Lymph Node Management in Thyroid Cancer

The outcome of thyroid cancer treatment depends on a number of different factors: the type of thyroid cancer (eg: PTC, FTC, MTC, etc), the extent of disease in the thyroid and outside it, and the presence of lymph node and distant metastases (secondary deposits).

Lymph node surgery involves the removal of lymph glands in the neck (or occasionally in the chest) to achieve two aims: cure of the cancer, and prevention of complications caused by invasion of surrounding structures, like the trachea, oesophagus or recurrent laryngeal nerve.

Surgery is the most important method for achieving a potential cure in thyroid cancer, not only for the thyroid itself, but also for the locally involved lymph nodes. Radioiodine treatment can complement but never replace surgery as the best option in the neck, but for more distant metastases generally surgery is not indicated.

When assessing the quality of thyroid cancer management, higher volume surgeons (who perform a lot of thyroid surgery each year, like me) have better outcomes in successfully removing cancers, and have a lower complication rate. Recent research suggests that the percentage thyroid remnant uptake (on postoperative radioactive iodine scanning) and the lymph node ratio (number of involved nodes over total nodes removed) are directly related to the risk of thyroid cancer recurrence and mortality. The higher the uptake, or ratio, the higher the risk of recurrence.

Fig.1: The neck and upper mediastinum lymph node levels, based on surgical compartments

Site of Nodal Metastases

The most commonly involved central lymph nodes in thyroid cancer are the nodes in front of the larynx and trachea, as well as the nodes on either side of the trachea, which are all part of the Level VI node group.

Lymph node metastases in the central compartment can be present in about 35% of patients at presentation. They are difficult to diagnose preoperatively due to the reduced ability of ultrasound to identify abnormal nodes before thyroidectomy, and even experienced surgeons are not good at identifying involved nodes by inspection during operation (<50% success rate). This has led to the idea of prophylactic central neck dissection, but it remains controversial.

This clinically undiagnosed nodal disease in fact appears to have minimal impact on postoperative thyroglobulin levels, local recurrence rates or long-term survival. Thus there is little consensus about whether doing a prophylactic central neck dissection (pCND) is appropriate when the lymph nodes are not obviously involved.

However, the site of most “local recurrence” is now recognised to be persistent disease in the paratracheal (Level VI) lymph nodes. A recent multicentre study demonstrates a 4-fold reduction in risk of need for re-operative surgery with pCND. Thus generally most patients will be recommended to have pCND in papillary cancers more than 1cm in size.

On the other hand, there is little argument that involved lymph nodes should be removed by formal neck dissection, based on the surgical compartments in the neck and upper chest (mediastinum) (Fig. 1). Lymph node ‘‘plucking’’ or ‘‘berry picking’’ involving only removal of the clinically involved nodes, rather than a complete compartment nodal group is not recommended.

A central neck dissection includes comprehensive removal of all of these Level VI nodes, although this may be confined to only one side.

Papillary Cancer (PTC)

Approximately 10–15% of patients with low-risk papillary cancer (PTC) develop palpable local recurrence in the lymph nodes of the neck, and up to 60% in those with high-risk disease. However, lymph node recurrence occurs in less than 1% of patients with micropapillary cancer (<1cm). Metastases in these cervical nodes account for 75% of overall recurrence in the neck.

Up to 35% of patients present with lymph node metastases either radiographically or at operation in the central compartment, although the clinical significance of this remains controversial. Nodal involvement detection is poor as well, either clinically or at ultrasound examination, and even intraoperative inspection is unreliable, as metastases are microscopic in 23-81%. That is, a large number of clinically negative nodes are actually positive on histopathology. 

There is currently no level 1 evidence that having cervical node disease by itself worsens survival. There are some higher risk groups that do have a worse survival however: age >45 years, lymph nodes larger than 3cm, and extranodal tumour extension.

It is generally accepted that surgical removal of grossly involved lymph node disease should be carried out, as it decreases tumour recurrence, and increases survival. The role of routine lymph node dissection, however, is more controversial. Surveillance with the more sensitive techniques of serum thyroglobulin measurement and high-resolution ultrasound has led to lymph node metastases being detected earlier and more frequently.

Routine Prophylactic Neck Dissection

Routine central neck lymph node dissection can be carried out with no increased morbidity and can achieve lower 6-month stimulated thyroglobulin levels when compared with total thyroidectomy alone. It lowers the recurrence rate and may increase survival, and also allows accurate pathological assessment of nodal status, which may allow more selective use of radioactive iodine. In addition, surgery for recurrent disease in the neck carries a much higher risk of damage to the recurrent laryngeal nerve and parathyroids.

The study performed at the Royal North Shore Hospital in Sydney showed that for those having a prophylactic central node dissection, the stimulated thyroglobulin levels were significantly lower prior to initial radio-iodine ablation (15.0 versus 6.6ng/ml, p=0.025), and the rate of re-operative surgery in the central compartment was significantly lower (1.5 versus 6.1%, p=0.004). The calculated number of CND procedures required to prevent one central compartment re-operation was 20.

For these reasons routine ipsilateral level VI lymph node dissection, in addition to total thyroidectomy, is recommended for the management of clinically significant (>10mm) PTC. Having said all that however, there is little randomised, prospective trial data to support the benefit of routine central compartment neck dissection.

Routine lateral compartment node dissection however, is not justified unless the lymph nodes are clinically involved. When lymph nodes are involved in the lateral compartment, a functional neck dissection including involved nodes in levels II–V is performed. There is rarely a role for radical neck dissection. If invasion occurs in aggressive tumours, a more radical approach is necessary, sacrificing involved structures.

It is possible for papillary cancer to skip the central compartment nodes and appear first in the lateral compartment, in as much as 20% of patients. This is usually in level III or II, and is more commonly associated with upper pole tumours, single primary tumours and small (<1cm) tumours. However, skip metastases are unpredictable and their clinical significance is not clear.

When lateral compartment nodes are not involved, there is considerable controversy. Many would perform a frozen section of one or two nodes and, if negative, leave well alone. This is now the most common approach. Patients older than 55 years and those with large or abundant metastatic nodes are more likely to develop recurrent nodes in previously dissected compartments, so particular care has to be taken in these groups.

Unlike the central compartment where re-exploration is difficult however, re-exploration of the lateral part of the neck is not so problematic and vital structures can be preserved with minimal morbidity.

Follicular Cancer (FTC)

Unlike in papillary cancer, lymph nodes in FTC carry no independent adverse effect on survival. In FTC, nodal metastases are associated with distant metastases, which carries a worse prognosis and is the main determinant of survival. For these reasons there is no indication for routine lymph node dissection in FTC or Hurthle cell cancer.

Medullary Cancer (MTC)

By the time of diagnosis up to 20% of MTC patients have developed distant metastases.  Lymph node metastases can occur with primary tumours as small as 5mm. Distant metastases can occur with primary tumours only 10mm in diameter.

Very useful information can be gained from the preoperative serum calcitonin and CEA, which can guide the extent of lymph node dissection. The higher the levels, the more likely nodal metastases were present, with the highest levels also more likely to indicate lateral nodal compartment disease. In a 2010 study of 300 consecutive patients with MTC treated by total thyroidectomy and compartment-oriented lymph node dissections, there was virtually no risk of lymph node metastases when the preoperative serum calcitonin level was less than 20 pg/mL (normal reference range < 10 pg/mL).

However, basal serum calcitonin levels exceeding 20, 50, 200, and 500 pg/mL were associated, respectively, with metastases to lymph nodes in the ipsilateral central and ipsilateral lateral neck, the contralateral central neck, the contralateral lateral neck, and the upper mediastinum. Bilateral compartment oriented neck dissection achieved postoperative biochemical cure in at least half of the patients with pretreatment basal calcitonin levels of 1000 pg/mL or less, but not in patients with levels greater than 10,000 pg/mL. 

Central and lateral lymph node involvement on the same side of the neck occurs equally often, but there is a strong correlation between the number of central nodes involved and the likelihood of lateral node involvement. One to three involved central nodes increases the likelihood of involved nodes in the ipsilateral neck from 10 to 77%, and four or more positive central nodes increase this to a 98% chance.

According to the latest Guidelines of the American Thyroid Association (published in 2015), both familial and sporadic type MTC should have total thyroidectomy with routine dissection of nodes in the central compartment of the neck. In patients with MTC and no evidence of neck metastases on US, and no distant metastases, dissection of lymph nodes in the lateral compartments (levels II–V) may be considered based on serum calcitonin levels, however consensus was not achieved with this guideline.

If central nodes are involved, then at least the lateral compartment on the side of the primary tumour should also be dissected. Patients with MTC confined to the neck and cervical lymph nodes should have a total thyroidectomy, dissection of the central lymph node compartment (level VI), and dissection of the involved lateral neck compartments (levels II–V).

The dissection of the neck should be meticulous and there is no justification for any form of ‘berry picking’. The major structures of the neck should be skeletonised and microdissection techniques should be encouraged. All too often recurrent disease arises either in the central part of the neck or laterally, due to inadequate primary lymph node clearance. Thymectomy should also be regularly performed, as metastatic disease is often present.

Contralateral Node Dissection?

When preoperative imaging is positive in the ipsilateral lateral neck compartment but negative in the contralateral neck compartment, contralateral neck dissection should be considered if the basal serum calcitonin level is greater than 200 pg/mL. For the contralateral neck and the mediastinum, the risk of involvement increases with the size of the tumour, with multifocal MTC in the thyroid, and with the number of involved central nodes. When no central nodes are involved the risk of contralateral nodal metastases is less than 5%, but if there are 10 or more positive central nodes the risk reaches 77% and dissection of the central and both lateral compartments is necessary.

With ipsilateral lymphatic drainage of tumour cells (i.e. involvement of only the central and lateral cervical lymph node compartments on the side of the primary cancer), surgical cure may be attainable in some patients, whereas metastases in the contralateral lateral compartment herald incurable disease.

In the presence of extensive regional or metastatic disease less aggressive surgery in the central and lateral neck may be appropriate to preserve speech, swallowing, parathyroid function, and shoulder mobility. External beam radiotherapy (EBRT), systemic medical therapy, and other nonsurgical therapies should be considered to achieve local tumour control. 

Persistent or Recurrent Disease

Occasionally, the diagnosis of MTC is made following a unilateral hemithyroidectomy. The opposite thyroid lobe should be removed in patients with hereditary MTC because the likelihood that MTC is already present or will develop in the future approaches 100%.

In patients with sporadic MTC the incidence of bilateral MTC ranges from 0% to 9%, and there are few studies evaluating patient management in this setting. The ATA Guidelines recommend that following unilateral thyroidectomy for presumed sporadic MTC, completion thyroidectomy should be performed in patients with a RET germline mutation, an elevated postoperative serum calcitonin level, or imaging studies indicating residual MTC. The management of a persistently raised calcitonin following surgery is a difficult problem. There is little evidence that reoperating on patients with mildly elevated calcitonin improves survival. The presence of an enlarged lymph node in association with a normal serum calcitonin level is not an indication for repeat surgery.

In patients having an inadequate lymph node dissection at the initial thyroidectomy a repeat operation, including compartment oriented lymph node dissection, should be considered only if the preoperative basal serum calcitonin level is less than 1000 pg/mL and five or fewer metastatic lymph nodes were removed at the initial surgery. The biochemical cure rate after repeat surgery drops markedly if either of these features are present.

It should be noted that patients whose basal serum calcitonin level is normal (< 10 pg/mL) following attempted complete lymph node dissection are said to be ‘‘biochemically cured’’ and have a 97.7% survival at 10 years. However, 3% of patients with a normal baseline serum calcitonin level following thyroidectomy will have a biochemical recurrence within 7.5 years. Even with extensive lymph node dissection, only 60% of node-negative and 10% of node-positive patients are cured. Despite this, the overall prognosis is still remarkably good at around 85% at 10 years.