Fig. 16.1
Anatomic landmarks for performing a central compartment neck dissection. The lymph nodes removed include the prelaryngeal (superior to the isthmus of the thyroid gland), pretracheal (inferior to the isthmus and anterior to the trachea), paratracheal (along the recurrent laryngeal nerves), and the lymph nodes along the innominate artery. H hyoid bone, I innominate (brachiocephalic) artery, C carotid artery, RLN recurrent laryngeal nerve
A therapeutic CCND is defined as a CCND performed in a patient with macroscopic or clinical lymph node metastases. Macroscopic lymph node metastases in patients with PTC are associated with higher recurrence rates [4]. In a large population-based, case–control study, Lundgren and colleagues demonstrated an increased mortality rate in patients 45 years and older with regional lymph node metastases [5]. There is evidence that for patients with macroscopic nodal disease, lymphadenectomy reduces recurrence and mortality [4, 6, 7]. As a result, there is general agreement that patients with clinically involved lymph nodes in the central compartment of the neck should be managed with a CCND preferably at the time of thyroidectomy.
Prophylactic CCND (pCCND) is a compartment-oriented lymph node dissection performed in a patient with thyroid cancer who has no evidence of lymph node metastases on preoperative clinical examination, imaging studies, or intraoperative assessment. The rationale that has been proposed for performing a pCCND is to: (1) reduce recurrence in the central compartment of the neck and to help avoid the need for reoperation in the central compartment of the neck and its associated potential for increased morbidity, (2) lower postoperative serum thyroglobulin (Tg) levels, and (3) improve selection of patients for postoperative radioiodine therapy and optimization of doses of iodine-131. The rationale against performing a pCCND is that there is no proven oncologic benefit and the associated morbidity is higher than a total thyroidectomy alone.
Some experts preferentially recommend an ipsilateral pCCND in patients with clinically node-negative disease [8]. An ipsilateral pCCND consists of removal of the pretracheal, the prelaryngeal, and the paratracheal lymph nodes from the side of the cancer. The contralateral paratracheal lymph nodes are not removed. The rationale for an ipsilateral CCND is to remove the lymph nodes in the central compartment of the neck that are most likely to be involved with cancer and, at the same time, reduce the potential for recurrent laryngeal nerve injury and hypoparathyroidism.
Preoperative Sonographic Staging of the Central and Lateral Neck
Macroscopic lymph node metastases are metastases detected on physical examination, intraoperative exploration, or ultrasound exam. Macroscopic lymph node metastases occur in approximately 35 % of patients with PTC [9–12]. In contrast, microscopic lymph node metastases refer to metastases that are undetectable on physical examination, imaging studies, or intraoperative assessment. Thirty-eight to 80 % of patients with PTC have occult microscopic lymph node metastases [13, 14]. The mean size of metastatic lymph nodes removed during a pCCND has been reported as 0.35 cm [15, 16].
An ultrasound examination of the central and lateral compartments of the neck is obtained prior to performing a thyroidectomy for PTC as recommended by the ATA [17]. Up to 40 % of macroscopic lymph node metastases in patients with PTC will be missed by physical examination [18, 19], making ultrasonography an important part of the management of patients with PTC. Stulak and colleagues evaluated the use of ultrasound in patients with PTC and identified nonpalpable, macroscopic lymph node metastases in 14 % of patients [20].
Microscopic and macroscopic lymph node metastases have different implications for recurrence and mortality. Microscopic metastases do not affect patient survival and are associated with much lower rates of recurrence compared to macroscopic metastases. Macroscopic lymph node metastases are associated with higher recurrence rates [5] as well as higher disease-specific mortality in patients 45 years or older [5, 21, 22].
Sonographic features of abnormal lymph nodes include diameter greater than 1 cm, loss of normal fatty hilum, irregular rounded contour with long-axis to short-axis ratio of less than 1.5, heterogeneous echogenicity, microcalcifications, hypervascularity, and cystic change [23–25]. The sensitivity of ultrasonography is better for detecting metastatic lymph nodes in the lateral neck compared to the central compartment of the neck (82–94 % vs. 30–60 %, respectively) [26–29]. With respect to the TNM staging system, preoperative sonographic staging of PTC offers an overall accuracy of 71.3 % for N staging [26].
Ultrasound can also be used to guide fine needle aspiration biopsy of suspicious cervical lymph nodes. Cytology specimens can be analyzed for the presence of malignant cells. In cases of inconclusive cytology, thyroglobulin can be measured in the aspirate to reliably identify metastatic lymph nodes in the preoperative setting [30].
Indications for CCND: Recommendations and Controversies
Therapeutic CCND is indicated for patients with biopsy-proven macroscopic lymph node metastases in the central compartment of the neck identified on physical examination, imaging studies, or intraoperative assessment. Compartment-oriented lymphadenectomy in patients with macroscopic disease minimizes the risk of recurrence and mortality [6]. All major endocrine societies recommend a therapeutic CCND for patients with clinically node-positive PTC, whereas recommendations differ for pCCND [2, 17, 19, 31–34].
Prophylactic CCND is an operation that was historically reserved for treatment of patients with sporadic and hereditary medullary thyroid carcinoma. The recommendation for pCCND for patients with PTC was introduced in 2006 with the publication of the ATA management guidelines for patients with thyroid nodules and differentiated thyroid cancer, which recommended that CCND be considered for all patients with PTC [17]. Prior to 2006, pCCND was not a consideration in the treatment of patients with PTC. This recommendation was said to be based on fair evidence that pCCND may improve health outcomes, and thus the strength of the recommendation was given a B rating. At the same time that the ATA guidelines were published, a consensus statement by the European Thyroid Association (ETA) for the management of patients with differentiated thyroid cancer was published stating that “there is no evidence that pCCND improves recurrence or mortality rates for PTC, but it does allow an accurate staging of the disease that may guide subsequent treatment and follow-up” [35]. Hence, this became an extremely controversial issue.
Modifications appeared in the revised ATA guidelines published in 2009 [33]. The new proposed recommendation was that “pCCND (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).” This new recommendation was formulated based on expert opinion alone, so the strength of the recommendation was lowered to C. The most recent ATA management guidelines published in 2015 state that for clinically node-negative disease, total thyroidectomy without pCCND is strongly recommended, based on moderate-quality evidence, while pCCND is a weak recommendation based on low-quality evidence [19]. It is apparent that, since 2006, we have come full circle in terms of the recommendation for pCCND in patients with clinically node-negative PTC.
Serum Thyroglobulin
Serum thyroglobulin (Tg) monitoring is recommended after thyroidectomy for thyroid cancer to help detect recurrence. It is unclear whether total thyroidectomy with pCCND will result in lower serum Tg levels compared to total thyroidectomy alone. Reduced serum Tg levels have been reported in patients who undergo pCCND [8]. However, it is unknown whether this was the result of a CCND or a more complete thyroidectomy. Other studies report no difference in serum Tg levels between patients who undergo total thyroidectomy with pCCND and total thyroidectomy alone [36, 37]. Furthermore, normalization of serum Tg is less important than the change in Tg over time for detection of recurrent disease.
Locoregional Recurrence
The reported rates of recurrence in the central compartment of the neck after surgical therapy are variable. Macroscopic lymph node metastases in patients with PTC are associated with a much higher recurrence rate than patients with microscopic lymph node metastases [4]. Recurrence rates in patients with macroscopic lymph node metastases have been reported to vary between 10 and 42 % [38–42]. Wada and colleagues described a higher risk of nodal recurrence in patients with palpable abnormal cervical lymph nodes compared to patients with undetectable lymph node metastases who underwent pCCND (17 % vs. 0.43 %) [40]. This finding of a higher nodal recurrence rate associated with clinically N1 disease has been corroborated by other studies [38, 39], with higher recurrence seen in both young and old patients [41].
In patients with clinically node-negative disease, recurrence in the central compartment of the neck occurs in 2–3 % of patients regardless of whether or not a pCCND is performed, with a range of 0–12 % following total thyroidectomy alone, compared to 0–11 % in patients undergoing total thyroidectomy with pCCND (Table 16.1) [8, 37, 39, 42–55]. There is no significant difference in the rate of recurrence in the central compartment of the neck between patients who underwent total thyroidectomy with pCCND and patients who underwent total thyroidectomy alone. A large meta-analysis of patients with PTC reported a recurrence rate of 1.9 % in the group who underwent thyroidectomy with pCCND versus 1.7 % in the group who underwent thyroidectomy alone [56]. Two additional large meta-analyses substantiated this finding that there is no difference in locoregional recurrence with total thyroidectomy with or without pCCND [13, 14]. Based on current information available in the literature, CCND is indicated for macroscopic lymph node metastases. In contrast, the available evidence suggests that occult microscopic metastatic disease in the lymph nodes of the central compartment of the neck rarely becomes clinically apparent and is therefore of little clinical significance.
Table 16.1
Central compartment recurrence of PTC following total thyroidectomy alone versus total thyroidectomy with pCCND
Recurrence after thyroidectomy alone | Recurrence after thyroidectomy + pCCND | Mean* follow-up | |
|---|---|---|---|
Barcynzski et al. [43] | 7.8 % (22/282) | 0.6 % (2/358) | 10 years |
Bardet et al. [42] | 5.6 % (22/391) | 11.1 % (4/36) | 69 months* |
Besic et al. [44] | 0 % (0/83) | 0 % (0/6) | 56 months |
Costa et al. [45] | 3.4 % (4/118) | 3.2 % (4/126) | 47 vs. 64 months |
Gemsenjager et al. [39] | 2.3 % (2/88) | 5.6 % (4/71) | 8.1 years |
Hartl et al. [46] | 12 % (11/91) | 3 % (2/155) | 6.3 years |
Hughes et al. [37] | 3.1 % (2/65) | 2.6 % (2/78) | 27.5 vs. 19.1 months |
Lang et al. [47] | 0 % (0/103) | 0 % (0/82) | 39.1 vs. 31.1 months |
Lee et al. [48] | 3.9 % (4/104) | 3.3 % (5/153) | 49 vs. 55 months |
Moo et al. [49] | 5.6 % (2/36) | 2.2 % (1/45) | 3.1 years |
Moreno et al. [50] | 2.3 % (3/133) | 1.7 % (2/119) | 71.5 monthsa |
Roh et al. [51] | 0 % (0/49) | 0 % (0/148) | 36 months |
Roh et al. [52] | 4.1 % (3/73) | 2.5 % (1/40) | 52 months |
Sywak et al. [8] | 1.8 % (7/391) | 0 % (0/56) | 70 vs. 24.5 months |
Sadowski et al. [53] | 1.4 % (4/281) | 0 % (0/180) | 38.8 months |
Ywata de Carvalho et al. [54] | 1.5 % (7/478) | 3.9 % (4/102) | 69.7 months |
Zhang et al. [55] | 8.3 % (9/108) | 2.2 % (3/134) | 66 vs. 61 months |
Survival
In a large, population-based, case–control study, Lundgren and colleagues demonstrated an increased mortality rate in patients 45 years of age and older with regional lymph node metastases [5]. There is evidence that for patients with macroscopic nodal disease, lymphadenectomy reduces recurrence and mortality [4, 6, 7]. As a result, there is general agreement that patients with clinically involved lymph nodes in the central compartment of the neck should be managed with a CCND.
In the past, a single Swedish study has been referenced to support the notion that pCCND may improve survival [57]. This was a retrospective study of 195 patients with PTC, 175 of whom underwent total or near-total thyroidectomy with pretracheal and paratracheal lymph node microdissection [6]. Outcomes were compared to two prior Scandinavian studies [58, 59]. The authors reported a disease-specific mortality of 1.6 %, compared to 8.4 % in a study from Norway and 11 % from a study from Finland.
There are two major limitations in the Swedish study [57]. First, it included all patients who underwent CCND, and the breakdown of therapeutic CCND versus pCCND was not specified. Second, the comparisons of mortality were problematic. In the Norwegian study, 12 of 15 patients who died from PTC only had a palliative operation because of the initial extent of disease [58]. If these 12 patients were excluded, the disease-specific mortality was 1.9 %, similar to the 1.6 % disease-specific mortality reported by Tisell and colleagues, who excluded patients who presented with distant metastases [6]. The study in Finland occurred during an earlier period (1956–1979) than the studies from Norway (1971–1989) and Sweden (1970–1989), and data regarding extent of thyroidectomy, lymph node dissection, and radioactive iodine therapy were either incomplete or not provided [59].
Radioactive Iodine Use
Retrospective studies have suggested that accurate staging of PTC using pCCND may be used to help determine the need for RAI therapy and the doses of iodine-131 to be used [37, 46]. Hughes and colleagues compared patients with clinically node-negative PTC who underwent total thyroidectomy alone versus total thyroidectomy with pCCND. Sixty-two percent of patients who underwent pCCND had lymph node metastases in the central compartment of the neck [37]. The median dose of iodine-131 given was significantly higher (150 mCi) in the group that underwent total thyroidectomy with pCCND than in the group that underwent total thyroidectomy alone (30 mCi). However, even with pCCND and higher doses of iodine-131, there were no differences in locoregional recurrence or Tg levels 1 year after treatment. Additional studies have corroborated findings that higher doses of iodine-131 are administered after pCCND. Hartl and colleagues reported that higher doses of iodine-131 were administered to patients who underwent total thyroidectomy with pCCND and level III and IV lateral neck dissection (100 mCi) versus those who underwent total thyroidectomy alone (30 mCi) [46]. In a retrospective study, Bonnet and colleagues found that lymph node staging, resulting from pCCND and ipsilateral lateral neck dissection in patients with clinically node-negative PTC, altered the decision to use iodine-131 ablation in 21.7 % of patients [60]. One might conclude from these studies that pCCND is valuable for determining doses of iodine-131. An alternative conclusion is that pCCND leads to administration of higher doses of iodine-131 with no apparent clinical benefit.
Recently, Viola and colleagues completed a prospective, randomized controlled study to investigate the role of pCCND for patients with clinically node-negative PTC [61]. Patients were randomized to treatment with total thyroidectomy alone or total thyroidectomy and CCND. The primary endpoints of the study were to evaluate the successful ablation rate and persistent and recurrent disease after 5 years of follow-up. The secondary endpoints were to evaluate the rate of surgical complications in the two groups and the effect of pCCND in the staging of the disease. After 5 years of follow-up, patients with clinically node-negative PTC randomized to treatment with total thyroidectomy alone had received a greater number of treatments with iodine-131 and had a lower rate of permanent hypoparathyroidism and no difference in outcome compared to patients randomized to total thyroidectomy and pCCND. Almost 50 % of patients had microscopic lymph node metastases. The authors concluded that the identification of micrometastases in lymph nodes from the central compartment of the neck does not improve cancer-related outcomes but that it reduces the necessity for repeated iodine-131 treatments.
The efficacy of 131-I ablation for treatment of microscopic lymph node metastases, however, remains unclear. Sawka and colleagues found no significant benefit of iodine-131 ablation in reducing recurrence or mortality in patients with lymph node micrometastases [62]. The usefulness of iodine-131 ablation is suboptimal partly because up to 30 % of PTCs do not concentrate iodine-131 [63].
Lamartina and colleagues, in a recent systematic review of the literature, examined the evidence for postoperative RAI in staging, follow-up, and recurrence for ATA low- and intermediate-risk class patients with differentiated thyroid cancer and made some important conclusions [64]. First, it is well established that RAI remnant ablation is not of value in patients with low-risk thyroid cancer since no benefit in reducing recurrence has been demonstrated. Also, ultrasound in combination with serum Tg monitoring is equivalent and probably superior to iodine-131 whole-body scanning in identifying residual disease.
Hypothetically, pCCND may be of value for selection of patients with microscopic lymph node metastases for postoperative RAI treatment. Patients with metastases in the lymph nodes of the central compartment of the neck are classified as intermediate risk for recurrence [65]. There are studies that have shown some benefit of postoperative RAI for patients with intermediate-risk PTC in reducing recurrence, but the majority of studies show no benefit. What is clear is that the recurrence rate is low, whether or not RAI is administered. It is also important to consider the potential adverse effects of RAI, which include xerophthalmia, chronic or recurrent conjunctivitis, xerostomia secondary to acute and chronic sialoadenitis, transient loss of taste and smell, nausea and vomiting, epistaxis, bone marrow suppression, transient ovarian or testicular failure, and secondary malignancies. In patients with intermediate-risk PTC – particularly those whose cancers have been upstaged due to the presence of microscopic nodal metastasis – the low recurrence rate following thyroidectomy with or without pCCND in combination with the questionable value of RAI in reducing recurrence, the higher morbidity associated with CCND, and the potential adverse consequences of RAI favor total thyroidectomy alone without pCCND.
Complications of CCND
A significantly higher incidence of transient hypocalcemia has been reported following total thyroidectomy with pCCND compared to total thyroidectomy alone [13, 14, 56]. Most studies report a higher incidence of recurrent laryngeal nerve injury and permanent hypoparathyroidism with thyroidectomy and pCCND compared to thyroidectomy alone; however, the differences have not been statistically significant. Table 16.2 shows reported rates of complications after CCND [37, 39, 48, 52, 54, 55, 61, 66, 67].
Table 16.2
Morbidity of central compartment neck dissection
