PTC is prone to early lymph node metastasis. About 20%-90% of PTC patients have suffered central lymph node metastasis at the time of diagnosis [7], of which only 21–30% of the patients can be detected with ultrasound [8]. Most central cervical recurrence is caused by incomplete central lymph node dissection and may inversely correlate to the number of central lymph nodes [9]. Therefore, comprehensive removal of central lymph nodes is of significance in reducing the cervical recurrence of PTC.
As a lymph node tracer, nano-carbon has been widely used in cervical lymph node dissection among PTC patients. With a diameter of 150 nm, nano-carbon particles can penetrate the gap between epithelial cells of lymphatic capillaries and then accumulate in the lymph nodes of the corresponding region, leading to black staining of the lymph nodes that facilitates the identification and dissection of cervical lymph nodes [9]. Conventionally, nano-carbon is injected into the thyroid immediately after the exposure of the thyroid, and then its penetration is accelerated under massage for several minutes. However, because of insufficient drainage time, the nano-carbon particles cannot fully penetrate into the capillary lymphatic vessels and largely accumulate within the thyroid mesenchyme. If the capsule is injured during the operation, the nano-carbon particles in the mesenchyme will spill over to the surgical field, affecting the post-procedure. In our study, nano-carbon extravasation attacked 33 patients in the IOI group, but did not occur in the POI group. The possible reason is that because of the adequate drainage time of nano-carbon in the POI group, most of the carbon nanoparticles fully penetrated into the lymphatic capillaries, and the surgical field was not stained even if the membrane was injured. Hematoma between the sternothyroid muscle and the thyroid gland occurred in 5 patients in the POI group all in the early stage of the trial. The possible cause was the injury of superficial blood vessels in the thyroid during the puncture. We applied routine Doppler examination of thyroid blood flow to avoid injury to blood vessels. In addition, the patients were advised to press the anterior cervical region firmly for 15 minutes after the injection. No hematoma occurred since then. The skin of puncture spot was dyed in 1 patient at the initial stage of the trial. We optimized it by previously retaining 0.2 ml of air in the syringe and withdrawing the syringe slowly at negative pressure after the injection. Skin staining did not occur after then.
Delphian lymph nodes, as a part of central lymph nodes, are usually located anterior to the cricothyroid membrane [10]. Studies show a significant association between Delphian lymph node metastasis and the metastasis of other central lymph nodes [11, 12]. In our study, the detection rate of Delphian lymph nodes is 61.3% (92/150) in the POI group and 57.2% (87/152) in the IOI group, which are consistent to previous findings of 31%-76% [11, 12, 13]. There is no significant difference between the two groups in the detection rate or number of prelaryngeal lymph nodes. This is possibly because Delphian lymph nodes are superficially located and relatively close to thyroid glands, and thus can be adequately stained regardless of the short drainage time when nano-carbon was injected intraoperatively.
Linea alba cervical lymph nodes are located beneath the conjugation line of bilateral sternohyoid and sternothyroid muscles. These lymph nodes are usually in small size and covered by fat tissues, and thus are easily ignored during the operation. However, operative omission of linea alba cervical lymph nodes can become a potential resource for cervical recurrence. In some of the patients with cervical recurrence, linea alba cervical lymph node metastasis was detected during the reoperation. In our study, 10.2% (9/88) of the linea alba cervical lymph nodes were metastatic, and all the patients were accompanied with metastasis of other central lymph nodes. In the POI group, the detection rate and number of linea alba cervical lymph nodes were higher than those in the IOI group. Moreover, the linea alba cervical lymph nodes were all stained black in the POI group, but none in the IOI group. In the IOI group, the cervical linea alba had to be dissected to expose the thyroid before the injection of the nano-carbon, so the linea alba cervical lymph nodes may be damaged in draining lymphatics and thus were unstained. In comparison, damage to the draining lymphatics can be avoided in the POI group, allowing the linea alba cervical lymph nodes to be stained.
Pretracheal and paratracheal lymph nodes are located between the contralateral margin of trachea and the medial margin of the ipsilateral cervical sheath, which is inferior to the hyoid bone and superior to the suprasternal notch [14]. Pretracheal and paratracheal lymph nodes, which account for the majority of central lymph nodes and are prone to early metastasis, have been studied extensively. Chung EJ et al. reported that the median number of retrieved pretracheal and paratracheal lymph nodes was 7 ± 6.59 [15]. The average number of harvested pretracheal and paratracheal lymph nodes was 8 [16], 9 [17] and 7.4 [18]. The total number of pretracheal and paratracheal lymph nodes ranged from 3 to 42. A higher yield of pretracheal and paratracheal lymph nodes is associated with a lower recurrent rate [19]. The completeness in dissection of pretracheal and paratracheal lymph nodes depends on surgical competence and skill. In the recent decade, nano-carbon has been demonstrated to be efficient in thyroid surgeries, leading to more extensive lymph node dissection [20, 21, 22]. In our study, the number of retrieved pretracheal and paratrachinal lymph nodes is larger in the POI group than in the IOI group. This may be due to the sufficient drainage time in the POI group, which is nearly 24 hours. In addition, the tissues below the thyroid isthmus are usually amputated in the initial stage of the surgery, which may damage the main lymphatic vessels and result in inadequate staining of the pretracheal and paratracheal lymph nodes. Remarkably, Yan found the number and staining rate of central lymph nodes were larger when nano-carbon was injected 1 month before surgery [6]. For central lymph nodes, especially those with diameter < 5 mm, adequate drainage and staining are beneficial to their identification and dissection during the operation.
Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, is a common autoimmune endocrine disease. It is characterized by the infiltration of abundant lymphocytes, fibrosis, and parenchymal atrophy of thyroid tissues [23]. Studies demonstrate a positive association between Hashimoto's thyroiditis and papillary thyroid carcinoma [24, 25, 26]. In our study, 20.9% of the enrolled patients had coexistent Hashimoto's thyroiditis, which is consistent with some previous studies [26, 27]. Chen PP et al. found for patients with Hashimoto's thyroiditis, central lymph nodes were prone to be unstained when nano-carbon was injected intraoperatively [28]. They presumed that the formation of fibrosis in patients with Hashimoto's thyroiditis affected the diffusion of nano-carbon, leading to poor staining of lymph nodes. Consistent results were obtained in our study. Further IHC examination showed the capillary lymphatic vessels in the thyroid glands of Hashimoto's thyroiditis patients were significantly dilated, indicating the lymph drainage was relatively obstructed. This may partly explain the mediocre staining of central lymph nodes in Hashimoto's thyroiditis patients. In the POI group, the staining of pretracheal and paratracheal lymph nodes was improved owing to the sufficient drainage time.
The advantage of preoperative injection of nano-carbon was also demonstrated in cN1 patients. Consistently, ultrasound is widely applied to assess central lymph nodes in PTC patients. However, preceding studies found that conventional ultrasound missed 33–90% of central lymph node metastasis, especially for early metastasis [29, 30, 31]. The metastatic features of central lymph nodes usually include node enlargement, loss of fatty hilum, a round rather than oval shape, hyperechogenicity, cystic change, peripheral vascularity, and calcification [32]. Central lymph nodes with these suspicious signs are usually at the advanced metastatic stage, and are more likely to involve the lymphatic hilum [33]. In our study, within 55.9% of the undyed metastatic lymph nodes detected in the IOI group were microscopically observed with a small amount of nano-carbon particles, which cannot be identified visually. However, in the POI group, no nano-carbon particles were detected within the undyed metastatic lymph nodes. We speculate that the lymphatic hilum of metastatic lymph nodes in advanced stage was partly invaded by the tumor. Inadequate drainage time may exacerbate the unstaining of pretracheal and paratracheal lymph nodes. Nevertheless, this disadvantage can be improved by preoperative injection of nano-carbon. However, for those metastatic lymph nodes, of which the lymphatic hilum was completely obstructed by the tumor, even ample drainage time provided by preoperative injection of nano-carbon cannot improve the staining of central lymph nodes.
As reported by Chen PP [28], tumor diameter >1cm was also one of the disadvantages affecting the staining of central lymph nodes by nanp-carbon. In our study, the number and staining rate of pretracheal and paratracheal lymph nodes in patients with tumor diameter>1 cm can be increased when nano-carbon was injected preoperatively under ultrasound guidance. There may be two reasons. First, patients with tumors larger than 1 cm may have more impaired lymphatic drainage channels [28]. Second, tumors with a larger size are more likely to be associated with central lymph node metastasis [5, 34, 35].
Our study has some limitations. For instance, the sample size of this study is small, especially in each subgroup. Thus, further case accumulation is needed to confirm the advantage of preoperative injection of nano-carbon.