Clinical analysis of cervical lymph node metastasis risk factors in patients with papillary thyroid microcarcinoma

During the period from October 2010 to January 2017, 1031 cases of PTMC in the department of Surgical Oncology in Hangzhou First People’s Hospital were included in the study. Among these patients, 1010 cases were preoperatively diagnosed or suspected as PTMC by either fine needle aspiration(FNA) (518 cases) or B ultrasound (492 cases), and 21 cases were initially diagnosed as benign nodular goiter (19 cases) or hyperthyroidism (2 cases). All cases were confirmed to be PTMC successively by the intraoperative frozen and postoperative pathologic examination of resected tumor tissues. Criteria for admission: patients who had unilateral/bilateral PTMC in first surgery. Exclusion criteria: patients who had a history of other malignant tumors. This study was approved by the Ethics committee of our hospital and stayed in line with STROCSS criteria [8] with a unique identifying number (UIN: 3665) from the Research Registry. The data were analyzed in relation to gender, age at diagnosis, tumor largest diameter, capsular invasion, T staging, multifocal, the sum of the tumor diameter if multifocal, bilateral, tumor location (upper third, middle third, lower third and isthmus), B ultrasonography characteristics such as ultrasound intensity, composition, echoic distribution, tumor border, shape, calcification, aspect ratio, blood flow, and LNM that includes CLNM and lateral lymph node metastasis (LLNM). To evaluate the suspicious lateral lymph node metastasis, we used FNA for lymph node size larger than or equal to 1 cm and intraoperative frozen pathological examination for those smaller than 1 cm. The size and number of thyroid tumors, and the presence or absence of capsular invasion were recorded by high-frequency B ultrasonography. Each thyroid cancer patient was independently examined by two ultrasonographists. If two ultrasonographists had different opinions, the third ultrasonographist would participate in the examination to verify the data.

The PTMC patients in this study underwent open surgeries by a surgical team. The primary lesion was performed simultaneously with the cervical lymph node dissection. Ipsilateral lobe and isthmus resection was performed for unilateral primary lesions. Total thyroidectomy was performed for unilateral primary lesions requiring iodine 131 treatment. We generally performed the lymph node dissection of ipsilateral cervical central VI, which is recommended in China. The mean number of removed lymph nodes of the central compartment is 9.2. Lymph node dissections of contralateral cervical central VI and bilateral lateral compartments were performed only if there was lymph node metastasis in these compartments. As for all bilateral primary lesions, total thyroidectomy and bilateral cervical central VI lymph node dissection were performed, and lateral lymph node dissection was performed only for those having lateral lymph node metastasis. Additional lateral compartment neck dissections including levels II, III, IV and Vb would be performed if metastases were present in the lateral compartment. Level I and Va lymph nodes were spared unless there were clinically positive lymph nodes. Two expert pathologists independently examined the surgical specimens. Specifically, the histological type, number, largest diameter, and the presence/absence of capsular invasion in the primary thyroid tumor and the lymph node were determined.

In the present study, each patient was followed up for more than a year. 92% patients (949 cases) were followed up from 15 to 90 months and none of them had distant metastasis. However, six patients suffered from local recurrence (one case of lateral compartment, and five cases of contralateral glands).

There were 1031 patients with PTMC involved in this study. The mean age of these patients is 45.99 ± 10.94 yr (ranged from 14 to 74). 35.6% (367/1031) of cases exhibited neck lymph node metastasis including central compartment and lateral compartment. 33.7% (347/1031) had CLNM and 5.6% (58/1031) had LLNM. We further found that 38 patients (3.7%) had both CLNM and LLNM, the situation of which should be considered to be relatively severe. In addition, to our surprise, 1.9% (20/1031) presented only LLNM (Table 1).

The serum parathyroid hormone and calcium levels were assayed to assess the postoperative parathyroid function. There was no permanent hypoparathyroidism, which was defined as persistently low blood calcium levels (< 2 mmol/L) and subnormal parathyroid hormone levels by 6 months after surgery. The presence of recurrent laryngeal nerve (RLN) injury was determined by reviewing the surgical records and postoperative laryngoscopy reports. 16 patients presented transient RLN paralyses and recovered within 2–3 months of surgery. There was no permanent RLN paralysis. The morbidities of hypoparathyroidism and RLN injury in this study were lower than the literatures (permanent hypoparathyroidism:3.5–6.3%; permanent RLN injury: 1.3–3.6%) [9‐12]. In the study, 0.39% (4/1031) patients exhibited pleura rupture (which was recognized during surgery and repaired), which is relatively higher than the literatures [13, 14]. The reason may be that there are more patients compared to the literatures undergoing dissections of lymph nodes posterior to the right recurrent laryngeal nerve. Some studies have reported that the incidence of chylous leakage in patients was from 0.5 to 8.3% [15‐17]. In our study, 2.04% (21/1031) patients presented chylous leakage which resolved within 2–3 weeks of surgery. Horner’s syndrome, a very rare complication with less than 30 cases so far reported in the literature [18], was not observed in this study.

First, we studied the relationship between these risk factors and LNM. And univariate analysis showed that LNM was significantly associated with tumor characteristics of age, gender, tumor largest diameter, capsular invasion, T staging, multifocality, bilateral, echoic distribution, calcification, and blood flow (Table 2). However, when these variables were included in multivariate analysis, bilateral was not a statistically significant predictor of the LNM. Some subgroups of the variables left were also excluded. Finally, male, young age (≤ 40 years), tumor largest diameter greater than 7 mm, T3, and multifocality were independent risk factors with odds ratios of 1.954, 1.916, 3.964, 1.924, and 1.858, respectively (Table 2).

After the integral analysis of LNM, we further studied the risk factors of CLNM. Univariate analysis showed that PTMC patients with CLNM were significantly associated with tumor characteristics of male, age, tumor largest diameter, capsular invasion, multifocality, bilateral, T staging, echoic distribution, calcification and blood flow (Table 2). However, when these variables were included in multivariate analysis, five factors were excluded. As a result, male, young age (≤ 40 years), tumor largest diameter greater than 5 mm, the multifocality, and non-uniform echoic distribution were independent risk factors with odds ratios of 1.961, 1.888, 1.917, 1.976, and 1.367 respectively (Table 2).

Univariate analysis showed that PTMC patients with LLNM were significantly associated with clinicopathological characteristics of tumor largest diameter, capsular invasion, T staging, ultrasound intensity, shape, and blood flow (Table 2). Nevertheless, after being included in multivariate analysis, tumor largest diameter, capsular invasion, ultrasound shape, and blood flow were excluded. T3 and ultrasound mix-echo were independent risk factors with odds ratios of 3.575, and 4.729, respectively (Table 2).

In this study, there were 803 PTMC patients with single lesions in a unilateral lobe, and we divided the gland into four parts according to the upper pole, the middle pole, the lower pole, and the isthmus. The CLNM rates of the lesions in the upper pole, the middle pole, the lower pole, and the isthmus were 25.30, 29.40, 39.70, and 28.30%, respectively (P = 0.011). However, PTMC patients with lesions in the upper pole were most prone to LLNM, with a metastasis rate of 8.10% (P = 0.013). The probabilities of CLNM and LLNM in PTMC patients with lesions in the isthmus were 28.30 and 1.90%, respectively (Table 3).

In this study, there were 140 unilateral lobes with multifocal PTMC. We not only found that patients with multifocal PTMC were associated with CLNM, but also found that the sum of the maximum diameter of multifocal in a unilateral lobe was closely related to CLNM and LLNM. The ROC analysis showed that the areas under the ROC curves for the prediction of CLNM and LLNM by the risk factor sum ≥ 8.5 and ≥ 10.75 mm were 0.644, 0.687, respectively (Fig. 1a, b).