Abstract
Regional lymph node metastases are present at the time of diagnosis in 20%–90% of patients with papillary carcinoma and a lesser proportion of patients with other histotypes. In many cases, these lymph nodes do not appear abnormal to inspection. Bilateral central (compartment VI) node dissection may improve survival (compared to historic controls) and reduce the risk for nodal recurrence. This central compartment dissection can be achieved with low morbidity in experienced hands (1, p. 118).
This led to the recommendation that routine central compartment neck dissection be “considered” in all patients with papillary thyroid cancer, although the door was left open to the possibility that radioiodine could also serve to ablate residual occult nodal disease in the context of adjuvant therapy. ▪ Routine central-compartment (level VI) neck dissection should be considered for patients with papillary thyroid carcinoma and suspected Hürthle carcinoma…. —Recommendation B (1, p. 118)
Interestingly, the European Consensus statement on differentiated thyroid cancer management published almost at the same time (2) also summarized the situation, but presented the evidence of benefit in a more negative way, and made no specific recommendation: The benefits of prophylactic ‘en bloc’ central node dissection in the absence of pre- or intraoperative evidence for nodal disease are controversial. There is no evidence that it improves recurrence or mortality rates, but it permits an accurate staging of the disease that may guide subsequent treatment and follow-up (2, p. 790).
Following the publication of the ATA guidelines (1) in February 2006, Recommendation 27 was met with skepticism by some, due to the lack of high-quality evidence of benefit and the potential for harm (3), but others were more supportive (4,5). This subject, possibly stimulated by the guidelines recommendation, has become a “hot topic” for clinical investigation. For example, a Medline search on December 30, 2011, using the terms “central neck dissection” and “papillary thyroid cancer” yielded 48 papers, 41 (85%) of which have been published since 2007.
A major limitation in evaluating the outcomes of studies on central neck dissection is that there has been no agreed upon standard for the reporting and performance of central neck dissection, making a meaningful interpretation of the results difficult. For example, there is often a lack of information and clarification in these studies on whether the dissection is being performed unilaterally or bilaterally, or with prophylactic or therapeutic intent. The ATA recognized this limitation, and convened a subcommittee that included a diverse group of thyroid cancer surgeons in order to clarify and formalize the definition of the “central neck” and a “prophylactic central neck dissection.” These definitions have subsequently been published and their usage is recommended to standardize reporting in studies evaluating the utility of central neck dissection (6). Based on this publication and on additional information, including data suggesting higher complication rates and lack of benefit of prophylactic neck dissection, the revised ATA guidelines, published in November 2009 (7) were a bit more cautious in their recommendation for central neck dissection in patients with small tumors and otherwise nonaggressive features: ▪ (a) Therapeutic central-compartment (level VI) neck dissection for patients with clinically involved central or lateral neck lymph nodes should accompany total thyroidectomy to provide clearance of disease from the central neck. Recommendation rating: B (b) Prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4). Recommendation rating: C (c) Near-total or total thyroidectomy without prophylactic central neck dissection may be appropriate for small (T1 or T2), noninvasive, clinically node-negative [papillary thyroid carcinomas] PTCs and most follicular cancer. Recommendation rating: C (7, p. 1179)
Since the 2009 publication of the revised ATA guidelines (7), there have been numerous reports on the topic, with divergent results. For example, short-term follow-up studies have shown the potential for improved outcomes with prophylactic central neck dissection (8,9), whereas other studies, including a meta-analysis (10), have not shown benefit (11,12). Of course, a controlled trial of low-risk patients randomized to receive prophylactic central neck dissection versus thyroidectomy alone would be the obvious solution. However, a recent study published by the ATA Surgical Affairs Committee evaluated the feasibility of a randomized trial designed to provide data on the utility of prophylactic central neck dissection, and concluded that “prohibitively large sample sizes would be required for sufficient statistical power to demonstrate significant differences in outcomes” (13). Despite this methodologic hurdle, there is an ongoing prospective prophylactic central neck dissection trial involving patients with papillary microcarcinoma in Korea that may provide some answers, but results will not be available until 2014 (14). It is with this background that the study by Moreno et al. (15) appears in this issue of Thyroid.
These authors retrospectively analyzed data from 331 patients with papillary thyroid cancer seen at M.D. Anderson Hospital (15). They found that the preoperative sonographic status of the central neck was a strong independent predictor of recurrence and disease-specific survival, presumably because metastatic lymph nodes large enough to be seen on ultrasound are indicative of more advanced disease. In contrast, prophylactic central neck dissection was of no demonstrable benefit, with similar recurrence and survival rates among patients who received prophylactic central neck dissection and those who did not. Additionally, there were no differences in recurrence or survival rates within the group that received what was reported as a prophylactic central neck dissection that proved or did not prove to have positive nodal histology for cancer. The authors acknowledge individual practice patterns within the study and also include an elective dissection based on intraoperative findings (presumably a suspicious lymph node) category in patients with a sonographically negative neck. It is unclear as to whether these patients were then included in the prophylactic or therapeutic neck dissection category, which makes interpretation of these results somewhat difficult. This further lends support to the universal adoption of a formal reporting system as espoused by the ATA consensus statement (6). Since the study was retrospective, the authors could not control for postoperative radioiodine use. However, the fraction of patients receiving radioiodine was similar in those who did or did not undergo prophylactic central neck dissection, and in patients who ultimately were found to have positive or negative nodal histology. But, as the authors point out, it is theoretically possible that the lack of a difference in outcomes between patients who did or did not have positive nodal histology is the result of the adjuvant effect of radioiodine in those patients with microscopic nodal metastases.
Perhaps the most relevant finding of the study by Moreno et al. (15) is that the presence of macroscopic central nodal disease, detected by ultrasound, was a significant prognostic indicator, whereas the presence of microscopic nodal disease, identified only among those patients who underwent prophylactic central neck dissection, was not. Whether the macroscopic nodal disease (clinically recognizable) is detected by ultrasound, as in the paper by Moreno et al. (15), other axial imaging, or upon intraoperative evaluation should not matter. Therefore, the most important conclusion may be that all N1 disease is “not created equal.”
The AJCC TNM staging system dictates that a patient >45 years of age with a T1 tumor and a single microscopic cervical lymph node metastasis in the central neck be upstaged from stage I (T1, N0, Mx) to stage III (T1, N1a, Mx). Prophylactic central neck dissection, done in the absence of clinically or radiologically detectable disease, may help to more accurately stage the patient with regard to nodal status but also may result in more aggressive treatment that may be unwarranted (12,16). It is likely that in patients with smaller primary tumors (T1 and T2), the AJCC staging system overestimates the risk of disease specific mortality (and recurrence risk) in patients with microscopic nodal metastases who are identified only through prophylactic central neck dissection.
In a literature review of the risk of recurrence for patients with papillary thyroid cancer performed by the ATA's Surgical Affairs Committee, the risk of recurrence for patients with papillary thyroid cancer deemed clinically N0 ranged from 0% to 9%, with a median of 2% (17). The group also found that being clinically N0 or having micrometastatic disease (defined as a <0.2 cm metastatic focus in a lymph node) was associated with a <5% risk of recurrence. Teixeira et al. (18) demonstrated that with a negative preoperative ultrasound evaluation and intraoperative inspection, the frequency of central compartment nodal disease for patients with PTC was 25%, and all metastatic deposits identified pathologically were <2 mm in diameter, supporting the recommendation of Moreno et al. (15) for observation in patients with smaller primary tumors (T1 and T2) and a clinically and radiographically N0 central compartment. This is also in accordance with recommendation 27c of the revised ATA guidelines (7).
Perhaps we may be able to stratify those in need of prophylactic central neck dissection more appropriately by preoperative molecular testing. For example, a recent meta-analysis and systematic review of the literature on the BRAF V600E mutation and the risk of recurrence in patients with PTC (19) demonstrated a statistically significant higher risk for tumor recurrence when the BRAF mutation was present. Furthermore, unpublished data from our group on over 120 central neck reoperations for PTC demonstrated a 75% prevalence of the BRAF mutation and a statistically significant shorter time to recurrence in those cases compared with patients with a wild-type BRAF genotype (20). This is also consistent with a recent retrospective study reporting that the V600E BRAF genotype was associated with an increased risk of nodal recurrence requiring surgery (21). Prospective studies are urgently needed to determine the potential influence of BRAF mutations and other molecular markers on individualized cancer treatment in low-risk patients, especially the proper roles of prophylactic central compartment dissection and postoperative radioiodine ablative therapy. Until we have more meaningful data to review, it seems appropriate to adopt a more circumspect view of prophylactic central neck dissection for low-risk patients with differentiated thyroid cancer.