A Vision for the Surgical Management of Papillary Thyroid Carcinoma: Extensive Lymph Node Compartmental Dissections and Selective Use of Radioiodine

To a man with a hammer, everything looks like a nail. —Mark Twain The natural history of papillary thyroid cancer (PTC) is such that many patients reach normal life expectancy after total thyroidectomy and radioiodine therapy (1). Still, a large number of patients experience locoregional recurrences, usually in cervical lymph nodes, and within 10 yr of initial therapy, about 7% die of disease (2). Yet despite the slow tumor growth and favorable prognosis for survival of patients with small PTCs, the major challenge is controlling locoregional recurrence. Whether this is best accomplished with surgery or radioiodine—or whether they should be treated at all—has been a matter of debate, especially in patients with microcarcinomas. What are the risks of lymph node metastases? The initial management of small PTCs has received considerable attention stemming from the relentlessly increasing incidence of small PTCs that has been observed over the past three decades in the United States (3). Nearly half were papillary microcarcinomas 1 cm or smaller, and nearly 90% were PTCs 2 cm or smaller, both of which have favorable survival rates. Yet a study of over 52,000 patients found the recurrence rate to be 4.6% for tumors smaller than 1 cm and 7.1% in patients with tumors 1–1.9 cm, with 10-yr cancer-specific mortality rates of 2 and 2.6%, respectively (4). To obfuscate initial management decisions further, the rates of lymph node metastases in both low- and high-risk patients range from 25 to 60%, depending upon the extent of surgery (5, 6). Although regional lymph node metastases have generally been regarded to increase local recurrence rates without affecting survival, several large studies suggest otherwise. A study of almost 10,000 patients found the 14-yr survival rate was 82% for patients with and 79% for patients without lymph node metastases (P < 0.05) (7). Another study (8) of 33,088 patients found a 46% increased risk for death with lymph node metastases in patients with follicular thyroid cancer and in patients 45 yr or older with PTC (P < 0.001) (8). Lastly, residual metastatic lymph nodes that remain after initial therapy are the most common cause of subsequent recurrence (5, 6). These facts sharply focus the debate concerning initial therapy for lymph node metastases, especially concerning the risks and benefits of surgery and radioiodine remnant ablation. What are the risks and benefits of central lymph node dissection? For lymph node metastases, the American Thyroid Association (ATA) guidelines (9) suggest systematic neck lymph node dissection, which refers to en bloc dissection of anatomic neck compartments, as compared with selectively excising lymph nodes (“berry picking”), which is not recommended. Prophylactic dissection denotes removal of lymph nodes that are considered normal preoperatively or intraoperatively, and therapeutic dissection refers to removal of malignant lymph nodes identified before or during surgery. The ATA guidelines under revision suggest that prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with PTC with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4), which is a Grade C Recommendation (Expert Opinion), and that near-total or total thyroidectomy without prophylactic central neck dissection may be appropriate for small (T1 or T2) noninvasive clinically node-negative PTCs and most follicular cancers (Grade C Recommendation). The ATA guidelines suggest preoperative cervical ultrasonography in all patients undergoing thyroidectomy. Although this may identify suspicious cervical adenopathy in up to half the cases, potentially altering the surgical approach in many patients, it has several limitations, particularly in evaluating extracapsular invasion in deep locations in the neck and lymph node metastasis in the central neck, which may lower the sensitivity of ultrasonography to 35% (10). White et al. (11) describe the spread of malignant thyroid tumor cells as flowing through the lymphatic system in a sequential fashion from the thyroid gland to the central compartment to ipsilateral compartments and to contralateral and mediastinal compartments. The rate of level VI metastases may be as high as 50 to 65% (12, 13) with involvement nearly as often in the ipsilateral lateral cervical compartment levels III and IV but with few metastases in level II high in the upper lateral neck, and skip metastases (unpredictable spread) in the contralateral neck (14). Level VI is particularly important, lying in a central position and extending to the hyoid bone superiorly and the suprasternal notch inferiorly, with bilateral borders at the level of the common carotid arteries. This area includes pretracheal and paratracheal nodes, the Delphian node, and perithyroidal nodes, including those along the recurrent laryngeal nerves. This area also contains the parathyroid glands. In a systematic review using evidence-based criteria, White et al. (11) found no prospective randomized studies to explain the impact on outcome of central lymph node dissection on patients with differentiated thyroid cancer. The authors concluded that systematic compartment-oriented central lymph node dissection may decrease recurrence of PTC and likely improves disease-specific survival (Grade C recommendation). Also, adding central lymph node dissection to total thyroidectomy can significantly reduce serum thyroglobulin (Tg) levels. They also found that there may be a higher rate of permanent hypoparathyroidism and unintentional permanent laryngeal nerve injury when compartment-oriented central lymph node dissection is performed. Furthermore, reoperation in the central neck compartment for recurrent PTC may increase the risk for hypoparathyroidism and unintentional nerve injury as compared with total thyroidectomy with or without central lymph node dissection (Grade C recommendation) supporting a more aggressive initial operation (12). What are the risks and benefits of radioiodine remnant ablation? Postoperative radioiodine therapy is administered to eradicate small amounts of normal residual thyroid tissue, referred to as remnant ablation, with the intent of destroying unrecognized occult residual lymph node metastases and facilitating follow-up with serum Tg measurements. A systematic review and metaanalysis of the effectiveness of remnant ablation (15) concluded that remnant ablation may be beneficial in decreasing recurrence, but the results were inconsistent for some outcomes. An updated analysis (16) found a 2% lower risk of distantly metastatic recurrences with remnant ablation (95% confidence interval, 4 to 1%; P < 0.0005). ATA guidelines for small PTCs link the decision to use radioiodine for remnant ablation to the presence of cervical lymph node metastases. The main concern about remnant ablation is the severity of adverse events produced by radioiodine, which poses a risk for radiation injury to salivary glands, oral tissues, lacrimal ducts, stomach, breast, bone marrow, and other body areas that increases the long-term risk of radioiodine-induced nonthyroidal second cancers (17). The risk increases with the amount of radioiodine administered (18). A European study (18) found a linear relationship between solid tumors and leukemias with cumulative activities of radioiodine greater than about 500 to 600 mCi. The authors estimated that 100 mCi of radioiodine administered to 10,000 patients will induce an excess of 54 solid malignant tumors and three leukemias during 10 yr of follow-up as compared with the general population. Yet it is not known whether a single treatment of 100 mCi increases the risk or whether this requires very high cumulative activities of radioiodine. Also unknown is the smallest amount of radioiodine that causes this effect (19). A recent study (20) confirmed that the radioiodine residence times in the stomach and in the rest of the body were significantly shorter in patients who received recombinant human TSH (rhTSH) compared with patients who underwent withdrawal, thus reducing radiation to these tissues. ATA guidelines (9) suggest administering the smallest amount of radioiodine necessary to achieve ablation. There are studies that have found that amounts of radioiodine as small as 30 mCi achieve successful ablation as effectively as 50 or 100 mCi. Administering 30 mCi for remnant ablation after rhTSH preparation thus further decreases whole body radiation from radioiodine therapy. In this issue of JCEM, Bonnet et al. (21) provide important information on prophylactic dissection of lymph node compartments in patients with small PTCs who had negative preoperative neck ultrasound examinations (T1N0). The mean size of the PTCs was 12.5 mm, ranging from less than 1 mm to 19 mm. Tumor extended beyond the thyroid capsule in 29% of the patients and was metastatic to the central compartment lymph nodes in 45% and the lateral compartment in 47%. Neither the size of lymph node metastases nor the extent of tumor invasion is known. Surgery was extensive. All 115 patients had total thyroidectomy with systematic bilateral level VI dissections, and 96 (94%) others had, for a number of reasons, ipsilateral systematic level II-III-IV dissections. In all, 67 patients (58%) were treated with radioiodine because of poor prognostic factors, including lymph node metastases, PTC larger than 18 mm, tumor invasion, vascular invasion, bad histology, and age younger than 18 yr. Prophylactic lymph node dissection modified the indication for radioiodine ablation for 30% of the patients who initially had stage T1N0 tumors. Twelve (10%) patients with PTCs smaller than 10 mm were treated with radioiodine because of the adverse pathology findings of the excised tumor. Thirteen (11%) others with PTCs larger than 10 mm without lymph node metastases were not treated with radioiodine. In all, radioiodine was not administered to 48 patients (42%) who had no adverse prognostic factors, had tumors T1 less than 10 mm with lymph node micrometastases, or were 18 yr or younger. At the 1-yr follow-up, all of the patients had negative neck ultrasound examinations, and 97% had an undetectable serum Tg during TSH suppression or with rhTSH stimulation. Only one patient had persistent foci of radioiodine uptake after therapy. One patient (0.9%) had permanent unilateral vocal cord paralysis, and another had permanent hypoparathyroidism. What is the impact of the Bonnet study (21)? This study provides important evidence that sheds considerable light on our understanding of the pre- and postoperative management of small PTCs. The inherent problem with the initial treatment of T1N1 PTCs—usually an indication for radioiodine treatment of small tumors—has been the uncertainty of accurately identifying lymph node metastases preoperatively by ultrasonography and by direct visualization of tissues in the operative site, especially of the central and ipsilateral neck compartments. Without prophylactically dissecting the central and ipsilateral lymph node compartments, lymph node metastases remain untreated, and postoperative remnant ablation, if performed, essentially becomes a surrogate for prophylactic compartment dissection, a decision that is based upon the high probability of unrecognized lymph node metastases in patients with small PTCs. Bonnet et al. (21) show how meticulous compartment dissection provides explicit information about tumor stage at the time of surgery, resulting in unambiguous radioiodine therapy for patients with lymph node metastases while forgoing this treatment for those without residual locoregional tumor. It also provides a path for using smaller than usual amounts of radioiodine in the range of 30 mCi to ablate the thyroid remnant and residual tumor in patients with known lymph node metastases or tumor invasion. Whether patients will accept such extensive surgery for what appears to be low-risk tumor remains to be seen. Yet it seems unlikely that patients will completely forgo both neck compartment dissection and remnant ablation if informed of the high risk of missing unrecognized lymph node metastases at surgery without performing prophylactic lymph node dissection, which must be provided by highly experienced surgeons. To advocates of postsurgical radiation, this should not be just another hammer and nail decision of surgery vs. radioiodine. The Bonnet study (21) points the way to accurate selection of patients for postoperative radioiodine therapy. Nonetheless, I believe much of the predictable controversy over this issue will undoubtedly be similar to the decades-old arguments concerning lobectomy vs. total thyroidectomy. Papillary thyroid cancer recombinant human TSH thyroglobulin