to evaluate the
Available online xxx efficacy and safety of prophylactic central compartment lymph node dissection in patients with papillary
thyroid carcinoma.
Methods: In this parallel-group randomized controlled trial, we assessed 101 patients aged 20 to 70 years
with small/noninvasive papillary thyroid carcinoma and no clinical metastases or history of cervical
surgery/radiation exposure. Randomization ran from April 2015 to November 2017. Data were collected
between April 2015 and October 2020. Of the 101 enrolled patients, 50 underwent total thyroidectomy
(TTx group) and 51 underwent total thyroidectomy as well as prophylactic central compartment lymph
node dissection (TTxþpCND group). Surgical completeness, local recurrence, successful ablation, post-
operative complication, and papillary thyroid carcinoma upstaging were compared between the 2
groups.
Results: No patient showed structural recurrence after 46.6 ± 9.1 months of follow-up. Both groups had
similar rates of surgical completeness and successful ablation. There was no difference in the incidence of
complications. More patients were upstaged to pN1a in the TTxþpCND group compared to those in the
TTx group (P < .05).
Conclusions: Prophylactic central compartment lymph node dissection detected more lymph node me-
tastases but did not affect recurrence. The 2 groups showed similar outcomes with regard to surgical
completeness, successful ablation, and complications. In conclusion, for small/noninvasive papillary
thyroid carcinoma without clinical evidence of lymph node metastases, prophylactic central compart-
ment lymph node dissection may not be required if total thyroidectomy is planned.
© 2021 Published by Elsevier Inc.

Background

The incidence of thyroid cancer (TC) is increasing worldwide.1

Papillary thyroid carcinoma (PTC) is the most common type of TC
Presented at the 41st Annual Meeting of the American Association of Endocrine and accounts for a significant proportion of observed cases in this
Surgeons, April 25e27, 2021, AAES Virtual Annual Meeting. increased incidence.1,2 The majority of patients with PTC frequently
* Reprint requests: Kyu Eun Lee, MD, PhD, Department of Surgery, Seoul National
present with regional neck lymph node metastasis (LNM), and
University Hospital and Seoul National University College of Medicine, 101,
Daehak-ro, Jongno-gu, Seoul, Republic of Korea, 03080. approximately 35% of patients with PTC are confirmed to have
E-mail address: kyueunlee@[Link] (K.E. Lee). occult cervical LNM priory to surgery (cN1).2,3

[Link]
0039-6060/© 2021 Published by Elsevier Inc.
2 J-h Ahn et al. / Surgery xxx (2021) 1e8

LNM in PTC is associated with local recurrence and increased with the largest tumor with confirmed PTC or suspicious PTC on
mortality and has been reported to be an independent risk factor preoperative biopsy. In cases where both tumors had similar
for decreased survival rate.3e5 Therefore, all guidelines recommend character and size, patients underwent bilateral pCND. All pro-
that patients with PTC cN1 undergo therapeutic cervical lymph cedures were performed by experienced endocrine surgeons in the
node dissection (tCND), as well as total thyroidectomy (TTx).1,6e8 same large-volume TC center.
In the absence of LNM (cN0) in PTC, up to 80% of the patients After confirming the pathologic results, patients were treated
were confirmed to present with micro-LNM.3 LNM is classified on with radioactive iodine (RAI) ablation, as recommended in the 2015
the basis of size as follows: (1) micro-LNM: 0.02 cm < size < 0.2 cm; ATA guidelines.6 If necessary, additional RAI ablation was imple-
(2) small LNM: 0.2 cm  size < 1.0 cm; (3) intermediate-sized LNM: mented. Patients visited the outpatient clinic 2 weeks, 3 months,
1.0 cm  size  3.0 cm; and (4) large LNM: size > 3.0 cm.9 Micro- and 6 months after surgery and once every year thereafter to
LNM, small LNM, small LNMs less than 5, as well as cN0 in PTC confirm thyroid function and loco-regional recurrence (LRR)
patients were reported to have a risk of recurrence of less than 5%, through the assessment of thyroglobulin (Tg), Tg antibodies, and
that is, low-risk stratification of N1 according to the 2015 American neck sonography. In addition to regular visits, patients scheduled to
Thyroid Association (ATA) guidelines.6,9 Therefore, the clinical ef- undergo RAI ablation visited the outpatient clinic according to RAI
ficacy of prophylactic central compartment lymph node dissection ablation schedules.
(pCND) for PTC cN0 patients remains controversial.2 Some studies
have reported that pCND improved disease-specific survival and Primary endpoints and secondary endpoints
local recurrence rates.10,11 However, others showed that pCND did
not improve long-term results, but rather increased complica- The primary endpoint was the rate comparison of LRR, surgical
tions.12,13 Treatment guidelines recommend that pCND should be completeness, and successful ablation between the 2 groups. LRR
considered in patients with advanced PTC (T3 or T4), clinically was defined according to the definition of response to therapy in
lateral compartment LNM, or cases requiring further information in the 2015 ATA guidelines.6 LRR was classified into 4 types according
order for a treatment plan to be determined.1,6e8 to Tg and imaging tests as follows: (1) disease-free status, (2)
Treatment guidelines were based on retrospective research, biochemical recurrence, (3) indeterminate response, and (4)
meta-analyses and systematic reviews, and expert opinions.2 structural recurrence (Supplementary Table S2).
Therefore, a well-designed randomized controlled trial (RCT) is Surgical completeness was defined as the absence of recurrence
needed to analyze the efficacy and safety of pCND. We performed a on the first imaging examination after surgery along with the first
prospective RCT and hypothesized that pCND would not signifi- postoperative assessment of Tg showing the following: (1) for pa-
cantly alter oncological efficacy or adversely affect surgical safety. tients undergoing RAI ablation, stimulated Tg <1 ng/mL; and (2) for
patients not receiving RAI treatment, unstimulated Tg <0.2 ng/mL.
Methods Successful ablation was defined as stimulated Tg levels <1 ng/mL at
the last ablation.
Study design The secondary endpoint was assessment of the incidence of
postoperative complications and the effect of pCND on PTC
Patients aged 20 to 70 years who had small, noninvasive PTC upstaging. Postoperative complications were divided into transient
cN0 and were scheduled to receive TTx were enrolled in this study (<6 months) and permanent (6 months) depending on the
from among those who visited the research institute between April duration. Hypoparathyroidism was diagnosed when patients
2015 and November 2017. Subjects with suspected advanced PTC needed oral calcium supplementation to relieve hypocalcemia
(clinically T3 or T4) and a history of cervical surgery or radiation symptoms or when serum parathyroid hormone levels were lower
exposure were excluded. Detailed criteria for inclusion and exclu- than baseline. Recurrent laryngeal nerve (RLN) injury was diag-
sion are included in Supplementary Table S1. Data from electronic nosed with laryngeal ultrasonography or laryngoscopy when vocal
medical records were collected in a prospective manner between cord movement was hypomobile or fixed. The stage of PTC was
April 2, 2015, and October 8, 2020. Informed consent was obtained defined according to the eighth edition of the American Joint
from all the participants before they were enrolled in the study. Committee on Cancer (AJCC) TNM staging system.
This prospective parallel-group RCT randomly assigned patients
to 1 of 2 groups at a ratio of 1:1 as follows: the TTx group, which Statistical analysis
received TTx only or the TTxþpCND group, which received TTx and
pCND. A simple randomization method was performed using a All statistical analyses were performed using R 4.0.2. Categorical
web-based randomization program provided by the research variables were analyzed using the c2 or Fisher exact test. Contin-
institution, Seoul National University Hospital ([Link] uous variables with normal distribution were analyzed by inde-
org/). The randomization results were blinded to all participants pendent t test, and non-normally distributed continuous variables
and medical staff, with the exception of the surgeons. were analyzed using the Mann-Whitney U test.
This study was in accordance with the Consolidated Standards
of Reporting Trials 2010 reporting guidelines for RCT.14 This RCT Results
was registered on [Link] (identifier: NCT02418390,
[Link] on April 16, 2015 Epidemiological and clinicopathological characteristics of the study
and was approved by the Institutional Review Board (IRB no. cohort (Table I)
1404e050e571).
A total of 112 patients were enrolled in the study, of whom 11
Intervention and postoperative management were excluded from the outcome analysis due to intraoperative LN
enlargement (n ¼ 4), benign lesions in the final pathology (n ¼ 2),
All patients underwent traditional open TTx. The central having underwent robotic surgery (n ¼ 1), postoperative bleeding
compartment lymph nodes (CLNs) consist of prelaryngeal, pre- (n ¼ 1), and being lost to follow-up (n ¼ 3) (Fig 1).
tracheal, and paratracheal LNs.3 Patients with bilateral tumors Of the 101 patients enrolled in this study, 50 were allocated to
underwent unilateral pCND on the dominant side, that is, the side the TTx group and 51 to the TTxþpCND group. The total follow-up
 J-h Ahn et al. / Surgery xxx (2021) 1e8 3

Table I
Epidemiological and clinicopathological characteristics of the study cohort

Variables Total (n ¼ 101) TTx group TTxþpCND group P value

(n ¼ 50) (n ¼ 51)

Age (years) 52.7 ± 9.4 51.8 ± 10.0 53.6 ± 8.8 .352

Sex .859
Female 77 (76.2 %) 39 (78.0%) 38 (74.5%)
Male 24 (23.8 %) 11 (22.0%) 13 (25.5%)
Preoperative BMI (kg/m2) 25.3 ± 3.6 25.1 ± 3.7 25.4 ± 3.5 .706
Length of follow-up (months) 46.6 ± 9.1 46.3 ± 9.7 46.8 ± 8.5 .751
Fine-needle aspiration cytology .366
Malignancy (VI) 87 (86.1%) 41 (82.0%) 46 (90.2%)
Suspicious of malignancy (V) 14 (13.9%) 9 (18.0%) 5 (9.8%)
Multifocality .439
Single 85 (84.2%) 44 (88.0%) 41 (80.4%)
Multifocal 16 (15.8%) 6 (12.0%) 10 (19.6%)
Tumor location .470
Right 40 (39.5%) 21 (42.0%) 19 (37.3%)
Left 42 (42.6%) 22 (44.0%) 21 (41.2%)
Bilateral 11 (10.9%) 3 (6.0%) 8 (15.7%)
Isthmus 7 (6.9%) 4 (8.0%) 3 (5.9%)
Size of dominant nodule on ultrasound (cm) 1.1 ± 0.5 1.1 ± 0.6 1.0 ± 0.4 .241

Values are presented as mean ± standard deviation or number (%).

TTx, total thyroidectomy; TTxþpCND, prophylactic central compartment lymph node dissection with total thyroidectomy; BMI, body mass
index.

Fig. 1. Flow diagram of the randomized controlled trial. TTx, total thyroidectomy; TTxþpCND, prophylactic central compartment lymph node dissection with total thyroidectomy.

period was 46.6 ± 9.1 months (TTx 46.3 ± 9.7 versus TTxþpCND estimated blood loss between the 2 groups (P ¼ .748 and P ¼ .538,
46.8 ± 8.5 months [P ¼ .751]). There was no difference in age or sex respectively).
between the 2 groups (P ¼ .352 and P ¼ .859, respectively). The There was no difference between the 2 groups with regard to
results of fine-needle aspiration cytology and the number, location, the final pathological results (P ¼ .358, Table III). A total of 44
and size of malignant nodules on preoperative ultrasound were (88.0%) and 50 (98.0%) patients had confirmed PTC in the TTx and
similar between the 2 groups (P ¼ .366, P ¼ .439, P ¼ .470, and P ¼ TTxþpCND groups, respectively. Pathological results revealed that
.241, respectively). the number, location, and size of nodules were similar between the
Of the 51 patients in the TTxþpCND group, 46 (90.2%) under- 2 groups (P ¼ .355, P ¼ .350, and P ¼ .234, respectively). There was
went unilateral pCND and 5 (9.8%) underwent bilateral pCND no significant difference between the 2 groups in the number of
owing to multiple suspicious nodules on the preoperative ultra- patients with extrathyroidal extension (ETE), lymphatic invasion, or
sound (Table II). There was no difference in total operation time and angioinvasion (P ¼ .757, P ¼ .610, and P ¼ .368, respectively).
4 J-h Ahn et al. / Surgery xxx (2021) 1e8

Table II
Surgical outcomes of the study cohort

Variables TTx group TTxþpCND group P value

(n ¼ 50) (n ¼ 51)

CND <.05
Bilateral 0 (0%) 5 (9.8%)
Left 0 (0%) 25 (49.0%)
Right 0 (0%) 21 (41.2%)
No 50 (100%) 0 (0%)
Total operation time (minutes) 75.7 ± 15.9 76.8 ± 17.8 .748
Estimated blood loss (mL) 17.5 ± 29.2 21.2 ± 31.3 .538

Values are presented as mean ± standard deviation or number (%).

TTx, total thyroidectomy; TTxþpCND, prophylactic central compartment lymph node dissection with
total thyroidectomy; CND, central compartment lymph node dissection.

Table III
Pathologic outcomes of the study cohort

Variables TTx group TTxþpCND group P value

(n ¼ 50) (n ¼ 51)

Pathologic diagnosis .358

PTC 44 (88.0%) 50 (98.0%)
PTC, follicular variant 3 (6.0%) 1 (2.0%)
PTC, oncocytic variant 1 (2.0%) 0 (0%)
PTC þ miFTC 1 (2.0%) 0 (0%)
PTC þ wiFTC 1 (2.0%) 0 (0%)
Multifocality .355
Single 32 (64.0%) 27 (52.9%)
Multifocal 18 (36.0%) 24 (47.1%)
Tumor location .350
Right 16 (32.0%) 16 (31.4%)
Left 20 (40.0%) 18 (35.3%)
Bilateral 10 (20.0%) 16 (31.4%)
Isthmus 4 (8.0%) 1 (2.0%)
Dominant tumor size on pathology (cm) 1.1 ± 0.6 1.0 ± 0.5 .234
Extrathyroidal extension .757
Absent 15 (30.0%) 20 (39.2%)
Minimal 32 (64.0%) 29 (56.9%)
Gross 2 (4.0%) 1 (2.0%)
Lymphatic invasion 12 (24.0%) 12 (23.5%) .610
Angioinvasion 49 (98.0%) 50 (98.0%) .368
Lymph nodes, retrieved (numbers) 35 (70.0%) 48 (94.1%) <.05
Numbers of retrieved LNs 2.1 ± 2.4 5.2 ± 3.5 <.05
N1a (metastasis of central compartment LNs) 3 (6.0%) 14 (27.5%) <.05
Numbers of metastasized LNs 1.0 ± 0.0 2.0 ± 1.4 .209
Size of metastasized LNs (cm) 0.04 ± 0.01 0.16 ± 0.10 .112
Micrometastasis 3 (100%) 8 (57.1%) .457
ENE 0 (0%) 2 (14.3%) 1.000
T-stage .721
1 45 (90.0%) 46 (90.2%)
2 3 (6.0%) 3 (5.9%)
3 2 (4.0%) 1 (2.0%)
N-stage <.05
X 15 (30.0%) 3 (5.9%)
0 32 (64.0%) 34 (66.7%)
1a 3 (6.0%) 14 (27.5%)
TNM stage .282
1 48 (96.0%) 45 (88.2%)
2 2 (4.0%) 6 (11.8%)

Values are presented as mean ± standard deviation or number (%).

TTx, total thyroidectomy; TTxþpCND, prophylactic central compartment lymph node dissection with total thyroid-
ectomy; PTC, papillary thyroid carcinoma; miFTC, minimally invasive follicular thyroid carcinoma; wiFTC, widely
invasive follicular thyroid carcinoma; LNs, lymph nodes; ENE, extranodal extension.

The TTxþpCND group had more patients with resected LNs (n ¼ 8 (15.7%) had micro-LNMs, 6 (11.8%) had small LNMs, and 2 (3.9%)
48, 94.1%) than the TTx group (n ¼ 35, 70.0%; P < .05). The number had LNMs with ENE.
of excised LNs was significantly higher in the TTxþpCND group
(5.2 ± 3.5 vs 2.1 ± 2.4 in the TTx group, P < .05). Metastatic CLN Primary endpoints: surgical completeness, local recurrence, and
(CLNM, pN1a) was confirmed more in the TTxþpCND group (n ¼ 14, successful ablation (Table IV)
27.5% vs 3 [6.0%] in the TTx group, P < .05). All 3 CLNMs in the TTx
group were identified as micrometastases without extranodal Surgical completeness was confirmed in 41 patients (82.0%) in
extension (ENE). Of the 14 CLNM patients in the TTxþpCND group, the TTx group and 42 (82.4%) in the TTxþpCND group (P ¼ 1.000).
 J-h Ahn et al. / Surgery xxx (2021) 1e8 5

Table IV
Primary endpoints of patients in the TTx and TTxþpCND groups

Variables TTx group TTxþpCND group P value

(n ¼ 50) (n ¼ 51)

Surgical completeness 41 (82.0%) 42 (82.4%) 1.000

RAI or scan (þ)* 7 (14.0%) 5 (9.8%) .842
RAI (-)y 35 (92.1%) 37 (92.5%) 1.000
Local recurrence .945
Disease-free status 42 (84.0%) 44 (86.3%)
Indeterminate response 7 (14.0%) 6 (11.8%)
Biochemical recurrence 1 (2.0%) 1 (2.0%)
Structural recurrence 0 (0%) 0 (0%)
RAI ablation 1.000
None 39 (78.0%) 40 (78.4%) .484
Yes 11 (22.0%) 11 (21.6%)
1 3 (27.3%) 2 (18.2%)
2 7 (63.6%) 9 (81.8%)
3 1 (9.1%) 0 (0%)
Last RAI ablation
Tg <1 ng/mL 9 (81.8%) 10 (90.9%) .328
Whole-body scan; no uptake 9 (81.8%) 6 (54.5%) .360
Whole-body scan; remnant uptake 2 (18.2%) 5 (45.5%) .360
RAI total dose (mCi) 65.5 ± 27.7 79.1 ± 45.9 .409

Values are presented as mean ± standard deviation or number (%).

TTx, total thyroidectomy; TTxþpCND, prophylactic central compartment lymph node dissection with total
thyroidectomy; RAI, radioactive iodine; Tg, thyroglobulin.
*
RAI or scan (þ), Surgical completeness was defined as cases with a negative finding on the first post-
operative ultrasonography along with stimulated thyroglobulin levels <1 ng/mL.
y
RAI (-), Surgical completeness was defined as cases with a negative finding on the first postoperative
ultrasonography along with unstimulated thyroglobulin levels <0.2 ng/mL.

During the follow-up period, no patients from either group devel- Discussion
oped structural recurrence. There was no significant difference in
the number of patients with LRR at the last assessment (P ¼ .945). PTC is the most common histologic type of TC, and approxi-
A total of 22 patients were treated with RAI ablation (TTx, n ¼ 11, mately 35% of PTC are diagnosed with CLNM before surgery.3,15,16
22.0% versus TTxþpCND, n ¼ 11, 21.6%, P ¼ 1.000). The number of Guidelines recommend that PTC cN1 patients on preoperative
RAI ablation treatments and the total RAI dose did not differ be- evaluation should undergo thyroidectomy with tCND because LNM
tween the 2 groups (P ¼ .484 and .409, respectively). After the last is associated with LRR and increased mortality.1,3e8
ablation, the number of patients with Tg levels <1 ng/mL was 9 However, the efficacy of pCND for PTC cN0 patients is contro-
(81.8%) in the TTx group and 10 (90.9%) in the TTxþpCND group versial.2 Treatment guidelines have recommended that pCND
(P ¼ .328). should be considered in patients with advanced PTC (T3 or T4),
clinically lateral compartment LNM, or when further information is
Secondary endpoints: postoperative complications (Table V) and required in order to develop a treatment plan.1,6e8 Meta-analysis
TNM stage (Table III) studies investigating the efficacy of pCND have reported that
pCND lowered the risk of LRR but increased the rate of post-
The number of patients with postoperative transient hypo- operative complications.17e19 Some studies have suggested risk
parathyroidism was 13 (26.0%) in the TTx group and 7 (13.7%) in the factors for CLNM, such as male sex, age under 45 years, and tumor
TTxþpCND group (P ¼ .194) (Table V). Transient postoperative RLN size, and recommended that pCND should be considered for pa-
injury was diagnosed in 3 patients (6.0%) in the TTx group and 5 tients with PTC cN0 and further risk factors.20,21 However, other
patients (9.8%) in the TTxþpCND group (P ¼ .734). All complications studies have shown that pCND did not improve long-term results,
were transient, all patients with hypoparathyroidism had normal but rather increased complications, suggesting that pCND had no
calcium test results within 6 months after surgery, and all patients clinical significance in PTC cN0 patients.12,13
with postoperative RLN injury had no hoarseness within 6 months Studies evaluating the efficacy of pCND for PTC cN0 patients
after surgery. have primarily included retrospective studies, meta-analyses, sys-
There was no difference in voice function test changes (voice tematic reviews, and expert opinions.2 To our knowledge, 3 RCTs
range profiles and voice handicap index) or the number of patients have evaluated the effectiveness of pCND for PTC cN0 patients2,22,23
complaining of at least 1 voice change symptom after surgery (P ¼ as follows: one reported that pCND for PTC cN0 patients who un-
.444, P ¼ .288, and P ¼ .751, respectively). derwent TTx could reduce the need for RAI ablation but could in-
ETE, lymphatic invasion, and angioinvasion status were similar crease the incidence of permanent hypoparathyroidism2; another
between the 2 groups (P ¼ .757, P ¼ .610, and P ¼ .368, respectively) reported that pCND enabled higher discovery of microscopic nodes
(Table III). T-stage PTC showed similar outcomes between the 2 in subjects, but the postoperative complication rate and 1-year
groups (P ¼ .721). When comparing the 2 groups for N-stage, the follow-up oncological outcomes, including sonographic evalua-
TTxþpCND group had 14 patients (27.5%) with pN1a compared to 3 tion and serum Tg levels, were similar between the TTx and the
(6.0%) in the TTx group (P < .05). According to the criteria detailed TTxþpCND group22; and the third showed that pCND for PTC cN0
in the eighth edition of the AJCC TNM staging system, 2 (4.0%) patients who underwent thyroid lobectomy enabled higher
patients were upstaged to stage II in the TTx group, whereas 6 detection of cases of occult LNM but was of no oncological
(11.8%) were upstaged in the TTxþpCND group; however, this did benefit.23 Herein, we performed the first RCT in patients with small,
not reach statistical significance (P ¼ .282). noninvasive PTC cN0. Our study has a strength over previously
6 J-h Ahn et al. / Surgery xxx (2021) 1e8

Table V
Surgical complications of patients in the TTx group and TTxþpCND group

Variables TTx group TTxþpCND group P value

(n ¼ 50) (n ¼ 51)

Hypoparathyroidism .194
Transient (POD <6 mo) 13 (26.0%) 7 (13.7%)
Permanent (POD 6 mo) 0 (0%) 0 (0%)
No 37 (74.0%) 44 (86.3%)
Recurrent laryngeal nerve injury .734
Transient (POD <6 mo) 3 (6.0%) 5 (9.8%)
Permanent (POD 6 mo) 0 (0%) 0 (0%)
No 47 (94.0%) 46 (90.2%)
Vocal cord sonography .319
Normal 47 (94.0%) 46 (90.2%)
Hypomobility 2 (4.0%) 5 (9.8%)
Fixed 1 (2.0%) 0 (0%)
Change of VRP e158.9 ± 234.3 e124.1 ± 183.7 .444
Change of VHI e9.3 ± 11.8 e6.9 ± 9.1 .288
Voice change (at least 1 of following Sx) 30 (60.0%) 28 (54.9%) .751
Hoarseness 5 (10.0%) 5 (9.8%) 1.000
Thickened voice 9 (18.0%) 8 (15.7%) .964
Difficulty in making high-pitched voice 19 (38.0%) 19 (37.3%) 1.000
Voice fatigue 8 (16.0%) 10 (19.6%) .831
Aspiration 1 (2.0%) 0 (0%) .922
Dyspnea 1 (2.0%) 0 (0%) .922

Values are presented as mean ± standard deviation or number (%).

TTx, total thyroidectomy; TTxþpCND, prophylactic central compartment lymph node dissection with total thy-
roidectomy; POD, postoperative day; VRP, voice range profiles; VHI, voice handicap index; Sx, symptom.

published studies in that we judged LRR in more detail and to either group was diagnosed with permanent hypoparathyroidism.
stricter criteria, including the criterion pertaining to Tg levels, ac- A previous study reported that the incidence of hypoparathyroid-
cording to the 2015 ATA guidelines and imaging evaluation.2,23 Our ism may be higher when pCND is performed by surgeons with less
study has the advantage of including 3 RLN injury evaluations, experience.3,25 The lack of difference between the TTx group and
namely, laryngeal imaging (sonography or laryngoscopy), voice TTxþpCND group might be attributable to the fact that the sur-
function test, and subjective complaints of voice change. geons who participated in this study were highly skilled with more
Tg is a protein produced by the thyroid gland that may help than 10 years of thyroid surgery experience in high-volume TC
assess thyroid tissue remnants, as well as disease persistence and centers. It is possible that this study underestimated the incidence
potential future disease recurrence.24 As a result of assessing Tg of hypoparathyroidism and, as such, pCND needs to be performed
levels as an indicator for complete resection, both groups were very carefully in nonspecialized or low-volume TC centers.
found to have similar results with regard to surgical completeness. The number of patients with RLN injury did not differ between
When comparing the surgical incompleteness and surgical the 2 groups. There was also no patient with permanent RLN in-
completeness group, more aggressive pathological diagnosis and juries, which is consistent with the findings of a previous study.2 In
bilateral tumor location were identified in the surgical incom- addition, there was no difference in the number of patients com-
pleteness group. The variables associated with poor prognosis plaining of subjective voice change and the change in voice function
tended to have higher values in the surgical incompleteness group. test. These results suggest that pCND is less associated with RLN
Although pCND administration had no effect on surgical injury and vocal cord paralysis.
completeness, the aggressiveness of the tumor may affect surgical A total of 8 patients were upstaged to stage II. The number of
completeness, and further study is needed in this regard. patients upstaged to stage II was not different between the 2
There were no differences in rates of LRR between the 2 groups, groups. Moreover, because only patients over 55 years of age have
including disease-free status, indeterminate response, biochemical TNM stage elevation, less than the expected number of patients (up
recurrence, and structural disease recurrence. During the follow-up to 80%) will be upstaged when performing pCND.2,3,25 So in this
period, no patient from either group confirmed structural disease study, 11 of 17 patients with LNM and 1 of 3 patients with gross ETE
recurrence. According to the 2015 ATA guidelines, less than 2% of were confirmed as stage I, not stage II, due to age. Therefore, per-
low-risk patients and 8% of intermediate-risk patients had struc- forming pCND in small, noninvasive PTC cN0 patients had little
tural disease recurrence 5 to 10 years after thyroid surgery without clinical importance for the upstaging of PTC.
RAI ablation therapy.6 Our study prescribed RAI ablation treatment An accurate assessment of LN in PTC cN0 patients should be
to patients in accordance with the 2015 ATA guidelines6; therefore, performed with pCND. In this study, 27.5% of patient in TTxþpCND
clinical outcomes associated with recurrence were superior to group were confirmed to have LNM, which is consistent with pre-
those of previous reports. vious studies.3,26 However, the clinical significance of accurate LN
The number of patients with successful ablation was similar assessment in PTC cN0 should be considered. In our study, of the 14
between the 2 groups with no difference in the number of times RAI patients with LNMs in the TTxþpCND group, 8 had micro-LNMs
ablation therapy was received, the total cumulative RAI dose, and and 6 had small LNMs. A previous study reporting on LNM risk
the whole-body scan results after the last RAI ablation treatment. In stratification for recurrence showed that small and micro-LNMs are
this study, implementation of pCND had no effect on RAI ablation stratified as low-risk in patients with PTC pN1 with a recurrence
treatment, which is different from that of a previous RCT.2 Further risk of <5%.9 Therefore, implementing pCND in patients with PTC
research is needed to clarify the effect of pCND on RAI ablation. cN0 has the advantage of accurate assessment of the nodal status,
There was no difference in the number of patients with transient but the clinical importance of pCND appears to be insignificant with
hypoparathyroidism between the 2 groups, and no patient from regard to LN risk stratification.
 J-h Ahn et al. / Surgery xxx (2021) 1e8 7

Limitations on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:

1e133.
7. Patel KN, Yip L, Lubitz CC, et al. The American Association of Endocrine Sur-
This study has some limitations. First, only a small number of geons Guidelines for the Definitive Surgical Management of Thyroid Disease in
patients were enrolled. Second, the follow-up duration for assess- Adults. Ann Surg. 2020;271:e21ee93.
ing the efficacy of pCND was relatively short and the incidence of 8. Sancho JJ, Lennard TWJ, Paunovic I, Triponez F, Sitges-Serra A. Prophylactic
central neck disection in papillary thyroid cancer: a consensus report of the
recurrence was relatively low. The possibility of recurrence was European Society of Endocrine Surgeons (ESES). Langenbeck’s Arch Surg.
lower than that in previous reports, because the inclusion criteria 2014;399:155e163.
for this study was small, noninvasive PTC cN0 patients, and RAI 9. Randolph GW, Duh QY, Heller KS, et al. The prognostic significance of nodal
metastases from papillary thyroid carcinoma can be stratified based on the size
therapy was performed in all patients when treatment was indi- and number of metastatic lymph nodes, as well as the presence of extranodal
cated. Therefore, the researchers decided not to proceed with extension. Thyroid. 2012;22:1144e1152.
further studies, deciding that the additional patient enrollment and 10. Popadich A, Levin O, Lee JC, et al. A multicenter cohort study of total thy-
roidectomy and routine central lymph node dissection for cN0 papillary thy-
follow-up would not have a significant effect on the results. roid cancer. Surgery. 2011;150:1048e1057.
Finally, the surgeons involved were skilled physicians with more 11. Barczyn  ski M, Konturek A, Stopa M, Nowak W. Prophylactic central neck
than 10 years of experience in a large-volume center. As such, the dissection for papillary thyroid cancer. Br J Surg. 2013;100:410e418.
12. Lang BHH, Ng SH, Lau LLH, Cowling BJ, Wong KP, Wan KY. A systematic review
association between postoperative complications and pCND and meta-analysis of prophylactic central neck dissection on short-term
administration may have been underestimated in this study. locoregional recurrence in papillary thyroid carcinoma after total thyroidec-
In conclusion, our study found that the number of patients with tomy. Thyroid. 2013;23:1087e1098.
13. Wang TS, Cheung K, Farrokhyar F, Roman SA, Sosa JA. A meta-analysis of the
LNM was higher in the TTxþpCND group and without increased
effect of prophylactic central compartment neck dissection on locoregional
incidence of postoperative complications. However, there was no recurrence rates in patients with papillary thyroid cancer. Ann Surg Oncol.
difference in LRR findings between the 2 groups. Therefore, the 2013;20:3477e3483.
implementation of pCND had no clinical benefit. In conclusion, in 14. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines
for reporting parallel group randomized trials. Ann Intern Med. 2010;152:
small, noninvasive PTC cN0 patients, pCND may not be required if 726e732.
TTx is planned. 15. Baloch ZW, LiVolsi VA, Asa SL, et al. Diagnostic terminology and morphologic
criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National
Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Confer-
Funding/Support ence. Diagn Cytopathol. 2008;36:425e437.
16. Ito Y, Higashiyama T, Takamura Y, et al. Risk factors for recurrence to the lymph
No support, financial or otherwise, was received from any or- node in papillary thyroid carcinoma patients without preoperatively detectable
lateral node metastasis: validity of prophylactic modified radical neck dissec-
ganization that may have an interest in the submitted work. tion. World J Surg. 2007;31:2085e2091.
17. Chen L, Wu YH, Lee CH, Chen HA, Loh EW, Tam KW. Prophylactic central neck
Conflict of interest/Disclosure dissection for papillary thyroid carcinoma with clinically uninvolved central
neck lymph nodes: a systematic review and meta-analysis. World J Surg.
2018;42:2846e2857.
The authors have no conflicts of interest to declare. 18. Zhao W Jun, Luo H, Zhou Y Mei, Dai W Yu, Zhu J Qiang. Evaluating the effec-
tiveness of prophylactic central neck dissection with total thyroidectomy for
cN0 papillary thyroid carcinoma: an updated meta-analysis. Eur J Surg Oncol.
Supplementary materials
2017;43:1989e2000.
19. Zhao W, You L, Hou X, et al. The effect of prophylactic central neck
Supplementary material associated with this article can be dissection on locoregional recurrence in papillary thyroid cancer after total
thyroidectomy: a systematic review and meta-analysis: pCND for the
found, in the online version, at [[Link]
locoregional recurrence of papillary thyroid cancer. Ann Surg Oncol.
03.071]. 2017;24:2189e2198.
20. Liu L Sen, Liang J, Li JH, et al. The incidence and risk factors for central lymph
References node metastasis in cN0 papillary thyroid microcarcinoma: a meta-analysis. Eur
Arch Oto-Rhino-Laryngology. 2017;274:1327e1338.
21. Ma B, Wang Y, Yang S, Ji Q. Predictive factors for central lymph node metastasis
1. Filetti S, Durante C, Hartl D, et al. Thyroid cancer: ESMO clinical practice guide- in patients with cN0 papillary thyroid carcinoma: a systematic review and
lines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30:1856e1883. meta-analysis. Int J Surg. 2016;28:153e161.
2. Viola D, Materazzi G, Valerio L, et al. Prophylactic central compartment lymph 22. Sippel RS, Robbins SE, Poehls JL, et al. A randomized controlled clinical trial.
node dissection in papillary thyroid carcinoma: clinical implications derived Ann Surg. 2020;272:496e503.
from the first prospective randomized controlled single institution study. J Clin 23. Kim BY, Choi N, Kim SW, Jeong HS, Chung MK, Son YI. Randomized trial of
Endocrinol Metab. 2015;100:1316e1324. prophylactic ipsilateral central lymph node dissection in patients with clini-
3. Agrawal N, Evasovich MR, Kandil E, et al. Indications and extent of central neck cally node negative papillary thyroid microcarcinoma. Eur Arch Oto-Rhino-
dissection for papillary thyroid cancer: an American Head and Neck Society Laryngology. 2020;277:569e576.
consensus statement. Head Neck. 2017;39:1269e1279. 24. Adkisson CD, Howell GM, McCoy KL, et al. Surgeon volume and adequacy of
4. Kouvaraki MA, Lee JE, Shapiro SE, Sherman SI, Evans DB. Preventable reoper- thyroidectomy for differentiated thyroid cancer. Surgery. 2014;156:
ations for persistent and recurrent papillary thyroid carcinoma. Surgery. 1453e1460.
2004;136:1183e1191. 25. Hughes DT, Rosen JE, Evans DB, Grubbs E, Wang TS, Solo rzano CC. Prophylactic
5. Zaydfudim V, Feurer ID, Griffin MR, Phay JE. The impact of lymph node central compartment neck dissection in papillary thyroid cancer and effect on
involvement on survival in patients with papillary and follicular thyroid car- locoregional recurrence. Ann Surg Oncol. 2018;25:2526e2534.
cinoma. Surgery. 2008;144:1070e1078. 26. Lee YC, Na SY, Park GC, Han JH, Kim SW, Eun YG. Occult lymph node metastasis
6. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association and risk of regional recurrence in papillary thyroid cancer after bilateral pro-
management guidelines for adult patients with thyroid nodules and differen- phylactic central neck dissection: a multi-institutional study. Surgery.
tiated thyroid cancer: the American Thyroid Association Guidelines Task Force 2017;161:465e471.

Discussant
Dr. Elizabeth Grubbs (Houston): For your central lymph node Dr. Jong-Hyuk Ahn: We tried to perform unilateral prophylactic
dissections, were those bilateral, meaning both the right and left CND, but in cases where the bilateral tumor had the same charac-
central neck, or were they just unilateral on the side of the known teristics and size or where bilateral tumors were confirmed as PTC
tumor? preoperatively by fine needle aspiration, we performed bilateral CND.
8 J-h Ahn et al. / Surgery xxx (2021) 1e8

Dr. Ashok Shaha (New York): What were your indications for with T1 or T2 papillary thyroid cancer with microscopic lymph
radioactive iodine, especially when the stimulated thyroglobulin node metastases in the central neck?
was less than 1 ng/mL? Dr. Jong-Hyuk Ahn: I think it is not necessary in general, but if a
Dr. Jong-Hyuk Ahn: We performed our RAI ablation according patient is an intermediate or high-risk patient, I think it would be
to ATA guidelines. If first ablation was successful with a stimulated good to perform RAI ablation for them.
level under 1 ng/mL, we did not perform further ablation. Dr. Richard Prinz (Evanston): Randomized controlled trials are
Dr. Elizabeth Grubbs (Houston): Was there a standard protocol difficult to do. However, do you have enough patients in your study
that you used to decide who got radioactive iodine, or was that at to come to a conclusion?
the discretion of individual clinicians? Dr. Jong-Hyuk Ahn: Yes, I think RCTs for PTC cN0 patients are
Dr. Jong-Hyuk Ahn: We followed the risk stratification of ATA very difficult. During the 46-month follow-up period, there was no
guidelines, and we discussed the decision with the specialists patient confirmed with recurrence, we ignored the small and non-
responsible for the ablation. invasive PTC cN0 patients, and we performed the RAI ablation when
Dr. Christopher McHenry (Cleveland): Your study reinforces treatment was indicated. We thought that further follow-up and
that although micrometastases are common in lymph nodes in the additional patient enrollment would not have a significant effect on
central neck, recurrence is uncommon, whether or not prophylactic the results. We thought that a 46-month follow-up period was
central neck dissection is done. Do you recommend RAI for patients enough, so we decided to end our study.