Quantification and Pattern of Central Compartment Lymph Nodes in pN1a Papillary Thyroid Cancer Patients

Abstract

Background: The background is to investigate the results of central compartment lymphadenectomy for pN1a papillary thyroid carcinoma (PTC) with regard to quantification and pattern of resected lymph nodes thereby providing basis for future compartment VI surgical intervention. Methods: The study comprised 443 pN1a PTC patients whose clinicopathological characteristics and central compartment lymphadenectomy results were compared and correlated with the primary thyroid cancer and lymph node metastasis (LNM) features. Ultimately, multivariate analysis was conducted to identify statistically significant impact factors for a high metastatic ratio (MR). Results: Dissected lymph nodes (DLNs) were more frequently identified in right level VI than left (P < .05) although there was no difference in in the number of resected metastatic lymph nodes (MLNs). Male sex, multifocality, extrathyroidal extension (ETE), and fewer DLNs were related to a high MR. There was a positive correlation between DLN and MLN, and a negative correlation between DLN and MR. Disease multifocality and ETE were identified more frequently in the left than the right thyroid lobe. Conclusion: The outcome of central compartment lymphadenectomy in pN1a PTC patients is associated with several factors, and a thorough dissection of lymph nodes improves the rate of metastatic lymph node resection.

Keywords

papillary thyroid carcinoma lymphadenectomy quantification pattern

Introduction

Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, and an explosive rise in the frequency of diagnosing PTC has increased nearly 800% in the United States over the preceding 35 years. Nearly 50% of the increase was due to PTC of 1 cm or less in diameter, with 87% being smaller than 2 cm. This dramatic rise in mostly subclinical disease has been attributed largely to more frequent and widespread use of imaging of the head and neck for unrelated investigations, with the unanticipated discovery of these incidental cancers.¹ Nevertheless, thyroid cancer mortality remained flat, and the overall survival rate is excellent. However, PTC has a high rate of lymph node metastasis, even for microcarcinomas, defined as PTC of ≤1 cm.^2-4 Studies have demonstrated that PTC patients with high-risk features such as male sex, larger tumor size, and extrathyroidal extension (ETE), in addition to the lower risk younger aged patients are at increased risk for lymph node metastasis.^5,6 The pattern of spread of cervical lymph nodes in PTC typically follows a logical sequence from perithyroidal to deeper central compartment VI nodes, to lower (compartment IV) then eventually higher (compartments III and II) lateral jugular nodes, documented by prior studies.^7,8 The intent of our study was to review the lymphadenectomy results of the central compartment in pN1a PTC patients, determine any associated influencing factors, and then quantify and identify any pattern that could provide a basis for future compartment VI surgical intervention.

Materials and Methods

Patients

The study comprised a retrospective review of 443 consecutive pN1a PTC patients treated at the Head and Neck Surgery, Fujian Cancer Hospital between May 2019 and January 2021. Inclusion criteria were as follows: 1) FNA biopsy confirmed stage T3-4 and high-risk (cN+, invasive) T1-2 PTC patients who underwent thyroidectomy combined with central neck dissection; and 2) pathology was PTC and stage pN1a. Excluded were patients with: 1) bilateral tumors and contralateral lobe dissemination; 2) evidence of lateral neck LNM or distant metastasis; and 3) any treatment history of thyroid-associated medication or prior thyroid surgery. Clinicopathologic features including gender, age at diagnosis, tumor location, tumor maximal diameter (TMD), multifocality, ETE, lymph node location, number of DLN, and number of MLN and MR (MLN/DLN) were collected.

Operation

To ensure the consistency of surgical strategies, the operations were performed by the same treatment group. In order to ensure the accuracy of pathological diagnosis, intraoperative frozen section was applied to all patients. Once malignancy of the thyroid nodule was confirmed; central neck dissection was performed on the side of malignancy. Central compartment refers to level VI. A consent to surgery was signed by patients and immediate family member before the operation.

Statistical Analysis

Descriptive statistics were presented as summarized data. Continuous variables were expressed as number (%) or $\bar{x} \pm s$ . Measurement data were tested for normality, non-normalized data was performed by non-parametric test, and results were expressed as median (p25-p75). Scatter charts and Spearman test were used for correlation analysis. The χ2-test was used to compare the enumeration data and impact factors were identified by logistic regression analysis. P < .05 was considered as statistically significant. All statistical analyses were performed by IBM SPSS statistics v26.0.

Results

The average age was (44.5 ± 11.5) years, and the mean TMD was (1.7 ± .99) cm. There were 275 left lobe PTCs and 168 in the right. The mean number of DLN, MLN, and MR were (6.9 ± 4.46), (3.1 ± 2.58), and (.5 ± .3), respectively. The incidence of postoperative hypoparathyroidism was low and transient because all patients underwent dissection limited to one side of the central compartment (4, .9%); 3 patients suffered temporary hoarseness that resolved within 3 months. Due to ETE or contralateral benign tumors with indications for surgery, 107 patients underwent total thyroidectomy and 61 were treated with radioactive I¹³¹ therapy. Patients were followed for 5–24 months postoperatively, and 5 were lost to follow-up, but none showed evidence of recurrence.

By comparing lymphadenectomy results with different clinicopathological characteristics, we found that MLN and DLN had a higher frequency in patients <55 years old, and there was more MLN associated with TMD ≤1 cm than in TMD >2 cm, but there was no significant difference in DLN of different TMD. Patients without multifocality and ETE had more frequent DLN, but no difference in MLN. Lymph node dissection results comparing males to females did not differ significantly (Table 1).

Table 1.

Comparison of Quantification of Lymphadenectomy Results.

Feature	Metastatic Lymph Nodes	Z/H(K)	P	Dissected Lymph Nodes	Z/H(K)	P
Gender		−1.111	.267		−.960	.337
Male	2 (1–4)			6 (3–9)
Female	2 (1–4)			6 (4–9)
Age		−3.239	.001		−2.769	.006
<55	2 (1–4)			7 (4–9)
≥55	2 (1–3)			5 (3–7)
Tumor maximal diameter		21.310	.000		7.195	.066
≤1 cm	3 (2–4)			7 (5∼10)
(1,2]	2 (1–4)			6 (3∼8.25)
(2,4]	2 (1–3)			6 (4∼9)
> 4 cm	2 (1–3.5)			6 (4∼10.25)
Multifocality		−.328	.743		−2.595	.009
Yes	2 (1∼4)			5 (3∼9)
No	2 (1∼4)			7 (5∼10)
Extrathyroidal extension		−.594	.553		−2.805	.005
Yes	2 (1∼4)			6 (3∼9)
No	2 (1∼4)			7 (4∼10)

The patients were stratified into groups according to the median number of DLN (6) and the MR (.50): high DLN group (HDLN, >6), low DLN group (LDLN, ≤6); high MR group (HMR, >.50) and low MR group (LMR, ≤.50). The results showed that MR was varied by gender, multifocality, ETE, and classified DLN groups (Table 2). Regression analysis results also indicated that male sex, multifocality, ETE, and LDLN were risk factors for HMR (Table 3).

Table 2.

Metastatic Ratio Pattern of Papillary Thyroid Carcinoma.

Feature	Cases (%)	Metastatic Ratio [Number (%)]		χ2	P
Feature	Cases (%)	High Metastatic Ratio Group	Low Metastatic Ratio Group	χ2	P
Gender				5.404	.020
Male	137 (30.9)	69 (50.4)	68 (49.6)
Female	306 (69.1)	118 (38.6)	188 (61.4)
Age				2.320	.128
<55	347 (78.3)	153 (44.1)	194 (55.9)
≥55	96 (21.7)	34 (35.4)	62 (64.6)
Tumor location				3.125	.077
Left	275 (62.1)	125 (45.5)	150 (54.5)
Right	168 (37.9)	62 (36.9)	106 (63.1)
Tumor maximal diameter				4.562	.207
≤1 cm	123 (27.8)	58 (47.2)	65 (52.8)
(1,2]	166 (37.5)	74 (44.6)	92 (55.4)
(2,4]	132 (29.8)	46 (34.8)	86 (65.2)
> 4 cm	22 (4.9)	9 (40.9)	13 (59.1)
Multifocality				10.824	.001
Yes	213 (48.1)	107 (50.2)	106 (49.8)
No	230 (51.9)	80 (34.8)	150 (65.2)
Extrathyroidal extension				15.938	.000
Yes	282 (63.7)	139 (49.3)	143 (50.7)
No	161 (36.3)	48 (29.8)	113 (70.2)
Dissected lymph nodes				7.246	.007
High dissected lymph nodes group	206 (46.5)	73 (35.4)	133 (64.6)
Low dissected lymph nodes group	237 (53.5)	114 (48.1)	123 (51.9)

Table 3.

Logistic Regression Analysis for Impact Factors for Metastatic Ratio

Category	OR (95% CI)	P-Value
Gender	1.742 (1.129–2.690)	.012
Multifocality	2.067 (1.349–3.166)	.001
Extrathyroidal extension	2.414 (1.560–3.736)	.000
Dissected lymph nodes	.626 (.412–.952)	.029

Scatter charts and Spearman tests showed positive correlation between DLN and MLN (ρ = .480, P = .000) (Figure 1), while negative correlation between DLN and MR (ρ = −.394 P = .000) (Figure 2).

Figure 1.

Correlation between dissected lymph nodes and metastatic lymph nodes.

Figure 2.

Correlation between dissected lymph nodes and metastatic ratio.

The lymphadenectomy results that compared right to left thyroid lobes showed that the number of DLN on the right side was significantly greater than the left, whereas the left side MR was higher; even so there was no significant difference in MLN (Table 4). We also found no difference between right and left sides comparing gender and TMD. Patients <55 years old accounted for 75.3% and 83.3% of the left and right sides, respectively. The incidence of both multifocality and ETE was significantly greater in the left lobe (Table 5).

Table 4.

Comparison of Lymphadenectomy Results in Different Lobes.

	Metastatic Lymph Nodes	Dissected Lymph Nodes	Metastatic Ratio
Left	2 (1–4)	5 (3–8)	.50 (.25–.80)
Right	2 (1–4)	7 (5–10)	.43 (.20–.67)
Z	−1.678	−4.794	−2.833
p	.093	.000	.005

Table 5.

Impact of Clinicopathological Features on Lymphadenectomy Results of Different Lobes.

Features	Tumor Location [Number (%)]		χ2	p
Features	Left	Right	χ2	p
Gender			.188	.665
Male	83 (30.2%)	54 (32.1%)
Female	192 (69.8%)	114 (67.9%)
Age			3.992	.046
<55	207 (75.3%)	140 (83.3%)
≥55	68 (24.7%)	28 (16.7%)
Tumor maximal diameter			4.836	.184
≤1 cm	72 (26.2%)	51 (30.4%)
(1,2]	100 (36.4%)	66 (39.3%)
(2,4]	85 (30.9%)	47 (28%)
>4 cm	18 (6.5%)	4 (2.4%)
Multifocality			41.266	.000
Yes	165 (60%)	48 (28.6%)
No	110 (40%)	120 (71.4%)
Extrathyroidal extension			4.098	.043
Yes	185 (67.3%)	97 (57.7%)
No	90 (32.7%)	71 (42.3%)

Discussion

Active surveillance has been applied to low-risk papillary thyroid microcarcinoma patients and proved to have low rates of size enlargement and appearance of nodal metastasis; over 70% of these cases did not progress with up to 10 years of follow-up.⁹ However , even though the majority of early-staged patients followed our advice for active surveillance rather than surgery, and despite prophylactic lymph node dissection being performed on noninvasive, cN0 stage T1 or T2 PTC was not recommended according to ATA guidelines,¹⁰ and patients with smaller tumors accounted for the majority of patients in this study (≤1 cm: 27.8%; 1–2 cm: 37.5%). We surmise that this may reflect the concern patients have with “watchful waiting” of a cancer, even if they are given reassurance about the relative innocence of very small PTCs and the excellent survival if subsequent surgery were to become necessary.^1,11,12

Thyroidectomy with central compartment lymph node dissection for advanced and high-risk early-stage PTC is recommended by ATA guidelines.¹⁰ Then, what extent of lymphadenectomy should be considered standard and adequate? Our experience demonstrated a wide range in the number of lymph nodes dissected (1–28), yet 53.5% cases had only 6 or fewer DLN. Therefore, from these data, it is difficult to delineate an appropriate value as a “threshold” for the minimum number of dissected lymph nodes to be considered adequate. Although we found more DLN in the right level VI than the left, there was no significant difference in MLN between the two. While this resulted in a lower MR of right side, similar to previous publications,^7,8,13 this ratio seems somewhat artificial and less meaningful in this circumstance. The presence of VIb lymph nodes deep to the right recurrent laryngeal nerve may be the reason, compared to the direct anatomic course of the left RLN along the posterolateral aspect of the trachea.

Statistical analysis showed both MLN and DLN were higher in patients <55 years old. Young age has been shown to be an independent risk factor for lymph node metastasis,^14,15 but usually refers to teenage or patients in their twenties. TMD ≤1 cm cases had more frequent MLN than cases with TMD >2 cm is a somewhat “odd” result. Review of the pathological data, however, showed that ETE of larger tumors could sometimes cause malignant adherence of tumor, lymph nodes, and surrounding soft tissues as an aggregate “cancer focus” that could have affected the count of individual lymph nodes. In addition, the small number of cases of advanced tumors could also have affected the accuracy of statistical results. It seems counterintuitive as to why more lymph nodes were obtained in patients without multifocality or ETE, but the statistical analysis did show a higher chance of HMR in patients with features above. As one of the independent risk factors for PTC, men in the study also showed a higher rate of HMR. These results are consistent with other studies on risk factors of PTC.^4-6,15-17 However, no differences in HMR rates were found between tumor sizes, suggesting that standardized lymph node dissection should be performed equally in N+ patients, regardless of tumor size.

Correlation analysis showed an inverse correlation between DLN and MR, and χ2-test indicated a higher LMR rate in LDLN, which suggested that lymph node number not only depends on tumor spread but could be influenced by other factors. Therefore, a “berry-picking” approach to lymph nodes is not advisable; thorough lymph node dissection can reduce the rate of overlooked positive lymph nodes.

With the quantification results and pattern we found in pN1a PTC patients, lymphadenectomy results were impacted by several factors, but precise, thorough, and careful central compartment dissection can ensure resection of metastatic nodes. Surgical complications are mostly temporary and can be minimized within acceptable limits.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Fujian Provincial Health Technology Project (Grant number: 2019-CXB-7) / (Grant number: 2019-ZQNB-4); Joint Funds for the innovation of science and Technology, Fujian province (Grant number: 2019Y9035); Natural Science Foundation of Fujian Province (Grant number: 2021J01446) / (Grant number: 2019J01190).

Ethical Statement

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Data Availability Statements

The data that support the findings of this study are available on request from the corresponding author.

ORCID iDs

Hui Liu

Cong Bian

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