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C H A P T E R

Oncologic Components of Lymphadenectomy

CRITICAL ELEMENTS ●● Resection of lymph nodes in the central compartment ●● Management of the recurrent laryngeal nerve when involved by extranodal exten- sion from lymph node metastases ●● Management of clinically positive lymph nodes in the lateral neck ●● Management of extranodal extension in the lateral neck

1. RESECTION OF LYMPH NODES IN THE CENTRAL COMPARTMENT

Recommendation: A central compartment neck dissection that includes resec- tion of the lymph nodes within the paratracheal, paraesophageal, prelaryngeal, and pretracheal areas should be performed routinely during thyroidectomy for papillary thyroid cancer with clinically involved lymph nodes in the central or ipsilateral lateral compartments. Type of Data: Retrospective case series. Grade of Recommendation: Strong recommendation, moderate-quality evidence. Rationale Involvement of cervical lymph nodes in papillary thyroid cancer (PTC) is common and occurs in 20% to 50% of patients. 52–56 The presence of lymph node metastases may increase recurrence rates and decrease long-term survival. 57–61 Both macroscopic (clinically involved) and microscopic (pathologically involved) lymph node metasta- ses are encountered in PTC; however, the significance of micrometastatic disease in relationship to outcomes may be minimal. 62–64 In the absence of macroscopic disease,

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a prophylactic neck dissection is controversial (see discussion later in this chapter’s Key Question). Preoperative ultrasonography is important in determining the pres- ence of macroscopic lymph node metastases, which will be clinically evident in ap- proximately 20% to 31% of cases and, if present, may potentially alter the surgical approach (Fig. 2-1). 65–69 Identification of involved central compartment (level VI) lymph nodes by ultrasonography may be limited because of the overlying thyroid, depth from the skin, or acoustic shadowing from the manubrium and clavicles. 70–73

FIGURE 2-1 Ultrasound images of metastatic lymph nodes (arrows) in papillary thyroid cancer in (A) central neck with cystic appearance and round shape and (B) lateral compartment with hy- perechoic tissue that resembles thyroid with microcalcifications; T: Trachea, C: Carotid; IJ: Internal jugular vein.

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

FIGURE 2-2 Level VI (A) and level VII (B) lymph node metastases on computed tomography imaging.

Therefore, adjunct cross-sectional imaging (typically contrast-enhanced computed tomography [CT]) can be helpful in analyzing the central compartment and superior mediastinal lymph node basins if there is suspicion of disease not readily visualized on ultrasonography (Fig. 2-2). 70–73 Gross inspection of the central neck compartment lymph tissue at the time of thyroidectomy should also be performed, given this ad- enopathy is readily encountered during the procedure. The most common site of lymph node metastasis in PTC is the central compart- ment. 74 Therapeutic surgical resection of involved lymph nodes with the use of compartment-oriented, en bloc resection of the lymph nodes in the involved com- partments provides the best treatment for cervical lymph node metastasis and is well established. 42,57,76–78 Macroscopic cervical lymph nodes cannot be adequately treated with radioactive iodine (RAI) therapy alone. Metastatic lymph nodes are the most common cause of persistent and recurrent PTC after initial treatment. 79–81 Persistent lymph node metastasis after thyroidectomy often occurs because of lack of or inac- curate preoperative imaging and subsequent omission of or incomplete lymphadenec- tomy in patients with clinically involved lymph nodes at the time of initial surgical

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treatment. 82,83 Reoperative lymph node dissection for persistent and recurrent PTC carries a higher risk of surgical complications than does primary surgery. 84 These is- sues underscore the utmost importance of accurate and complete preoperative and intraoperative analysis to allow for a definitive resection of both local and regional disease at the time of initial surgical treatment of PTC. An ipsilateral therapeutic CCND should be performed for macroscopic metastatic lymphadenopathy; if macroscopic disease is seen in the contralateral central compart- ment, bilateral therapeutic CCND should be performed. 85–87 The role of a contra- lateral CCND, in the absence of a known contralateral cancer and no macroscopic evidence of metastatic lymphadenopathy in the contralateral central compartment, is controversial. However, intraoperative inspection of the central compartment has a poor predictive value for the presence of metastatic disease, and consideration could be given to proceeding with a contralateral dissection in the presence of ipsilateral macroscopic disease. 88,89 Intraoperative decision-making plays an important role in the conduct of CCND. After ipsilateral dissection, the functional status of the RLN should be considered prior to completing the contralateral CCND, if being considered. Intraoperative RLN monitoring can be helpful in this decision-making process. For example, if the RLN is nonfunctional after the ipsilateral CCND, surgeons should carefully consider the implications before proceeding with a contralateral dissection. This is especially per- tinent in the absence of clinically involved lymph nodes, considering the ramifications of bilateral RLN paralysis and the subsequent need for tracheostomy. A staged pro- cedure might also be considered; however, if a total thyroidectomy has already been performed, the contralateral central compartment will become a reoperative field, which may be associated with higher rates of RLN injury or hypoparathyroidism. The viability of the parathyroid glands should also be a consideration during bilateral CCND. Care should be taken to preserve all parathyroid glands. If multiple glands have questionable viability, a limited contralateral dissection can be considered in order to preserve viable parathyroid tissue in those patients with no evidence of con- tralateral metastatic lymphadenopathy. Technical Aspects CCND typically can be accomplished through the lower cervical collar incision used for thyroidectomy. The central compartment of the neck is defined by anatomic boundaries, and CCND should be performed in a compartment-oriented manner, with en bloc resection of the lymph nodes contained within these boundaries. 78,90,91 The central compartment is bounded cranially by the hyoid bone, caudally by the innominate artery on the right and the corresponding axial plane on the left, later- ally by the common carotid arteries, posteriorly by the deep layer of the cervical fascia, and anteriorly by the superficial layer of the cervical fascia (Fig. 2-3). The thyroid and parathyroid glands, the level VI lymph nodes, the upper portion of the level VII lymph nodes, and the cervical portion of the thymus are within the central compartment. Common locations of metastatic central compartment lymph nodes include the paratracheal and paraesophageal lymph nodes inferior and posterior to

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

Hyoid bone

External branch of superior laryngeal nerve

Common carotid artery

Parathyroid glands

Recurrent laryngeal nerve

Thymus

VII

FIGURE 2-3 Central neck. Roman numbers indicate levels.

the thyroid, the pretracheal lymph nodes inferior to the thyroid isthmus, and the prelaryngeal (Delphian) lymph node(s) just superior to the thyroid isthmus (Fig. 2-4). The majority of the level VI lymph nodes are located inferior to the cricoid cartilage and posterior and inferior to the thyroid gland. The RLN can be situated anterior or posterior to involved central compartment lymph nodes, and care should be taken to examine behind the RLN to avoid missing lymph node metastasis, particularly on

Delphian node

Preserved superior parathyroid gland Left RLN

Metastatic lymph nodes Preserved superior parathyroid gland Right RLN

Metastatic lymph nodes

FIGURE 2-4 Central compartment neck dissection after thyroidectomy. Dotted lines mark the border of the central neck dissection. Note Delphian node preserved superior parathyroid glands, bilateral recurrent laryngeal nerves, and metastatic lymph nodes. RLN, recurrent laryngeal nerve.

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Cricoid cartilage

Superior parathyroid gland Common carotid artery

RLN Inferior parathyroid gland Esophagus Metastatic lymph nodes

FIGURE 2-5 Metastatic lymph nodes posterior to recurrent laryngeal nerve (RLN).

the right side (Fig. 2-5). Central compartment nodal metastasis can also be situated posterior to the common carotid arteries and posterior to the innominate artery on the right, and care should be taken to include these lymph nodes during CCND. The retropharyngeal lymph nodes are rarely involved in PTC; however, primary tumors in the superior pole can metastasize to this location. 92,93 Cervical ultrasonography will not visualize the retropharyngeal space, and contrast-enhanced cross-sectional imag- ing (typically CT) can be useful in evaluation if retropharyngeal and retroesophageal space involvement is suspected (Fig. 2-6). A CCND can be executed either by en bloc resection of the lymph nodes with the thyroid specimen or by separate resection. Removal of the thyroid initially may allow for easier visualization of the lymph nodes posterior to the thyroid and along the course of the RLN. Removal of the entire lymph node basin is recommended in patients with clinical involvement, and “berry picking” or “plucking” of individually involved nodes is not recommended and is associated with higher rates of persistent disease. 42,94,95 Typical nodal yield from a bilateral level VI lymph node dissection can vary greatly; however, a recent study noted that patients with recurrent papillary thy- roid cancer (PTC) had a lower mean nodal yield than those without recurrence, thus suggesting the importance of a complete CCND in the presence of nodal metastasis. 96 Exposure of the entire anterior surface of the RLN is recommended, from its insertion point at the cricothyroid muscle to its proximal extent as it emanates from the medi- astinum. This allows for removal of the lymph nodes anterior to the RLN with direct

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

FIGURE 2-6 Right retropharyngeal lymph node metastasis (arrow) visible on computed tomogra- phy scan enhanced with intravenous contrast.

visualization of the nerve as dissection progresses either distally or proximally along the nerve. In some instances individual lymph nodes situated posterior to the RLN can be removed separately if en bloc removal with the lymph nodes anterior to the nerve would stretch or place undue tension on the RLN. 97 Common locations of missed metastatic central compartment lymph nodes include nodes posterior to the RLN, those posterior to the common carotid artery, and those extending below the level of the sternal notch in the paraesophageal and paratracheal spaces and into the superior portion of level VII. Preservation of parathyroid gland function is important during CCND. The su- perior parathyroid glands typically derive arterial supply from branches of the infe- rior thyroid artery, and avoidance of high ligation of the inferior thyroid artery can help with preservation of the vascular pedicle. In some circumstances, a branch of the superior thyroid artery supplies the superior parathyroid glands, and confirma- tion of viability after thyroidectomy is warranted. The inferior parathyroid glands are typically more closely associated with the lymph nodes removed during CCND and may therefore be difficult or impossible to preserve in situ on their vascular pedicles (Fig. 2-7). The inferior parathyroid glands also are often in close association to or within the thyrothymic tract, which runs through the anterior aspect of the inferior level VI lymph nodes. The thyrothymic tract and cervical portion of the thymus do not necessarily need to be excised during a CCND, and preservation may aid in preserving the viability of the inferior parathyroid glands that reside in the cervical thymus. 98 De- vascularization or inability to preserve the parathyroid glands in situ should prompt reimplantation of parathyroid tissue into a viable muscle within the operative field (typically the sternocleidomastoid muscle [SCM]). Confirmation of parathyroid tissue

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Superior parathyroid gland

Inferior thyroid artery (ligated)

Inferior parathyroid gland Right RLN

Cervical thymus

FIGURE 2-7 Level VI lymph node dissection. RLN, recurrent laryngeal nerve.

by microscopic examination may help avoid inadvertent reimplantation of tumor or nodal metastasis. Addition of a CCND to total thyroidectomy has been shown to in- crease parathyroid reimplantation rates and temporary hypoparathyroidism but not permanent hypoparathyroidism. 52,77,99–103 At least an ipsilateral CCND should be performed in patients with lateral com- partment lymph node (levels II to V) involvement. In general, lymph node metasta- ses spread in a centripetal manner, and although “skip metastases” (no evidence of central compartment lymph nodes in the presence of lateral compartment nodal in- volvement) are described, their occurrence is atypical. Most patients with lateral com- partment nodal involvement will also have metastatic central compartment lymph nodes. 104–106 Level VII lymph nodes reside in the superior mediastinum caudal to the innominate artery on the right and the corresponding axial plane on the left. The level VII nodal basin is not typically involved in a CCND; however, lymph node involvement in this basin is not uncommon in patients whose lymph node metastasis is more extensive than usual. 107 Transcervical access to level VII is feasible in the initial and reoperative settings, and partial or complete sternotomy is rarely indicated. When central compartment lymph nodes encountered during thyroidectomy are suspected of harboring metastases, intraoperative pathology consultation can be help- ful in determining the presence of metastatic disease. 108 Visual inspection has been shown to have poor predictive value in central compartment nodal metastasis. 88,89 Sentinel lymph node biopsy for PTC has been described, but the practice has not been

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

widely adopted. 109,110 If microscopic examination is consistent with cervical lymph node metastases, a compartment-oriented ipsilateral or bilateral CCND should be performed. Given the poor predictive value of ultrasonography of the central com- partment and of visual inspection, surgeons should anticipate the need for CCND at the time of initial thyroidectomy for PTC and discuss this potential with the patient; if a surgeon is not experienced with CCND, consideration should be given to referring the patient to a surgeon with a high-volume CCND caseload, because complication rates are lower in high-volume centers. 111–114 2. MANAGEMENT OF THE RECURRENT LARYNGEAL NERVE WHEN INVOLVED BY EXTRANODAL EXTENSION FROM LYMPH NODE METASTASES Recommendation: Lymph nodes with extranodal extension that involves the recurrent laryngeal nerve should be resected to avoid leaving gross residual disease while attempting to preserve the integrity of the recurrent laryngeal nerve. Type of Data: Retrospective case series. Grade of Recommendation: Strong recommendation, moderate-quality evidence. Rationale Gross extranodal extension of PTC nodal metastasis is uncommon, but it is associ- ated with increased risk of recurrence. 60,64,115–117 Extranodal extension rarely involves the recurrent laryngeal nerve (RLN). Preoperatively, this may be evident in patients presenting with unilateral RLN paralysis. Intraoperative discovery of extranodal ex- tension involving a functional RLN is also a rare occurrence; however, the surgeon should attempt disease resection to preserve the nerve anatomically and functionally without leaving gross disease. Intraoperative RLN monitoring can be especially help- ful in these more difficult situations. Technical Aspects Intraoperative management of central compartment lymph node metastases with ex- tranodal extension involving the RLN should be considered in the context of the functionality of the nerve. In patients with extranodal macroscopic disease and a non- functional nerve, the nerve should be resected to achieve a complete (R0) resection. In patients with extranodal macroscopic disease with a functioning RLN, attempts at preservation of the nerve anatomically and functionally should be made with a shave resection to remove all gross disease, even if this achieves only an R1 resection (microscopically positive margin), because outcomes appear similar between R0 and R1 resections. 118 A shave resection can be performed with sharp dissection of the involved node away from the neural sheath, excising as much of the node as possible while preserving the nerve. Immediate nerve reconstruction in short segment resec- tions with direct neural anastomosis can be considered if a surgeon with experience in microanastomotic techniques is available. 119,120

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3. MANAGEMENT OF CLINICALLY POSITIVE LYMPH NODES IN THE LATERAL NECK Recommendation: In patients with clinically involved lateral compartment lymph nodes, a compartment-oriented, en bloc lymphadenectomy should be per- formed. A prophylactic lateral compartment neck dissection is not recommended. Type of Data: Retrospective case series. Grade of Recommendation: Strong recommendation, moderate-quality evidence. Rationale Macroscopic lymph node involvement is not effectively treated with RAI therapy alone; therefore, surgical excision of metastatic lymph nodes provides the best option for regional control of disease. A compartment-oriented lymphadenectomy provides the most effective clearance of metastatic lymph nodes rather than removal of indi- vidually involved nodes (“berry picking”). In patients with PTC, metastases to the regional lymph nodes is common. Metas- tases are most common in the central compartment, followed by the ipsilateral lateral compartment. 94,95,121 Metastases to the contralateral lateral compartment or skip me- tastases (no clinical or pathologic evidence of central compartment metastasis with verified ipsilateral lateral compartment metastasis) can occur, but both are rare. 104–106 The presence of lateral compartment lymph node metastasis has been shown to confer a decrease in long-term survival in older patients with PTC. 64,122 Preoperative imaging of the lateral compartments is important because it can identify lymph nodes with abnormalities suggestive of metastasis. 65,66–69,71,73,74,94,95 Confirmation of metastasis by fine-needle aspiration (FNA) biopsy should be per- formed prior to lateral compartment lymph node dissection. Even if there is only one metastatic node identified preoperatively, additional microscopic metastases are often present; therefore, a compartment-oriented dissection of the involved compartment should be performed. 73,107,123–127 “Berry picking” lymph nodes in the lateral neck is discouraged, because it underestimates the extent of disease, may undertreat patients, and may make a future reoperative neck dissection more difficult. 33,127–133 Technical Aspects The lateral compartment comprises lymph node levels I, II, III, IV, and V, which are divided by anatomic landmarks and generally defined as follows (Fig. 2-8): ●● Level I (submandibular): Body of mandible superiorly, stylohyoid muscle pos- teriorly, and the anterior belly of the digastric muscle on the contralateral side anteriorly. ●● Level II (upper jugular): Upper third of the jugular vein, extending from the skull base to the inferior border of the hyoid. The spinal accessory nerve divides the group into IIA (anterior and inferior to the nerve) and IIB (superior and posterior to the nerve).

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

IA IB

IIB

IIA

III

VII

FIGURE 2-8 Levels I to VII of the lateral compartment.

●● Level III (mid-jugular): Located between the hyoid bone and a horizontal plane defined by the inferior border of the cricoid cartilage. The anterior border is the sternohyoid muscle, and the posterior border is the SCM. ●● Level IV (lower jugular): Adjacent to the lower third of the jugular vein and between the inferior border of the cricoid cartilage and the clavicle, with anterior and posterior borders similar to those of level III. ●● Level V (posterior triangle): Posterior to the posterior border of the SCM and anterior to the anterior border of the trapezius muscle. Level V is divided into VA and VB by a plane defined by the inferior border of the cricoid cartilage. VA is inclusive of nodes surrounding the spinal accessory nerve, and VB includes the transverse cervical and supraclavicular nodes. In metastatic PTC, the key levels in the lateral compartment are IIA, III, IV, and VB. These levels should be included routinely in a lateral compartment neck dissec- tion. Level I is rarely involved with metastasis from PTC; however, because it is not uncommon to find enlarged lymph nodes adjacent to the salivary glands after upper respiratory infection or sinusitis, FNA biopsy of suspicious lymph nodes in level I should be performed prior to inclusion in a lateral compartment neck dissection for PTC. Similarly, inclusion of levels IIB and VA in a lateral compartment neck dissection

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should be based on the burden of disease in adjacent compartments. If, however, there is clinical evidence of disease at the time of surgery, dissection of these compartments should be included. A number of incisions can be utilized to approach the lateral compartment: some surgeons prefer a low-lying collar incision, while others utilize a vertical extension toward the angle of the jaw. Irrespective of the specific incision, the end point must allow for appropriate exposure to the lymph node compartments (Fig. 2-9). After the incision, subplatysmal flaps are made to maximize exposure to the operative field. The superior flap should extend to the hyoid bone, and the inferior flap should extend to the sternum (midline) and clavicle more laterally. Disruption of the sensory cervi- cal nerves, including the greater auricular nerve, may lead to numbness of the lateral neck and ear. Patients should be advised of this possibility before surgery. During the procedure, care should be taken in the retraction of the upper, or cranial, skin flap because the marginal mandibular branch of the facial nerve runs just below the man- dible and may be compressed by enthusiastic retraction. Once adequate exposure has been obtained, the anterior border of the SCM should be incised longitudinally along the anterior border to expose the plane between the SCM and the strap (sternohyoid and sternothyroid) muscles. This allows for identification of the underlying omohyoid muscle, which can be divided to further expose the carotid sheath (internal jugular vein [IJV], common carotid artery, and vagus nerve) posteriorly. The fascia along the posterior border of the SCM should also be incised to allow for full mobility of the muscle, which can be retracted with instruments or encircled with a Penrose drain. The SCM is rarely divided in a primary operation.

Platysma

Anterior jugular nodes

Anterior cervical fascia Strap muscles

Sternoclei- domastoid muscle Common carotid artery Internal jugular vein Omohyoid muscle (separated)

Sternoclei- domastoid muscle

FIGURE 2-9 Modified radical neck dissection incision, subplatysmal flaps, and dissection be- tween sternocleidomastoid muscle and strap muscles (left) . Initial dissection along lateral border of internal jugular vein above level of clavicle (right) .

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

Anterior and inferior nodes Internal jugular vein Carotid bifurcation

Middle scalene muscle

Vagus nerve

Subclavian vein Anterior scalene muscle Phrenic nerve Brachial plexus

Thoracic duct Transverse cervical artery Common carotid artery

FIGURE 2-10 En bloc dissection of internal jugular vein lymph nodes and exposure of the floor of the neck.

The lateral compartment can be dissected in either a medial to lateral (starting at the carotid sheath) or lateral to medial (starting posterior to the SCM) fashion as well as inferior to superior (starting at the clavicle) or superior to inferior (starting at the posterior belly of the digastric) manner. A medial to lateral/inferior to supe- rior approach is described here. Whichever approach is chosen, the dissection should be comprehensive and progressive. The dissection may be initiated superior to the clavicle (level IV) by incising the fascia over the carotid artery and IJV to expose the contents of the carotid sheath. Particular care should be taken to include the soft tissue posterior to the IJV to avoid missing lymph node metastases (Fig. 2-10). At this point during a left neck dissection, the surgeon may encounter the thoracic duct where it enters the confluence of the IJV and the subclavian vein. If either the tho- racic duct or smaller lymphatic channels are disturbed during dissection, they should be ligated to avoid development of a postoperative chyle leak. As the lymph node bundle is dissected, the phrenic nerve, which runs craniocaudally along the anterior scalene muscle, should be identified. Care should be taken to avoid dissection of the fascia overlying the anterior scalene muscle, thereby avoiding injury to the phrenic nerve, as well as the fascia overlying the brachial plexus located between anterior and middle scalene muscles. As the dissection proceeds in a caudal to cranial fashion and level II is exposed, the surgeon should appreciate the course of the hypoglossal nerve in relationship to the superior-medial aspect of the dissection (Fig. 2-11). The facial vein may need to be ligated to expose fully the level II lymph nodes and to avoid injury to the hypoglossal nerve. Superior laterally and emerging under the posterior belly of

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Hypoglossal nerve Carotid bifurcation Facial vein (ligated) Internal jugular vein Cervical plexus

Spinal accessory nerve Digastric muscle

Anterior and inferior nodes Hypoglossal nerve

Internal jugular vein Carotid bifurcation

Cervical plexus

FIGURE 2-11 Spinal accessory nerve and cervical plexus dissection to level II.

the digastric muscle, the spinal accessory nerve will be encountered as it heads under the SCM toward the posterior triangle. The dissection is completed superiorly when the surgeon encounters the posterior belly of the digastric muscle. The nodal content of level V may be exposed by either retracting the SCM later- ally or medially (Fig. 2-12). Retraction of the SCM laterally is often facilitated by

Proximal spinal accessory nerve Internal jugular vein

Carotid bifurcation Hypoglossal nerve Digastric muscle

SCM

Anterior and inferior nodes

Distal spinal accessory nerve

Omohyoid (separated)

Transverse cervical artery Brachial plexus

FIGURE 2-12 From under the sternocleidomastoid muscle (SCM), the specimen and the fat tissues of the neck and lymphatics are re- sected as one as all are removed from the great vessels and passed from under the SCM. As the mandible is pulled in a superior direc- tion with a retractor and the proximal spinal accessory and hypo- glossal nerves are preserved, the surgeon pulls the entire specimen from its inferior-medial position.

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

administering muscle relaxation during this portion of the procedure. As level V is dissected, the transverse cervical artery will be identified and can be ligated, if neces- sary. At the posterior aspect of the level V dissection, the spinal accessory nerve will be encountered, running laterally and diagonally entering the trapezius muscle. Injury to the spinal accessory nerve results in paralysis of the trapezius muscle, with shoulder drop and decreased abduction of the arm. A small plexus of nerve branches posterior and parallel to the spinal accessory nerve should be preserved; injury may cause sen- sory loss of the shoulder. 4. MANAGEMENT OF EXTRANODAL EXTENSION IN THE LATERAL NECK Recommendation: Lymph nodes with extranodal extension that involves the key structures of the lateral compartment should be resected to avoid leaving gross residual disease while attempting to preserve the integrity of the motor nerves. The internal jugular vein can be ligated if necessary. Type of Data: Retrospective case series and observational data. Grade of Recommendation: Strong recommendation, low-quality evidence. Rationale Extranodal extension of PTC is uncommon but is associated with an increased risk of recurrence. It can involve the surrounding soft tissue and internal jugular vein (IJV), sometimes in conjunction with intravenous tumor thrombus. The carotid artery and key nerves (vagus, phrenic, and spinal accessory) are rarely involved. Resection of gross disease should be performed, with attempts made to preserve the anatomic in- tegrity of the nerves and vascular structures. Intraoperative nerve monitoring can be helpful, particularly in the reoperative setting. Technical Aspects Intraoperative management of lateral compartment lymph node metastases with extranodal extension involving key structures should take into account the ability to resect completely all gross disease and to preserve the anatomic integrity of key nerves and vascular structures. In patients with extension into the IJV, with or with- out intravascular tumor thrombus, unilateral ligation of the ipsilateral IJV should be performed in an attempt to obtain a complete (R0) resection, as long as the con- tralateral IJV is patent. A staged procedure should be performed if bilateral venous involvement is known or suspected. If extranodal extension involves the nerves within the lateral compartment, attempts at anatomic and functional preservation of these nerves should be made, while resecting all gross disease, even if this achieves only an R1 resection. Resection of overlying muscle for direct extranodal extension can be performed but is rarely necessary in PTC. An attempt to preserve muscle volume should be made for cosmetic appearance and to enable coverage of key underlying structures.

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Oncologic Components of Lymphadenectomy: Key Question

In patients with papillary thyroid cancer (PTC), should routine (prophylactic/elective) central compartment neck dissection (pCCND) be performed to reduce the risk of locoregional recurrence? Population: Patients (all . 16 years old) with PTC and cN0 disease (i.e., no clinical evidence of central or lateral compartment lymphadenopathy on preoperative ultra- sonography, physical examination, or intraoperative visual inspection of the central compartment). Microcarcinoma represented no more than 50% of cases in each study. Intervention: pCCND (ipsilateral or bilateral) at the time of total thyroidectomy for PTC. Comparative/control: Patients with PTC with clinically node-negative disease who undergo a total thyroidectomy without pCCND. Outcome: This review should answer the questions (1) does routine pCCND decrease rates of locoregional recurrence, and (2) is pCCND associated with increased rates of postoperative morbidity? INTRODUCTION PTC commonly metastasizes to the central compartment lymph nodes, and when such lymph nodes are dissected routinely, metastatic deposits are found in up to 80% of pa- tients. 134 Furthermore, lymph node spread in PTC follows a predictable pattern, with primary tumors initially metastasizing to the ipsilateral paratracheal nodes followed by the lymph nodes in the ipsilateral lateral compartment. 135,136 In patients with cN0 staging, occult lymph node metastases are present in 24% to 82% of patients, depend- ing on the size of the primary tumor. 137 When a pCCND is performed, surgeons find ipsilateral paratracheal lymph nodes involved in up to 40% of patients, followed by the pretracheal/prelaryngeal nodes in 23% of patients, and contralateral paratracheal nodes in 10% of patients. 134,138 Risk factors associated with central compartment lymph node metastases in patients with cN0 staging include patient age, larger pri- mary tumors, extrathyroidal extension, and multifocal tumors. 138–141 The impact of occult, or microscopic, lymph node metastases on survival is thought to be minimal, if any. 142–144 Because lymph node metastases to the central compart- ment lymph nodes in PTC are so common, the use of routine dissection of this com- partment has been proposed by many to improve cancer staging, reduce the burden of disease, and consequently lower the risk of locoregional recurrence. 42,145 The cur- rent literature, primarily single-institution, retrospective studies with relatively short follow-up, suggests that the use of pCCND in patients with cN0 staging may lead to (1) decreased cancer burden, manifested by lower or undetectable postthyroidectomy

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

thyroglobulin levels and lower RAI uptake; 147 (2) improved cancer staging, which can then allow for proper use of RAI ablation/treatment; 145,148–152 and (3) a decrease in lo- coregional recurrence and improved disease-free survival rates. 142,151,153 Other studies have reported no improvement in patient outcomes and an increased use of postoper- ative RAI, as well as increased morbidity for patients who undergo pCCND. 140,154–157 The incidence of temporary hypocalcemia is reported to be significantly higher in patients who have undergone pCCND, although there is no difference in the risk of permanent hypoparathyroidism or RLN injury when the procedure is performed at specialized centers. 137,158 METHODOLOGY Relevant reports in English published between January 1990 and March 2016 and included in the PubMed database were reviewed. Randomized trials were preferred; however, when this type of data was not available, retrospective institutional stud- ies with a minimum of 100 patients and cohort studies were used. Search terms included central neck, prophylactic, routine, elective, lymph node, dissection, lymphadenectomy, papillary thyroid cancer, local recurrence, locoregional recur- rence, regional recurrence, hypoparathyroidism, recurrent laryngeal nerve, and survival. Previously published guidelines and consensus statements from the American Thy- roid Association, 42 the National Cancer Center Network, 37 and the European Society of Endocrine Surgeons 159 were also reviewed. Five published meta-analyses on the subject were reviewed. A search of references from meta-analyses and expert reviews on the topic was also performed by hand (Fig. 2-13). Articles that included patients who underwent therapeutic CCND or lateral com- partment neck dissection were excluded, as were articles focused on patients with pap- illary thyroid microcarcinoma or that included patients with benign thyroid disease. Fifteen studies were included that were relevant to the key question and met inclusion criteria. Only one prospective, randomized controlled study comparing total thyroidec- tomy and bilateral pCCND to total thyroidectomy without pCCND was identified. 140 The remaining studies were nonrandomized, retrospective studies with . 100 patients who had preoperative imaging to assess the central compartment and postoperative follow-up with reasonable assessment of local recurrence (cervical ultrasonography, serum thyroglobulin levels, and results of RAI) (Table 2-1). 137,142,147,150,151,154,160–165 Also of interest were meta-analyses of such studies (Table 2-2). 137,157,158 FINDINGS It may be difficult to demonstrate that pCCND and removal of cN0 disease ultimately will lead to a decrease in locoregional recurrence rates. A study evaluating the feasi- bility of performing a prospective, randomized controlled trial to evaluate the use of pCCND in patients with PTC found that the sample size required for adequate statis- tical power would be prohibitive. With this in mind, the only prospective, randomized controlled trial evaluating pCCND in patients with PTC is a single-institution report by Viola et al. 140 In their power calculation, the authors used a noninferiority margin

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Central neck dissection ( n = 1,090)

Non-english publications excluded ( n = 140)

English ( n = 950)

Publications unrelated to humans excluded ( n = 45)

Humans ( n = 905)

Publications unrelated to papillary thyroid cancer and central neck dissection excluded ( n = 478)

Central neck dissection, papillary thyroid cancer ( n = 427) Central neck dissection, level 6 ( n = 81) Central neck dissection, prophylactic ( n = 189) Central neck dissection, elective ( n = 62) Central neck dissection, routine ( n = 104) Central neck dissection, recurrence ( n = 301) Central neck dissection, local recurrence ( n = 206) Central neck dissection, locoregional recurrence ( n = 10)

Publications unrelated to reducing locoregional recurrence excluded ( n = 402)

Full-text articles reviewed ( n = 25)

Publications did not meet inclusion criteria ( n = 10)

Full-text articles included ( n = 15)

FIGURE 2-13 Flow diagram of literature review conducted in early 2016 of prophylactic central neck dissection. The initial 1,090 documents identified in the search were reduced to 25, of which 15 were included.

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

lymph nodes; nodes . 2 cm,

age . 45 years,

(continued)

had positive

lymph nodes;

most received RAI therapy.

TT 1 ibpCCND 126 1.7 47 6.3 NR NR 69 47% of patients lymph nodes. P-value NR NS TT 130 NR Overall, 6.9 y 19 NR NR 42 11 had positive

had positive

ETE, or positive

nodes prompted RAI therapy.

Grade of

Evidence and Comments

TT 391 2.3 70* 5 0.5 1 NR 11

TT 1 ipCCND 56 2 24.5* 3.6 1.8 0 NR 38% of patients P-value NR NS NS NS TT 118 1.5 64 7.7 NR NR 53 11

TT 1 bpCCND 136 NR 14 NR NR 58 82% of patients P-value NS 5-y DFS:

Permanent (%) RAI Use

RLN,

Hypoparathyroidism, Permanent (%)

85.6%

vs. 88%; NS

Recurrence Rate (%)

Follow-up (mo)

Mean

Tumor Size (cm)

Mean

No. of

Patients

TABLE 2-1 Selected Retrospective Studies Comparing Total Thyroidectomy with or without Prophylactic Central Compartment Neck Dissection Author, Years of Trial Procedure Sywak et al, 147 1995–2005 Costa et al, 161 1994–2001 Zuniga and Sanabria, 165 1983–1999

S E C T I O N I | T H Y R O I D

had positive

lymph nodes. 29% were

upstaged.

2.3 32 5 0.8 0.4 49% of patients had positive

lymph nodes, and 5%

had disease

upstaged.

RFS was lower for TT.

Grade of

Evidence and Comments

TT 65 2* 27.5 4.6 0 3.1 86 11

TT 1 bpCCND 78 1.9 19.1 5.1 2.6 0 92 62% of patients P-value 0.05 NS NS NS TT 347 2.2 50 8.4 † 0.45 1.8 Overall, 98

Permanent (%) RAI Use

P-value , 0.001 NS NS NS

RLN,

Hypoparathyroidism, Permanent (%)

Recurrence Rate (%)

Follow-up (mo)

Mean

Tumor Size (cm)

Mean

Author, Years of Trial Procedure TABLE 2-1 Selected Retrospective Studies Comparing Total Thyroidectomy with or without Prophylactic Central Compartment Neck Dissection (continued) No. of Patients Hughes et al, 150 2002–2009 Popadich et al, 151 1995–2009 TT 1 ibpCCND 259 (78% ipsi)

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

positive nodes, nodes . 1 cm, age . 45 years,

( P 5 0.003)—

(continued)

TT 1 bpCCND.

had positive

lymph nodes; 12.5% had

disease up-

staged. All with

or ETE received RAI therapy.

TT 1 bpCCND 358 NR 126 4.2 2.2 1.3 65 30.2% of patients P-value 0.001 NS NS All with positive nodes got 10-y DFS: 92.5% had positive lymph nodes.

RAI therapy.

LCR, 87.6% vs. 94.5%

better for

TT 1 bpCCND 362 1.9 3.3 3.6 1.7 41% of patients had positive lymph nodes, P-value NS 0.018 NS

and all had RAI therapy.

TT 103 1 27* 2.9% 1 0.5 28 11

TT 282 NR 129 13.1 0.7 1.1 28 11

TT 390 1.7 Overall, 3.8 1 0.8 Overall, 86%

TT 1 ipCCND 82 1.5 25 3.7 2.4 0.6 65 54.9% of patients P-value NS NS NS

vs. 98%; P 5 0.03

114 mo

Conzo et al, 154

Lang et al, 141

Barczynski et al, 142

2004–2010

1993–1997 and

1997–2002

1998–2005

S E C T I O N I | T H Y R O I D

TT 1 bpCCND 65 1.7 3.1 10.7 0 100% 26.2% of patients lymph nodes. P-value NS NS NS TT 478 1 67.4 1.5 2.3 1.5 44 11 had positive

TT 1 ibpCCND 102 1.5 80.2 3.9 11.8 5.9 56 67.2% of patients lymph nodes. P-value 0.001 NS 0.001 0.02 Raffaelli et al, 163 2008–2010 TT 62 1.2 25.5 0 0 0 NR 11 had positive

TT 1 ipCCND 62 1.2 8.5 1 0 1 42% of patients had positive TT 1 bpCCND 62 1.4 25 0 1 0

lymph nodes.

Patients with high risk

received RAI therapy.

Grade of

Evidence and Comments

2.1 4.5 0 88% 11

P-value NS NS NS RLN, recurrent laryngeal nerve; RAI, radioactive iodine; TT, total thyroidectomy; CCND, central compartment neck dissection; bpCCND, bilateral prophylactic CCND; ibpCCND, ipsilateral bilateral prophylactic CCND; ipCCND, ipsilateral prophylactic CCND; NR, not recorded; NS, not significant; DFS, disease-free survival; ETE, extrathyroidal extension; ipsi, ipsilateral; RFS, relapse-free survival; LCR, local control rate. Grades: 11 low; 111 moderate. *Median. † The overall rate of reoperations was not significantly different, but the central compartment reoperation rate was higher with TT (6.5% vs. 1.5%: P-value 5 0.004).

Permanent (%) RAI Use

RLN,

Hypoparathyroidism, Permanent (%)

Recurrence Rate (%)

Follow-up (mo)

100 mo

Mean

TT 220 1.6* Overall,

Tumor Size (cm)

Mean

Author, Years of Trial Procedure TABLE 2-1 Selected Retrospective Studies Comparing Total Thyroidectomy with or without Prophylactic Central Compartment Neck Dissection (continued) No. of Patients Calo et al, 160 2002–2010 Ywata de Carvalho et al, 164 1996–2007

C H A P T E R 2 | Oncologic Components of Lymphadenectomy

TABLE 2-2 Locoregional Recurrence Rate (Central or Lateral Compartment) from Meta-analyses

Locoregional Recurrence (%)

No. of Patients

Meta-analysis

TT 1 pCCND TT

Difference in LRR

Zetoune et al, 157 2010

161

713

5.6

5.5

Wang et al, 158 2013

745

995

4.7

7.9

Lang et al, 137 2013

1,592

1,739

4.7

8.6

Total

2,498

3,447

5.0*

7.3*

—

TT, total thyroidectomy; CCND, central compartment neck dissection; pCCND, prophylactic CCND; LRR, locoregional recurrence; NS, not significant; SS, statistically significant. *Mean.

of 15%, an expected ablation success and clinical remission rate of 85%, and a power of 90%. Adequate power required 98 patients per treatment group. The study enrolled 181 consecutive patients with PTC. All patients received total thyroidectomy (TT) and were randomly assigned to undergo bilateral pCCND (TT 1 bpCCND) or not (TT). Inclusion criteria were (1) PTC documented by FNA, (2) no evidence of lymph node metastases (cN0) at cervical ultrasonography or physical examination, (3) no clinical evidence of distant metastases at diagnosis, and (4) age of at least 18 years. Patients with lymph node metastases identified during thyroidectomy were excluded. Primary end points were the successful ablation rate and the incidence of persistent or recurrent disease after 5 years of follow-up. The secondary end points were the rate of surgical complications in the two groups and the effect of bilateral pCCND on the staging of PTC. The mean tumor size was 1.6 cm for both groups, and the median follow-up was 60 months (range, 41 to 71 months). Of the 93 patients who under- went TT 1 bpCCND, 43 (46%) had occult lymph node metastases (pN1a). Among 88 patients who underwent TT alone, six (6.8%) had lymph node metastases inci- dentally removed in the perithyroidal soft tissue. The rate of biochemical or persistent structural disease was 7.5% (TT 1 bpCCND) and 8% (TT) ( P 5 0.9). Patients were considered disease-free when, after recombinant thyroid-stimulating hormone admin- istration, serum thyroglobulin levels were , 1 ng/mL, a study by cervical ultrasound was normal, and thyroglobulin antibodies were undetectable. In those without RAI ablation, disease-free status was defined as a cervical ultrasound study with normal findings and undetectable/stable levels of serum thyroglobulin and thyroglobulin an- tibodies. However, significantly more patients with TT alone (17.4% vs. 3.4%, P 5 0.002) required more than one course of RAI. With respect to postoperative com- plications, a significantly higher prevalence of permanent hypoparathyroidism was observed in the TT than in the TT 1 bpCCND group (19.4% vs 8%, P 5 0.02). As a whole, the authors concluded that there were no clinical advantages in performing bilateral pCCND in patients with cN0 preoperatively.

S E C T I O N I | T H Y R O I D

Eleven retrospective studies comparing TT with TT 1 pCCND (either ipsilateral or bilateral) were selected and are summarized in Table 2-1. The incidence of oc- cult lymph node metastases among patients with pCCND ranged from 26% to 82% (mean, 49%). Overall, the incidence of locoregional recurrence ranged from 1.5% to 19% (mean, 6.2%) and 3.1% to 14% (mean, 4.7%) in the TT and TT 1 pCCND groups, respectively. However, the majority of the retrospective studies have relatively short ( , 5 years) follow-up. Of the large retrospective studies, the one with the longest mean follow-up (129 months) reported improved 10-year local control and disease- free survival for patients who underwent pCCND, noting significant improvement over TT alone. Overall, the proportion of patients receiving RAI therapy was higher in patients undergoing pCCND. Furthermore, the rates of temporary hypocalcemia were significantly higher in patients undergoing pCCND, whereas the rates of perma- nent hypoparathyroidism and RLN palsy were generally equal. 142 The locoregional recurrence rates reported by three meta-analyses, which evalu- ated the use of pCCND in clinically node-negative PTC, are included in Table 2-2. Two meta-analyses showed no statistically significant differences in the overall rate of lymph node recurrence when comparing TT 1 pCCND with TT alone in patients with PTC. In the study by Wang et al, 158 the authors found that the number of patients needed to treat with pCCND to prevent one locoregional recurrence was 31. The study by Lang et al 137 showed that patients who underwent TT with pCCND were more likely to have postoperative RAI ablation, temporary hypocalcemia, and a lower risk of locoregional recurrence than were those who had TT alone (35% reduction in risk of recurrence). 137 The authors cautioned that it was unclear how much of the risk reduction in recurrence is related to the increased use of RAI therapy and cited the potential selection bias in some of the studies examined. SUMMARY When pCCND is performed, metastatic lymph nodes are found in nearly 50% of patients with cN0 disease. With relatively short follow-up ( , 5 years), locoregional re- currence rates are similar in patients who do not undergo pCCND and those who do. Furthermore, when pCCND is performed in specialized centers, rates of permanent hypoparathyroidism and recurrent laryngeal nerve injury appear to be similar between groups. Because of the discovery of micrometastatic lymphadenopathy, pCCND leads to upstaging of PTC, and an increase in the use of RAI therapy when metastatic lymph nodes are identified is noticeable. Therefore, it may be reasonable to offer pCCND to patients with PTC if the information will change practice. Whether the added knowl- edge afforded by pCCND regarding the presence or absence of microscopic disease in the regional lymph nodes will lead to future modulations in the use of RAI therapy cannot be answered at this time. The use of RAI therapy appears to be universal when metastatic lymph nodes are found and appears to occur regardless of whether the lymph node metastases are occult and microscopic or not. Lack of consensus and multidisciplinary decision-making coupled with poor understanding regarding the biology of the disease contributes to the use (or abuse) of RAI in PTC. 149,167 With the publication of the most recent American Thyroid Association guidelines, 42 which

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