**1.3 Classification of cervical lymph nodes**

The cervical levels system has been used to accurately communicate the location of nodal disease, standardize terminology in research and guidelines, and define the boundaries of areas where lymph node dissection should be performed. Lymph nodes in the lateral neck compartment are grouped into level I–V, whereas levels VI and VII refer to lymph nodes in the central neck compartment. Several refinements and addition of sublevels were summarized in **Table 1** [11–13].


#### **Table 1.**

*The levels and sublevels of the neck.*

#### **1.4 Risk factors predicting nodal metastasis**

Understanding the risk factors predicting nodal metastasis in DTC is imperative for identifying the group of patients most vulnerable of nodal metastasis and best indicated for neck dissection. The most consistently reported risk factor for central compartment nodal metastasis is PTC of size larger than 1 cm [14, 15]. The presence of ipsilateral central compartment nodal metastasis is also associated with greater risks of contralateral central compartment involvement. Other reported risk factors include multifocal tumors, extrathyroidal extension, and younger age [14–19]. The only risk factor for lateral compartment nodal metastasis is the presence of central compartment nodal metastasis [19–21].

With advances in molecular techniques, researchers have explored the utility of biomarkers in addition to conventional clinicopathologic features to predict lymph node metastasis in DTC. BRAF is a proto-oncogene which has received frequent attention. Multiple studies have reported the presence of BRAFV600E mutation as a factor associated with nodal metastasis in DTC [22–24]. Yet, other studies have refuted such associations [25, 26]. To date, only seven heterogenous prospective studies have been published but with conflicting conclusions [27–33]. Hence, the true utility of BRAFV600E mutation in risk stratifying nodal metastasis in clinically node negative (cN0) patients remains controversial.

Another potential prognostic marker of differentiated thyroid cancer is the Telomerase Reverse Transcription (TERT) promoter gene which regulates chromosomal integrity. The somatic mutation TERT-C228T was found in up to 11% of DTC [34]. PTC with TERT-C228T was associated with more aggressive tumor behaviors and poorer clinical outcomes when compared with patients exhibiting BRAF mutation alone [35]. The presence of TERT-C228T mutation has been found to be associated with nodal metastasis with an OR of 1.5–1.8 but its prospective role in stratifying patients for neck dissection remains to be elucidated [36, 37].
