Should Level V Be Routinely Dissected in N1b Papillary Thyroid Carcinoma?

Abstract

Background:

For N1b papillary thyroid carcinoma (PTC) patients, modified radical neck dissection (MRND) encompassing levels II–V is generally recommended. However, routine level V dissection is controversial because of the low incidence of metastasis/recurrence in level V and the increased morbidities associated with level V dissection.

Methods:

This study retrospectively reviewed 646 N1b PTC patients who underwent unilateral MRND between January 1997 and June 2015. Specifically, to assess surgery-related outcomes of level V dissection, outcomes from N1b PTC patients who underwent unilateral MRND (levels II–V) were compared with those who underwent unilateral selective neck dissection (SND; levels II–IV) using propensity score matching.

Results:

Overall and occult level V metastases were observed in 13.9% and 8.6% of patients, respectively. Level V recurrences were observed in only 2.26 (7.7%) recurred N1b PTC patients who underwent unilateral MRND. In multivariate analysis, three-level (II, III, and IV) simultaneous metastasis (adjusted odds ratio = 3.079, p = 0.003) was an independent predictor for level V metastasis. Under a matched condition, “shoulder syndrome” encompassing shoulder dysfunction and pain (9.1% vs. 2.7%, p = 0.002) was significantly more frequent in the MRND group than it was in the SND group.

Conclusions:

Because of the low incidence of metastasis/recurrence in level V and the clear evidence of increased morbidities, level V dissection in N1b PTC patients may be reserved for those with three-level simultaneous metastasis or clinically/radiologically evident level V metastasis.

Introduction

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and its incidence has increased rapidly worldwide (1). Regional lymph node (LN) metastasis is an independent risk factor for locoregional recurrence (2,3) and mortality in PTC patients (4). At the time of diagnosis, 20–90% of PTC patients show regional LN metastasis (5,6), and the most commonly involved area is the central neck compartment (7,8). Although lateral neck compartment involvement is less common, it is thought to be associated with worse prognosis than central LN metastasis is (9). To attain regional control of lateral LN metastasis, the American Thyroid Association consensus (10) and British Thyroid Association Guidelines (11) recommend therapeutic modified radical neck dissection (MRND) for PTC patients with clinically suspicious N1b.

MRND refers to the excision of the lateral neck LNs, including levels II–V, with preservation of one or more non-lymphatic structures, such as the spinal accessory nerve, internal jugular vein, or sternocleidomastoid muscle (10). Level I dissection is generally excluded from MRND because of the rarity of metastatic disease (12,13). However, some studies have argued that routine level V dissection is also unnecessary for the treatment of PTC patients with clinically suspicious N1b because of the relatively low incidences of level V metastasis and recurrence (14 –16). Moreover, despite gross preservation of the spinal accessory nerve, level V dissection may lead to certain degrees of shoulder dysfunction due to neuropraxia from excessive retraction or ischemia during the clearance of LNs (17 –19).

Therefore, the purpose of this study was to determine the clinical risks and benefits of routine level V dissection in N1b PTC patients. Several features distinguish this study from the previous studies: (i) >600 cases were recruited from a single institution; (ii) not only overall but also occult level V metastasis from routine dissection was investigated in patients who were clinically negative for level V metastasis; (iii) the predictive factors for level V metastasis in N1b PTC patients were investigated; (iv) the incidence and pattern of lateral neck recurrence were analyzed to determine the possibility of “wait and see” in level V metastasis; and (v) surgery-related outcomes were assessed according to routine level V dissection status, under a matched condition using propensity score matching.

Materials and Methods

Patient selection

This study was approved by the Institutional Review Board at the Samsung Medical Center (IRB No. 2016-07-154). A retrospective cohort study was conducted at the Thyroid Cancer Center of Samsung Medical Center, a tertiary referral center in Korea, by analyzing data collected between January 1997 and June 2015. A total of 646 patients who met the following inclusion and exclusion criteria were enrolled. The inclusion criteria were: pathologically proven PTC, preoperative results of both ultrasonography (US) and computed tomography (CT), total thyroidectomy with central neck dissection and unilateral MRND (levels II–V dissection), and evidence of lateral LN metastasis by histopathologic examination. The exclusion criteria were: history of previous thyroidectomy, non-PTC carcinomas (follicular/medullary/anaplastic), mixed type PTC, distant metastasis, level I dissection, or follow-up duration less than six months (i.e., residual tumor or suspicious LN detected within six months after initial surgery, underwent reoperation within six months after the initial surgery, or loss to follow-up within six months). In particular, bilateral MRND cases were excluded to avoid potential complications in the assessment of predictive factors for level V metastasis and recurrence patterns by bilateral neck involvement. None of the enrolled patients had undergone endoscopic or robotic thyroidectomy.

Preoperative US and CT

US scanners (HDI 5000 or IU22; Philips Medical Systems; Bothell, WT) equipped with commercially available 7–12 MHz linear array transducers were used for the primary assessment of cervical LNs. The US criteria for cervical LN metastasis were: focal or diffuse hyperechogenicity, microcalcifications, cystic changes, loss of fatty hilum, round shape (long/transverse diameter ratio <1.5), and abnormal vascular patterns (chaotic or peripheral) (20 –22). CT scans were performed preoperatively on patients who showed aggressive features on US scans. Aggressive features included tumor size >1 cm, upper pole–located tumor, multifocality, extrathyroidal extension (ETE), and clinically suspicious lymphadenopathy. CT scans were also performed according to each clinician's preference when planning surgery. CT scans were obtained using a 16-detector-row CT scanner (MX8000 Infinite Detector Technology; Philips, Haifa, Israel) with a reconstructed slice thickness of 3 mm for both axial and coronal images. The CT criteria for cervical LN metastasis were: calcification, cystic or necrotic changes, heterogeneous cortical enhancement, and strong enhancement without hilar vessel enhancement (20 –22). Two or more experienced radiologists interpreted each US and CT image. Suspicious LNs were defined as LNs meeting at least one of the US and CT criteria listed above. US and CT results were reported on a “per level” basis (21). For patients with multiple follow-up examinations, the result closest to the operation date was selected for analysis.

Surgical strategy

In the authors' institution, total thyroidectomy and central neck dissection are performed before lateral neck dissection following principles that have been previously described (23). Moreover, only therapeutic lateral neck dissection is performed in patients with clinically suspicious lateral LN metastasis as confirmed by US, CT, and/or fine-needle aspiration biopsy. Lateral neck dissection is defined as any excision of lateral neck LNs, including MRND and selective neck dissection (SND) (24). MRND refers to the excision of lateral neck LNs, including levels II–V, with preservation of one or more non-lymphatic structures, such as the spinal accessory nerve, internal jugular vein, or sternocleidomastoid muscle. Level I dissection was not performed unless indicated. SND refers to the excision of suspicious lateral neck LNs accompanied by preservation of one or more of the LN groups that are routinely removed in MRND. During surgery, the cervical LN levels present in the dissected specimens were classified individually with a labeling suture.

Histopathological examination of surgical specimens

Surgical specimens were microscopically examined by two or more experienced pathologists. The following histopathologic parameters were assessed: cell type of the main lesion, primary tumor size (longest diameter of the largest lesion), location, multifocality, bilaterality, ETE, lymphovascular invasion, margin involvement, regional LN metastasis, and underlying thyroid conditions such as chronic lymphocytic thyroiditis (CLT). To distinguish bilaterality from multifocality, multifocality was defined as having two or more lesions of conventional PTC in one lobe, regardless of the presence of bilaterality. Of particular note, histopathology results of LN status were reported on a “per level” basis (10), and were indicated by surgeons during operation. Thyroid cancer staging was determined in accordance with the American Joint Committee on Cancer recommendations (25).

Postoperative follow-up and management

After the initial surgery, all patients underwent regular follow-up at 6–12-month intervals with clinical evaluations including physical examinations, US, CT, ¹³¹I scans, and serum thyroglobulin testing. After total thyroidectomy, thyrotropin (TSH) suppression therapy (serum TSH 0.5 mIU/L) by levothyroxine with or without radioactive iodine (RAI) ablation was considered as an initial postoperative therapy. RAI ablation was administered after thyroid hormone withdrawal or after stimulation with recombinant TSH. Although RAI ablation was generally proposed for aggressive features as recommended by the established guidelines (11,26), the final decision was based on the physician's or patient's preference. The number of RAI administrations and cumulative doses of RAI by the end of follow-up were recorded. RAI ablations after recurrence and diagnostic doses of RAI were not included. When patients no longer needed RAI treatment, they received regular follow-up. Loss to follow-up, withdrawal, and deaths were all censored as the last follow-up date. When suspicious lesions were detected, they were confirmed by US-guided fine-needle aspiration biopsy, with or without measurement of washout thyroglobulin levels and/or CT or positron emission tomography. Recurrence was defined as the presence of a tumor or metastatic LN by cytologic examination from a fine-needle aspiration biopsy or by histopathological examination during reoperations that occurred six months after the initial surgery. In particular, “shoulder syndrome” was defined as symptoms encompassing shoulder dysfunction and pain, which were persistent after six months from the initial surgery.

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics for Windows v22.0 (IBM Corp,, Armonk, NY). Statistically significant differences were defined as those with p-values <0.05. Continuous variables are presented as mean ± standard deviation (SD), whereas categorical variables are presented as the number of cases with percentage and odds ratio (OR). The chi-square test and the linear-by-linear association technique were used to compare differences between categorical variables, whereas Student's t-test was used to test the significance between continuous variables. Multivariate logistic regression analysis was carried out on all variables that achieved p < 0.05 in the univariate analysis. To assess surgery-related outcomes according to routine level V dissection status, propensity score matching was performed (27). The study compared 556 N1b PTC patients who were clinically negative for level V and underwent MRND (levels II–V) with 329 N1b PTC patients who were clinically negative for level V and underwent SND (levels II–IV). The following clinicopathologic characteristics that can influence surgical difficulty were stringently adjusted using propensity score matching: sex, age (per 10 years), Asia-Pacific body mass index consensus (<18.5 kg/m², 18.5–23 kg/m², 23–25 kg/m², 25–30 kg/m², or ≥30 kg/m²) (28), and extent of central neck dissection (unilateral or bilateral).

Results

Clinicopathologic characteristics of 646 N1b PTC patients who underwent unilateral MRND

Of the 646 N1b PTC patients, 197 (30.5%) were men and 449 (69.5%) were women (Table 1). The mean age was 44.7 years, and 310 (48.0%) were >45 years of age. Right-sided MRND was performed in 343 (53.1%) patients, whereas left-sided MRND was performed in 303 (46.9%) patients. Since BRAF mutation analysis started to be performed at the authors' institution in 2008, BRAF status was available for only 298 patients. The BRAF positivity rate among these patients was 71.5%. There were 11 (17.0%) follicular, 12 (18.5%) diffuse sclerosing, and one (0.2%) tall-cell variant. The mean tumor size was 1.6 cm, and 209 (32.4%) patients had tumors <1.0 cm. Multiplicity, bilaterality, microscopic ETE, gross ETE, and CLT were seen in 234 (36.2%), 207 (32.0%), 428 (66.3%), 114 (17.6%), and 168 (26.0%) patients, respectively. Skip metastases, defined as lateral LN metastasis without central LN metastasis, were found in 91 (14.1%) patients.

Table 1.

Baseline Clinicopathologic Characteristics of 646 N1b PTC Patients who Underwent Unilateral MRND

Clinicopathologic characteristics	n (%)
Male	197 (30.5)
Age (years)
Mean ± SD	44.7 ± 12.5
>45	310 (48.0)
MRND side
Right	343 (53.1)
Left	303 (46.9)
BRAF positivity^a	213 (71.5)
PTC variants
Conventional	622 (96.3)
Follicular	11 (17.0)
Diffuse sclerosing	12 (18.5)
Tall cell	1 (0.2)
Tumor size (cm)
Mean ± SD	1.6 ± 1.1
≤0.5	49 (7.6)
0.5–1.0	160 (24.8)
1.0–2.0	278 (43.0)
2.0–4.0	137 (21.2)
>4.0	22 (3.4)
Multiplicity	234 (36.2)
Bilaterality	207 (32.0)
ETE
Microscopic	428 (66.3)
Gross	114 (17.6)
CLT	168 (26.0)
Regional LN metastasis
Central	555 (85.9)
Lateral	646 (100.0)
Simultaneous metastasis^b
Single level	165 (25.5)
Multilevel	481 (74.5)
Follow-up period (months)
Median ± SD	53.4 ± 31.1
Lateral neck recurrence	26 (4.0)

BRAF mutation analysis was implemented in 2008 and was performed in 298 PTC patients.

Among level II–IV metastasis.

PTC, papillary thyroid carcinoma; MRND, modified radical neck dissection; SD, standard deviation; ETE, extrathyroidal extension; CLT, chronic lymphocytic thyroiditis; LN, lymph node.

Distribution of lateral LN metastasis in 646 N1b PTC patients who underwent unilateral MRND

Of the 646 dissections for each level, 349 (54.0%), 485 (75.1%), 499 (77.2%), and 90 (13.9%) had metastatic LNs in level II, III, IV, and V, respectively (Table 2). Even when preoperative US and CT did not show any evidence of metastasis in a given level, occult metastatic LNs were detected in 166/411 (40.4%), 124/219 (56.6%), 52/111 (46.8%), and 48/556 (8.6%) of the level II, III, IV, and V dissections, respectively.

Table 2.

Distribution of Lateral LN Metastasis in 646 N1b PTC Patients who Underwent Unilateral MRND

	Overall metastasis			Occult metastasis ^a
Level	Metastatic levels	Dissected levels	%	Metastatic levels	Dissected levels	%
II	349		54.0	166	411	40.4
III	485		75.1	124	219	56.6
IV	499	646	77.2	52	111	46.8
V	90^b		13.9	48	556	8.6

Nodal yield from dissections without preoperative evidence of suspicious metastasis on the corresponding levels by both US and CT.

Isolated level V metastasis was observed in only four (4.4%) patients. The remaining 86 (95.6%) patients showed simultaneous metastasis with levels II, III, and/or IV.

US, ultrasound; CT, computed tomography.

Predictive factors for level V metastasis in 642 N1b PTC who underwent unilateral MRND

To investigate the predictive factors for level V metastasis, four patients with isolated level V metastasis were excluded. Ultimately, a total of 642 N1b PTC patients were assessed. Univariate analysis revealed that tumor size (p = 0.019), central LN metastasis (p = 0.007), and simultaneous metastasis (p < 0.001) were significantly associated with level V metastasis (Table 3). However, sex (p = 0.976), age >45 years (p = 0.339), BRAF positivity (p = 0.600), multiplicity (p = 0.295), bilaterality (p = 0.920), ETE (p = 0.467), and CLT (p = 0.221) were not significantly associated with level V metastasis. In multivariate analysis, only three-level (levels II–IV) simultaneous metastasis (adjusted odds ratio = 3.079, p = 0.003) was an independent predictor for level V metastasis. However, tumor size and central LN metastasis were not independent predictors for level V metastasis.

Table 3.

Predictive Factors for Level V Metastasis in the 642^a N1b PTC Patients who Underwent Unilateral MRND

	Level V metastasis, n (%)			Multivariate analysis ^b
Clinicopathologic characteristic	Absent	Present	p-Value	Adjusted OR [CI]	p-Value
Total	556 (86.6)	86 (13.4)	NA	NA	NA
Sex
Female	387 (69.6)	60 (69.8)		NA	NA
Male	169 (30.4)	26 (30.2)	0.976	NA	NA
Age (years)
≤45	286 (51.4)	49 (57.0)		NA	NA
>45	270 (48.6)	37 (43.0)	0.339	NA	NA
BRAF positivity^c
Absent	71 (27.7)	13 (31.7)		NA	NA
Present	185 (72.3)	28 (68.3)	0.600	NA	NA
Tumor size (cm)
≤0.5	46 (8.3)	3 (3.5)		Ref.	NA
0.5–1.0	141 (25.4)	18 (20.9)		1.764 [0.488–6.381]	0.387
1.0–2.0	240 (43.2)	35 (40.7)		1.721 [0.496–5.970]	0.392
2.0–4.0	110 (19.7)	27 (31.4)		2.532 [0.712–9.013]	0.151
>4.0	19 (3.4)	3 (3.5)	0.019	1.499 [0.269–8.399]	0.644
Multiplicity
Absent	349 (62.8)	59 (68.6)		NA	NA
Present	207 (37.2)	27 (31.4)	0.295	NA	NA
Bilaterality
Absent	378 (68.0)	58 (67.4)		NA	NA
Present	178 (32.0)	28 (32.6)	0.920	NA	NA
ETE
Absent	94 (16.9)	10 (11.6)		NA	NA
Microscopic	363 (65.3)	61 (70.9)		NA	NA
Gross	99 (17.8)	15 (17.4)	0.467	NA	NA
CLT
Absent	416 (74.8)	59 (68.6)		NA	NA
Present	140 (25.2)	27 (31.4)	0.221	NA	NA
Central LN metastasis
Absent	87 (15.6)	4 (4.7)		Ref.	NA
Unilateral	313 (56.3)	50 (58.1)		2.444 [0.837–7.136]	0.102
Bilateral	156 (28.1)	32 (37.2)	0.007	2.717 [0.893–8.260]	0.078
Simultaneous metastasis^d
1-level	161 (29.0)	10 (11.6)		Ref.	NA
2-level	218 (39.2)	33 (38.4)		2.062 [0.975–4.364]	0.058
3-level	177 (31.8)	43 (50.0)	<0.001	3.079 [1.462–6.485]	0.003

Four cases with isolated level V metastasis were excluded from a total of 646 N1b PTC patients who underwent unilateral MRND.

All variables that reached p < 0.05 in univariate analysis were included.

BRAF mutation analysis was implemented in 2008 and was performed in 297 PTC patients.

Among level II–IV metastasis.

NA, not available.

Distribution of lateral neck recurrence in 26 N1b PTC patients who showed lateral neck recurrence after unilateral MRND

The median follow-up time was 53.4 months (Table 1). Lateral neck recurrence was found in 26 (4.0%) N1b PTC patients who underwent unilateral MRND, and the mean time to recurrence was 27.6 months. Among the 26 patients with lateral neck recurrence, ipsilateral, contralateral, and bilateral recurrences developed in 18 (69.2%), seven (26.9%), and one (3.8%) patients, respectively. Of the 18 ipsilateral neck recurrences, one-, two-, and three-level involvements were detected in 14 (53.9%), one (3.8%), and three (11.6%) patients, respectively. Of the seven contralateral neck recurrences, one-, two-, and three-level involvements were detected in four (15.4%), two (7.7%). and (3.8%) patients, respectively. Only one (3.8%) patient had bilateral neck recurrence. In particular, only two (7.7%) patients showed level V recurrence in the ipsilateral side, and there was no contralateral level V recurrence (Table 4).

Table 4.

Distribution of Lateral Neck Recurrence in the 26 N1b PTC Patients who Showed Lateral Neck Recurrence After Unilateral MRND

	Recurred levels
Lateral neck levels	Ipsilateral, n (%)	Contralateral, n (%)
II	11/26 (42.3)	2/26 (7.7)
III	5/26 (19.2)	5/26 (19.2)
IV	7/26 (26.9)	6/26 (23.1)
V	2/26 (7.7)	0/26 (0.0)

Surgery-related outcomes in the 526 propensity score-matched N1b PTC patients according to level V dissection status

To compare various surgery-related outcomes under adjusted conditions, propensity score matching was performed in 556 N1b PTC patients who were clinically negative for level V and underwent unilateral MRND (levels II–V) with 329 N1b PTC patients who were clinically negative for level V and underwent unilateral SND (levels II–IV). Of the 885 patients, 263 matched pairs were obtained after stringent propensity score matching (Table 5). No significant differences were observed between the two groups with respect to any of the matching variables (p = 1.0). Under a matched condition, the MRND group exhibited a significantly longer operation time (221.4 min vs. 175.0 min; p < 0.001) compared with the SND group. Furthermore, “shoulder syndrome,” encompassing shoulder dysfunction and pain, was significantly more frequent in the MRND group compared with the SND group (9.1% vs. 2.7%; p = 0.002).

Table 5.

Surgery-Related Outcomes in the 526 Propensity Score-Matched ^a N1b PTC Patients According TO Level V Dissection Status

	Level V dissection, n (%)
Surgery-related outcomes	Absent (n = 263)	Present (n = 263)	p-Value
Operation time (min)
Mean ± SD	175.0 ± 51.8	221.4 ± 52.9	<0.001
Total drainage (ml)
Mean ± SD	264.6 ± 712.9	298 ± 337.0	0.487
Hemorrhage
Absent	262 (99.6)	263 (100.0)
Present	1 (0.4)	0 (0.0)	1.000
Chyle leakage
Absent	262 (99.6)	258 (98.1)
Present	1 (0.4)	5 (1.9)	0.216
Wound infection
Absent	263 (100.0)	263 (100.0)
Present	0 (0.0)	0 (0.0)	1.000
Shoulder syndrome^b
Absent	256 (97.3)	239 (90.9)
Present	7 (2.7)	24 (9.1)	0.002

Matching variables: sex, age (per 10 years), Asia-Pacific body mass index consensus (<18.5 kg/m², 18.5–23 kg/m², 23–25 kg/m², 25–30 kg/m², or ≥30 kg/m²), and extent of central neck dissection (unilateral or bilateral).

Subjective symptoms encompassing shoulder dysfunction or shoulder pain, which were persistent after six months from the initial surgery.

Discussion

The American Thyroid Association consensus statement (10), the British Thyroid Association Guidelines (11), and a number of recent reports (29 –31) have proposed that comprehensive lateral neck dissection (i.e., dissection that encompasses levels II–V) is necessary for optimal disease control for N1b PTC patients. However, it is still controversial regarding whether not level V should be routinely dissected, considering the potential of morbidity associated with injury to the spinal accessory nerve (17 –19). Therefore, several studies have argued against routine level V dissection for N1b PTC patients because of the relatively low incidence of level V metastasis and recurrence (14 –16). Moreover, one report did not observe any survival advantage in classic MRND (levels I–V) compared to SND (levels II–IV) (32). Therefore, the current study was designed to determine whether routine level V dissection should be included in MRND for clinically suspicious N1b PTC patients.

As shown in Table 1, skip metastases were found in 91 (14.1%) patients, a finding that is consistent with results from other studies (33,34). Simultaneous multilevel metastasis was also observed in 481 (74.5%) N1b PTC patients. Previous studies regarding lateral LN metastasis patterns (12,35) reported an incidence of multilevel lateral LN metastasis in N1b PTC patients that was >80%. The incidence of lateral neck recurrence after MRND in this study was 3.7%. However, higher incidences of recurrence after MRND have been seen in other studies (15,29,36 –38). This comparatively low incidence of recurrence in this study could be explained by (i) shorter follow-up time, (ii) exclusion of bilateral MRND cases, and (iii) exclusion of other recurrences, including operation bed and central neck area. As shown in Table 3, most of the lateral neck recurrences occurred in the previously dissected side. A similar pattern of lateral neck recurrence has been observed in previous studies (15,36,37).

In this study, the incidence of overall metastasis in levels II–IV was >50%, and that of occult metastasis in levels II–IV was >40%. Other studies focusing on the extent of lateral neck dissection have reported incidences of level II–IV metastasis that were consistently >50% (29 –31,39,40). Therefore, comprehensive dissection of levels II–IV may be necessary in N1b PTC patients. However, incidence of level V metastasis in the previous studies ranged from 8% to 53% (41). Since the above previous studies regarding level V metastasis only focused on the incidence of overall metastasis and included <300 cases, the present study analyzed >600 cases, and focused not only on overall level V metastasis but also occult level V metastasis. As shown in Table 2, the incidence of overall level V metastasis was 13.9% and that of occult level V metastasis was only 8.6% in this study. Moreover, as shown in Table 3, only two (7.7%) level V recurrences were observed among the 26 recurred N1b PTC patients who underwent unilateral MRND. From the low incidence of occult level V metastasis and level V recurrence after MRND, it was concluded that routine level V dissection might not be necessary in N1b PTC patients.

The sensitivity of preoperative imaging is particularly poor for detecting the presence of level V metastasis (39). Therefore, the predictive factors of level V metastasis were investigated to help establish indications for level V dissection in clinically suspicious N1b PTC patients (Table 3). In this study, only three-level (levels II–IV) simultaneous metastasis (adjusted odds ratio = 3.079, p = 0.003) was an independent predictor for level V metastasis. Therefore, although the finding is not statistically significant in patients with two-level simultaneous metastasis, it was concluded that there is a greater tendency for level V metastasis to occur as more levels exhibit simultaneous metastasis in N1b PTC patients. Other studies have also shown that simultaneous multilevel metastasis is an independent predictor for level V metastasis (14,31).

Under a matched condition in N1b PTC patients, the MRND (level II–V) group had a significantly longer operation time (221.4 min vs. 175.0 min; p < 0.001) and hospital stay (6.0 days vs. 5.4 days; p = 0.021) compared with the SND (level II–IV) group (Table 4). Moreover, “shoulder syndrome,” defined as chronic painful and limited shoulder movement, was significantly more frequent in N1b PTC patients who underwent routine level V dissection (9.1% vs. 2.7%; p = 0.002). As shown in previous studies, level V dissection, which involves clearance of the posterior triangle, has the potential to increase the risk of spinal accessory nerve injury, despite gross preservation (17 –19). Injury to the spinal accessory nerve can lead to a dropped shoulder and the inability to raise the arm >90°, otherwise known as “shoulder syndrome.” Furthermore, spinal accessory nerve-associated morbidity has a negative impact on patients' social activities, decreasing their ability to participate in daily and leisure activities and also having a negative impact on work ability (42).

This study has several limitations. First, certain features were inevitable due to its nonrandomized retrospective nature. Therefore, the patient information in the data might be incomplete. Second, since not all specimens were labeled by sublevel, it was not possible to analyze the incidence of sublevel metastasis Va and Vb. However, regardless of the analysis of sublevel metastasis, the incidence of occult level V metastasis was definitely low in this study (only 8.6%). Therefore, the conclusion of this study would not change, even if sublevel metastasis of level V had been analyzed. Third, inter-observer variability might have occurred in the neck level interpretation during surgery. Fourth, the mean follow-up period (43.2 months) in this study might have been too short to observe all the relevant recurrence incidences and to assess survival accurately. To address this, further studies with longer follow-up periods will be required. Fifth, “shoulder syndrome” was defined as symptoms encompassing shoulder dysfunction and pain, which were persistent after six months from the initial surgery. Therefore, despite the detailed chart review involved in this study, the incidence of “shoulder syndrome” might be under- or overestimated. Sixth, a total of 11 follicular variant of PTC cases were included in this study. Follicular variant of PTC is a heterogeneous disease composed of two distinct groups: non-encapsulated and encapsulated forms (43). Moreover, a recently published article suggested that the noninvasive encapsulated form should be referred to as “noninvasive follicular thyroid neoplasms with papillary-like nuclear features” due to its very low risk of adverse outcomes (44). However, due to the long period covered for patient enrollment (between January 1997 and June 2015), not all follicular variant cases were separately recorded as encapsulated (invasive or noninvasive) or non-encapsulated at the authors' institution. However, this study also has several strengths. First, >600 cases of N1b PTC were analyzed. To the best of the authors' knowledge, this is the largest study regarding the extent of lateral neck dissection. Second, the study analyzed not only the incidence of overall metastasis, but also that of occult level V metastasis. Third, data from a single institution were used, and rigorous exclusion/inclusion criteria were used to produce a clear and accurate analysis. In particular, only unilateral MRND cases with pathologically proven nodal yield through levels II–V were included.

In conclusion, in clinically suspicious N1b PTC patients, levels II, III, and IV may be comprehensively dissected. However, because of the low incidence of metastasis/recurrence in level V and the clear evidence of increased morbidities from level V dissection, level V dissection in N1b PTC patients may be reserved for patients with three-level simultaneous metastasis or clinically/radiologically evident level V metastasis.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Siegel

, Ma

, Zou

, Jemal

. 2014. Cancer statistics, 2014. CA Cancer J Clin, 64:9–29.

Leboulleux

, Rubino

, Baudin

, Caillou

, Hartl

, Bidart

, Travagli

, Schlumberger

. 2005. Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis. J Clin Endocrinol Metab, 90:5723–5729.

Mazzaferri

, Jhiang

. 1994. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med, 97:418–428.

Lundgren

, Hall

, Dickman

, Zedenius

. 2006. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study. Cancer, 106:524–531.

Grebe

, Hay

. 1996. Thyroid cancer nodal metastases: biologic significance and therapeutic considerations. Surg Oncol Clin N Am, 5:43–63.

Kouvaraki

, Shapiro

, Fornage

, Edeiken-Monro

, Sherman

, Vassilopoulou-Sellin

, Lee

, Evans

. 2003. Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery, 134:946–954.

Machens

, Andreas, Hinze M, Raoul, Thomusch M, Oliver, Dralle M, Henning 2002. Pattern of nodal metastasis for primary and reoperative thyroid cancer. World J Surg, 26:22–28.

Wada

, Duh

Q-Y

, Sugino

, Iwasaki

, Kameyama

, Mimura

, Ito

, Takami

, Takanashi

. 2003. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg, 237:399.

de Meer

, Dauwan

, de Keizer

, Valk

, Rinkes

, Vriens

. 2012. Not the number but the location of lymph nodes matters for recurrence rate and disease-free survival in patients with differentiated thyroid cancer. World J Surg, 36:1262–1267.

10.

Stack

Jr ., Ferris

, Goldenberg

, Haymart

, Shaha

, Sheth

, Sosa

, Tufano

; American Thyroid Association Surgical Affairs Committee 2012. American Thyroid Association consensus review and statement regarding the anatomy, terminology, and rationale for lateral neck dissection in differentiated thyroid cancer. Thyroid, 22:501–508.

11.

Perros

, Boelaert

, Colley

, Evans

, Gerrard Ba

, Gilbert

, Harrison

, Johnson

, Giles

, Moss

, Lewington

, Newbold

, Taylor

, Thakker

, Watkinson

, Williams

; British Thyroid Association 2014. Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf), 81:1–122.

12.

Sivanandan

, Soo

. 2001. Pattern of cervical lymph node metastases from papillary carcinoma of the thyroid. Br J Surg, 88:1241–1244.

13.

Ahmadi

, Grewal

, Davidson

. 2011. Patterns of cervical lymph node metastases in primary and recurrent papillary thyroid cancer. J Oncol, 2011:735678.

14.

Lim

, Choi

, Yoon

, Koo

. 2010. Occult lymph node metastases in neck level V in papillary thyroid carcinoma. Surgery, 147:241–245.

15.

Caron

, Tan

, Ogilvie

, Triponez

, Reiff

, Kebebew

, Duh

, Clark

. 2006. Selective modified radical neck dissection for papillary thyroid cancer-is level I, II and V dissection always necessary?. World J Surg, 30:833–840.

16.

W-B

, Tao

S-Y

, Zhang

N-S

. 2012. Is level V dissection necessary for low-risk patients with papillary thyroid cancer metastasis in lateral neck levels II, III, and IV. Asian Pac J Cancer Prev, 13:4619–4622.

17.

Laverick

, Lowe

, Brown

, Vaughan

, Rogers

. 2004. The impact of neck dissection on health-related quality of life. Arch Otolaryngol Head Neck Surg, 130:149–154.

18.

Cappiello

, Piazza

, Giudice

, De Maria

, Nicolai

. 2005. Shoulder disability after different selective neck dissections (levels II–IV versus levels II–V): a comparative study. Laryngoscope, 115:259–263.

19.

Terrell

, Welsh

, Bradford

, Chepeha

, Esclamado

, Hogikyan

, Wolf

. 2000. Pain, quality of life, and spinal accessory nerve status after neck dissection. Laryngoscope, 110:620–626.

20.

Lesnik

, Cunnane

, Zurakowski

, Acar

, Ecevit

, Mace

, Kamani

, Randolph

. 2014. Papillary thyroid carcinoma nodal surgery directed by a preoperative radiographic map utilizing CT scan and ultrasound in all primary and reoperative patients. Head Neck, 36:191–202.

21.

Kim

, Park

, Son

, Kim

, Jeon

, Na

. 2008. Preoperative diagnosis of cervical metastatic lymph nodes in papillary thyroid carcinoma: comparison of ultrasound, computed tomography, and combined ultrasound with computed tomography. Thyroid, 18:411–418.

22.

Choi

, Kim

, Kwak

, Kim

, Chang

, Kim

. 2009. Preoperative staging of papillary thyroid carcinoma: comparison of ultrasound imaging and CT. AJR Am J Roentgenol, 193:871–878.

23.

Kim

, Woo

, Park

, Lee

, Choe

, Kim

. 2016. Influence of body mass index and body surface area on the behavior of papillary thyroid carcinoma. Thyroid, 26:657–666.

24.

Robbins

, Clayman

, Levine

, Medina

, Sessions

, Shaha

, Som

, Wolf

; American Head and Neck Society; American Academy of Otolaryngology—Head and Neck Surgery. 2002. Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology—Head and Neck Surgery. Arch Otolaryngol Head Neck Surg, 128:751–758.

25.

Edge

, Compton

. 2010. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol, 17:1471–1474.

26.

American Thyroid Association (ATA Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer; Cooper

, Doherty

, Haugen

, Kloos

, Lee

, Mandel

, Mazzaferri

, McIver

, Pacini

, Schlumberger

, Sherman

, Steward

, Tuttle

. 2009. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19:1167–1214.

27.

D'Agostino

Jr . 1998. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med, 17:2265–2281.

28.

World Health Organization. 2000. The Asia-Pacific Perspective: Redefining Obesity and its Treatment. Health Communications Australia, Sydney, Australia.

29.

Javid

, Graham

, Malinowski

, Quinn

, Carling

, Udelsman

, Callender

. 2016. Dissection of levels II through V is required for optimal outcomes in patients with lateral neck lymph node metastasis from papillary thyroid carcinoma. J Am Coll Surg, 222:1066–1073.

30.

, Fraser

, Pai

, Farrag

, Ladenson

, Tufano

. 2012. Determining the extent of lateral neck dissection necessary to establish regional disease control and avoid reoperation after previous total thyroidectomy and radioactive iodine for papillary thyroid cancer. Head Neck, 34:1418–1421.

31.

Zhang

X-J

, Liu

, Xu

D-B

, Mu

Y-Q

, Chen

W-K

. 2013. Should level V be included in lateral neck dissection in treating papillary thyroid carcinoma?. World J Surg Oncol, 11:1.

32.

Turanli

. 2007. Is the type of dissection in lateral neck metastasis for differentiated thyroid carcinoma important?. Otolaryngol Head Neck Surg, 136:957–960.

33.

Park

, Lee

, Kim

, Chang

, Park

. 2012. Skip lateral neck node metastases in papillary thyroid carcinoma. World J Surg, 36:743–747.

34.

Machens

, Holzhausen

, Dralle

. 2004. Skip metastases in thyroid cancer leaping the central lymph node compartment. Arch Surg, 139:43–45.

35.

Roh

, Kim

, Park

. 2008. Lateral cervical lymph node metastases from papillary thyroid carcinoma: pattern of nodal metastases and optimal strategy for neck dissection. Ann Surg Oncol, 15:1177–1182.

36.

Ito

, Kudo

, Takamura

, Kobayashi

, Miya

, Miyauchi

. 2012. Lymph node recurrence in patients with N1b papillary thyroid carcinoma who underwent unilateral therapeutic modified radical neck dissection. World J Surg, 36:593–597.

37.

Kim

, Park

, Lee

, Kim

, Jung

, Ryu

, Myong

, Chung

. 2014. Risk factors for recurrence after therapeutic lateral neck dissection for primary papillary thyroid cancer. Ann Surg Oncol, 21:1884–1890.

38.

Lee

, Roh

, Gong

, Cho

, Choi

, Nam

, Kim

. 2015. Risk factors for recurrence of papillary thyroid carcinoma with clinically node-positive lateral neck. Ann Surg Oncol, 22:117–124.

39.

Kupferman

, Weinstock

, Santillan

, Mishra

, Roberts

, Clayman

, Weber

. 2008. Predictors of level V metastasis in well-differentiated thyroid cancer. Head Neck, 30:1469–1474.

40.

Keum

, Ji

, Kim

, Jeong

, Choi

, Ahn

, Tae

. 2012. Optimal surgical extent of lateral and central neck dissection for papillary thyroid carcinoma located in one lobe with clinical lateral lymph node metastasis. World J Surg Oncol, 10:221.

41.

Khafif

, Medina

, Robbins

, Silver

, Weber

, Rinaldo

, Owen

, Shaha

, Ferlito

. 2013. Level V in therapeutic neck dissections for papillary thyroid carcinoma. Head Neck, 35:605–607.

42.

Inoue

, Nibu

, Saito

, Otsuki

, Ishida

, Onitsuka

, Fujii

, Kawabata

, Saikawa

. 2006. Quality of life after neck dissection. Arch Otolaryngol Head Neck Surg, 132:662–666.

43.

Lloyd

, Buehler

, Khanafshar

. 2011. Papillary thyroid carcinoma variants. Head Neck Pathol, 5:51–56.

44.

Nikiforov

, Seethala

, Tallini

, Baloch

, Basolo

, Thompson

, Barletta

, Wenig

, Al Ghuzlan

, Kakudo

, Giordano

, Alves

, Khanafshar

, Asa

, El-Naggar

, Gooding

, Hodak

, Lloyd

, Maytal

, Mete

, Nikiforova

, Nose

, Papotti

, Poller

, Sadow

, Tischler

, Tuttle

, Wall

, LiVolsi

, Randolph

, Ghossein

. 2016. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol, 2:1023–1029.