The Role of Node Dissection for Thyroid Cancer

Background:

Well-differentiated thyroid cancer includes the most common type of thyroid cancer, papillary, as well as follicular and hürthle cell cancers. Other thyroid cancers include medullary thyroid cancer, which derives from the parafollicular c cells, and anaplastic thyroid cancer. Although the frequency of regional lymph node metastases varies depending on the type of thyroid cancer, nodal involvement is generally common. While the utility of a node dissection for low-risk tumors with micrometastatic disease is questionable, macroscopic nodal disease is easily identified pre-operatively and should be addressed. Therefore, it is important to include a thorough assessment of the cervical lymph nodes during the evaluation of thyroid nodules for potential malignancy. Similarly, attention to these regional lymph nodes is a vital part of monitoring thyroid cancer patients for recurrence.

Epidemiology:

Thyroid cancer is the most common endocrine malignancy, and the observed increase in incidence in recent years is not fully attributable to earlier detection.¹ Current estimates indicate that nearly 2% of women in the United States will be diagnosed during their lifetime, and thyroid cancer accounts for approximately 3% of all new cancer diagnoses each year.² Papillary is the most common type of thyroid cancer accounting for nearly 90% of cases³, and regional nodal disease is present in about a third of patients.^1,4 Nodal metastases are much less common for patients with follicular or hürthle cell cancer as these tend to spread hematogenously. Although medullary thyroid cancer accounts for a much smaller proportion of thyroid malignancies than well-differentiated types³, over a third will have nodal metastases at diagnosis⁵, and due to its more aggressive biology, lymph node dissection is recommended regardless of the tumor size.⁶ Therefore, clinicians treating thyroid cancer should be familiar with the management of nodal metastases and the role of lymph node dissection for patients with thyroid cancer.

Patient Evaluation Overview:

Initial Evaluation

When a patient presents with a thyroid nodule, the history should include discussion of risk factors for thyroid cancer including a family history, prior neck radiation exposure, and obesity.^7,8 In addition to palpation of the thyroid and nodule itself, palpation of the central and lateral neck for evidence of lymphadenopathy is also important. All patients presenting with a thyroid nodule should receive an ultrasound to characterize the nodule and thoroughly evaluate cervical lymph nodes. Many high-volume surgeons prefer to perform their own preoperative ultrasound to evaluate the surrounding lymph nodes. High resolution ultrasound in skilled hands detects non-palpable lymph node metastases from thyroid cancer in up to a third of patients presenting with papillary thyroid cancer.⁴ Additionally, population based data indicate the proportion of patients with medullary thyroid cancer presenting with regional lymph node metastases is increasing making a thorough evaluation at presentation vital.⁵

Evaluation for recurrence

Attention to the cervical lymph nodes during post-operative surveillance allows clinicians to detect early recurrence, which will often present as regional nodal metastases in the central or lateral neck. Many early recurrences reflect persistent often microscopic disease missed at the initial operation, underscoring the importance of a thorough initial evaluation.^9,10 If the thyroid was entirely removed, unstimulated thyroglobulin levels can be a sensitive indicator of persistent or recurrent disease.¹¹ In the case of medullary thyroid cancer, calcitonin and CEA levels can indicate the presence or absence of disease even if the initial operation was less extensive than recommended by guidelines.¹² While tumor markers help detect recurrence, imaging is necessary even if markers are reassuring.

Lymph Node Imaging

Ultrasound is the primary modality supported by American Thyroid Association (ATA) to image lymph nodes in patients with suspected or confirmed thyroid cancer and provides actionable information during the initial evaluation and follow-up.¹³ Specific ultrasound findings associated with thyroid metastases are listed in Table 1.^14,15 Unfortunately, in practice, over a third of thyroid nodule ultrasound reports do not even mention a lymph node evaluation.¹⁶ When ultrasound does evaluate the central and lateral neck for evidence of lymphadenopathy, the sensitivity for detecting disease is 0.33 in the central neck and 0.70 in the lateral neck.¹⁷ When high-volume surgeons perform their own ultrasound, the sensitivity for detecting disease in the lateral neck is as high as 0.88 with a negative predictive value of 0.97.¹⁸ Taken together, these findings indicate that ultrasound quality and results vary substantially based on where the ultrasound is performed and who performs it. Importantly, ultrasound helps guide the extent of surgery and alters the planned operation in over 40% of thyroid cancer operations and reoperations.⁴

Table 1:

Ultrasound findings associated with thyroid cancer lymph node metastases^14,15

Ultrasound Finding	Prevalence in involved nodes	Sensitivity	Specificity
Hyperechoic relative to muscle	8%	86%	96%
Cystic component	21%	20%	100%
Calcifications	5%	50%	100%
Loss of a fatty hilum	99%	88%	90%
Rounded shape*	34%	80%	71%

^*short to long axis ratio 0.5 or greater

Cross sectional imaging with computed tomography (CT) or magnetic resonance imaging is recommended for patients with suspected advanced disease and not part of the routine initial evaluation.¹³ While ultrasound tends to be more sensitive than CT in detecting lateral neck metastases¹⁹, the combination of CT with ultrasound is more sensitive in the central and lateral neck than ultrasound alone.²⁰ CT also characterizes disease in areas otherwise inaccessible with ultrasound such as the superior mediastinum (Figure 1). Similar to ultrasonography, detection of metastatic disease on preoperative CT depends upon who is reading the CT. In one report, over half of patients with persistent cancer following the initial resection, had evidence of the missed disease on preoperative CT.¹⁰

Figure 1:

Coronal Neck CT imaging depicting significant nodal disease extending into the superior mediastinum not fully evaluated with preoperative ultrasound (A). The specimen that correlates with the nodal disease seen on preoperative CT (B).

Functional Imaging

While functional imaging is not routinely used before the initial resection of thyroid cancer, it may play a role in recurrent nodal evaluations. For patients who receive a total thyroidectomy, a radioactive iodine whole body scan typically alerts clinicians to persistent or recurrent disease in the cervical lymph nodes. However, in cases where thyroid cancer is not iodine avid, PET scan may help characterize the location and extent of nodal involvement.

Lymph Node Biopsy

Once a suspicious lymph node is identified in the central or lateral neck, fine needle aspiration (FNA) biopsy should be performed to confirm disease and planning of the extent of the operation (Figure 2).^13,21 The exception to this practice is the unexpected presence of pathologic appearing central neck nodes at the time of the initial thyroidectomy. In this case, a frozen section could be performed, but it is also acceptable to perform a central neck dissection to remove the suspicious nodes without pathologic confirmation. FNA is also useful to confirm recurrent or persistent disease in the central or lateral neck before planning excision in a re-operative field. In addition to cytologic evaluation, a thyroglobulin washout can help identify well-differentiated thyroid cancer metastases with high sensitivity and specificty.²²

Figure 2:

Small Lymph node on ultrasound detected when thyrogloblulin increased from less than 0.1 ng/mL to 2.8 ng/mL. On transverse view, the lymph node demonstrated loss of a fatty hilum, increased echogenicity, and a rounded shape. FNA revealed recurrent papillary thyroid cancer. LN = lymph node, IJ = internal Jugular Vein, CC = Common Carotid Artery, SCM = sternocleidomastoid muscle

Treatment Options:

Node dissections play an important role in the treatment and staging of thyroid cancer. When performed, a node dissection should be compartment based and not “berry-picking” as the later is associated with a higher risk of recurrence. Cervical lymph nodes are divided into seven levels, or compartments, based on their location (FIGURE 3). Levels 6 and 7 are considered to be in the central neck and are the most common location of thyroid cancer nodal metastases. The boundaries of level 6 are the hyoid bone superiorly, the common carotid artery laterally, and the sternal notch inferiorly. Level 7 includes the superior mediastinal nodes behind the sternum, inferior to the sternal notch and superior to the aortic arch. The lateral neck includes levels 2–5. Levels 2 through 4 run along the jugular vein, lateral to the carotid artery and deep to the sternocleidomastoid from the skull base superiorly to the clavicle inferiorly and are where thyroid cancer tends to metastasize laterally. Level 2 is separated from level three by an imaginary horizontal line at the level of the hyoid bone, and level 3 is separated from level 4 by a similar line extending from the cricoid cartilage. Level 5 begins at the posterior border of the sternocleidomastoid and extends to the border of the trapezius muscle. Level 1 is bound by the hyoid bone inferiorly and the mandible. Levels 1 and 5 are rarely involved in thyroid cancer. The lymphatic drainage of the thyroid is variable, but most thyroid cancer involving the lymph nodes spreads to the central neck before moving to the lateral neck. Tumors in the superior poles of the thyroid, however, can “skip” the central neck and metastasize directly to the lateral compartments.²³

Figure 3:

Lymph Node Levels in the neck.

Central Neck Dissection-

Indications-

Any patient undergoing a thyroidectomy for thyroid cancer should have a thorough lymph node evaluation pre- and intraoperatively. Any clinically evident disease in level 6 lymph nodes should prompt a formal dissection of the central compartment. If grossly abnormal or suspicious central neck nodes are discovered at the time of the initial operation, it is appropriate to perform a central neck dissection without biopsy confirmation. Patients should be made aware of this possibility during the consent process. A frozen section can be useful to distinguish reactive nodes from nodes with metastatic disease in ambiguous situations, but cannot rule out micrometastases.

Technique-

Exposure to the central neck is generally the same as that for an open thyroidectomy. Following a transverse incision between the sternal notch and the cricoid cartilage, subplatysmal flaps are raised. The median raphe is separated, and the sternohyoid and sternothyroid muscles are retracted laterally. These strap muscles can be divided if necessary for greater exposure. Thyroidectomy facilitates the exposure of the deeper nodal tissue and can also make accessing inferior nodal tissue easier. However, nodes can also be removed en bloc with the thyroid. The recurrent nerve is exposed from its insertion into the cricothyroid muscle as low as possible into the thoracic inlet. On the right, nodal tissue resides lateral, medial, and deep to the recurrent nerve. On the left, the esophagus tends to occupy the space deep to the nerve so most nodal tissue is either lateral or medial to the nerve. Caution is required to avoid devascularizing the parathyroid glands during this dissection. Any parathyroid glands unable to be preserved can be set aside in saline for reimplantation. It is also important to remove the pretracheal nodal tissue superior to the thyroid along its developmental path of descent from the base of the tongue, anterior to the larynx. In the case of bulky nodal disease, dissection can be carried down into level 7.

Special Considerations- Prophylactic

Prophylactic central neck dissection at the time of thyroidectomy for thyroid cancer is controversial. The American Joint Committee on Cancer 8^th Edition Staging System for differentiated thyroid cancer added a category specifically for clinically unremarkable cervical lymph nodes on dedicated ultrasound or palpation²⁴, which will allow population based registries to record outcomes for patients with a nodal assessment but not sampling. Some physicians recommend prophylactic central neck dissection given high rates of occult disease in the central nodes and the difficulty of identifying such nodes with ultrasound. One meta-analysis found the rate of central nodal metastases in differentiated thyroid cancer to be as high has 48%, and the sensitivity of ultrasound to detect central nodal metastases as low as 0.33.¹⁷ Yet other physicians suggest prophylactic dissections are unnecessary for low-risk disease.^25,26 Recurrence rates remain much lower in patients with low-risk disease than estimated rates of microscopic nodal disease, and a nodal evaluation is not associated with a decreased risk of recurrence in population based data.²⁷ Lastly, a recent randomized trial showed similar oncologic outcomes including thyroglobulin levels up to one year following thyroidectomy with or without prophylactic neck dissection.²⁸

Special Considerations- Medullary

Patients with medullary cancer, sporadic or familial, without evidence of nodal disease should undergo a total thyroidectomy with a prophylactic bilateral central neck dissection at the initial operation.²⁹ This recommendation stems from the findings that over 80% of patients with medullary thyroid cancer have ipsilateral level 6 nodal metastases at their initial operation and over 40% have contralateral level 6 disease. The technique is similar to that for well-differentiated thyroid cancer. Although the proportion of patients with medullary thyroid cancer receiving the appropriate extent of nodal dissection at their initial operation is increasing, nearly a quarter of patients receive less than a total thyroidectomy with bilateral central neck dissection.⁵ For patients that receive less than the optimal extent of surgery at the onset, calcitonin levels are helpful guides as to whether or not residual disease is present.¹² Detectable calcitonin levels following total thyroidectomy and bilateral central neck dissection might also be an early indicator of disease outside of the central compartment.

Lateral Neck Dissection-

Indications-

Regardless of the type of thyroid cancer, when thyroid tissue is confirmed in a lateral neck lymph node during the initial evaluation of a thyroid nodule or during follow-up for thyroid cancer, a compartment-based dissection is indicated. Disease should be confirmed on each side prior to a dissection for the respective side. The ATA recommends an initial comprehensive modified radical neck dissection of nodal levels IIa, III, IV, and Vb at minimum, but more extensive dissections may be required based on the extent of the disease.²¹

Technique-

A long transverse incision with extensive subplatysmal flaps or an incision along the anterior border of the sternocleidomastoid muscle provides ample access to levels II through V. The sternocleidomastoid is mobilized and the omohyoid is either divided or retracted off the nodal tissue below. While a radical neck dissection involves resection of the sternocleidomastoid, internal jugular vein, and the spinal accessory nerve, these structures are almost always able to be preserved in thyroid cancer. Dissection begins inferiorly at the level of the clavicle. The internal jugular vein is skeletonized as are the muscles deep to the nodal tissue. On the left, care should be taken to identify and ligate the thoracic duct both where it enters the nodal tissue from behind the clavicle and where it enters the jugular vein. The phrenic nerve runs along the anterior scalene muscle and should be identified and protected (Figure 4). Dissection is carried superiorly and laterally until the spinal accessory nerve is identified or further if gross nodal disease is still present. In general, a substantial margin of grossly unremarkable nodes is favorable to optimize the ratio of positive to negative lymph nodes. Care should be taken to remove the nodal tissue between the jugular vein and the common carotid as well as nodes behind the vein and those overlying the bifurcation of the carotid. The hypoglossal nerve crosses the carotid artery at the level of the bifurcation and should be preserved.

Figure 4:

Image showing a completed right level IIa - Vb neck dissection for recurrent papillary thyroid cancer. The superior retractor is at the angle of the mandible, the left retractor is reflecting the sternocleidomastoid (SCM), the right retractor is reflecting the mobilized internal jugular vein, and the Penrose drain is encircling the omohyoid muscle. All of the nodal tissue beneath the SCM and around the internal jugular vein to the carotid has been removed. The Phrenic vein is visible running along the anterior scalene muscle.

Re-operative Neck Dissection

Indications-

Although targeting recurrent thyroid cancer in scarred fields presents challenges, re-operative neck dissections are safe and effective in both the central and lateral compartments.^30–32 Disease should be confirmed with an FNA biopsy or thyroglobulin or calcitonin washout before re-exploring a re-operative field. In contrast to the initial dissection, a compartment based comprehensive dissection is often problematic due to the loss of normal tissue planes. Therefore, a re-operative dissection often involves a more targeted approach.

Technique-

When recurrence is identified, care should be taken to ensure the targeted lesion can be identified during exploration. Finding small lesions can be challenging even if the lesion is readily identifiable on ultrasound or CT. It is helpful to make a map of the known lesion or lesions with a skin marker and an ultrasound in the operating room just prior to incision. Ultrasound guided injection of a scant amount of isosulfan blue into the involved lymph node or local recurrence can also aid in intra-operative identification. If nodal disease is easily identified with ultrasound, an intraoperative ultrasound can be performed after the resection to confirm all positive disease has been removed.

Evaluation of Outcomes:

Complications-

Complications from neck dissections tend to correlate with the extent of the dissection. For central neck dissections, hypoparathyroidism can occur from injuring, devascularizing or inadvertently removing parathyroid glands. One large retrospective review identified a higher risk of transient and permanent hypoparathyroidism with central neck dissections over that associated with a total thyroidectomy alone.³³ On the other hand, a randomized trial identified no difference in rates of hypoparathyroidism between total thyroidectomy alone or with central neck dissection indicating that central neck dissection is safe with high volume surgeons.²⁸ Injury to the recurrent laryngeal nerve is also a concern, though many nerves are at risk during central and lateral neck dissection. A list of these nerves, their location in the neck, and the symptoms from an injury are in Table 2. While functional deficits result from injury to motor nerves, some sensory nerves or branches can be injured and cause decreased sensation to parts of the neck and shoulder. Injury to the greater auricular nerve is rare during a neck dissection for thyroid cancer, but causes numbness to an area behind the ear and may even include part of the earlobe.

Table 2:

Structures at Risk for Injury During Neck Dissection

Structure	Location	Possible Symptoms and Consequences
Recurrent Laryngeal Nerve	Level VI, VII	Weak or hoarse voice, aspiration
External Branch of the Superior Laryngeal Nerve	Level VI	Decreased pitch and voice projection
Spinal Accessory Nerve	Level II, V	Difficulty shrugging or turning neck
Hypoglossal Nerve	Level II	Deviation of tongue
Phrenic Nerve	Level III, IV	Diaphragmatic dysfunction
Vagus Nerve	Level II, III, IV	Weak or hoarse voice, aspiration
Brachial Plexus	Level IV, V	Varies
Thoracic Duct	Left Level IV	Lymphatic Leak
Parathyroid glands	Level VI, VII	Hypocalcemia

Injury to the thoracic duct can result in a lymphatic leak or potentially a chylothorax. Attempts to manage lymphatic leaks conservatively may include elimination of long chain fatty acids from the diet and drainage, but often an injury to the thoracic duct requires re-exploration and ligation. Administering cream into the patient’s stomach with a nasogastric tube during exploration can aid in identification of the thoracic duct.

Hematomas, although rare, are more common when a thyroidectomy is combined with a neck dissection than for a thyroidectomy alone.³⁴ When compressive symptoms occur, hematomas should be evacuated immediately to prevent airway compromise. Infection is rare after neck dissections for thyroid cancer.

Completeness of Resection

Lymph node dissections for thyroid cancer should, at a minimum, aim to remove all macroscopic disease, but ideally be compartment based and remove a “margin” of benign nodes. One helpful marker in determining the likelihood of a complete resection is the lymph node ratio, or the number of positive nodes divided by the total number of nodes removed. In general, higher ratios are associated with increased recurrence rates following central and lateral neck dissections.^35–37

Tumor markers can also gauge the completeness of resection, direct further management and estimate the risk of recurrence. For well-differentiated thyroid cancer, unstimulated thyroglobulin levels checked 6 weeks following resection accurately identify the presence of persistent disease and help direct patients to no additional treatment, adjuvant treatment with radioactive iodine or additional resection.¹¹ Post-operative thyroglobulin also helps predict the likelihood of additional structural recurrence following re-operative cases.^38,39 Unfortunately, many patients have persistently detectable thyroglobulin levels following re-operative neck dissections underscoring the importance of a complete and thorough initial operation.^30,39 For medullary thyroid cancer, calcitonin and CEA levels can serve as early indicators of persistent or recurrent disease following resection.^12,40,41

Recurrence

Although the presence of nodal metastases in thyroid cancer can be associated with a higher risk of disease recurrence^27,42,43, biochemical remission is achieved in the majority of patients that present with regional nodal metastases following a total thyroidectomy and compartment based nodal dissection.⁴⁴ Furthermore, at a median follow-up of nearly 3 years, two-thirds of these patients will remain disease free.⁴⁵ Patients with well-differentiated thyroid cancer with 5 or fewer positive lymph nodes are considered to have a low risk of recurrence as long as nodal involvement is with micrometastatic disease (metastases measuring less than 2 mm). Patients with more than 5 positive lymph nodes or metastases measuring between 2 mm and 3 cm have an intermediate risk for recurrence, while those with positive lymph nodes >3 cm have a high risk of recurrence. Unlike initial nodal dissections, re-operative neck dissections are less likely to achieve biochemical remission, but the median decrease in preoperative thyroglobulin levels can be as high as 98% indicating that re-operative neck dissections are effective at reducing disease burden.³⁰

Survival

Most patients with well-differentiated thyroid cancer will not die from their disease. While nodal metastases are associated with worse cancer specific mortality, the majority of patients with nodal metastases experience long term survival.⁴² In one study of over 100 patients presenting with regional metastases in the lateral neck, no cancer specific mortality was observed within 3 years follow-up.⁴⁵

Long-Term Recommendations:

Surveillance

In general, patients with thyroid cancer metastatic to the regional lymph nodes experience higher rates of recurrence than those without nodal involvement. As such, these patients should be followed closely for recurrence with tumor markers and imaging at regular intervals. Since neither thyroglobulin or calcitonin are 100 percent sensitive, imaging should occur at regular intervals even when tumor markers are undetectable.

Adjuvant RAI

For patients with well-differentiated thyroid cancer and nodal involvement, adjuvant radioactive iodine should be considered. However, patients without structural or biochemical evidence of disease and micrometastatic disease in less than 5 lymph nodes might not require adjuvant therapy.²⁴ Nevertheless, these patients are best treated with a multidisciplinary approach.

Summary:

Regional nodal metastases are common in patients presenting with thyroid cancer. Therefore, lymph node examination and imaging during the evaluation of a thyroid nodule is imperative. Furthermore, attention to the nodal compartments is a vital component of follow-up for patients with a history of thyroid cancer. Compartment based nodal dissections in both the central and lateral neck are safe and effective at reducing disease burden. While lymph node metastases are associated with increased risk of recurrence and cancer specific mortality, a thorough lymph node dissection is associated with decreased recurrence and long-term survival.

Future Directions:

Arguably, the biggest debate in thyroid cancer in recent years has been over the optimal extent of the initial operation including the role of prophylactic central neck dissection. Additional population level data are needed to determine both short- and long-term outcomes for patients with thyroid cancer as well as outcomes for lobectomy with ipsilateral central neck dissection. These studies would be facilitated by revising ICD-10 diagnosis codes to include subtypes of well-differentiated thyroid cancer. The role of radiofrequency ablation of in management of thyroid cancer is also an area that deserves additional investigation.

Key Points:

• Regional lymph node metastases are common in patients with thyroid cancer.

• Thorough assessment of regional lymph nodes should be included in the evaluation of any thyroid nodule, and ultrasound is both sensitive and specific in identifying lymph node metastases.

• Complications are uncommon for high-volume surgeons.

• Lymph node dissections for thyroid cancer should be compartment based to help lower the ratio of positive to total lymph nodes removed.

• Lymph node metastases are associated with a higher risk of thyroid cancer recurrence, but, lymph node dissections are able to provide biochemical remission in most patients.

Synopsis.

Regional nodal metastases are common in patients presenting with thyroid cancer. Therefore, lymph node examination and imaging during the evaluation of a thyroid nodule is imperative. Furthermore, attention to the nodal compartments is a vital component of follow-up for patients with a history of thyroid cancer. Compartment based nodal dissections in both the central and lateral neck are safe and effective at reducing disease burden. While lymph node metastases are associated with increased risk of recurrence and cancer specific mortality, a thorough lymph node dissection is associated with decreased recurrence and long-term survival.

Clinics Care Points:

• Regional lymph node metastases are common in patients with thyroid cancer.

• Thorough assessment of regional lymph nodes should be included in the evaluation of any thyroid nodule, and ultrasound is both sensitive and specific in identifying lymph node metastases.

• Complications are uncommon for high-volume surgeons.

• Lymph node dissections for thyroid cancer should be compartment based to help lower the ratio of positive to total lymph nodes removed.

• Lymph node metastases are associated with a higher risk of thyroid cancer recurrence, but, lymph node dissections are able to provide biochemical remission in most patients.

• When evaluating thyroid nodules or thyroid cancer, look for evidence of lymph node metastases with a preoperative ultrasound.

• Obtain a thyroglobulin washout during fine needle aspiration of suspicious lymph nodes to help detect metastases in well-differentiated thyroid cancer.

• During a node dissection for thyroid cancer, use a compartment-based approach rather than “berry-picking” abnormal nodes.

• Include levels IIa through Vb when performing the initial lateral neck lymph node dissection for thyroid cancer.

• When monitoring thyroid cancer patients for recurrent disease, look for increases in tumor markers and abnormal nodes on imaging.