1. Introduction
As the most common malignancy of the endocrine system, the incidence of thyroid carcinoma has shown a constant increase in recent years [
1,
2]. Papillary thyroid carcinoma (PTC) is the most prevalent among all pathological types of thyroid cancer. Due to its relatively indolent characteristic, patients with PTC often exhibit satisfactory prognosis in long-term follow-up [
3]. However, cervical lymph node metastasis (LNM) occurs frequently in PTC, with reported occurrence rates ranging from 40–90% [
4]. Even patients in the early stages of PTC can suffer from LNM [
5]. LNM is also regarded as an independent risk factor for tumor recurrence after initial surgery for PTC patients [
6,
7,
8], making it an important aspect of cervical management.
Usually, the cervical lymph node metastases of PTC patients occur first in the central compartment and subsequently in the lateral neck [
8]. For patients with preoperatively detected CLNM by ultrasonography or fine-needle aspiration (FNA) examinations, surgical intervention covering both primary tumor site and central lymph node regions would be performed to avoid postoperative recurrence. This is the approach worldwide. In addition, prophylactic central lymph node dissection (CLND) is also recommended by the Japanese Society of Thyroid Surgeons for patients with negative central lymph node metastasis (CLNM) based on the probability of occult CLNM, with incidence rates ranging from 30–80% [
9,
10]. Some researchers also suggest that prophylactic CLND should be routinely conducted for cases with T3 or T4 tumors [
11]. For the management of lateral cervical compartment, studies have revealed that 18.6% to 39.5% of PTC patients may present with occult lateral lymph node metastasis (LLNM) [
12,
13], and up to 21.1% of papillary thyroid microcarcinoma (PTMC) patients could have LLNM [
14]. Conventionally, PTMC is perceived as a low-risk subgroup in terms of lateral neck involvement. On the other hand, the diagnostic sensitivity of preoperative ultrasonography for LLNM was reported to be lower than 30% [
15], indicating the difficulty of LLNM detection. Therefore, some LLNM in PTC patients may be ignored and present as cervical lymph node recurrence during postoperative follow-up. However, considering the increased risk of postoperative complications resulting from lateral lymph node dissection (LLND), prophylactic LLND is generally not accepted as a standard strategy for patients with PTC [
16]. Reflecting on these considerations, it would be unwise to either blindly oppose or routinely extend the usage of prophylactic LLND, warranting further meticulous risk assessment of lateral neck involvement for PTC patients with positive CLNM to guide individualized surgical strategies. This may be valuable in avoiding unnecessary surgery-related complications that may result from prophylactic LLND.
Numerous studies have focused on overall LNM or CLNM [
9,
17]. Yet, studies targeting LLNM in PTC patients are limited, only qualitatively summarizing the risk factors of LLNM in patients with general PTC [
5,
6,
15] and lacked more refined stratifications based on the patients’ characteristics. Here in our study, a meticulous evaluating system that can efficaciously quantify risks of LLNM for PTC with different clinical features was established.
2. Materials and Methods
2.1. Patient Cohort
Between 2018 and 2020, 568 thyroid carcinoma patients received initial surgery at the following three hospitals: Department of Otorhinolaryngology, Head and Neck Surgery at the Eye, Ear, Nose and Throat Hospital of Fudan University; the Department of General Surgery at Ruijin Hospital of Shanghai Jiao Tong University School of Medicine; and the Department of General Surgery, Civil Aviation Shanghai Hospital. All patients were diagnosed as positive CLNM by postoperative pathological analyses. Patients with any of the following criteria were excluded from this research: (1) non-PTC pathological type (n = 41); (2) having received thyroid-related surgery previously (n = 16); and (3) history or coexistence of other primary tumors (n = 8). Following these criteria, a total of 503 patients were included and analyzed. This study was approved by the Institutional Ethics Committee of the Eye & ENT Hospital of Fudan University and the Ruijin Hospital of Shanghai Jiao Tong University School of Medicine.
2.2. Surgical Management
Clinicopathological data were collected to set up the retrospective database. A total of 280 (55.7%) patients received thyroid lobectomy and the other 223 (44.3%) patients received total thyroidectomy. Central lymph node dissection was conducted for all patients enrolled. Therapeutic LLND was performed for those with clinically detected LLNM using both preoperative ultrasonography and fine-needle aspiration (FNA). The prophylactic LLND was conducted only for those with clinical detected lateral lymph nodes that were highly suspected as having tumor involvement using preoperative ultrasonography but later proven LLNM negative by FNA biopsy. Patients enrolled were treated with postoperative TSH suppression therapy and RAI (Radioactive Iodine) therapy according to the 2015 ATA Guidelines. The pathological diagnoses were confirmed by at least two board-certified pathologists. For patients who received CLND only, if positive LLNM were found by ultrasonography and FNA within six months after initial surgery, they will be regarded as having lateral involvement at the time of operation. The thyroid glands were categorized into three equal volumes (upper portion, middle portion, and lower portion) based on the consensus of most clinical medical centers. Tumors with a maximum diameter of more than 2 cm that were primarily located in the upper portion and did not exceed the lower 1/3 thyroid gland were also defined as upper portion tumor in this study.
2.3. Statistical Analyses
Chi-square and independent t-tests were used for comparing categorical and continuous variables, respectively. Logistic univariate and multivariate regression analyses were used to select risk factors that were significantly correlated with LLNM by the SPSS 24.0 package (SPSS Inc., Chicago, IL, USA). Variables screened by multivariate analysis were further used for the establishment of a risk prediction model nomogram, performed by R software (version 3.5.1; R Development Core Team, Vienna, Australia). Then the discrimination and consensus degree of our newly established predictive model was tested by the concordance index (C-index), receiver operating characteristic (ROC) curve, and the calibration curve.
4. Discussion
There is an ongoing debate about the optimal strategy of lateral neck management for PTC patients with positive CLNM. Here in our study, a meticulous risk assessment system was created for these patients to quantitatively assess the lateral neck involvement risk. Patients with ≥5 positive CLN was classified into high-risk group based on their significantly higher rate of LLNM than other patients.
For those with <5 positive CLN, PTMC and LPTC patients with evaluation scores no less than 100 and 150 according to their respective nomogram were also categorized into the high-risk group, both with LLNM rates of over 40%. On the contrary, those with evaluation scores = 0 and less than 100 according to nomograms for PTMC and LPTC patients, respectively, were stratified as a low LLNM risk group due to the extremely low lateral neck involvement rates (0.7% and 2.2% for PTMC and LPTC patients, respectively).
Previous studies have revealed that patients with more than five metastatic lymph nodes showed significantly stronger tendencies towards LLNM and could be used as a predictive index for lateral neck involvement in PTC patients [
18], which was consistent with our study. LLNM rates in patients with ≥5 positive CLN was 45.4% for all patients, while it was 35.2% and 52.6% for PTMC and LPTC groups, respectively. Considering that nearly half of the patients exhibited LLNM, those with no fewer than five positive lymph nodes were regarded as LLNM high-risk patients and were separated from all patients to further screen out high-risk patients within those with <5 positive CLN.
Several previous studies have regarded tumor size as an independent risk factor for LLNM [
5,
15,
20,
21]. Those with larger tumor sizes also showed significant tendencies towards tumor recurrence compared to those with small tumor sizes [
22]; a reminder that careful consideration should be taken in the selection of surgical procedures in the management of PTC patients with different primary tumor sizes. Our study also indicated that for patients who exhibited fewer than five positive CLN, significantly different incidence rates in terms of lateral neck involvement (11.0% vs. 25.7%) was found for the PTMC and LPTC groups. Thus, the two groups will be discussed separately.
PTMC is generally defined as a low degree of invasive tumor considering their quite indolent nature. Recently, an active surveillance strategy is considered an alternative to immediate resection for patients with low-risk PTMC who exhibit no clinical evidence of local metastases [
23,
24]. Even for those receiving surgical treatment, a “wait and see” strategy is enough and prophylactic LND is unnecessary at most clinical centers. However, few reports investigated PTMC patients with lymph node metastases. The existing literature shows that several factors are significantly associated with LLNM in PTMC patients, including tumors located in the upper portion, the number of CLNM, extrathyroidal extension, and multifocal lesions [
25,
26,
27]. Based on this, we wondered whether there is a unique subgroup of patients with a high risk of lateral neck metastasis in this traditionally considered low-risk population, which would have significant implications for the decision-making of lateral neck management. Here in our research, we used statistical methods to screen out risk factors for PTMC patients with <5 positive CLN. The results showed that the maximum diameter of positive CLN > 0.5 cm and the presence of ipsilateral nodular goiter (iNG) were identified as independent risk factors of LLNM for these patients. A predictive nomogram was then established, and all patients enrolled received a total score that could efficiently quantify their risk of LLNM. Three subgroups were then formed according to the nomogram score for further division of these patients. Those with a total score of 0 were classified as low-risk LLNM subgroup, where only 1 in 135 (0.7%) patients in this subgroup exhibited LLNM. This means those with a maximum diameter of positive CLN ≤ 0.5 cm and negative iNG within PTMC patients exhibiting < 5 positive CLN, the incidence rate of LLNM is extremely low; thus, LND covering the central lymph node region is enough. However, although the majority of the PTMC patients with <5 positive CLN were categorized into low the LLNM risk subgroup (135 in 237, 57.0%), a small portion of patients with nomogram scores ≥ 100 were screened out and were regarded as a high-risk subgroup of LLNM within these patients, with LLNM rate of 41.5% (22 in 53).
An investigation was also conducted on LPTC patients with fewer than five positive CLN in our research. Unlike those of the PTMC group, iNG showed no significant association with LLNM in the LPTC group, while four factors including tumor located in the upper portion of thyroid, maximum tumor diameter (MTD) ≥ 2.0 cm, maximum diameter of positive CLN > 0.5 cm, and the presence of thyroid capsular invasion (TCI) were proven to be independent risk factors of LLNM for patients within LPTC group, which further indicates the important implications of our study to separate patients by different tumor sizes. LPTC patients with fewer than five positive CLN were also divided into low- (total score < 100), moderate- (100 ≤ total score < 150), and high- (total score ≥ 150) risk LLNM subgroups. The incidences of LLNM rates were 2.2%, 15.4%, and 46.9%, respectively, confirming the rationality and validity of our classification.
Finally, all the aforementioned results were integrated as a detailed LLNM risk stratification flow chart for PTC patients with CLNM. All patients exhibiting no fewer than five positive CLN, PTMC and LPTC patients who exhibited fewer than five positive CLN and with a total score no less than 100 and 150 based on their respective nomograms are considered as at a high-risk of LLNM. For those patients, a closer follow-up scheme should be conducted as the first choice. Prophylactic LLND could be considered as a second choice after synthesizing the patients’ preference as well as the surgeon’s overall assessment to address the relatively high LLNM risk. However, for those with low LLNM risk (PTMC and LPTC patients who exhibited fewer than five positive CLN and with total score of 0 and less than 100 based on their respective nomograms), neck dissection for the positive central region is enough, and no intervention of lateral neck region is needed. For patients in the moderate-risk group, the patients’ basic physical status and preference as well as the surgeon’s overall assessment should be comprehensively considered for individual treatment decisions.