Number of Foci Increases Risk of Central Compartment Lymph Node Metastasis in Papillary Thyroid Cancer

Hou, et al., Number of Foci Increases Risk of Central Compartment Lymph Node Metastasis in Papillary Thyroid Cancer. &

The prevalence of the multifocal PTC ranged from 32% to 39% in large series of PTC [3][4][5]. In clinics, multifocality is often empirically treated as a high-risk factor for aggressiveness of PTC and reported to be associated with extensive LNM [4], higher recurrence rate [5], and more aggressive biological behavior [6,7], compared with unifocal PTC. However, inconsistent and even contradictory findings also exist [4,8,9]. It is well accepted that active surveillance should be recommended to patient with microcarcinoma at low risk. However, a clinical dilemma is how do physicians handle with multifocal microcarcinoma which all the foci are less than 1cm in diameter. In other words, whether multifocality could be used as a quantified parameter rather than a qualitative parameter need to be addressed. Moreover, although prophylactic central compartment neck dissection is not routinely recommended according to ATA guidelines, insidious LNM do exist and be the cause for the recurrence of PTC. Thus, is it safe to recommend not receiving central compartment neck dissection for all patients with multifocal papillary thyroid microcarcinoma?
In this study, we retrospectively analyzed 1034 patients with papillary thyroid carcinoma to evaluate the how the multifocality affects the central compartment LNM and try to quantify the multifocality to further predict the possible insidious central compartment LNM.

Data Collection/ Definition of Parameter
Bilateral disease was defined as the presence of PTC foci in the right and left lobes of the thyroid gland. The size of the largest focus of PTC was used for analysis. Multifocal disease was defined as the presence of two or more foci of PTC.

Determination of Number of Tumor Foci and Tumor Size
To define the number tumor foci and tumor diameter of each tumor, ultrasonographic and histopathological reports were reviewed by two independent researchers. The number of tumor foci is determined according to the histopathological reports. As for each tumor's largest diameter, we refer to the ultrasonographic reports for each tumor and record its ultrasonographic diameter.
The largest diameter is recorded if three-dimensional data is given by the ultrasonographers.

Statistical Analysis
Statistical analysis was performed using IBM SPSS Statistics for Windows v21 (IBM Corp., Armonk, NY). Univariate analysis was performed using Chi-squared test or Fisher's exact tests for categorical variables, Student's t-tests for normally distributed data, and Mann-Whitney U-tests for continuous variables that were not normally distributed. Cox regression analyses was used for univariate and multivariate analysis. All p-values represented were two-sided and considered statistically significant when p<0.05.

Factors Associated with Central Compartment LNM
Univariate analysis was done to assess the risk factors of central compartment LNM. As for all the patients included, male gender, tumor size larger than 1cm, multifocality, bilateral disease, diffuse calcification were risk factors for central compartment LNM Table 2.
Interestingly, when multifocal diseases were considered (including both multifocal PTCs and multifocal PTMCs), bilateral disease was no longer a risk factor (P=0.053, P=0.095, respectively). We then calculated the independent risk factor for LNM by multivariate analysis, we found that male gender, multifocality, diameter larger than 1cm, diffuse calcification on ultrasonography are all independent risk factors for LNM. However, age and bilaterality are not independent risk factors for LNM Table 3.
Central compartment LNM rate is associated with multifocality irrespective of unilateral or bilateral disease.

Number of Foci Increases the LNM Rate
The above results showed that multifocality is a risk factor for increased LNM rate irrespective of unilateral or bilateral disease.
This finding suggests that multifocality might be interpreted in the setting of one "thyroid lobe", rather than "one thyroid gland". Thus, the effect of the number of PTC foci on central compartment LNM was further examined. As shown in

LNM Rate for Multifocal PTMC Is Comparable to Unifocal PTC When Ptmcs Largest Diameter is Between 6-10 mm
To further assess the effect of multifocality on LNM, patients were stratified according to the largest diameter. Patients were divided into three groups: A. largest diameter is ≤5mm; B. 6mm≤largest diameter≤10mm; C. largest diameter >10mm. As shown in Table   5  lymph node metastasis in patients with one and two foci [11].
These findings identify multifocality in PTC as an indicator of tumor aggressiveness, manifesting in a higher propensity for locoregional metastasis.
Both univariate and multivariate analysis identified male gender, tumor size larger than 1cm, multifocality, diffuse metastasis in the study population. These findings are consistent with previously published studies identifying risk factors for level VI metastasis in PTC [12][13][14]. Of note, our data indicated a rare phenomenon diffuse calcification as significant predictors of level VI lymph node metastasis. Diffuse calcification has been implicated with thyroid malignancy [15,16].