Introduction

 

THYROID CANCER IS THE MOST COMMON endocrine malignancy. In the United States, an estimated 44,670 new cases of thyroid cancer were diagnosed in 2010 with a total of 1690 deaths due to the disease (1). The discrepancy between the total number of cases of all endocrine cancers arising in the thyroid (95.2%) and the total proportion of endocrine cancer deaths (65.8%) reflects the long-term survival associated with thyroid malignancies, given its relatively indolent nature (1). The vast majority (85%–95%) of these patients have papillary thyroid cancer (PTC).

Surgery, radioactive iodine treatment, and thyroid hormone suppression are the mainstays of treatment for PTC (2). Due to the overall excellent outcomes in patients with PTC and the lack of prospective controlled trials, many of the current recommendations and guidelines for treatment of PTC are controversial, such as the extent of surgery, the role of radioactive iodine treatment in low-risk patients, and the extent and frequency of surveillance. With regard to the extent of surgery for PTC, the debate has shifted from thyroid lobectomy versus total thyroidectomy (3), to a debate regarding the initial management of cervical lymph nodes (4).

Lymph nodes typically involved in PTC are level VI (central compartment); levels II, III, and IV lymph nodes along the internal jugular vein corresponding to the upper, mid, and lower neck; and less frequently the level V (posterior triangle of the neck) lymph nodes. There is general agreement that formal lymph node dissection should be performed in the setting of imageable, biopsy-proven, or palpable nodal disease. The American Thyroid Association (ATA) Guidelines Taskforce published in 2006 a statement that “Routine central-compartment (level VI) neck dissection should be considered for patients with papillary thyroid carcinoma and suspected Hürthle cell carcinoma” (5). These recommendations caused significant controversy because of the ambiguity leading to vastly different interpretations amongst clinicians and the paucity of strong supporting data. Thus, the revised 2009 management guidelines state “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; Grade C recommendation; expert opinion)” (2). The current guidelines also indicate that “these recommendations should be interpreted in the light of available surgical expertise,” acknowledging that this approach could be associated with increased morbidity especially among low-volume surgeons with less experience (2).

Although central lymph node dissection can be achieved with low morbidity in experienced hands, prophylactic dissection is, to date, of unproven benefit (4,6). The importance of regional lymph node disease in PTC may have been understated in the past partly due to the excellent overall prognosis associated with well-differentiated thyroid cancer and the observation that lymph node metastases did not influence survival rates (7). More recent large-scale population-based studies, mainly from Sweden, have shown that regional lymph node metastases among patients with thyroid cancer impact both local recurrence and cause-specific mortality (8,9). The association between lymph node metastasis and mortality seems to be preferentially identified in older patients (10,11), whereas such an association is less certain in their younger counterparts. Further complicating these analyses are potential prognostic differences including BRAF mutation status, and between microscopic (more likely to be clinically N0; cN0) and macroscopic lymph node metastases (less likely to be cN0), which are often not independently evaluated in retrospective cohort analyses. These competing considerations coupled with the drive to achieve low or undetectable thyroglobulin (Tg) levels in surveillance have refocused the debate on how best to manage regional nodal spread. The goals of treatment are no longer aimed at simply avoiding mortality. The secondary goals of achieving athyroglobulinemia, avoiding reoperative surgery, and simplifying follow-up have become the primary endpoints of therapy for many patients and treating physicians (12).

While possibly beneficial, prophylactic central lymph node dissection in patients with PTC could also lead to an increased rate of complications, including permanent hypoparathyroidism and recurrent laryngeal nerve injury (4,6). In an attempt to better define the risk–benefit ratio of prophylactic central lymph node dissection, several groups have considered embarking on prospective clinical trials to address this issue.

The inherent weakness of retrospective analyses limits the ability to extrapolate the findings to a broad population. Thus, in order to provide the basis for a prospective randomized controlled trial comparing prophylactic central node dissection versus no prophylactic central node dissection for cN0 PTC, the feasibility of such a study was analyzed by a multidisciplinary subcommittee of the ATA Surgical Affairs Committee. The data are extrapolated from current retrospective and meta-analysis studies and examined in terms of their implications on trial design and sample size.