Analysis of risk factors for cervical lymph node metastasis of papillary thyroid microcarcinoma: a study of 268 patients

According to the World Health Organization (WHO) report, the number of new cases of thyroid cancer in China accounted for 15.6% of that worldwide, and the number of deaths accounted for 13.8% [1]. Papillary thyroid carcinoma (PTC) is the most common pathological type of thyroid malignancy and accounts for about 85 to 90% of all cases of thyroid malignancies. PTC with a maximum tumor diameter of 10 mm or less is defined as papillary thyroid microcarcinoma (PTMC) [2]. Several studies have indicated that PTMC has a low rate of recurrence and metastasis [3] as well as an extremely high 10-year survival rate [4]. In recent years, improvements in diagnostic methods such as imaging and ultrasound-guided fine needle aspiration biopsy have led to a significant increase in the diagnosis rate of PTMC [5].

The most common site of PTMC metastasis is cervical lymph nodes, especially the central lymph nodes (known as level 6) [6, 7]. Surgery remains the main therapeutic modality for PTMC: it is a consensus that patients with cervical LN metastasis be managed by LN dissection; however, the necessity of LN dissection in patients with clinically negative lymph nodes (cN0) has been debated [8]. Active surveillance data from Japan suggested that even those at risk for disease progression such as young age and pregnancy should be actively monitored instead of surgery [2]. On the other hand, cervical LN metastasis increases the risk of loco-regional recurrence of PTC [9]. As a result, it is important to identify predictors of cervical LN metastasis.

In the current retrospective analysis, we examined the potential correlation between pre-operative variables with cervical LN metastasis in 268 PTMC patients.

The current study (including access to raw data) was approved by the Ethics Committee of Shanghai Ruijin Rehabilitation Hospital (Committee Chairman: Ms. Yuezhen Dai) and performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Patient consent was not required because of the retrospective nature of the study. Anonymized patient data (in the Chinese language) are available upon request.

In the current study, approximately 30% PTMC patients had cervical LN metastasis. Independent risk factors included the male sex, younger age and tumor size on ultrasound at > 5 mm. Given the fact that cervical LN metastasis increases the risk of loco-regional recurrence of PTC [9], our findings suggest that this non-insignificant proportion of at risk PTMC patients should be actively monitored. Based on these findings, we believe that LN dissection is necessary in young men with PTMC with tumor diameter at > 5 mm. Skip metastasis was identified in 4 out of the 268 cases. We therefore did not attempt an analysis to examine the risk of skip metastasis.

In recent years, there has been a noticeable increase in the incidence of thyroid malignancies in China and globally, in which PTMC accounts for a large proportion of all thyroid cancer cases [10]. The rate of cervical LN metastasis in PTMC patients has been reportedly from 12 to 64% [7]; the rate of cervical LN metastasis in our study (29.5%) falls within this range. Cervical LN metastasis is associated with tumor stage, invasiveness and recurrence rate, and serves as one of the essential prognostic predictors of PTMC [11, 12]. Although thyroid malignancies are now diagnosed at an early stage owing to recent advances in imaging technologies, image reading can be influenced by multiple factors such as tumor characteristics and physicians’ skills.

In current consensus, LN dissection should be performed in PTMC patients with pathologically confirmed cervical LN metastasis. Whether cervical LNs should be routinely dissected in cN0 PTMC patients remains controversial. A previous study suggested that LN dissection had no significant effect on the recurrence and metastatic rate of PTMC [13].

Based on previous literature, independent risk factors of cervical LN metastasis in PTMC patients include age over 45 years [14], male sex [14, 15], larger tumor diameter [16] and capsule invasion [6, 7, 16]. Other clinicopathologic variables associated with cervical LN metastasis may include lesion location [17], multifocality (the number of lesions no less than 2) [18‐21], and concurrent Hashimoto’s thyroiditis [15, 22]. Our study focused on solitary PTMC and found that tumor diameter on ultrasound at > 5 mm is an independent risk of cervical LN metastasis in PTMC (OR = 3.172, P = 0.006). The current study also revealed an association between cervical LN metastasis with younger age (OR = 0.977, P = 0.042) and the male sex (OR = 2.362, P = 0.007). We failed to show an association between cervical LN metastasis with tumor location, capsule invasion or Hashimoto’s thyroiditis, possibly due to insufficient sample size.

The availability of gene sequencing data may allow molecular stratification of cancer patients. Lai et al. showed in a meta-analysis that BRAF^V600E mutation was associated with extra-thyroid infiltration, lymph node and distant metastasis, and advanced TNM staging. Therefore, determination of BRAF mutation status preoperatively may allow preoperative evaluation of capsule invasion and cervical LN metastasis. However, more studies are required to validate of molecular markers such as BRAF.

With the development of medical technology, PTMC patients now have more options for treatment. In addition to the more aesthetically pleasing surgical methods such as thyroidectomy with laparoscopy or robot-assisted surgery, radiofrequency ablation therapy has also garnered the interest of clinicians. Based on the findings from the current study, we believe that ablation may be suitable for selected patients (older age, women, tumor diameter at ≤5 mm) with low risk of cervical LN metastasis.

Cervical LN metastasis is not a rare occurrence in PTMC patients. Independent risks for metastasis include the male sex, younger age and tumor diameter on ultrasound at > 5 mm.