20 Surgical Management of the Lateral Neck in Thyroid Cancer
20.1 Introduction
The propensity of differentiated thyroid cancer (DTC), especially papillary thyroid cancer (PTC), with its predilection for lymphatic metastases, to demonstrate early spread to cervical lymph nodes has been well described in the literature over the past several decades. 1 The first echelon of thyroid cancer metastases are found in the paratracheal and central neck lymph node compartments, with the lateral cervical lymphatic chain along the jugular vein comprising the second echelon of lymph nodes. The rate of metastases, including micrometastases, for PTC ranges from 50 to 90%. 2 , 3 , 4 , 5 The central compartment is a frequent site of lymph node recurrence in thyroid cancer. This has prompted considerable debate regarding the need for prophylactic central neck dissection in an attempt to avoid the increased risk of complication associated with reoperative surgery. The debate on the initial surgical management of regional lymph nodes also includes the lateral neck, because recurrence is possible there in up to 30% of cases. 6 It is undeniable that clinically evident or progressive cervical metastases require treatment to improve outcome, but the treatment of subclinical disease is less clear with regard to cost, risks, and benefit of treatment. Additionally, although cervical metastatic disease has been implicated in some studies as an independent risk factor for locoregional recurrence, its effect on overall mortality is inconclusive. 7 , 8 There is potentially significant additional morbidity and surgical risk associated with lateral cervical lymph node dissection compared with thyroidectomy and central neck dissection alone. As methods of thyroid cancer detection have improved significantly over the past several decades, an increasing number of patients face the possibility of neck surgery. This chapter addresses the evaluation, treatment, and implications of lateral neck lymph node metastases in thyroid cancer.
20.2 Risk Factors
A number of risk factors are associated with the presence of lateral neck metastases in thyroid cancer. Papillary carcinoma often demonstrates early lymphatic spread, and therefore has a high incidence of lateral cervical lymph node metastasis. Follicular and Hürthle cell carcinomas have lower rates of lateral cervical nodal metastases, though these do infrequently occur. 9 In addition to primary tumor histology and the presence of central compartment disease, lateral neck metastases are more likely in the presence of the following factors: younger patients, male sex, increased size of primary tumor, lymphovascular invasion, extrathyroidal extension, multifocal disease, and BRAF mutations. 5 , 10 , 11 , 12 , 13
The following are factors affecting lateral neck nodal metastases in well-differentiated thyroid cancer:
Primary tumor histology.
Primary tumor size.
Age.
Extrathyroidal extension.
Gender.
Molecular markers have recently been investigated regarding their utility to predict aggressive disease and lymph node metastasis, as well as their being a basis for targeted therapy. BRAF is a gene that codes for B-raf, a protein in the mitogen-activated protein kinase cell signaling pathway. Mutations in the BRAF gene have been implicated in a variety of human cancers, including melanoma and lung and thyroid cancers. In papillary thyroid cancer, mutations have been demonstrated in some studies to be the most important independent clinicopathologic feature of aggressive disease, including lymph node metastasis, recurrence, and death. 14 However, some of the more recent studies are demonstrating a much higher prevalence of BRAF mutations than previously described and fail to find an association with lateral cervical lymph node metastases. 15 , 16 , 17 , 18 Other molecular markers, such as the expression of tumor-suppression protein p53, have also been investigated as risk factors for disease aggressiveness and nodal metastasis. 19 These markers have not been established to be independent indications for elective neck dissection in thyroid cancer but may serve to stratify risk and guide further preoperative evaluation. Patients with additional risk factors will be the most likely to benefit from either ultrasound or advanced imaging, such as computed tomography (CT) and magnetic resonance imaging (MRI), to evaluate the central and lateral lymphatic compartments for the presence of metastatic disease.
20.3 Preoperative Evaluation
The lateral neck should be assessed in all patients undergoing surgery for thyroid cancer. A complete history should inquire about the presence of any new neck masses or any first-degree relatives with a history of metastatic thyroid carcinoma. Physical examination should include laryngoscopy to determine vocal fold mobility and careful bimanual examination of the neck for abnormal lymph nodes. In postoperative patients, elevated levels of thyroglobulin (Tg) and Tg antibody can serve as a harbinger of recurrent primary or metastatic disease.
20.3.1 Imaging
Radiographic detection of macroscopic cervical lymph node metastases is crucial because removal of macroscopic disease at the initial surgery will decrease the need for revision surgery as well as repeated radioactive iodine (RAI) treatments. High-resolution ultrasound of the thyroid and lateral neck has been found to be reliable and low cost for the evaluation of thyroid cancer when employed by experienced clinicians. Unfortunately, routine diagnostic thyroid ultrasound frequently does not address the lateral neck. However, a protocol employing dedicated, comprehensive, consistent preoperative ultrasound assessment of the lateral neck results in the detection of suspicious lymphadenopathy in up to 20 to 30% of patients with known thyroid cancers, and ultimately alters surgical treatment in approximately 20% of these patients. 20 , 21 The sensitivity of ultrasound in detecting cervical lymphadenopathy in the central compartment has been reported as 30 to 50%, largely due to the shadowing effect of the thyroid gland. The low sensitivity of ultrasound (US) in the central neck is one reason why CT imaging is preferred by many surgeons in the initial imaging evaluation of high-risk patients. However, in the lateral neck, ultrasound has up to 90% sensitivity in detecting suspicious lymph nodes. Specificities approach 90% in both central and lateral compartments using US. 15 , 22 Concerning features of lymph nodes on US include size > 1 cm, hypoechoic consistency, round shape, irregular borders, absence of hilum, peripheral vasculature, calcifications, and cystic changes. 23 , 24 , 25
Below are US features of lymph nodes suggestive of metastases in thyroid cancer:
> 1 cm in size.
Hypoechoic lymph node/cystic changes.
Irregular border.
Absence of normal hilum architecture.
Peripheral vasculature.
Calcification.
US has many advantages over other imaging modalities, such as CT and MRI. There is no radiation exposure with US, it can be performed in the outpatient office during the initial visit, and it is rapid, easily repeatable, and relatively inexpensive. Fine-needle aspiration (FNA) biopsy has been shown to be more accurate when coupled with US guidance and has become the standard for thyroid and cervical biopsies. 26 Despite these advantages, limitations in evaluating substernal regions and invasion of surrounding organs, as well as interoperator reliability, present some challenges for the universal acceptance of US as the sole imaging modality for initial or recurrent high-risk thyroid cancers. Advanced imaging modalities, such as CT, MRI, or positron emission tomography (PET-CT) have similarly high sensitivity and specificity in assessing central compartment and lateral neck lymph nodes. 27 , 28 They offer the advantages of better visualization of adjacent neck tissues and periclavicular neck levels and less operator dependence. Additionally, combining imaging modalities, such as US and CT, has been shown to offer higher sensitivity than the individual modalities. 29 At this time, most surgeons are more comfortable reviewing CT or MRI scans, rather than US images, to determine the locations of metastases. Thus these modalities are widely preferred for preoperative planning and locating metastases in uncommon locations. However, the routine use of CT results in considerable expense and additional radiation exposure. The Food and Drug Administration (FDA) has begun to consider the effects of CT radiation on long-term health and has issued several statements requesting the decrease of exposure to medical radiation. 30 Also, the use of CT contrast dye may delay the administration of postoperative RAI for at least 3 months after administration while the stunning effect of the contrast on the thyroid wears off.
Despite these limitations, CT imaging will provide the most reliable clinical staging and surgical planning of any current imaging modality. The use of MRI has similar advantages to CT, but the presence of vascular flow voids, movement artifacts, and inferior osseocartilaginous delineation limit its utility in imaging advanced thyroid malignancy.
20.3.2 Pathological Staging
Cervical lymphadenectomy is associated with increased morbidity, and every effort should be made preoperatively to establish a cytological diagnosis of suspicious lateral cervical nodes. FNA has remarkably improved the ability to pathologically detect malignancy in central compartment and lateral cervical lymph nodes. 31 However, the accuracy of cytopathologic diagnosis is highly dependent on adequate sampling of the lesion and the proficiency of the pathologist. Palpation-guided FNA results in a false-negative rate of ~ 6%, with an additional 10% of samples found to be inadequate. 32 However, when US-guided FNA (US-FNA) is performed, the diagnostic yield improves, and inadequate sampling rates decrease to approximately 3 to 7%. 26 , 33 This is possible due to real-time visualization of needle passes through the targeted lymph node. 34 The diagnostic yield of US-FNA can also be increased by selecting nodes with more suspicious features (as listed in the previous section), with sensitivities and specificities approaching 100% when multiple features are present. 35
Sensitivity and specificity of US-FNA can be further increased when Tg assay of the aspirated fluid is performed in addition to routine cytopathologic analysis. 36 This is especially helpful for sampling small-volume lymph nodes or nodes with significant cystic components, which might yield an inadequate number of cells. 37 , 38 The utility of Tg serology in FNA is limited for sampling undifferentiated, anaplastic, or medullary thyroid cancers, which do not typically produce Tg. In addition, the presence of Tg antibody may theoretically affect the measurement of Tg, although studies have shown that FNA-Tg measurement is useful, even in the presence of circulating serum Tg antibody. 36 Inclusion of any thyroid tissue would obviously create a false-positive; however, this is typically more relevant to central compartment nodes where the needle could mistakenly pass through the thyroid gland and where small foci of remnant thyroid may mimic lymph nodes. 39 Thus Tg assessment with FNA is most useful when sampling lateral neck nodes in athyrotic, Tg antibody–negative patients after RAI administration. 40 With or without Tg, US-FNA should be performed in all clinical scenarios with suspected lymph node metastasis, whether primary or recurrent.
20.3.3 Laboratory Evaluation
Serum Tg and Tg antibodies are useful tools in surveillance and are thought of as surrogate measures of functional thyroid tissue, benign or malignant. 41 , 42 The presence of a progressively rising Tg or Tg antibody after surgery and primary ablation of thyroid tissues may be a sign of persistent or recurrent thyroid malignancy. In addition, testing for the presence of certain biomarkers, such as BRAF mutations, which has been associated with lymph node metastases, may aid in risk stratification. 17 , 43 , 44 , 45 Studies have explored the utility of gene assays for BRAF in FNA samples to predict disease behavior, including lymph node metastases. 46 However, the significance of many of these biomarkers are still under investigation and the assays are not widely available.
20.4 Cervical Lymph Node Compartments
The neck compartments have been standardized for several decades based on well-studied lymph node drainage pathways and oncological patterns of spread. 47 , 48 , 49 Defining key boundaries and landmarks has been instrumental in relating metastatic cancerous deposits with likely sites of unknown primary tumors in squamous cell carcinoma of the upper aerodigestive tract and also for defining lymph node basins most appropriate for evaluation when treating patients with these malignancies. This has resulted in standardized nomenclature for communication of lymph node basins most likely to be affected by well-differentiated cancer as well. For practical purposes, there are six lymph node compartments or “levels” in the neck that are described following here (Fig. 20.1). These compartments encompass the lymph nodes in the fibro-fatty soft tissue located between the superficial investing fascia superiorly, and the visceral and prevertebral fascia layers deep. Level I is known as the submandibular space, and levels II through IV, the jugular nodes.
20.4.1 Level I
Level I is bound by the mandible superiorly and the body of the hyoid inferiorly. The anterior border is the anterior belly of the contralateral digastric muscle, and the posterior border is the stylohyoid muscle. Level I is divided into IA and IB by the anterior belly of the ipsilateral digastric muscle.
20.4.2 Level II
Level II is bound superiorly by the skull base and inferiorly by the horizontal plane of the inferior border of the hyoid bone. The anterior border is the stylohyoid muscle, whereas the posterior border is the lateral border of the sternocleidomastoid (SCM) muscle. Level II is also divided into two sublevels, IIA and IIB, by the vertical plane of the spinal accessory nerve.
20.4.3 Level III
Level III is bound superiorly by the horizontal plane of the inferior border of the hyoid bone and inferiorly by the horizontal plane created by the inferior aspect of the cricoid cartilage. The lateral sternohyoid muscle is the anterior border, and the lateral border of the SCM and/or cervical rootlets serve as the posterior border.
20.4.4 Level IV
Level IV is bound superiorly by the horizontal plane of the inferior cricoid cartilage and inferiorly by the clavicle. Similarly to level III, the anteromedial border is the lateral sternohyoid muscle, and the lateral border is the lateral SCM and cervical rootlets posteriorly.
20.4.5 Level V
Level V is bound superiorly by the convergence of the SCM and trapezius muscles and inferiorly by the clavicle. The lateral edge of the SCM and/or cervical rootlets is the anterior border, whereas the anterior border of the trapezius muscle serves as the posterior border. This level is divided into VA and VB by the horizontal plane of the inferior cricoid cartilage.
20.4.6 Level VI
Level VI is bound by the hyoid bone superiorly and laterally by the common carotid arteries. The inferior limit is sometimes defined as the sternal notch, whereas others use the innominate artery as the inferior border. These lymph nodes inferior to the sternal notch in the anterior mediastinum are often included in the definition of the central compartment due to the contiguous lymphatic drainage of the perithyroidal and paratracheal lymph nodes into the mediastinum. Superior mediastinal lymph nodes accessible through the neck are often referred to as level VII lymph nodes, though this is not supported by the consensus statement of the American Head and Neck Society as well as the American Academy of Otolaryngology–Head and Neck Surgery. 50
20.5 Lateral Neck Dissection Definitions
Similar to the definition of the cervical lymph node compartments, nomenclature and definitions of neck dissections are important for consistency in the medical literature and research and for communication among clinicians. Lateral neck dissections have been relatively well defined in the literature, based on the previously described lymph node levels.
The radical neck dissection (RND), popularly described by Crile in 1906, is defined by removal of all ipsilateral cervical lymph node structures in compartment levels I through V along with the spinal accessory nerve, SCM, and internal jugular vein. The boundaries of this dissection are the mandible superiorly, the clavicle inferiorly, the lateral hyoid bone, the sternohyoid muscle, and the contralateral anterior digastric muscle medially, and the anterior border of the trapezius laterally.
The modified radical neck dissection (MRND), introduced several decades later, refers to the removal of all lymphatic structures included in the radial neck dissection (levels I–V), but with the preservation of at least one of the nonlymphatic structures (spinal accessory nerve, SCM, internal jugular vein). Despite the preference for the terms radical neck dissection and modified radical neck dissection, there is some variety in the nomenclature found in the literature in reference to the removal of lymph node levels I through V, including complete neck dissection or comprehensive neck dissection. 51
Most recently, selective neck dissection (SND) has emerged as a general term that refers to the removal of some but not all of the lymphatic compartments of the lateral neck. The use of SND represents one of the major changes in head and neck oncological surgery, where targeted lymphadenectomy is guided by knowledge of lymphatic drainage patterns specific to the primary malignancy site and histology. 52 Due to this more selective approach to the neck, the literature refers to several classifications, such as supraomohyoid neck dissection, anterolateral neck dissection, lateral neck dissection, and extended neck dissection. However, the extent of excision described by these terms varies among institutions. Therefore the extent of neck dissection, according to the individual levels excised, should be specifically described when departing from the more standardized terminology of RND and MRND. This includes comments on inclusion or exclusion of lymph node sublevels as well as lymph nodes not included in the compartment classifications, such as perifacial, periparotid, parapharyngeal, superior mediastinal, and suboccipital lymph nodes. Additionally, any sacrificed nonlymphatic structure should be noted as well. This is especially important when one is dealing with the lateral neck in thyroid cancer because cervical metastases may vary, especially in the setting of recurrent disease.
Traditionally, the extent of lateral neck dissection for thyroid cancer had been largely left to the discretion of the individual surgeon, leading to disparate procedures and operative descriptions. To codify these differences, the 2009 American Thyroid Association (ATA) guidelines recommended “therapeutic lateral neck compartmental lymph node dissection” for lateral cervical metastases. 53 With the exception of RND and MRND, lateral neck dissections for thyroid cancer should now specifically describe the nodal compartments, which are dissected, and excision of individual nodes (“berry picking”) is no longer recommended.
20.6 Cervical Lymph Node Metastasis in Differentiated Thyroid Cancer
Papillary thyroid cancer is the predominant thyroid cancer resulting in cervical lymph node metastasis due to its prevalence and high propensity for lymphatic spread.
20.6.1 Drainage Patterns
Cervical metastasis in differentiated thyroid cancer typically occurs in the central compartment, the first nodal basin, with subsequent stepwise spread to the lateral neck in levels II through V. There is also evidence of spread to the lateral neck directly from the thyroid gland. 54 These “skip metastases” have been shown to occur in up to 38% of cases, most commonly from upper pole lesions. 55 Level I is not commonly affected by thyroid cancer metastasis. Levels III and IV are the most common sites of lateral cervical metastases, but the incidence of multilevel disease affecting all levels II through V is high once the disease has progressed to the lateral neck. 56 , 57 Spread to level IIB is less common (~ 15%), with rates of involvement ranging from 5 to 62%. Similarly, level VA is only involved in approximately 8% of cases (Fig. 20.1). 56 Finally, it is important to recognize that contralateral neck metastasis may occur, especially in multifocal tumors and tumors involving the isthmus. Even in cases of unilateral thyroid cancer, contralateral or bilateral lateral neck metastases have been seen in up to 24% of cases in one study. 58 These cases correlated highly with the presence of clinically evident ipsilateral lateral and contralateral paratracheal nodal metastases, leading the authors to suggest bilateral neck dissection in those cases.
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