Thyroidectomy
Surgery is the most important method to treat PTC, which ranges from lobectomy to total thyroidectomy (TT) [15]. There were no surgical treatment guidelines specific for children with thyroid carcinoma in China, and only adult guidelines can be referred to. The 2015 ATA pediatric guidelines recommended TT for the majority of children with PTC. The rationale for this recommendation is based on multiple studies showed an increased incidence of bilateral and multifocal lesions (30% and 65%, respectively) [16, 17], while a near-TT or TT can greatly reduce the risk of recurrence and subsequent second surgery [18–20]. TT can also optimize or reduce the utilization of postoperative 131I treatment, and benefits serum Tg as tumor marker to detect recurrent or persistent lesions. In our study, the bilateral and multifocal lesions were 23.81% and 30.95%, respectively, which was lower than that quoted in ATA children guidelines [17, 21].
According to ATA adult guidelines [8], NCCN guidelines(Version 2.2020)and ATA pediatric guidelines [11], DTC patients with LNM should be treated with TT. Our results revealed that LNM rate in central and lateral compartment were 83.33%and 62.96༅, respectively. Palaniappan et al reported LNM rate 71.6% [22]. Thus, based on high LNM rate, TT should be conducted in the majority of children with PTC.
Although TT is recommended for the majority of children with PTC, the extent of thyroidectomy is still controversial. The main problem is the influence of surgical resection scope on tumor recurrence and potential complications (such as transient/permanent postoperative hypoparathyroidism and recurrent laryngeal nerve injury) [19, 20, 23, 24]. Wang et al [25] reported that TT can not reduce recurrence, but only increase the surgical complications. Kluijfhout et al [26] proposed lobectomy as an option for ATA low-risk patients. Spinelli et al [23] believed that lobectomy could be applied in patients with unifocal lesion without distant metastases. Sugino et al [27] considered lobectomy with prophylactic unilateral CND was acceptable for patients without the risk factors of recurrence. Another study by Sugino et al [28] believed lobectomy may be sufficient as the initial surgical procedure for low-risk pediatric patients [no risk factors related to poorer DFS, cN1, ETE, and NMLNs (≥ 10)]. In fact, it is difficult to make accurate risk stratification and the recurrence risk of each patient pre-operatively or intra- operatively. There is no quantitative index to find the best balance between the risks and benefits of surgery.
In this study, we performed TT for children with bilateral lesions, multifocal tumors, locally advanced (T3 or T4) tumors and clinical evidence of lymph node or distant metastasis, and 10 patients with lobectomy and isthmus resection were selected (including T1a in 5, T1b in 4 and T2 in 1). The CLNM rate was revealed to be 50% pathologically in those 10 patients, and subsequent operation (remnant thyroidectomy) should be considered according to guidelines. We did not perform reoperation, TSH suppression therapy was conducted and 1 patient recurred during follow-up. There are no serious or permanent complications occurred in patients performed TT in this study. Therefore, we believe that the majority of children PTC should be treated with TT, and lobectomy be considered for a few patients with caution.
Central Neck Dissection
Central lymph nodes metastasis are common in PTC patients. Literatures reported that PTC in children were more likely to have CLNM [25, 29, 30], which increased the risk of pulmonary metastasis [17, 31, 32]. CND is associated with a decreased risk of locoregional persistent or recurrent disease, so as to increase disease free survival (DFS) [33], as well as the potential to increase the efficacy of 131I treatment [17, 34]. Additionally, some studies have shown that TT with prophylactic CND can increase 5-year and 10-year DFS to 95% [35]. It is recommended in ATA children guidelines [11] that CND should be performed in children with malignant cytology and clinical evidence of gross extrathyroidal invasion and/or locoregional metastasis on preoperative staging or intraoperative findings, and prophylactic ipsilateral or bilateral CND should be selectively considered in patients with no clinical evidence of gross extrathyroidal invasion and/or locoregional metastasis.
Owing to the possibility of permanent hypoparathyroidism following CND, some authors argued that CND in children with DTC is controversial. Unfortunately, there are no intraoperative data that reliably to predict which patient is at increased risk of locoregional metastasis or recurrence. Rubinstein et al [36] reported that LNM ratio > 0.45 may predict the likelihood of recurrence in pediatric PTC patients undergoing TT with prophylactic CND.
CND was routinely performed in our study, and the results revealed the CLNM rate in ipsilateral and contralateral of central compartment were 83.33%and 57.41%༅, respectively, and the CLNM rate in patients with T1, T2, T3 and T4 tumor were 63.64%, 88.89%, 100༅and 100༅, respectively.
Our data also revealed the CLNM rate in cN1b (-) and cN1b (+) patients were 55.00% and 100%, respectively. Study by Machens et al [37] showed that TT plus prophylactic CND can significantly decrease the need for subsequent surgeries, which was as high as 77% for patients without CND. Rubinstein et al [38] found a trend toward lower recurrence in patients undergoing thyroidectomy with CND compared with thyroidectomy alone in cN1b (-) patients (p = 0.07). Kim, et al [39] reported that tumor ≥ 1.1cm, ETE and multifocality are the independent risk factors for LNM, and suggested careful evaluation of the central compartment intraoperatively, so as to perform CND. However, as preoperative ultrasounds and intraoperative palpation are difficult to make an accurate assessment on the lymph node. In our study, only 12 (22.22%) patients were cN1a (+), and CLNM was confirmed to be 88.33% following routine CND. Recurrences were revealed in contralateral central compartment in 2 patients underwent lobectomy with unilateral CND and 1 in patient underwent TT, bilateral CND and bilateral LND patient. No permanent hypoparathyroidism occurred in this cohort of children.
Based on the high prevalence of lymph node involvement and difficulties in evaluating central compartment, we suggest prophylactic bilateral CND for PTC children underwent TT. Otherwise, prophylactic unilateral CND is acceptable for children underwent lobectomy.
Lateral Neck Dissection
Consensus has been reached on therapeutic LND for DTC patients [14]. Literature showed that therapeutic LND is associated with a reduction in persistent or recurrent disease and improved DFS in children [11]. The 2015 ATA children guidelines also recommended therapeutic LND, including Levels III, IV, anterior V, and II, and routine prophylactic LND is not recommended [11]. Ito et al [40, 41] suggested prophylactic LND for children with risk factors of lateral nodes involvement.
In current study, therapeutic LND ( including SSLND or SLND) was performed on the basis of the preoperative evaluation by physical examination, US and CT, and results show that the LLNM rate gradually increased with the increase of T stage, and the LLNM rate in patients with T1, T2, T3 and T4 tumor were 36.36% (T1a: 25.00%, T1b: 42.86%), 55.56%,85.71%和100%, respectively. Our results indicate the importance of preoperative evaluation. For this cohort of patients, our data also revealed 62.96% and 31.48% of LLNM in ipsilateral and contralateral of lateral neck, respectively; 100% of LLNM was observed in 34 cN1b (+) patients. Jeon et al [42] recently revealed that LLNM was independent predictors for structural persistent or recurrent disease.
We observed lowest LNM rate in Level V (15.69%), which was lower than in Levels II, III and IV (p = 0.000). The LNM rate in Level III was significantly higher than in Level II, but no significant difference between sub-Level IIa and IIb. We also observed no significant difference in metastasis rate between Level III and Level IV. As it is a retrospective study, some patients underwent SSLND (Levels II-IV dissection in 6 procedures and Levels III-IV dissection in 11 procedures), which was inconsistent with the recommendations of ATA children guideline. This may be due to the arbitrary decision by the surgeon, and someone will argue that the un-dissected nodes with occult metastasis would result in recurrence in patients underwent SSLND. Excellent outcome was reached with 38.56 months of follow-up, no significant difference in reoperation rate was observed between cN1b (-) and cN1b (+) children (9.09 vs 9.38%, p = 676), and no difference in recurrence rate between SLND and SSLND groups (0% vs 8.82%, p = 0.287) was observed. Such excellent outcome in this study may be due to non-randomized LND procedure or short follow-up time, and this group of patients are also being followed up.
Based on ATA guidelines recommendation [11] and our data, we also suggest therapeutic LND for pediatric PTC with clinical lateral lymph node involved, and SLND is preferred other than SSLND.