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

Clinical analysis of cervical lymph node metastasis risk factors in patients with papillary... Purpose Lymph node metastasis (LNM) is a vital prognosis factor in patients with papillary thyroid microcarcinoma (PTMC). The study tried to identify clinicopathological factors for LNM of PTMC. Methods The clinicopathological data of 1031 patients with PTMC were extracted and analyzed. Univariate and multivari- ate analyses were used to identify risk factors associated with cervical lymph node metastasis. ROC analysis was used to determine the ideal critical points of the sum of the maximum diameter of multifocal in a unilateral lobe. Results The probability of LNM, central lymph node metastasis (CLNM) and lateral lymph node metastasis(LLNM)of PTMC patients were 35.6, 33.7 and 5.6%, respectively. In addition, 1.9% PTMC had LLNM only. Male, age ≤ 40 years, tumor largest diameter ≥ 5 mm, multifocal, non-uniform echoic distribution, the sum of the maximum diameter of multifo- cal in a unilateral lobe ≥ 8.5 mm, tumors in the lower pole location were prone to CLNM. Ultrasound mix-echo, the sum of the maximum diameter of the multifocal ≥ 10.75 mm, tumors in the upper pole location were extremely prone to LLNM. T3 were prone to LLNM or skip LLNM. Conclusions According to the clinicopathological characteristics of PTMC, the cervical lymph nodes should be correctly evaluated to guide the surgical treatment. Keywords Papillary thyroid microcarcinoma · Lymph node metastasis · Neck dissection · Risk factors * D. Luo Z. Li ldc65@163.com lizhe_0816@foxmail.com Y. Luo West China School of Medicine, Sichuan University, roy_1405@163.com Sichuan, China Y. Zhao Department of General Surgery, Zhang jia-gang First 1395951776@qq.com People’s Hospital, Jiangsu, China K. Chen Nanjing Medical University, Jiangsu, China 215458862@qq.com Department of Surgical Oncology, Hangzhou First People’s J. Shen Hospital, Nanjing Medical University, No. 261, Huansha 644412807@qq.com Road, Shangcheng district, Hangzhou 310006, Zhejiang, J. Shi China jingjingshi123@163.com Zhejiang Chinese Medical University, Zhejiang, China S. Lu Thyroid Surgery, West China Hospital of Sichuan University, roselu1104@163.com Chengdu, China J. Lei leijianyong11@163.com Vol.:(0123456789) 1 3 Journal of Endocrinological Investigation the sum of the tumor diameter if multifocal, bilateral, Introduction tumor location (upper third, middle third, lower third and isthmus), B ultrasonography characteristics such as ultra- Papillary thyroid carcinoma (PTC) is the most frequent sound intensity, composition, echoic distribution, tumor malignancy of the thyroid gland. The incidence of PTC border, shape, calcification, aspect ratio, blood flow, and rapidly increases worldwide in recent years and up to 43% LNM that includes CLNM and lateral lymph node metas- of all these thyroid cancers are papillary thyroid micro- tasis (LLNM). To evaluate the suspicious lateral lymph carcinoma (PTMC) with a maximum diameter of 1.0 cm node metastasis, we used FNA for lymph node size larger or less [1]. At present, it remains controversial whether than or equal to 1 cm and intraoperative frozen pathologi- PTMC needs surgery. Ito [2] does not recommend surgery cal examination for those smaller than 1 cm. The size and for some PTMC patients. Sugitani et al. [3] suggest that number of thyroid tumors, and the presence or absence the delayed surgery has no effect on outcomes. Similarly, of capsular invasion were recorded by high-frequency B the guideline of the American Thyroid Association (ATA) ultrasonography. Each thyroid cancer patient was indepen- suggests that cautious observation is a safe and effective dently examined by two ultrasonographists. If two ultra- alternative to immediate surgical resection for PTMC [4]. sonographists had different opinions, the third ultrasonog- However, PTC has a high metastasis rate especially central raphist would participate in the examination to verify the lymph node metastasis (CLNM), about 20 to 50% of PTC data. patients have CLNM [5]. Moreover, the CLNM can signifi- cantly affect the prognosis of thyroid cancer [5 , 6]. PTMC is also potentially aggressive with a lymph node metasta- Surgical procedures and Pathological examination sis (LNM) rate of 37.3% [7]. The ultrasonic examination is important for the preoperative diagnosis of CLNM for The PTMC patients in this study underwent open surger- PTMC patients, but this ultrasonic diagnosis can be dif- ies by a surgical team. The primary lesion was performed ficult in some cases. We conducted this retrospective study simultaneously with the cervical lymph node dissection. of the clinicopathological features of PTMC to explore the Ipsilateral lobe and isthmus resection was performed for uni- lymph node metastasis of PTMC, and to provide evidence lateral primary lesions. Total thyroidectomy was performed that is helpful for the clinical management of PTMC. for unilateral primary lesions requiring iodine 131 treatment. We generally performed the lymph node dissection of ipsi- lateral cervical central VI, which is recommended in China. The mean number of removed lymph nodes of the central Materials and methods compartment is 9.2. Lymph node dissections of contralateral cervical central VI and bilateral lateral compartments were General clinical materials performed only if there was lymph node metastasis in these compartments. As for all bilateral primary lesions, total During the period from October 2010 to January 2017, thyroidectomy and bilateral cervical central VI lymph node 1031 cases of PTMC in the department of Surgical Oncol- dissection were performed, and lateral lymph node dissec- ogy in Hangzhou First People’s Hospital were included in tion was performed only for those having lateral lymph node the study. Among these patients, 1010 cases were preop- metastasis. Additional lateral compartment neck dissections eratively diagnosed or suspected as PTMC by either fine including levels II, III, IV and Vb would be performed if needle aspiration(FNA) (518 cases) or B ultrasound (492 metastases were present in the lateral compartment. Level cases), and 21 cases were initially diagnosed as benign I and Va lymph nodes were spared unless there were clini- nodular goiter (19 cases) or hyperthyroidism (2 cases). cally positive lymph nodes. Two expert pathologists inde- All cases were confirmed to be PTMC successively by pendently examined the surgical specimens. Specifically, the the intraoperative frozen and postoperative pathologic histological type, number, largest diameter, and the pres- examination of resected tumor tissues. Criteria for admis- ence/absence of capsular invasion in the primary thyroid sion: patients who had unilateral/bilateral PTMC in first tumor and the lymph node were determined. surgery. Exclusion criteria: patients who had a history of other malignant tumors. This study was approved by the Follow‑up Ethics committee of our hospital and stayed in line with STROCSS criteria [8] with a unique identifying number In the present study, each patient was followed up for more (UIN: 3665) from the Research Registry. The data were than a year. 92% patients (949 cases) were followed up from analyzed in relation to gender, age at diagnosis, tumor 15 to 90 months and none of them had distant metastasis. largest diameter, capsular invasion, T staging, multifocal, However, six patients suffered from local recurrence (one 1 3 Journal of Endocrinological Investigation case of lateral compartment, and five cases of contralateral paralysis. The morbidities of hypoparathyroidism and RLN glands). injury in this study were lower than the literatures (perma- nent hypoparathyroidism:3.5–6.3%; permanent RLN injury: Statistical analysis 1.3–3.6%) [9–12]. In the study, 0.39% (4/1031) patients exhibited pleura rupture (which was recognized during The clinicopathologic features were compared using the surgery and repaired), which is relatively higher than the Pearson Chi-square test. In multivariate analysis, the odds literatures [13, 14]. The reason may be that there are more ratio (OR) and the 95% confidence interval (CI) for rela- patients compared to the literatures undergoing dissections tionships between each significant variable and lymph node of lymph nodes posterior to the right recurrent laryngeal metastasis were calculated using backward stepwise binary nerve. Some studies have reported that the incidence of chy- logistic regression. P < 0.05 was considered to indicate a lous leakage in patients was from 0.5 to 8.3% [15–17]. In statistically significant difference. The receiver-operating our study, 2.04% (21/1031) patients presented chylous leak- characteristic (ROC) analysis was used to identify the cutoff age which resolved within 2–3 weeks of surgery. Horner’s point of the sum largest diameter of multifocal tumors for syndrome, a very rare complication with less than 30 cases defining the risk of CLNM and LLNM. All analyses were so far reported in the literature [18], was not observed in performed using IBM SPSS, version 20. this study. Risk factors of LNM Results First, we studied the relationship between these risk factors Clinicopathological characteristics of PTMC and LNM. And univariate analysis showed that LNM was significantly associated with tumor characteristics of age, There were 1031 patients with PTMC involved in this study. gender, tumor largest diameter, capsular invasion, T staging, The mean age of these patients is 45.99 ± 10.94 yr (ranged multifocality, bilateral, echoic distribution, calcic fi ation, and from 14 to 74). 35.6% (367/1031) of cases exhibited neck blood flow (Table  2). However, when these variables were lymph node metastasis including central compartment included in multivariate analysis, bilateral was not a statisti- and lateral compartment. 33.7% (347/1031) had CLNM cally significant predictor of the LNM. Some subgroups of and 5.6% (58/1031) had LLNM. We further found that 38 the variables left were also excluded. Finally, male, young patients (3.7%) had both CLNM and LLNM, the situation of age (≤ 40 years), tumor largest diameter greater than 7 mm, which should be considered to be relatively severe. In addi- T3, and multifocality were independent risk factors with tion, to our surprise, 1.9% (20/1031) presented only LLNM odds ratios of 1.954, 1.916, 3.964, 1.924, and 1.858, respec- (Table 1). tively (Table 2). The serum parathyroid hormone and calcium lev- els were assayed to assess the postoperative parathyroid Risk factors of CLNM function. There was no permanent hypoparathyroidism, which was defined as persistently low blood calcium levels After the integral analysis of LNM, we further studied the (< 2 mmol/L) and subnormal parathyroid hormone levels risk factors of CLNM. Univariate analysis showed that by 6 months after surgery. The presence of recurrent laryn- PTMC patients with CLNM were significantly associated geal nerve (RLN) injury was determined by reviewing the with tumor characteristics of male, age, tumor largest diam- surgical records and postoperative laryngoscopy reports. 16 eter, capsular invasion, multifocality, bilateral, T staging, patients presented transient RLN paralyses and recovered echoic distribution, calcification and blood flow (Table  2). within 2–3 months of surgery. There was no permanent RLN 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, Table 1 Number of neck lymph nodes the multifocality, and non-uniform echoic distribution were Neck lymph nodes Metastasis independent risk factors with odds ratios of 1.961, 1.888, 1.917, 1.976, and 1.367 respectively (Table 2). Negative Positive LNM 664 (64.4%) 367 (35.6%) Risk factors of LLNM CLNM 684 (66.3%) 347 (33.7%) LLNM 973 (94.4%) 58 (5.6%) Univariate analysis showed that PTMC patients with CLNM and LLNM 993 (96.4%) 38 (3.7%) LLNM were significantly associated with clinicopatho- LLNM only 1011 (98.1%) 20 (1.9%) logical characteristics of tumor largest diameter, capsular 1 3 Journal of Endocrinological Investigation 1 3 Table 2 Univariate and multivariate analyses of LNM, including CLNM and LLNM, and clinicopathological characteristics of PTMC Risk factors LNM Univariate Multivariate analysis CLNM Univariate Multivariate analysis LLNM Univariate Multivariate analysis analysis analysis analysis P OR (95% CI) P P OR (95% CI) P P OR (95% CI) P Age, n (%) < 0.001 < 0.001 0.384  ≤ 30 45 (49.5%) 2.103 (1.268– 0.004 42(46.20%) 1.969 (1.188– 0.009 7 (7.70%) 3.487) 3.263)  30–40 100 (43.10%) 1.916 (1.328– 0.001 96 (41.40%) 1.888 (1.307– 0.001 16 (6.90%) 2.763) 2.726)  40–50 109 (31.60%) 1.088 (0.775– 0.627 103 (29.90%) 1.067 (0.759– 0.709 14 (4.10%) 1.525) 1.500)  > 50 113 (31.10%) 1 106 (29.20%) 1 21 (5.80%) Gender, n (%) < 0.001 < 0.001 < 0.001 < 0.001 0.111  Female 276 (32.70%) 1 260 (30.80%) 1 43 (5.10%)  Male 91 (48.90%) 1.954 (1.387– 87 (46.80%) 1.961 (1.392– 15 (8.10%) 2.752) 2.762) Size, n (%) < 0.001 < 0.001  <0.001  ≤ 2 mm 18 (19.10%) 1 16 (17.00%) 1 2 (2.10%) 1  2–5 mm 138 (29.40%) 1.459 (0.831– 0.188 132 (28.10%) 1.586 (0.883– 0.123 14 (3.00%) 1.266 (0.281– 0.759 2.56) 2.850) 5.710)  5–7 mm 83 (35.80%) 1.721 (0.945– 0.076 79 (34.10%) 1.917 (1.032– 0.039 14 (6.00%) 2.242 (0.494– 0.296 3.131) 3.561) 10.185)  7–10 mm 128 (54.50%) 3.964 (2.188– < 0.001 120 (51.10%) 4.236 (2.299– < 0.001 28 (11.90%) 4.036 (0.920– 0.064 7.181) 7.803) 17.705) Capsular inva- 0.016 0.021 < 0.001 sion, n (%)  Negative 312 (34.30%) 297 (32.60%) 42 (4.60%)  Positive 55 (45.50%) 50 (41.30%) 16 (13.20%) T staging, n (%) 0.003 0.029 <0.001  T1 331 (34.30%) 1 315 (32.60%) 44 (4.60%) 1  T3 33 (55.90%) 1.924 (1.086– 0.025 29 (49.20%) 12 (20.30%) 3.575 (1.692– 0.001 3.408) 7.552)  T4 3 (42.90%) 1.253 (0.26– 0.779 3 (42.90%) 2 (28.60%) 4.208 (0.702– 0.116 6.035) 25.223) Multifocality, < 0.001 < 0.001 < 0.001 < 0.001 0.092 n (%)  Negative 261 (32.50%) 1 243 (30.30%) 1 40 (5.00%)  Positive 106 (46.50%) 1.858 (1.348– 104 (45.60%) 1.976 (1.434– 18 (7.90%) 2.56) 2.724) Bilateral, n (%) 0.007 0.002 0.172  Negative 299 (33.90%) 280 (31.80%) 46 (5.20%)  Positive 68 (45.30%) 67 (44.70%) 12 (8.00%) Journal of Endocrinological Investigation 1 3 Table 2 (continued) Risk factors LNM Univariate Multivariate analysis CLNM Univariate Multivariate analysis LLNM Univariate Multivariate analysis analysis analysis analysis P OR (95% CI) P P OR (95% CI) P P OR (95% CI) P Ultrasound 0.385 0.417 < 0.001 intensity, n (%)  Hypo-echo 338 (35.30%) 320 (33.40%) 47 (4.90%) 1  Moderate- 7 (30.40%) 6 (26.10%) 1 (4.30%) 0.842 (0.105– 0.871 echo 6.771)  Iso-echo 6 (37.50%) 6 (37.50%) 2 (12.50%) 3.387 (0.724– 0.121 15.846)  High-echo 1 (20.00%) 1 (20.00%) 0 (0.00%) – –  Mix-echo 15 (51.70%) 14 (48.30%) 8 (27.60%) 4.729 (1.859– 0.001 12.033) Composition, 0.301 0.112 0.546 n(%)  Solid 365 (35.70%) 346 (33.90%) 57 (5.60%)  Solid–cystic 2 (20.00%) 1 (10.00%) 1 (10.00%) Echo distribu- 0.004 0.003 0.038 0.905 tion, n(%)  Uniform 108 (29.80%) 101 (27.80%) 1 20 (5.50%)  Non-uniform 259 (38.80%) 246 (36.80%) 1.367 (1.018– 38 (5.70%) 1.835) Border, n (%) 0.062 0.116 0.077  Regular 101 (31.50%) 97 (30.20%) 12 (3.70%)  Irregular 266 (37.50%) 250 (35.20%) 46 (6.50%) Shape, n (%) 0.232 0.37 0.045  Regular 125 (33.20%) 120 (31.90%) 14 (3.70%)  Irregular 242 (36.90%) 227 (34.70%) 44 (6.70%) Calcification, 0.016 0.016 0.075 n (%)  Negative 201 (32.20%) 189 (30.30%) 28 (4.50%)  Fine 71 (39.20%) 68 (37.60%) 16 (8.80%)  Thick 95 (42.04%) 90 (39.80%) 14 (6.20%) Aspect ratio, 0.19 0.17 0.548 n (%)  Proportioned 204 (33.90%) 192 (31.90%) 36 (6.00%)  Dispropor- 163 (37.90%) 155 (36.00%) 22 (5.10%) tionality Journal of Endocrinological Investigation invasion, T staging, ultrasound intensity, shape, and blood flow (Table  2). Nevertheless, after being included in multi- variate 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). LNM is related to the location of the gland in PTMC patients 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). LNM is related to the multifocal in PTMC patients In this study, there were 140 unilateral lobes with multifo- cal 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). Discussion Generally most of PTMC has a good prognosis, but some PTMC patients can suffer from cancer death or poor quality of life. These poor outcome cases mainly occur in PTMC with metastatic lymph node or/and invasion of thyroid peripheral tissues, such as recurrent laryngeal nerve, internal jugular vein, trachea or esophagus. Compared with the intra- thyroid PTC group, the PTC group with LNM showed higher recurrence rates (5.2 vs. 31.5%), and higher disease-spe- cific mortality (1.3 vs. 12.6%) [19]. In this study, no distant metastasis was found in all 1031 PTMC patients enrolled. Therefore, the distant metastasis is rare in PTMC and we focused on the association of LNM of PTMC patients with the clinicopathological characteristics and B ultrasonogra- phy characteristics. Our data analysis indicated a significant correlation between LNM and several risk factors. Some studies used a tumor largest diameter of 5, 5.5, 7 mm to indicate the aggressiveness of PTMC [20–23]. In 1 3 Table 2 (continued) Risk factors LNM Univariate Multivariate analysis CLNM Univariate Multivariate analysis LLNM Univariate Multivariate analysis analysis analysis analysis P OR (95% CI) P P OR (95% CI) P P OR (95% CI) P Blood flow, n 0.014 0.03 0.002 (%)  Negative 192 (32.40%) 183 (30.90%) 22 (3.70%)  Positive 175 (39.90%) 164 (37.40%) 36 (8.20%) Journal of Endocrinological Investigation Table 3 The risk of location in 2 2 Location CLNM Metastasis X P Location LLNM Metasta- X P the solitary primary tumor for rate (%) sis rate CLNM and LLNM No Yes No Yes (%) Upper 204 69 25.30 11.153 0.011 Upper 251 22 8.10 10.774 0.013 Middle 207 86 29.40 Middle 286 7 2.40 Lower 111 73 39.70 Lower 174 10 5.40 Isthmus 38 15 28.30 Isthmus 52 1 1.90 Fig. 1 Outcomes of receiver-operating characteristic (ROC) curve tively, with an AUC of 0.644. b ROC curve analysis for the sum of analyses. a ROC curve analysis for the sum of the maximum diameter the maximum diameter of multifocal in a unilateral lobe of LLNM: of multifocal in a unilateral lobe of CLNM: An index point ≥ 8.5 mm An index point ≥ 10.75 mm of the sum of the maximum diameter of of the sum of the maximum diameter of multifocal was found to be multifocal was found to be the optimal point to distinguish between the optimal point to distinguish between PTMC with and without PTMC with and without LLNM. The sensitivity and specificity were CLNM. The sensitivity and specificity were 64.4 and 59.3%, respec- 58.3 and 74.2%, respectively, with an AUC of 0.687 the present study, the tumor largest diameter ≥ 5 mm was that male and younger PTMC patients were prone to cervical an independent risk factor for CLNM. We suggested that LNM, especially CLNM (Table 2). patients with PTMC greater than 5 mm must be paid atten- Additionally, we found that the multifocal lesion in tion to the CLNM. Furthermore, the tumor largest diam- PTMC was an important risk factor in CLNM. This find- eter ≥ 7 mm was an independent risk factor for LNM. There- ing is consistent with the data reported [7, 20, 21, 26–29]. fore, for patients with PTMC larger than 7 mm, we should Furthermore, with the increase of the sum of the maximum pay attention not only to CLNM, but also to LLNM. diameter of multifocal in a unilateral lobe, not only was the The association of PTMC with gender and age remains probability of CLNM increased, but also the probability of controversial. Jeon et al. [24] showed that age ≥ 45 years was LLNM (Table 4). In the group with the sum of the maximum at a higher risk of LNM while male was not an independ- diameter > 8 mm, the rate of CLNM was 47.50%. The ROC ent risk factor. On the contrary, some studies revealed that analysis showed that the optimal point was 8.5 mm of the both male and younger age were risk factors [21, 22, 25, sum of the maximum diameter of multifocal. The sensitiv- 26]. In our study, male was an independent risk factor for ity and specificity were 64.4 and 59.3%, respectively. In the LNM and CLNM, rather than for LLNM. We also found that group with the sum of the maximum diameter > 11 mm, the age ≤ 40 years was an independent risk factor for LNM and rate of LLNM was 19.40%. The ROC analysis showed that CLNM, rather than for LLNM. These findings suggested the optimal point was 10.75 mm of the sum of the maximum 1 3 Journal of Endocrinological Investigation Table 4 The sum of the 2 2 Sum of maximum CLNM Metastasis X P LLNM Metastasis X P maximum diameters of all diameters (mm) rate (%) rate (%) multifocal tumors No Yes No Yes ≤ 8 48 21 30.40 9.011 0.011 66 3 4.30 6.229 0.044 8–11 21 19 47.50 37 3 7.50 > 11 12 19 61.30 25 6 19.40 diameter of multifocal. The sensitivity and specificity were patients with mix-echo and LLNM (P < 0.01, OR = 4.729) 58.3 and 74.2%, respectively (Fig.  1a, b). Therefore, we (Table 2). These phenomenon suggested that PTMC patients should pay more attention to the PTMC patients with multi- with features of non-uniform echoic distribution and mix- focal lesion and their sum of the maximum diameter. echo should be paid attention to their respective the cervical In clinical practice, we used to observe a phenomenon CLNM and LLNM. In addition, other ultrasound features with small tumor lesion but invaded extra thyroid tissues. such as shape, composition, tumor border, calcification, and There were 59 PTMC patients with T3 in our study. We aspect ratio, were not associated with the cervical LNM. found that T3 was associated with LLNM (P = 0.001, There are some limitations in our study. First, the study OR = 3.575), which was similar to Lu et  al. [26] At the is a single center study though it has a large sample size. same time, we found 20 PTMC patients with only LLNM. Second, we did not divide the subtypes of PTMC so there Of these, four cases belonged to stage T3, and 16 cases may be some statistical bias. Third, it may omit few occult were intra-thyroid lesions. The only LLNM rates of PTMC lymph node metastases because we did not perform lymph patients with T3 and with intra-thyroid lesion were 6.78% node dissection in patients not identified having contralateral and 1.66%, respectively (P < 0.05), the former being 4.08 lymph node metastasis. Finally, due to the difficulty in stand- times more than the latter. The above results demonstrated ardization of preoperative imaging diagnostic techniques of that PTMC patients with T3 were prone to having LLNM or the lymph node assessment in the central compartment, the skip LLNM. LLNM shall be considered as a risk factor for proportion of the suspicious lymph nodes in the central com- distant metastatic spread and for cancer-related death [30]. partment was not calculated. Additional studies are required Thus, we suggest that attention should be paid to the PTMC to address these issues. patients with T3 (Table 2). The location of PTMC was related to the compartment of cervical lymph node metastasis [31]. We found that location in the lower third of the thyroid lobe conferred a higher risk Conclusion for CLNM (P < 0.05), and that the location of upper third was related to a higher risk for LLNM (P < 0.05). However, We found that the probability of cervical LNM was the PTMC patients with lesions in the thyroid isthmus were closely related to the clinical and pathological character- prone to CLNM and rare to LLNM (Table  3). Thus, we istics of PTMC. Male, age ≤ 40 years, tumor largest diam- should pay attention to estimate the compartment of cervi- eter ≥ 5 mm, multifocal, non-uniform echoic distribution, the cal lymph node metastasis according to the location of the sum of the maximum diameter of multifocal in a unilateral solitary primary tumor in the thyroid. lobe ≥ 8.5 mm, tumors in the lower pole location were prone With the development of ultrasound technology, the to CLNM. Ultrasound mix-echo, the sum of the maximum diagnosis of PTMC has been improved. However, limited diameter of the multifocal ≥ 10.75 mm, tumors in the upper studies were performed to correlate LNM with ultrasound pole location were extremely prone to LLNM. Patients with characteristics. A previous report [22] has reported that T3 were prone to LLNM or skip LLNM. Therefore, accord- blood flow (present vs. absent) may improve the efficacy of ing to the clinical and pathological characteristics of PTMC, predicting LNM (P < 0.001, OR = 5.3). In our study, blood the regional lymph nodes should be correctly evaluated to flow was not a significant predictor of the LNM, CLNM or guide the surgical treatment of cervical LNM in PTMC. LLNM (P > 0.05). The present result indicated that PTMC Acknowledgements The authors are grateful to all members of the patients with blood flow had limited value in predicting cer - Department of Surgical Oncology at Hangzhou First People’s Hospi- vical LNM. But in this study, we found that the probability tal for assistance with surgical treatment of PTMC and clinical data of CLNM of PTMC patients with non-uniform or uniform collection. echoic distribution was significantly different ( P = 0.003). It showed non-uniform echoic distribution was an independ- Funding This work was supported by the Key Project of Scientific and Technological Innovation in Hangzhou (20131813A08). ent predictive factor for CLNM (OR = 1.367). As for ultra- sound intensity, we found that strong correlations of PTMC 1 3 Journal of Endocrinological Investigation 10. Zhao W, You L, Hou X, Chen S, Ren X, Chen G, Zhao Y (2017) Compliance with ethical standards The effect of prophylactic central neck dissection on locore- gional recurrence in papillary thyroid cancer after total thy- Conflict of interest The authors declare that they have no conflict of roidectomy: a systematic review and meta-analysis: pCND for interest. the locoregional recurrence of papillary thyroid cancer. Ann Surg Oncol 24(8):2189–2198. h ttps ://d oi.o r g/10 .1245 /s104 3 Ethical approval All procedures performed in studies involving human 4-016-5691-4 participants were in accordance with the ethical standards of the insti- 11. Barczyński M, Konturek A, Stopa M, Nowak W (2013) Prophy- tutional and/or national research committee and with the 1964 Helsinki lactic central neck dissection for papillary thyroid cancer. Br J declaration and its later amendments or comparable ethical standards. Surg 100:410–418 12. Zetoune T, Keutgen X, Buitrago D, Aldailami H, Shao H, Informed consent Informed consent was obtained from all individual Mazumdar M, Rd FT, Zarnegar R (2010) Prophylactic central participants included in the study. neck dissection and local recurrence in papillary thyroid cancer: a meta-analysis. Ann Surg Oncol 17:3287 13. Lee SJ, Lee DJ, Kim MC, Im UJ (2010) Pneumothorax in a Open Access This article is distributed under the terms of the Crea- post-anesthetic care unit after right thyroidectomy with left neck tive Commons Attribution 4.0 International License (http://creat iveco dissection -A case report. Korean J Anesthesiol 59:429–432 mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- 14. 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Clinical analysis of cervical lymph node metastasis risk factors in patients with papillary thyroid microcarcinoma

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Abstract

Purpose Lymph node metastasis (LNM) is a vital prognosis factor in patients with papillary thyroid microcarcinoma (PTMC). The study tried to identify clinicopathological factors for LNM of PTMC. Methods The clinicopathological data of 1031 patients with PTMC were extracted and analyzed. Univariate and multivari- ate analyses were used to identify risk factors associated with cervical lymph node metastasis. ROC analysis was used to determine the ideal critical points of the sum of the maximum diameter of multifocal in a unilateral lobe. Results The probability of LNM, central lymph node metastasis (CLNM) and lateral lymph node metastasis(LLNM)of PTMC patients were 35.6, 33.7 and 5.6%, respectively. In addition, 1.9% PTMC had LLNM only. Male, age ≤ 40 years, tumor largest diameter ≥ 5 mm, multifocal, non-uniform echoic distribution, the sum of the maximum diameter of multifo- cal in a unilateral lobe ≥ 8.5 mm, tumors in the lower pole location were prone to CLNM. Ultrasound mix-echo, the sum of the maximum diameter of the multifocal ≥ 10.75 mm, tumors in the upper pole location were extremely prone to LLNM. T3 were prone to LLNM or skip LLNM. Conclusions According to the clinicopathological characteristics of PTMC, the cervical lymph nodes should be correctly evaluated to guide the surgical treatment. Keywords Papillary thyroid microcarcinoma · Lymph node metastasis · Neck dissection · Risk factors * D. Luo Z. Li ldc65@163.com lizhe_0816@foxmail.com Y. Luo West China School of Medicine, Sichuan University, roy_1405@163.com Sichuan, China Y. Zhao Department of General Surgery, Zhang jia-gang First 1395951776@qq.com People’s Hospital, Jiangsu, China K. Chen Nanjing Medical University, Jiangsu, China 215458862@qq.com Department of Surgical Oncology, Hangzhou First People’s J. Shen Hospital, Nanjing Medical University, No. 261, Huansha 644412807@qq.com Road, Shangcheng district, Hangzhou 310006, Zhejiang, J. Shi China jingjingshi123@163.com Zhejiang Chinese Medical University, Zhejiang, China S. Lu Thyroid Surgery, West China Hospital of Sichuan University, roselu1104@163.com Chengdu, China J. Lei leijianyong11@163.com Vol.:(0123456789) 1 3 Journal of Endocrinological Investigation the sum of the tumor diameter if multifocal, bilateral, Introduction tumor location (upper third, middle third, lower third and isthmus), B ultrasonography characteristics such as ultra- Papillary thyroid carcinoma (PTC) is the most frequent sound intensity, composition, echoic distribution, tumor malignancy of the thyroid gland. The incidence of PTC border, shape, calcification, aspect ratio, blood flow, and rapidly increases worldwide in recent years and up to 43% LNM that includes CLNM and lateral lymph node metas- of all these thyroid cancers are papillary thyroid micro- tasis (LLNM). To evaluate the suspicious lateral lymph carcinoma (PTMC) with a maximum diameter of 1.0 cm node metastasis, we used FNA for lymph node size larger or less [1]. At present, it remains controversial whether than or equal to 1 cm and intraoperative frozen pathologi- PTMC needs surgery. Ito [2] does not recommend surgery cal examination for those smaller than 1 cm. The size and for some PTMC patients. Sugitani et al. [3] suggest that number of thyroid tumors, and the presence or absence the delayed surgery has no effect on outcomes. Similarly, of capsular invasion were recorded by high-frequency B the guideline of the American Thyroid Association (ATA) ultrasonography. Each thyroid cancer patient was indepen- suggests that cautious observation is a safe and effective dently examined by two ultrasonographists. If two ultra- alternative to immediate surgical resection for PTMC [4]. sonographists had different opinions, the third ultrasonog- However, PTC has a high metastasis rate especially central raphist would participate in the examination to verify the lymph node metastasis (CLNM), about 20 to 50% of PTC data. patients have CLNM [5]. Moreover, the CLNM can signifi- cantly affect the prognosis of thyroid cancer [5 , 6]. PTMC is also potentially aggressive with a lymph node metasta- Surgical procedures and Pathological examination sis (LNM) rate of 37.3% [7]. The ultrasonic examination is important for the preoperative diagnosis of CLNM for The PTMC patients in this study underwent open surger- PTMC patients, but this ultrasonic diagnosis can be dif- ies by a surgical team. The primary lesion was performed ficult in some cases. We conducted this retrospective study simultaneously with the cervical lymph node dissection. of the clinicopathological features of PTMC to explore the Ipsilateral lobe and isthmus resection was performed for uni- lymph node metastasis of PTMC, and to provide evidence lateral primary lesions. Total thyroidectomy was performed that is helpful for the clinical management of PTMC. for unilateral primary lesions requiring iodine 131 treatment. We generally performed the lymph node dissection of ipsi- lateral cervical central VI, which is recommended in China. The mean number of removed lymph nodes of the central Materials and methods compartment is 9.2. Lymph node dissections of contralateral cervical central VI and bilateral lateral compartments were General clinical materials performed only if there was lymph node metastasis in these compartments. As for all bilateral primary lesions, total During the period from October 2010 to January 2017, thyroidectomy and bilateral cervical central VI lymph node 1031 cases of PTMC in the department of Surgical Oncol- dissection were performed, and lateral lymph node dissec- ogy in Hangzhou First People’s Hospital were included in tion was performed only for those having lateral lymph node the study. Among these patients, 1010 cases were preop- metastasis. Additional lateral compartment neck dissections eratively diagnosed or suspected as PTMC by either fine including levels II, III, IV and Vb would be performed if needle aspiration(FNA) (518 cases) or B ultrasound (492 metastases were present in the lateral compartment. Level cases), and 21 cases were initially diagnosed as benign I and Va lymph nodes were spared unless there were clini- nodular goiter (19 cases) or hyperthyroidism (2 cases). cally positive lymph nodes. Two expert pathologists inde- All cases were confirmed to be PTMC successively by pendently examined the surgical specimens. Specifically, the the intraoperative frozen and postoperative pathologic histological type, number, largest diameter, and the pres- examination of resected tumor tissues. Criteria for admis- ence/absence of capsular invasion in the primary thyroid sion: patients who had unilateral/bilateral PTMC in first tumor and the lymph node were determined. surgery. Exclusion criteria: patients who had a history of other malignant tumors. This study was approved by the Follow‑up Ethics committee of our hospital and stayed in line with STROCSS criteria [8] with a unique identifying number In the present study, each patient was followed up for more (UIN: 3665) from the Research Registry. The data were than a year. 92% patients (949 cases) were followed up from analyzed in relation to gender, age at diagnosis, tumor 15 to 90 months and none of them had distant metastasis. largest diameter, capsular invasion, T staging, multifocal, However, six patients suffered from local recurrence (one 1 3 Journal of Endocrinological Investigation case of lateral compartment, and five cases of contralateral paralysis. The morbidities of hypoparathyroidism and RLN glands). injury in this study were lower than the literatures (perma- nent hypoparathyroidism:3.5–6.3%; permanent RLN injury: Statistical analysis 1.3–3.6%) [9–12]. In the study, 0.39% (4/1031) patients exhibited pleura rupture (which was recognized during The clinicopathologic features were compared using the surgery and repaired), which is relatively higher than the Pearson Chi-square test. In multivariate analysis, the odds literatures [13, 14]. The reason may be that there are more ratio (OR) and the 95% confidence interval (CI) for rela- patients compared to the literatures undergoing dissections tionships between each significant variable and lymph node of lymph nodes posterior to the right recurrent laryngeal metastasis were calculated using backward stepwise binary nerve. Some studies have reported that the incidence of chy- logistic regression. P < 0.05 was considered to indicate a lous leakage in patients was from 0.5 to 8.3% [15–17]. In statistically significant difference. The receiver-operating our study, 2.04% (21/1031) patients presented chylous leak- characteristic (ROC) analysis was used to identify the cutoff age which resolved within 2–3 weeks of surgery. Horner’s point of the sum largest diameter of multifocal tumors for syndrome, a very rare complication with less than 30 cases defining the risk of CLNM and LLNM. All analyses were so far reported in the literature [18], was not observed in performed using IBM SPSS, version 20. this study. Risk factors of LNM Results First, we studied the relationship between these risk factors Clinicopathological characteristics of PTMC and LNM. And univariate analysis showed that LNM was significantly associated with tumor characteristics of age, There were 1031 patients with PTMC involved in this study. gender, tumor largest diameter, capsular invasion, T staging, The mean age of these patients is 45.99 ± 10.94 yr (ranged multifocality, bilateral, echoic distribution, calcic fi ation, and from 14 to 74). 35.6% (367/1031) of cases exhibited neck blood flow (Table  2). However, when these variables were lymph node metastasis including central compartment included in multivariate analysis, bilateral was not a statisti- and lateral compartment. 33.7% (347/1031) had CLNM cally significant predictor of the LNM. Some subgroups of and 5.6% (58/1031) had LLNM. We further found that 38 the variables left were also excluded. Finally, male, young patients (3.7%) had both CLNM and LLNM, the situation of age (≤ 40 years), tumor largest diameter greater than 7 mm, which should be considered to be relatively severe. In addi- T3, and multifocality were independent risk factors with tion, to our surprise, 1.9% (20/1031) presented only LLNM odds ratios of 1.954, 1.916, 3.964, 1.924, and 1.858, respec- (Table 1). tively (Table 2). The serum parathyroid hormone and calcium lev- els were assayed to assess the postoperative parathyroid Risk factors of CLNM function. There was no permanent hypoparathyroidism, which was defined as persistently low blood calcium levels After the integral analysis of LNM, we further studied the (< 2 mmol/L) and subnormal parathyroid hormone levels risk factors of CLNM. Univariate analysis showed that by 6 months after surgery. The presence of recurrent laryn- PTMC patients with CLNM were significantly associated geal nerve (RLN) injury was determined by reviewing the with tumor characteristics of male, age, tumor largest diam- surgical records and postoperative laryngoscopy reports. 16 eter, capsular invasion, multifocality, bilateral, T staging, patients presented transient RLN paralyses and recovered echoic distribution, calcification and blood flow (Table  2). within 2–3 months of surgery. There was no permanent RLN 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, Table 1 Number of neck lymph nodes the multifocality, and non-uniform echoic distribution were Neck lymph nodes Metastasis independent risk factors with odds ratios of 1.961, 1.888, 1.917, 1.976, and 1.367 respectively (Table 2). Negative Positive LNM 664 (64.4%) 367 (35.6%) Risk factors of LLNM CLNM 684 (66.3%) 347 (33.7%) LLNM 973 (94.4%) 58 (5.6%) Univariate analysis showed that PTMC patients with CLNM and LLNM 993 (96.4%) 38 (3.7%) LLNM were significantly associated with clinicopatho- LLNM only 1011 (98.1%) 20 (1.9%) logical characteristics of tumor largest diameter, capsular 1 3 Journal of Endocrinological Investigation 1 3 Table 2 Univariate and multivariate analyses of LNM, including CLNM and LLNM, and clinicopathological characteristics of PTMC Risk factors LNM Univariate Multivariate analysis CLNM Univariate Multivariate analysis LLNM Univariate Multivariate analysis analysis analysis analysis P OR (95% CI) P P OR (95% CI) P P OR (95% CI) P Age, n (%) < 0.001 < 0.001 0.384  ≤ 30 45 (49.5%) 2.103 (1.268– 0.004 42(46.20%) 1.969 (1.188– 0.009 7 (7.70%) 3.487) 3.263)  30–40 100 (43.10%) 1.916 (1.328– 0.001 96 (41.40%) 1.888 (1.307– 0.001 16 (6.90%) 2.763) 2.726)  40–50 109 (31.60%) 1.088 (0.775– 0.627 103 (29.90%) 1.067 (0.759– 0.709 14 (4.10%) 1.525) 1.500)  > 50 113 (31.10%) 1 106 (29.20%) 1 21 (5.80%) Gender, n (%) < 0.001 < 0.001 < 0.001 < 0.001 0.111  Female 276 (32.70%) 1 260 (30.80%) 1 43 (5.10%)  Male 91 (48.90%) 1.954 (1.387– 87 (46.80%) 1.961 (1.392– 15 (8.10%) 2.752) 2.762) Size, n (%) < 0.001 < 0.001  <0.001  ≤ 2 mm 18 (19.10%) 1 16 (17.00%) 1 2 (2.10%) 1  2–5 mm 138 (29.40%) 1.459 (0.831– 0.188 132 (28.10%) 1.586 (0.883– 0.123 14 (3.00%) 1.266 (0.281– 0.759 2.56) 2.850) 5.710)  5–7 mm 83 (35.80%) 1.721 (0.945– 0.076 79 (34.10%) 1.917 (1.032– 0.039 14 (6.00%) 2.242 (0.494– 0.296 3.131) 3.561) 10.185)  7–10 mm 128 (54.50%) 3.964 (2.188– < 0.001 120 (51.10%) 4.236 (2.299– < 0.001 28 (11.90%) 4.036 (0.920– 0.064 7.181) 7.803) 17.705) Capsular inva- 0.016 0.021 < 0.001 sion, n (%)  Negative 312 (34.30%) 297 (32.60%) 42 (4.60%)  Positive 55 (45.50%) 50 (41.30%) 16 (13.20%) T staging, n (%) 0.003 0.029 <0.001  T1 331 (34.30%) 1 315 (32.60%) 44 (4.60%) 1  T3 33 (55.90%) 1.924 (1.086– 0.025 29 (49.20%) 12 (20.30%) 3.575 (1.692– 0.001 3.408) 7.552)  T4 3 (42.90%) 1.253 (0.26– 0.779 3 (42.90%) 2 (28.60%) 4.208 (0.702– 0.116 6.035) 25.223) Multifocality, < 0.001 < 0.001 < 0.001 < 0.001 0.092 n (%)  Negative 261 (32.50%) 1 243 (30.30%) 1 40 (5.00%)  Positive 106 (46.50%) 1.858 (1.348– 104 (45.60%) 1.976 (1.434– 18 (7.90%) 2.56) 2.724) Bilateral, n (%) 0.007 0.002 0.172  Negative 299 (33.90%) 280 (31.80%) 46 (5.20%)  Positive 68 (45.30%) 67 (44.70%) 12 (8.00%) Journal of Endocrinological Investigation 1 3 Table 2 (continued) Risk factors LNM Univariate Multivariate analysis CLNM Univariate Multivariate analysis LLNM Univariate Multivariate analysis analysis analysis analysis P OR (95% CI) P P OR (95% CI) P P OR (95% CI) P Ultrasound 0.385 0.417 < 0.001 intensity, n (%)  Hypo-echo 338 (35.30%) 320 (33.40%) 47 (4.90%) 1  Moderate- 7 (30.40%) 6 (26.10%) 1 (4.30%) 0.842 (0.105– 0.871 echo 6.771)  Iso-echo 6 (37.50%) 6 (37.50%) 2 (12.50%) 3.387 (0.724– 0.121 15.846)  High-echo 1 (20.00%) 1 (20.00%) 0 (0.00%) – –  Mix-echo 15 (51.70%) 14 (48.30%) 8 (27.60%) 4.729 (1.859– 0.001 12.033) Composition, 0.301 0.112 0.546 n(%)  Solid 365 (35.70%) 346 (33.90%) 57 (5.60%)  Solid–cystic 2 (20.00%) 1 (10.00%) 1 (10.00%) Echo distribu- 0.004 0.003 0.038 0.905 tion, n(%)  Uniform 108 (29.80%) 101 (27.80%) 1 20 (5.50%)  Non-uniform 259 (38.80%) 246 (36.80%) 1.367 (1.018– 38 (5.70%) 1.835) Border, n (%) 0.062 0.116 0.077  Regular 101 (31.50%) 97 (30.20%) 12 (3.70%)  Irregular 266 (37.50%) 250 (35.20%) 46 (6.50%) Shape, n (%) 0.232 0.37 0.045  Regular 125 (33.20%) 120 (31.90%) 14 (3.70%)  Irregular 242 (36.90%) 227 (34.70%) 44 (6.70%) Calcification, 0.016 0.016 0.075 n (%)  Negative 201 (32.20%) 189 (30.30%) 28 (4.50%)  Fine 71 (39.20%) 68 (37.60%) 16 (8.80%)  Thick 95 (42.04%) 90 (39.80%) 14 (6.20%) Aspect ratio, 0.19 0.17 0.548 n (%)  Proportioned 204 (33.90%) 192 (31.90%) 36 (6.00%)  Dispropor- 163 (37.90%) 155 (36.00%) 22 (5.10%) tionality Journal of Endocrinological Investigation invasion, T staging, ultrasound intensity, shape, and blood flow (Table  2). Nevertheless, after being included in multi- variate 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). LNM is related to the location of the gland in PTMC patients 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). LNM is related to the multifocal in PTMC patients In this study, there were 140 unilateral lobes with multifo- cal 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). Discussion Generally most of PTMC has a good prognosis, but some PTMC patients can suffer from cancer death or poor quality of life. These poor outcome cases mainly occur in PTMC with metastatic lymph node or/and invasion of thyroid peripheral tissues, such as recurrent laryngeal nerve, internal jugular vein, trachea or esophagus. Compared with the intra- thyroid PTC group, the PTC group with LNM showed higher recurrence rates (5.2 vs. 31.5%), and higher disease-spe- cific mortality (1.3 vs. 12.6%) [19]. In this study, no distant metastasis was found in all 1031 PTMC patients enrolled. Therefore, the distant metastasis is rare in PTMC and we focused on the association of LNM of PTMC patients with the clinicopathological characteristics and B ultrasonogra- phy characteristics. Our data analysis indicated a significant correlation between LNM and several risk factors. Some studies used a tumor largest diameter of 5, 5.5, 7 mm to indicate the aggressiveness of PTMC [20–23]. In 1 3 Table 2 (continued) Risk factors LNM Univariate Multivariate analysis CLNM Univariate Multivariate analysis LLNM Univariate Multivariate analysis analysis analysis analysis P OR (95% CI) P P OR (95% CI) P P OR (95% CI) P Blood flow, n 0.014 0.03 0.002 (%)  Negative 192 (32.40%) 183 (30.90%) 22 (3.70%)  Positive 175 (39.90%) 164 (37.40%) 36 (8.20%) Journal of Endocrinological Investigation Table 3 The risk of location in 2 2 Location CLNM Metastasis X P Location LLNM Metasta- X P the solitary primary tumor for rate (%) sis rate CLNM and LLNM No Yes No Yes (%) Upper 204 69 25.30 11.153 0.011 Upper 251 22 8.10 10.774 0.013 Middle 207 86 29.40 Middle 286 7 2.40 Lower 111 73 39.70 Lower 174 10 5.40 Isthmus 38 15 28.30 Isthmus 52 1 1.90 Fig. 1 Outcomes of receiver-operating characteristic (ROC) curve tively, with an AUC of 0.644. b ROC curve analysis for the sum of analyses. a ROC curve analysis for the sum of the maximum diameter the maximum diameter of multifocal in a unilateral lobe of LLNM: of multifocal in a unilateral lobe of CLNM: An index point ≥ 8.5 mm An index point ≥ 10.75 mm of the sum of the maximum diameter of of the sum of the maximum diameter of multifocal was found to be multifocal was found to be the optimal point to distinguish between the optimal point to distinguish between PTMC with and without PTMC with and without LLNM. The sensitivity and specificity were CLNM. The sensitivity and specificity were 64.4 and 59.3%, respec- 58.3 and 74.2%, respectively, with an AUC of 0.687 the present study, the tumor largest diameter ≥ 5 mm was that male and younger PTMC patients were prone to cervical an independent risk factor for CLNM. We suggested that LNM, especially CLNM (Table 2). patients with PTMC greater than 5 mm must be paid atten- Additionally, we found that the multifocal lesion in tion to the CLNM. Furthermore, the tumor largest diam- PTMC was an important risk factor in CLNM. This find- eter ≥ 7 mm was an independent risk factor for LNM. There- ing is consistent with the data reported [7, 20, 21, 26–29]. fore, for patients with PTMC larger than 7 mm, we should Furthermore, with the increase of the sum of the maximum pay attention not only to CLNM, but also to LLNM. diameter of multifocal in a unilateral lobe, not only was the The association of PTMC with gender and age remains probability of CLNM increased, but also the probability of controversial. Jeon et al. [24] showed that age ≥ 45 years was LLNM (Table 4). In the group with the sum of the maximum at a higher risk of LNM while male was not an independ- diameter > 8 mm, the rate of CLNM was 47.50%. The ROC ent risk factor. On the contrary, some studies revealed that analysis showed that the optimal point was 8.5 mm of the both male and younger age were risk factors [21, 22, 25, sum of the maximum diameter of multifocal. The sensitiv- 26]. In our study, male was an independent risk factor for ity and specificity were 64.4 and 59.3%, respectively. In the LNM and CLNM, rather than for LLNM. We also found that group with the sum of the maximum diameter > 11 mm, the age ≤ 40 years was an independent risk factor for LNM and rate of LLNM was 19.40%. The ROC analysis showed that CLNM, rather than for LLNM. These findings suggested the optimal point was 10.75 mm of the sum of the maximum 1 3 Journal of Endocrinological Investigation Table 4 The sum of the 2 2 Sum of maximum CLNM Metastasis X P LLNM Metastasis X P maximum diameters of all diameters (mm) rate (%) rate (%) multifocal tumors No Yes No Yes ≤ 8 48 21 30.40 9.011 0.011 66 3 4.30 6.229 0.044 8–11 21 19 47.50 37 3 7.50 > 11 12 19 61.30 25 6 19.40 diameter of multifocal. The sensitivity and specificity were patients with mix-echo and LLNM (P < 0.01, OR = 4.729) 58.3 and 74.2%, respectively (Fig.  1a, b). Therefore, we (Table 2). These phenomenon suggested that PTMC patients should pay more attention to the PTMC patients with multi- with features of non-uniform echoic distribution and mix- focal lesion and their sum of the maximum diameter. echo should be paid attention to their respective the cervical In clinical practice, we used to observe a phenomenon CLNM and LLNM. In addition, other ultrasound features with small tumor lesion but invaded extra thyroid tissues. such as shape, composition, tumor border, calcification, and There were 59 PTMC patients with T3 in our study. We aspect ratio, were not associated with the cervical LNM. found that T3 was associated with LLNM (P = 0.001, There are some limitations in our study. First, the study OR = 3.575), which was similar to Lu et  al. [26] At the is a single center study though it has a large sample size. same time, we found 20 PTMC patients with only LLNM. Second, we did not divide the subtypes of PTMC so there Of these, four cases belonged to stage T3, and 16 cases may be some statistical bias. Third, it may omit few occult were intra-thyroid lesions. The only LLNM rates of PTMC lymph node metastases because we did not perform lymph patients with T3 and with intra-thyroid lesion were 6.78% node dissection in patients not identified having contralateral and 1.66%, respectively (P < 0.05), the former being 4.08 lymph node metastasis. Finally, due to the difficulty in stand- times more than the latter. The above results demonstrated ardization of preoperative imaging diagnostic techniques of that PTMC patients with T3 were prone to having LLNM or the lymph node assessment in the central compartment, the skip LLNM. LLNM shall be considered as a risk factor for proportion of the suspicious lymph nodes in the central com- distant metastatic spread and for cancer-related death [30]. partment was not calculated. Additional studies are required Thus, we suggest that attention should be paid to the PTMC to address these issues. patients with T3 (Table 2). The location of PTMC was related to the compartment of cervical lymph node metastasis [31]. We found that location in the lower third of the thyroid lobe conferred a higher risk Conclusion for CLNM (P < 0.05), and that the location of upper third was related to a higher risk for LLNM (P < 0.05). However, We found that the probability of cervical LNM was the PTMC patients with lesions in the thyroid isthmus were closely related to the clinical and pathological character- prone to CLNM and rare to LLNM (Table  3). Thus, we istics of PTMC. Male, age ≤ 40 years, tumor largest diam- should pay attention to estimate the compartment of cervi- eter ≥ 5 mm, multifocal, non-uniform echoic distribution, the cal lymph node metastasis according to the location of the sum of the maximum diameter of multifocal in a unilateral solitary primary tumor in the thyroid. lobe ≥ 8.5 mm, tumors in the lower pole location were prone With the development of ultrasound technology, the to CLNM. Ultrasound mix-echo, the sum of the maximum diagnosis of PTMC has been improved. However, limited diameter of the multifocal ≥ 10.75 mm, tumors in the upper studies were performed to correlate LNM with ultrasound pole location were extremely prone to LLNM. Patients with characteristics. A previous report [22] has reported that T3 were prone to LLNM or skip LLNM. Therefore, accord- blood flow (present vs. absent) may improve the efficacy of ing to the clinical and pathological characteristics of PTMC, predicting LNM (P < 0.001, OR = 5.3). In our study, blood the regional lymph nodes should be correctly evaluated to flow was not a significant predictor of the LNM, CLNM or guide the surgical treatment of cervical LNM in PTMC. LLNM (P > 0.05). The present result indicated that PTMC Acknowledgements The authors are grateful to all members of the patients with blood flow had limited value in predicting cer - Department of Surgical Oncology at Hangzhou First People’s Hospi- vical LNM. But in this study, we found that the probability tal for assistance with surgical treatment of PTMC and clinical data of CLNM of PTMC patients with non-uniform or uniform collection. echoic distribution was significantly different ( P = 0.003). It showed non-uniform echoic distribution was an independ- Funding This work was supported by the Key Project of Scientific and Technological Innovation in Hangzhou (20131813A08). ent predictive factor for CLNM (OR = 1.367). 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Journal of Endocrinological InvestigationSpringer Journals

Published: Jun 6, 2018

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