To date, with an increasing prevalence and overdetection rate of PTC around the world, the management of this disease becomes more precise and particularly crucial. For preventing unnecessary diagnostic workup and possible surgical intervention, the Japan Association of Endocrine Surgery (JAES) and the American Thyroid Association (ATA) separately updated the consensus statements and guidelines about the indications and strategy for active surveillance (AS) of low-risk PTMC (cT1N0M0) patients, especially for the elderly population 22,23. As the cost-effective outcomes from the long-term follow-up have been recently determined, AS is gradually accepted as a positive management option by clinicians and patients in developed countries. However, surgical intervention is still the first-line treatment for PTC patients in China 24, especially recommended for patients with suspicious CLNM. Besides, the role of prophylactic central lymph node dissection (CLND) in PTC is continuous to be debatable around the world, especially reviewing different guidelines from Asia and West countries 23,24. Furthermore, TNM staging is a common method to predict the prognosis of cancer, but TNM staging in differentiated thyroid carcinoma (DTC) has limitations as a result of “Age (55 years)” playing a significantly important role in defining the tumor stage and cannot provide clinicians with personalized prognosis prediction 25. Therefore, it’s crucial to develop more convenient and intuitive models for making an individualized clinical decision in PTC patients.
In the present study, we aimed to establish a visualized nomogram for predicting CLNM in PTC patients. The CLNM was histopathologically confirmed in 251 (33.6%) PTC patients which were consistent with reports by other similar works 13,14,26. Besides, 58 (7.8%) patients were diagnosed to suffer from LLNM which was consistent with Homma et al. study (8.4%) 6 but much lower to the observation result (25.6%) made by Yang et al. 26. This divergence might due to the possibly different study location, population, and number of patients. We selected seven variables including gender, age, tumor size, multifocality, BRAFV600E mutation, and HT for univariate analysis. Neither multifocality nor BRAFV600E mutation was analyzed to be associated with CLNM which was believed to be the frequent risk factors in lymph node metastasis. These differences were potential due to that approximately 15% of patients did not undergo fine-needle aspiration (FNA) or BRAFV600E testing before the surgery which was a common limitation in recent studies 26,27. Besides, a relatively smaller sample size compared with other large cohort studies also contributed to this difference. Hence, gender, age, tumor size, and HT were finally screened out for multivariable analysis, similar to the recently reported studies 28,29. Interestingly, it’s believed that tumor size was one of the pivotal risk factors in CLNM and the risk of CLNM increased as the diameter of the primary nodule increases. However, our data suggested that the highest risk ratio was not appeared in tumors with a diameter larger than 4cm, instead of in tumors with a diameter larger than 2cm but smaller than 4cm (Fig. 1). This phenomenon was potentially associated with the limited sample size (only 7 cases) of PTC patients with a diameter larger than 4cm. Additionally, in our study, the diagnosis of HT was based on the pathology of the surgical specimen. We observed that there was a lower rate of coexistence HT in male PTC patients than in female PTC patients (94.3% vs. 5.7%, p < 0.001), which was consistent with that in previous studies, and no significant difference was found between PTC patients with HT or without HT except for gender and CLNM. Based on multivariate analysis, the HT condition in our study was determined to be an independent risk factor in CLNM (p = 0.006) which was partially different from the conclusion in the previous study. Therefore, the role of HT in the progression of PTC contained several points that were worth discussing.
Currently, a range of works 13,21,30,31, especially retrospective study, have determined a high concurrence rate of HT and PTC from surgical specimens but the relationship between these two diseases, as well as HT and CLNM, has been controversial. Immunologically, emerging evidence has shown that an abnormal inflammatory response, especially the imbalanced subsets of T cells, NK cells, and cytokines were presenting in HT condition 12,32, which could potentially affect the tumor microenvironment and subsequent prognosis. For instance, in vitro experiment, Lubin et al. 33 conducted that the presence of background HT was contributed to a higher risk of CLNM via increased programmed death ligand-1(PD-L1). On the contrary, results from Hu et al. 17 suggested that enhanced MHC class I expression in HT conditions could decrease the PD-L1 and further overcome the CLNM in PTC patients. Serologically, Wen et al. 21 conducted that different thyroid antibody status was significantly associated with the CLNM in PTC patients concurrent with HT. They concluded single TgAb was a risk factor in CLNM, whereas TPOAb played a protective role in preventing CLNM. By contrast, a few studies hold the opposite view on the role of serum TPOAb level in CLNM, with the results they analyzed 34. The inconsistent result in these studies inspired us to provide our own experience in the following works.
Reviewing similar works on predicting CLNM 13,26,27,35, our study had a partial difference and takes it a step further. To our knowledge, compared with other works, our data indicated that HT was one of the independent risk factors in promoting CLNM which deserved further evaluation. Although the C-index in the previous study achieved 0.764 based on 914 PTC patients 36 and 0.854 based on a sample size of 1,252 PTC patients 26, the C-index of our nomogram was still more than 0.7, indicating that it has sufficient discrimination ability. The DCA results show that the nomogram we developed has good clinical practical value. Combined with other established nomograms based on ultrasound signatures, our nomogram with clinical pathological characteristics with the strongest risk factors including gender, age, size, and HT can increase the accuracy for predicting CLNM. These prognostic factors collected from preoperative and intraoperative could further help surgeons to decide the extent of the initial thyroidectomy and whether prophylactic central neck dissection is warranted.
Nonetheless, there were still some limitations that should be mentioned. Firstly, this was a retrospective study from a single-center teaching hospital center which did introduce some selection biases. There were only 747 patients enrolled in this study which were still not large enough for the deepening predicting of the clinical risk factors in CLNM. Secondly, body mass index (BMI), ultrasound signatures, and some laboratory testing results which were determined to be associated with CLNM in PTC patients 26,27 were not included in our study. Lastly, there were only four variables finally added to the nomogram, which indicated there might be potential variables waiting to be discovered that could make our nomogram complete and more reliable.