Safety and Prognostic Impact of Prophylactic Level VII Lymph Node Dissection for Papillary Thyroid Carcinoma

Papillary thyroid cancer (PTC) is the most common type of thyroid cancer accounting for about 80% of all thyroid cancers, and is the fifth leading malignancy in females (Cisco et al., 2012; Siegel et al., 2013). Given the high rate of subclinical nodal metastases in PTC, many centers, have moved to routine prophylactic central nodal dissection (pCND) at the time of total thyroidectomy (TT) for all patients with PTC, pCND allows for more accurate assessment of nodal status, decreases the rate of local recurrence, reduces morbidity from reoperation if required, and may guide the dose of ablative postoperative radioiodine given (Mazzaferri EL Jhiang 1994; Scheumann et al., 1994; Hughes et al., 1996). Dralle (2012) reports a significant risk of postoperative hypoparathyroidism after CND but suggests that pCND


Introduction
Papillary thyroid cancer (PTC) is the most common type of thyroid cancer accounting for about 80% of all thyroid cancers, and is the fifth leading malignancy in females (Cisco et al., 2012;Siegel et al., 2013).
Given the high rate of subclinical nodal metastases in PTC, many centers, have moved to routine prophylactic central nodal dissection (pCND) at the time of total thyroidectomy (TT) for all patients with PTC, pCND allows for more accurate assessment of nodal status, decreases the rate of local recurrence, reduces morbidity from reoperation if required, and may guide the dose of ablative postoperative radioiodine given (Mazzaferri EL Jhiang 1994;Scheumann et al., 1994;Hughes et al., 1996).Dralle (2012) reports a significant risk of postoperative hypoparathyroidism after CND but suggests that pCND

Safety and Prognostic Impact of Prophylactic Level VII Lymph Node Dissection for Papillary Thyroid Carcinoma
Ihab Samy Fayek 1 *, Ahmed Ahmed Kamel 2 , Nevine FH Sidhom 3 improves prognosis for papillary thyroid cancer Dralle (2013).Many studies showed an increased risk of recurrent paralysis in patients undergoing CND, with rates of recurrent lesions ranging between 1% and 12% (Moo et al., 2009;Choi et al., 2010;Hughes and Doherty 2011).However, Tartaglia et al, 2014 reported no significant difference between TT alone or TT with CND.The American Thyroid Association's consensus statement on terminology of CND defines the innominate artery as the lower limit of a CND and this equates CND to level VI and the superior portion of level VII (ATA consensus, 2009).
Many studies highlighted the prognostic importance of additional dissection of level VII nodes as an integral and complementary component to Level VI neck nodes in pCND through the same cervical neck incision required for PTC (Choi et al., 2011;Wang et al., 2013;Fayek 2015), However only one study addressed the safety of the procedure regarding hypoparathyroidism and vocal cord dysfunction (Wang et al., 2013) requesting further studies to highlight and evaluate the previous results.
In this study, the author aims to study the safety of adding dissection of level VII nodes to the routine dissection of level VI nodes in pCND for PTC regarding hypoparathyroidism (temporary and permanent) and vocal cord dysfunction (temporary and permanent) and its impact on disease free survival.

Materials and Methods
This is a prospective study of 63 patients with papillary thyroid carcinoma (PTC) proved by Fine Needle Aspiration Cytology (FNAC) from December 2009 to May 2013.All patients had N0 neck nodes clinically and by Hi-Res neck ultrasound.All patients underwent Total Thyroidectomy (TT) and Central Neck Dissection (CND) in the form of dissection of levels VI and VII lymph nodes (LNs) in group A (31 patients) and level VI only in group B (32 patients).Level VI dissection was defined as including the prelaryngeal, pretracheal, and paratracheal nodes between the hyoid bone and the suprasternal notch.Level VII dissection was defined as the pretracheal and paratracheal superior mediastinal lymph nodes between the suprasternal notch and the innominate artery.Level VII dissection without opening the sternum was performed through the same collar neck incision for thyroidectomy, dissecting the anterior superior mediastinal lymph nodes above the innominate artery and vein (Figure 1a, b).For group A, the thyroid gland, level VI as well as level VII nodes were submitted each separately for histopathological examination.For group B, the thyroid gland and level VI nodes were also submitted each separately for histopathological examination.Patients' demographics, tumor size, multicentricity, bilaterality, extrathyroidal extension, number of dissected nodes and number of metastatic nodes in each level separately were recorded and analyzed.
Postoperatively serial measurements of serum calcium levels were recorded, defining hypocalcemia due to temporary hypoparathyroidism as a serum calcium A B concentration of less than 8 mg/dL at any point after operation up to 6 months postoperatively.Whereas permanent hypoparathyroidism was defined as the ongoing need for calcium and/or vitamin D supplementations for more than 6 months postoperatively to maintain normal serum calcium levels.All patients underwent routine preoperative and postoperative laryngoscopic evaluation.
Temporary vocal cord dysfunction (VCD) was defined as sluggish or absent vocal cord motility on direct laryngoscopy that resolved subsequently within 6 months postoperatively.Permanent vocal cord dysfunction was defined as the decrease or absence of vocal cord motility on direct laryngoscopy persisting for 6 months or more postoperatively.
Preoperative and postoperative laryngoscopy was done at the otorhinolaryngology department at Cairo University hospital.
Follow-up of all patients in both groups extended up to 61 months.
Data was analyzed using IBM SPSS advanced statistics version 20 (SPSS Inc., Chicago, IL).Numerical data were expressed as mean and standard deviation or median and range as appropriate.Qualitative data were expressed as frequency and percentage.Chi-square test (Fisher's exact test) was used to examine the relation between qualitative variables.For quantitative data, comparison between two groups was done using Mann-Whitney test (non-parametric t-test).A P-value <0.05 was considered significant.

Results
Female: Male ratio was 24:7 and 27:5 in group A and B respectively (P=0.482) [

Discussion
In 1956, Crile noted the anatomical continuity of level VI and level VII nodes Crile (1956), which was described later, by Grebe and Hay in 1996, as a lymphatic continuity between the neck and the superior mediastinum (Grebe and Hay, 1996).
Since level VI, which sits high up in the neck, as well as level VII, which is hidden behind the manubrium sterni and medial thirds of both clavicles, cannot be assessed accurately by ultrasound and CT with poor sensitivity ranging between 50 and 70 % Mulla (2012), in addition, normal-sized, Level VII lymph nodes can still harbor macrometastatic disease (Wang et al., 2013), and since level VII nodes are an important and integral prognostic factor in papillary thyroid carcinoma (Choi et al., 2011;Wang et al., 2013;Fayek 2015); the dissection of those nodal groups is an important step in the management plan of PTC.
Putting in mind that pCND was advised by the European Thyroid Association, the British Thyroid Association, and the American Thyroid Association (Pacini et al., 2006;Grubbs et al., 2007) and its benefit in the accurate staging of the tumor, which may guide subsequent treatment and follow-up, in addition to decreasing the recurrence of PTC, improving disease-specific survival, and significantly reducing levels of serum thyroglobulin, increasing the rate of athyroglobulinemia (White et al., 2007) so pCND was done in all patients (including level VII in group A) of this study.
It should be remembered that the rate of permanent hypoparathyroidism and unintentional permanent nerve injury is higher when cervical lymph node dissection is performed with total thyroidectomy than with total thyroidectomy alone (White et al., 2007).In this study, the permanent hypoparathyroidism was documented in 6.5% for group A and 9.4% for group B patients which was much less than that reported by Tartaglia et al, 2014 25.4% of patients who underwent TT + CND, within the range reported by White et al, 20070-14.3% while Pereira et al., 2005;Choi et al., 2011;Popadich et al.,2011;Wang et al., 2013;and Lee et al., 2015 reported only 2%, 3% ,0.8%, 4.6% and 3.3% permanent hypoparathyroidism respectively.Temporary hypoparathyroidism was  (Tartaglia et al., 2014), 6% (Wang et al., 2013) and 9.7% (Popadich et al., 2011) but sometimes as high as 60% (Pereira et al., 2005).In this study, the permanent VCD was documented in 3.2% in group A and 6.3% in group B which was within the reported range (0-12%) in other studies (Choi et al., 2011;Hughes and Doherty, 2011;Popadich et al., 2011;Giordano et al., 2012;Wang et al., 2013;Tartaglia et al., 2014;Lee et al., 2015), while temporary VCD was reported to be 12.9% in group A and 9.4% in group B which was slightly higher than the reported range (0.4-9%) in other studies (Pereira et al., 2005;Popadich et al., 2011;Wang et al., 2013;Tartaglia et al., 2014;Lee et al., 2015).
In this study, we couldn't prove a statistically significant difference between both groups regarding hypoparathyroidism and VCD.Two studies evaluated the complication rate of TT+ pCND compared to TT alone and the only statistical difference between the 2 groups was in the transient hypoparathyroidism (P<0.02)(Sywak et al., 2006;Roh et al., 2007).Wang et al, 2013 also added level VII to CND with no increased risk of permanent complications of hypoparathyroidism or recurrent laryngeal nerve injury.Another finding in this study, that may point to the safety of level VII nodal dissection, is that the occurrence of either hypoparathyroidism or VCD was significantly affected by the No. of dissected level VI LNs only in both groups, while the dissected No. of level VII LNs in group A didn't affect the occurrence of neither of these 2 complications [Tables 5 and 6].
Tumor size >1 cm.significantly affected nodal metastases in group A (levels VI and VII), but not in group B (level VI alone) which is considered complementary to the results of Choi et al., 2010 who concluded that tumor size ≥1.5 cm.increased level VII nodal metastases significantly and that complications due to level VII LN dissection are not at a higher rate than level VI LN dissection alone, Both studies, revealed the prognostic impact of level VII nodal dissection especially when the tumor size is larger than 1 cm. in PTC , in addition Roh et al, 2011 andChen et al, 2015 documented that tumor size >1 cm. was a predictor of ipsilateral central lymph node metastasis (CLNM) recommending pCND in patients with a tumor size >1 cm.DFS was not statistically different between both groups [Table 8], as many studies comparing TT+ pCND versus TT alone didn't find a survival benefit between both groups (Sywak et al., 2006;Costa et al., 2009;Zuniga et al., 2009;So et al., 2012).The most recent controversy has been provided by Barczewski et al, 2013 who published the first paper in the literature showing a benefit not only for local recurrence (5.5% vs 12.4%) but also for specific disease survival (98% vs 92.5%) for patients with PTC having TT + pCND in comparison with those who had only TT, major bias in this study are its retrospective nature and that patients considered at risk in any group had RAI treatment.
An extensive review of the literature stated that no arguments favoring pCND as a universal rule for patients with PTC.The guidelines and consensus documents of the most important medical and surgical societies are in the direction of selecting subgroups of patients with high risk of recurrence for pCND, especially T3 or T4 tumors, multifocal/bilateral tumors and patients with BRAF V600E mutation detected in the preoperative setting.In the rest of PTC, which are the majority, TT must be considered an oncological proper treatment providing the best overall survival.Ramírez-Plaza (2015) Further studies are needed to define the need of level VII in addition to level VI nodal dissection in selected subgroups of patients with PTC.
In conclusion, adding level VII nodal dissection as a complementary and integral part to level VI nodes for prophylactic CND in patients with PTC is a safe procedure regarding either hypoparathyroidism or VCD.The occurrence of these complications was related to the no. of dissected level VI LNs but not to level VII LNs.Tumor size > 1 cm.significantly affects nodal metastases in both level VI and VII LNs.

FigureFigure 1b :Figure 1a :
Figure 1.A) Operative field after Total Thyroidectomy and complete dissection of Levels VI and VII neck nodes B) Operative field after Total Thyroidectomy and complete dissection of Levels VI and VII neck nodes (Tagged) Figure 1b: Operative field after Total Thyroidectomy and complete dissection of Levels VI and VII neck node (tagged) Figure 1a: Operative field after Total Thyroidectomy and complete dissection of Levels VI and VII neck nodes.

Table 7 . Correlation between tumor size (mm.) and LN metastasis in both groups
The occurrence of either hypoparathyroidism or VCD was significantly affected by the No. of dissected level VI LNs only in both groups, while the dissected No. of level VII LNs in group A didn't affect the occurrence of neither of these 2 complications [Tables5 and 6].Tumor size significantly affected nodal metastases in group A (P<0.001), but not in group B (P=0.138) [Table7].No

Table 8 . DFS in Relation to Patients and Tumor Characteristics and Complications
DOI:http://dx.doi.org/10.7314/APJCP.2015.16.18.8425Safety and Prognostic Impact of Prophylactic Level VII LymphNode Dissection for Papillary Thyroid Carcinoma documented in 32.3% and 21.9% in group A and B of the current study respectively, coinciding with the findings of Lee et al, 2007 with 20.5%-48% incidence and Lee et al, 2015 with 36.6% of transient hypoparathyroidism; with a higher incidence than other studies 12.7%