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Locally advanced differentiated thyroid cancer
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Surgical Oncology 12 (2003) 91–99
Locally advanced differentiated thyroid cancer Electron Kebebew*, Orlo H. Clark Department of Surgery, University of California, San Francisco, UCSF/Mount Zion Medical Center, 513 Parnassus, S-343, San Francisco, CA 94143-1674, USA
Abstract Although most patients with differentiated thyroid cancer (DTC) of follicular cell origin enjoy a relatively good prognosis, some patients unfortunately present with or develop locally advanced DTC which leads to significant local morbidity and mortality. DTC accounts for 54–94% of all locally advanced thyroid cancers. DTC invasion of the recurrent laryngeal nerve, strap muscles and trachea are the most common followed by invasion of the esophagus, internal jugular vein and carotid artery. Surgical resection is the primary treatment for locally advanced DTC. Although the optimal surgical approach (ranging from conservative shave excision to aggressive en bloc resection of tumor and vital structures) in patients with locally advanced DTC is controversial, a curative resection should be the goal unless complete tumor resection results in unwanted perioperative morbidity and mortality or widely metastatic disease is present. Postoperative radioiodine ablation with TSH suppression is imperative after surgical resection of locally advanced DTC. Patients with microscopic or small gross residual disease, after surgical resection, may benefit from postoperative external radiotherapy for local control of disease. r 2003 Elsevier Ltd. All rights reserved.
1. Introduction Although most patients with differentiated thyroid cancer (DTC) have a relatively good prognosis, some patients present with locally advanced DTC. Up to 22% of patients with DTC have direct tumor extension with invasion of surrounding tissue [1,2]. The presence of extrathyroidal invasion is one of the main risk factors for developing DTC recurrence and mortality from DTC [3]. Most individuals who die from DTC have significant local complications from locally advanced disease such as airway obstruction, vascular invasion and hemorrhage [4]. Locally advanced DTC may involve the central neck, lateral neck and/or mediastinum by direct tumor invasion or by lymphatic invasion. The presence of extrathyroidal invasion and extracapsular lymph node metastasis (locally advanced DTC) in patients with DTC is associated with a higher risk of aerodigestive invasion than in patients with intrathyroidal DTC and no lymph node metastasis [1,5]. In fact, patients with invasive DTC involving more than four adjacent structures have a uniformly lethal clinical course [1]. Locally advanced DTC most commonly occurs in patients who present with recurrent DTC, extensive *Corresponding author. Tel.: +1-415-885-3617; fax: +1-415-8857617. E-mail address: [email protected] (E. Kebebew). 0960-7404/03/$ - see front matter r 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0960-7404(03)00032-X
nodal metastasis and distant metastasis [6–10]. Surgical resection is the primary treatment in patients with locally advanced DTC. Postoperative radioiodine ablation with thyroid hormone for TSH suppression is also imperative after surgical resection in order to decrease the risk of recurrence and improve survival [3]. Rarely, when there has been incomplete resection or positive margins after surgical resection, external radiotherapy may be useful [11]. The optimal surgical approach for locally advanced DTC is controversial. Some experts support a ‘‘shave’’ resection whereas others advocate an en bloc resection of involved structures when technically feasible [8,12]. Because locally advanced DTC can involve vital structures such as the laryngotracheal tree, esophagus and carotid artery, the trade-off of achieving a complete resection with negative margins at the expense of significant perioperative or long-term morbidity and mortality is unclear. In this article, the presentation and work up of patients with locally advanced DTC is discussed as well as the different surgical approaches and adjuvant therapy that may be utilized in managing these patients with a difficult problem.
2. Clinical features and preoperative evaluation Most patients who present with locally advanced DTC have clinical evidence of a palpable neck mass in
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the central or lateral neck compartments (Fig. 1A). Although locally advanced DTC is infrequent, a high index of suspicion is necessary to identify such patients preoperatively, which allows for planning of the optimal surgical approach. In patients with locally advanced DTC, the neck mass is often hard on palpation and fixed to surrounding structures. Although, in general, DTC is more common in women, locally advanced DTC is more common in men [12,13]. Most patients will complain of neck pain and/or stiffness but rarely otodynia [14]. When patients have voice fatigue or hoarseness this usually indicates involvement of the recurrent laryngeal nerve(s). Patients may also have dysphagia, cough, hemoptysis, and a recent episode of pneumonia or even frank stridor [6,7,10,15–21]. This usually indicates laryngotracheal involvement. The presence of dysphagia may be due to esophageal invasion or extrinsic
(A)
compression. Some patients with locally advanced DTC may have no local symptoms [12]. In addition to fine-needle aspiration (FNA) cytology of the patient’s neck mass to determine the diagnosis, patients with locally advanced DTC or any change in their voice should have direct laryngoscopy to evaluate their vocal cord function. We recommend preoperative direct laryngoscopy in all patients undergoing cervical or mediastinal reoperation for recurrent DTC regardless of the presence or absence of local symptoms. When laryngotracheal or esophageal invasion is suspected, a bronchoscopy and esophagoscopy should be performed to determine if intraluminal invasion is present. Neck and chest imaging with a CT scan or an MRI should be obtained preoperatively in all patients with locally advanced DTC (Fig. 1B). These imaging studies are useful for defining the extent of disease in the neck and mediastinum and identifying involved surrounding structures (Fig. 2). The risk of distant DTC metastasis is higher in patients with locally invasive DTC [22]. Therefore, these patients should have a work up for metastatic disease before considering surgical resection. The most common sites of DTC metastases are to the lung and bone and less frequently to the liver and brain [23,24]. When the tumor traps radioiodine, whole body radioiodine scanning with 131-I is best for detecting possible sites of tumor metastases. In patients who have positive serum thyroglobulin levels but negative radioiodine scans, PET scanning may be useful for identifying metastatic disease instead of obtaining multiple imaging studies (CT and MRI scanning of the chest and abdomen and bone scan) [25,26]. Furthermore, patients with poorly differentiated thyroid cancer whose tumors do not take up radioiodine are more likely to be PET scan positive [25]. As previously stated, most locally advanced DTC occur in patients with recurrent DTC or widely
(B) Fig. 1. Locally advanced DTC. (A) A 61-year-old man who had delayed presentation for an exophytic, fungating locally advanced poorly DTC involving his left neck. (B) CT scan of the neck in this patient demonstrates encasement of the left carotid artery and internal jugular vein with thrombosis.
Fig. 2. In a 84-year-old woman with recurrent DTC, CT scan demonstrates tumor in the central neck extending into the mediastinum with bulky lymph node metastases and tracheal deviation to the left.
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metastatic DTC. About one-third of patients with recurrent DTC have dedifferentiated tumors [27]. Children with DTC may present with locally advanced DTC as well as patients with tall cell, diffuse sclerosing and columnar variants of papillary thyroid cancer and Hurthle . cell carcinoma [3]. In this review, locally advanced DTC refers to thyroid cancers of follicular cell origin (papillary, its histological variants, follicular and Hurthle . cell) which invade local surrounding structures. In patients with locally advanced DTC, the most commonly involved structures in the central neck are the recurrent laryngeal nerve, laryngotracheal tree, esophagus and strap muscles [1,2,5,6,10,12– 14,17,19,28]. In the lateral neck compartment, locally advanced DTC either by direct tumor extension from a primary thyroid tumor or extracapsular invasion from lymph node metastasis invade the carotid artery, internal jugular vein, nerves (e.g. vagus, spinal accessory and phrenic) and sternocleidomastoid muscle [29–32]. Some patients with aggressive DTC may also have mediastinal extension of tumor or extranodal extension of tumor that invades the thoracic trachea and/or esophagus as well as the sternum and great vessels [5,14,19,22,30,31,33].
3. Invasive DTC in the central neck 3.1. Recurrent laryngeal nerve invasion The recurrent laryngeal nerve is the most commonly involved structure in patients with locally invasive DTC [1,5,6,10,13,14,28,34]. Recurrent laryngeal nerve palsy occurs as a result of direct primary tumor extension or from involved tracheoesophageal lymph nodes. Patients with recurrent laryngeal nerve palsy due to tumor invasion usually have dysphonia or voice fatigue [3,12,14]. Some patient may also have stridor due to recurrent laryngeal nerve palsy but it may also occur in patients with airway tumor invasion. Direct laryngoscopy to assess vocal cord function is imperative and helps determine if the unilateral recurrent laryngeal nerve can be resected at the time of surgical exploration. If the patient does or is suspected to have recurrent laryngeal nerve palsy, a preoperative CT scan or MRI imaging of the neck is useful for determining the extent of local disease. However, if the vocal cord is functioning, the nerve should almost always be preserved during tumor resection. Concern for leaving microscopic disease should not lead to nerve resection because leaving microscopic DTC on the recurrent laryngeal nerve does not lead to decreased survival or increased loco-regional recurrence as compared to resection of the nerve [12,34,35]. Patients with microscopic disease involving the recurrent laryngeal nerve after resection of the tumor should have postoperative radioiodine
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ablation and TSH suppression with thyroid hormone. External radiotherapy may be also used if the tumor does not trap radioiodine but it is unclear if this approach leads to improved survival or decreased risk of recurrence in patients with DTC [11,36]. When there is a recurrent laryngeal nerve palsy on the side of the DTC, en bloc resection with the nerve should be done. Patients with unilateral vocal cord palsy should have medialization of the involved vocal cord when the contralateral vocal cord is functioning. Patients with bilateral vocal cord paresis from invasive DTC or after an operation often require a tracheostomy. 3.2. Muscle invasion Direct tumor invasion into the strap muscles is common because of the close relationship of the thyroid gland to the strap muscles [2,11,13,28,35–37]. When DTC tracheal invasion is present, up to 70% of these patients have strap muscle invasion [2]. Patients who have strap muscle invasion from recurrent and metastatic DTC have a higher risk of distant metastasis and a worse prognosis [2,22]. However, isolated strap muscle invasion by DTC does not necessarily portend a worse prognosis [35,37]. When the strap muscles (sternohyoid, sternothyroid, thyrohyoid and omohyoid) are invaded with DTC, the involved portion may be resection with the tumor to obtain negative margins. This approach does not result in any morbidity. 3.3. Laryngotracheal invasion Invasion of the laryngotrachea by DTC commonly results from direct tumor extension (Fig. 3). A pathologic staging system for depth of tracheal wall invasion has been proposed and those patients with complete tumor invasion into the mucosa have a worse prognosis than patients with incomplete tracheal wall invasion [38]. When determining the resectability of DTC involving the laryngotracheal tree, several considerations should be taken into account and include (1) longitudinal extent and laterality of DTC involvement, (2) depth of DTC invasion into the tracheal wall, (3) level of invasion (cervical versus mediastinum, trachea, cricoid, thyroid cartilage or larynx), and (4) associated structures involved by the tumor (Fig. 3). Depending on the extent of DTC local invasion, a limited ‘‘shave’’ resection (tumor debulking) to complete en bloc resection have been used to successfully treat patients with invasive DTC involving the laryngotrachea [1,4,5,8,13,14,18–21,35,39–45]. Shave resection of all gross tumor involving the trachea and larynx is possible when DTC is not infiltrating the tracheal perichondrium [8,12,20,39–41]. Several investigators have demonstrated that this approach has a lower morbidity and similar survival rates when compared to en bloc resection
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be considered in patients with laryngotracheal invasion from DTC depending on the extent of disease and local structures involved. Complete circumferential tracheal resection can be accomplished of up to six tracheal rings with preservation of the voice. First, the recurrent laryngeal nerves are dissected free from the tumor and trachea. The trachea is then mobilized from within the mediastinum and by dividing the thyroid muscles above the thyroid cartilage. The tumor involved trachea is then resected and a primary anastomosis performed. A penrose drain is placed near the anastamosis in case there is an air leak. 3.4. Esophageal invasion (A)
(B) Fig. 3. Locally advanced DTC involving the trachea. (A) CT scan demonstrates left tracheal wall invasion (arrow) by DTC in a patient with locally advanced DTC. (B) MRI of the neck with reconstruction demonstrates cervical tracheal invasion (arrow) in a patient with DTC recurrence.
[2,12,13,35,42]. In patients who have laryngotracheal wall invasion, shave resection may be associated with a higher recurrence rate than extended resection [6,17,18,28,41]. Some small retrospective studies comparing shave resection to extended resection (en bloc) in patients with tracheal wall invasion have documented improved survival rates in patients who had an extended resection [6,17,18,28,41]. It is unclear if shave resection with postoperative radioiodine ablation and/or external radiation therapy is clearly associated with a higher recurrence rate and worse prognosis as compared to aggressive resection with airway reconstruction, because studies comparing these surgical approaches have had small study cohorts, the extent of disease was different among patients with DTC, different surgical techniques were used and a retrospective, non-randomized or unmatched cohorts were compared. Listed in Table 1 are the different types of surgical approaches that may
Esophageal invasion by DTC is usually associated with tracheal invasion as is pharyngeal invasion with laryngeal invasion. DTC invasion of the esophagus is usually confined to the muscularis without extension into the submucosa or mucosa layers [6,12]. Dysphagia or odynophagia occurs as a result of direct DTC invasion of the esophagus or as a result of extrinsic compression in association with laryngotracheal invasion [6,10,12,19,39]. The presence of concurrent tracheoesophageal DTC invasion is associated with a grim prognosis as is isolated esophageal invasion [2,35]. In addition to CT scanning and MR imaging, barium esophagram demonstrates any esophageal stricture and the level of esophageal narrowing. Esophagoscopy also helps determine if there is intraluminal invasion, the level of narrowing and allows for tissue biopsy to confirm DTC invasion [39,43]. As with laryngotracheal invasion, shave resection to en bloc resection has been used for DTC involving the esophagus. Placement of an esophageal tube helps to facilitate the resection of DTC involving the esophagus [40]. If there is a partial esophageal invasion, a portion of the muscular layer, to obtain clear margins, can be resected without repair when the submucosa is intact. For patients with full-thickness or circumferential esophageal wall DTC invasion, a segmental or partial full-thickness resection with reconstruction using a myocutaneous, myofascial flap or primary anastamosis may be used [6,12,19,40]. In patients with DTC invading a long segment of esophagus, mobilization of the distal and proximal esophagus may be necessary or a jejunal free flap or gastroplasty may be used [43]. A colonic interposition graft is also an alternative approach if an esophagectomy can be done for DTC invading a long segment of esophagus [6]. If esophageal resection cannot be done because of extensive involvement of the esophagus with DTC, patients with symptomatic esophageal strictures may be palliated with dilation or stent placement [20]. External radiation may also provide palliation in nonoperable candidates.
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Table 1 Surgical approaches to DTC involving the laryngotrachea Surgical approach
Indication(s)
Definition
Comments
Shave excision
Tumor adherent to trachea/ perichondrium
Gross tumor removed without resecting adjacent structures
Avoids morbidity of extended resection, results similar to extended resection
Window resection
Unilateral invasion of laryngotrachea—superficial/ causing airway obstruction
Partial tracheal/laryngeal resection
o1/3 cricoid/trachea circumference may be resected without reconstruction Larger defects require flap coverage Up to 2.5 cm in length may be resection
Vertical hemilaryngectomy
Extensive unilateral invasion of trachea/larynx
Resection of larynx (cricoid/ thyroid cartilage)
Goal is to preserve speech and swallowing Closure with muscular or myocutaneous flaps
Circumferential tracheal resection
Tracheal invasion >60% of circumferene or length up to six tracheal rings
Tracheal resection required when bilateral involvement of trachea or more than two-thirds defect is created
Thyrotracheal and cricotracheal anastomosis possible
‘‘Step’’ resection is a variant of tracheal resection (laryngotracheal resection) Can be staged to reduce risk of perioperative complications Total laryngopharyngectomy/ total laryngectomy
Tumor invading the posterior trachea not allowing preservation of any laryngeal function
4. Invasive DTC in the lateral neck compartment 4.1. Vascular invasion The carotid artery is rarely invaded by advanced DTC whereas the internal jugular vein is frequently involved by poorly DTC. Limited data exist in the literature that compares surgical approaches in patients with DTC invasion of the lateral neck vascular structures [29–32, 46]. In most cases, although there is no clear direct vascular invasion of the lateral neck vascular structure, bulky extranodal extension of DTC lymph node metastasis are intimately adherent to these structures and require preoperative planning for vascular control and/or possible arterial reconstruction or venous ligation (Fig. 1B). As mentioned, internal jugular vein invasion with tumor thrombus is more common than carotid artery invasion [2,19,28,35,37]. A tumor thrombus extending to the superior vena cava and heart may lead to superior vena cava syndrome and sudden death from pulmonary embolus [33,46]. Superior vena cava syndrome in patients with advanced DTC is more common from extrinsic tumor compression than from intraluminal tumor invasion or thrombus. Superior vena
Resection of larynx without any laryngeal function preserved
Palliative surgery for decreasing the risk of airway obstruction/ hemorrhage Does not prolong survival rate
cava syndrome should be suspected in patients with advanced DTC when a positive Pemberton’s sign is present: head and neck and upper extremity edema, dilated neck veins, collateralization of venous drainage through the chest wall veins and sometimes dyspnea. Direct DTC invasion into the internal jugular vein occurs in up to 13% of patients and is most common with follicular thyroid cancer and is associated with tracheal invasion [1]. CT scanning with intravenous contrast is useful for detecting vascular invasion (Fig. 1B) [30,31,33]. Enlarged veins associated with tumor invasion or compression and filling defects on CT scan should raise concern for venous invasion. When the carotid artery is suspected to be involved, angiography will help to evaluate the arterial anatomy if reconstruction is necessary. Although intravenous contrast is iodinated and may delay the use of postoperative radioiodine ablation, these imaging studies should be used liberally when vascular involvement is suspected in order to plan the operative approach for locally advanced DTC. DTC involving the internal jugular vein may be resected en bloc with the vein without any significant morbidity or mortality [31]. Although most patients do
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not have bilateral internal jugular vein invasion from DTC, a staged operation should be performed delaying the less involved side at least 6 weeks. First, an en bloc resection is performed with reconstruction of the internal jugular vein with autologous tissue. After a delay of about 6 weeks, enough collateral vein drainage develops and the contralateral vein with the tumor can be resected. Although graft thrombosis of the venous grafts may occur, collateral venous drainage form thereby avoiding intracranial hypertension and facial edema. DTC invasion of the superior vena cava with or without venous thrombus should not preclude operative resection [33,37,46]. Some surgeons have reported successful resection of these tumors through a median sternotomy or right thoracotomy [33,37]. Such an aggressive surgical approach has been advocated because patients with superior vena cava invasion and tumor thrombus have a risk of tumor embolism and tricuspid valve obstruction [46,47]. Removal of the tumor and thrombus may be done through a cavatomy or with segmental resection of the cava and reconstruction with autogenous, cadaveric or prosthetic grafts. When the tumor thrombus extends proximal, a catheter embolectomy has also been used successfully [30]. Cardiopulmonary bypass should be available during these procedures especially when the tumor extends into the right ventricle. Carotid artery invasion by DTC has been successfully treated with shave resection, en bloc resection and reconstruction or by simple ligation [6,8,10,19,30,41]. A balloon occlusion of the involved carotid artery should be done preoperatively to determine that sacrificing the carotid artery does not result in cerebrovascular insufficiency [32]. Shave resection should be done when possible but arterial replacement with autologous arterial grafting is recommended when the artery is invaded. 4.2. Lymphatic invasion Patients with papillary thyroid cancer frequently have lymph node metastases [3]. Extranodal tumor extension and lymph node metastases larger than 2 cm are associated with a high risk of recurrence, distant metastases and a lower survival rate [3,22,48]. These patients can usually be recognized clinically because the nodal metastases are matted together. Direct invasion from DTC lymph node metastasis in the lateral neck compartment may be associated with vascular, nerve and muscle invasion. A functional modified radical neck dissection preserving the sternocleidomastoid muscle, carotid artery, internal jugular vein, vagus nerve, spinal accessory nerve and phrenic nerve is the standard approach for patients who have lymph node metastasis at the time of initial total thyroidectomy or at reoperation for recurrent DTC [3]. The transverse
Fig. 4. Cervical and mediastinal lymph node compartments. Level I— submental and submandibular nodes, Level II—upper internal jugular chain nodes, Level III—middle internal jugular chain nodes, Level IV—lower internal jugular chain nodes, Level V—spinal accessory and transverse cervical nodes, Level VI—tracheoesophageal groove nodes and perithyroidal nodes, and Level VII—infraclavicular and upper anterior mediastinal nodes (thymic).
cervical incision is extended laterally (McFee extension) to allow access to the level II, III, IV and V lymph node compartments (Fig. 4). Placement of the Kocher transverse collar incision at the level of the cricoid cartilage makes removal of high cervical nodes (level II) easier. If level I and level II lymph node compartments are involved and cannot be reached through this incision, we recommend a transverse counter-incision just below the angle of the mandible to facilitate lymph node dissection. Some surgeons extend the transverse cervical incision superiorly for the lateral neck lymph node dissection. Occasionally, in patients with extensive DTC lymph node metastases involving level VII lymph nodes, a median sternotomy may be required to allow complete excision of the involved lymph nodes (Fig. 2) [7].
5. Adjuvant therapy Although surgery remains the most effective treatment for thyroid cancer, patients with locally advanced DTC warrant additional treatment (Fig. 5). Postoperative radioiodine treatment and thyroid hormone for TSH suppression decreases the risk of recurrence and may increase survival [3,48]. Particularly in high-risk patients with DTC, a general consensus exists that
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Neck mass
FNA
Primary/recurrent DTC
Clinical features suggesting locally advanced DTC
Yes
Neck/Chest CT/MRI scan Local invasion of trachea/esophagus/carotid?
No
Metastatic disease
Curable ^ No
Surgery
Incurable ^
Yes, metastatic workup*
Locoregional disease Surgery
Surgery
Surgery vs observation**
Fig. 5. Evaluation and management of patients with locally advanced DTC. The risk of distant DTC metastasis is higher in patients with locally invasive DTC. 4Generally surgical resection of locally advanced DTC should be done to avoid morbidity and mortality from local disease. However, if the patient has widely metastatic DTC and has no local symptoms that require palliation, observation or adjuvant therapy may be considered.
radioiodine therapy and TSH suppression are beneficial. Thus total or near-total thyroidectomy should be done so that the 131-I treatment can effectively treat metastatic disease rather than just ablate the remnant thyroid tissue. The benefit of external beam radiotherapy in patients with locally advanced DTC is unclear [11,36]. This is because all the studies evaluating adjuvant external beam radiotherapy for DTC are retrospective, the extent of disease was different in the study cohorts, and different radiation fields and doses were used [11,36]. Several investigators, however, have shown that external beam radiotherapy reduces the local recurrence rate in patients who have microscopic residual disease, age older than 45 years or locally advanced DTC [11,36,49– 51]. The use of external beam radiotherapy with adriamycin may improve responses to radiation treatment [52]. For adjuvant external beam radiotherapy, 40–50 Gy in 15–20 fractions over 3–4 weeks is recommended [11]. We recommend, after as complete a surgical resection as possible, postoperative external radiotherapy in patients with locally advanced DTC when microscopic disease or gross residual disease is present.
Several chemotherapeutic regimens, mostly doxorubicin based, have been evaluated in patients with widely metastatic DTC without any significant clinical complete response or only transient partial response [53]. Preclinical studies with a variety of agents (methyltransferase inhibitors, histone deacetylase inhibitors, PPARg agonist) show promise as potential alternative treatment agents for patients with locally advanced DTC or widely metastatic DTC [53]. In addition to their antineoplastic effect, many of these agents may have a redifferentiating effect on thyroid cells (i.e. increased iodine uptake and TSH responsiveness) which could make radioiodine treatment and TSH suppression therapy more effective.
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Surgical Oncology 12 (2003) 91–99
Locally advanced differentiated thyroid cancer Electron Kebebew*, Orlo H. Clark Department of Surgery, University of California, San Francisco, UCSF/Mount Zion Medical Center, 513 Parnassus, S-343, San Francisco, CA 94143-1674, USA
Abstract Although most patients with differentiated thyroid cancer (DTC) of follicular cell origin enjoy a relatively good prognosis, some patients unfortunately present with or develop locally advanced DTC which leads to significant local morbidity and mortality. DTC accounts for 54–94% of all locally advanced thyroid cancers. DTC invasion of the recurrent laryngeal nerve, strap muscles and trachea are the most common followed by invasion of the esophagus, internal jugular vein and carotid artery. Surgical resection is the primary treatment for locally advanced DTC. Although the optimal surgical approach (ranging from conservative shave excision to aggressive en bloc resection of tumor and vital structures) in patients with locally advanced DTC is controversial, a curative resection should be the goal unless complete tumor resection results in unwanted perioperative morbidity and mortality or widely metastatic disease is present. Postoperative radioiodine ablation with TSH suppression is imperative after surgical resection of locally advanced DTC. Patients with microscopic or small gross residual disease, after surgical resection, may benefit from postoperative external radiotherapy for local control of disease. r 2003 Elsevier Ltd. All rights reserved.
1. Introduction Although most patients with differentiated thyroid cancer (DTC) have a relatively good prognosis, some patients present with locally advanced DTC. Up to 22% of patients with DTC have direct tumor extension with invasion of surrounding tissue [1,2]. The presence of extrathyroidal invasion is one of the main risk factors for developing DTC recurrence and mortality from DTC [3]. Most individuals who die from DTC have significant local complications from locally advanced disease such as airway obstruction, vascular invasion and hemorrhage [4]. Locally advanced DTC may involve the central neck, lateral neck and/or mediastinum by direct tumor invasion or by lymphatic invasion. The presence of extrathyroidal invasion and extracapsular lymph node metastasis (locally advanced DTC) in patients with DTC is associated with a higher risk of aerodigestive invasion than in patients with intrathyroidal DTC and no lymph node metastasis [1,5]. In fact, patients with invasive DTC involving more than four adjacent structures have a uniformly lethal clinical course [1]. Locally advanced DTC most commonly occurs in patients who present with recurrent DTC, extensive *Corresponding author. Tel.: +1-415-885-3617; fax: +1-415-8857617. E-mail address: [email protected] (E. Kebebew). 0960-7404/03/$ - see front matter r 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0960-7404(03)00032-X
nodal metastasis and distant metastasis [6–10]. Surgical resection is the primary treatment in patients with locally advanced DTC. Postoperative radioiodine ablation with thyroid hormone for TSH suppression is also imperative after surgical resection in order to decrease the risk of recurrence and improve survival [3]. Rarely, when there has been incomplete resection or positive margins after surgical resection, external radiotherapy may be useful [11]. The optimal surgical approach for locally advanced DTC is controversial. Some experts support a ‘‘shave’’ resection whereas others advocate an en bloc resection of involved structures when technically feasible [8,12]. Because locally advanced DTC can involve vital structures such as the laryngotracheal tree, esophagus and carotid artery, the trade-off of achieving a complete resection with negative margins at the expense of significant perioperative or long-term morbidity and mortality is unclear. In this article, the presentation and work up of patients with locally advanced DTC is discussed as well as the different surgical approaches and adjuvant therapy that may be utilized in managing these patients with a difficult problem.
2. Clinical features and preoperative evaluation Most patients who present with locally advanced DTC have clinical evidence of a palpable neck mass in
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the central or lateral neck compartments (Fig. 1A). Although locally advanced DTC is infrequent, a high index of suspicion is necessary to identify such patients preoperatively, which allows for planning of the optimal surgical approach. In patients with locally advanced DTC, the neck mass is often hard on palpation and fixed to surrounding structures. Although, in general, DTC is more common in women, locally advanced DTC is more common in men [12,13]. Most patients will complain of neck pain and/or stiffness but rarely otodynia [14]. When patients have voice fatigue or hoarseness this usually indicates involvement of the recurrent laryngeal nerve(s). Patients may also have dysphagia, cough, hemoptysis, and a recent episode of pneumonia or even frank stridor [6,7,10,15–21]. This usually indicates laryngotracheal involvement. The presence of dysphagia may be due to esophageal invasion or extrinsic
(A)
compression. Some patients with locally advanced DTC may have no local symptoms [12]. In addition to fine-needle aspiration (FNA) cytology of the patient’s neck mass to determine the diagnosis, patients with locally advanced DTC or any change in their voice should have direct laryngoscopy to evaluate their vocal cord function. We recommend preoperative direct laryngoscopy in all patients undergoing cervical or mediastinal reoperation for recurrent DTC regardless of the presence or absence of local symptoms. When laryngotracheal or esophageal invasion is suspected, a bronchoscopy and esophagoscopy should be performed to determine if intraluminal invasion is present. Neck and chest imaging with a CT scan or an MRI should be obtained preoperatively in all patients with locally advanced DTC (Fig. 1B). These imaging studies are useful for defining the extent of disease in the neck and mediastinum and identifying involved surrounding structures (Fig. 2). The risk of distant DTC metastasis is higher in patients with locally invasive DTC [22]. Therefore, these patients should have a work up for metastatic disease before considering surgical resection. The most common sites of DTC metastases are to the lung and bone and less frequently to the liver and brain [23,24]. When the tumor traps radioiodine, whole body radioiodine scanning with 131-I is best for detecting possible sites of tumor metastases. In patients who have positive serum thyroglobulin levels but negative radioiodine scans, PET scanning may be useful for identifying metastatic disease instead of obtaining multiple imaging studies (CT and MRI scanning of the chest and abdomen and bone scan) [25,26]. Furthermore, patients with poorly differentiated thyroid cancer whose tumors do not take up radioiodine are more likely to be PET scan positive [25]. As previously stated, most locally advanced DTC occur in patients with recurrent DTC or widely
(B) Fig. 1. Locally advanced DTC. (A) A 61-year-old man who had delayed presentation for an exophytic, fungating locally advanced poorly DTC involving his left neck. (B) CT scan of the neck in this patient demonstrates encasement of the left carotid artery and internal jugular vein with thrombosis.
Fig. 2. In a 84-year-old woman with recurrent DTC, CT scan demonstrates tumor in the central neck extending into the mediastinum with bulky lymph node metastases and tracheal deviation to the left.
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metastatic DTC. About one-third of patients with recurrent DTC have dedifferentiated tumors [27]. Children with DTC may present with locally advanced DTC as well as patients with tall cell, diffuse sclerosing and columnar variants of papillary thyroid cancer and Hurthle . cell carcinoma [3]. In this review, locally advanced DTC refers to thyroid cancers of follicular cell origin (papillary, its histological variants, follicular and Hurthle . cell) which invade local surrounding structures. In patients with locally advanced DTC, the most commonly involved structures in the central neck are the recurrent laryngeal nerve, laryngotracheal tree, esophagus and strap muscles [1,2,5,6,10,12– 14,17,19,28]. In the lateral neck compartment, locally advanced DTC either by direct tumor extension from a primary thyroid tumor or extracapsular invasion from lymph node metastasis invade the carotid artery, internal jugular vein, nerves (e.g. vagus, spinal accessory and phrenic) and sternocleidomastoid muscle [29–32]. Some patients with aggressive DTC may also have mediastinal extension of tumor or extranodal extension of tumor that invades the thoracic trachea and/or esophagus as well as the sternum and great vessels [5,14,19,22,30,31,33].
3. Invasive DTC in the central neck 3.1. Recurrent laryngeal nerve invasion The recurrent laryngeal nerve is the most commonly involved structure in patients with locally invasive DTC [1,5,6,10,13,14,28,34]. Recurrent laryngeal nerve palsy occurs as a result of direct primary tumor extension or from involved tracheoesophageal lymph nodes. Patients with recurrent laryngeal nerve palsy due to tumor invasion usually have dysphonia or voice fatigue [3,12,14]. Some patient may also have stridor due to recurrent laryngeal nerve palsy but it may also occur in patients with airway tumor invasion. Direct laryngoscopy to assess vocal cord function is imperative and helps determine if the unilateral recurrent laryngeal nerve can be resected at the time of surgical exploration. If the patient does or is suspected to have recurrent laryngeal nerve palsy, a preoperative CT scan or MRI imaging of the neck is useful for determining the extent of local disease. However, if the vocal cord is functioning, the nerve should almost always be preserved during tumor resection. Concern for leaving microscopic disease should not lead to nerve resection because leaving microscopic DTC on the recurrent laryngeal nerve does not lead to decreased survival or increased loco-regional recurrence as compared to resection of the nerve [12,34,35]. Patients with microscopic disease involving the recurrent laryngeal nerve after resection of the tumor should have postoperative radioiodine
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ablation and TSH suppression with thyroid hormone. External radiotherapy may be also used if the tumor does not trap radioiodine but it is unclear if this approach leads to improved survival or decreased risk of recurrence in patients with DTC [11,36]. When there is a recurrent laryngeal nerve palsy on the side of the DTC, en bloc resection with the nerve should be done. Patients with unilateral vocal cord palsy should have medialization of the involved vocal cord when the contralateral vocal cord is functioning. Patients with bilateral vocal cord paresis from invasive DTC or after an operation often require a tracheostomy. 3.2. Muscle invasion Direct tumor invasion into the strap muscles is common because of the close relationship of the thyroid gland to the strap muscles [2,11,13,28,35–37]. When DTC tracheal invasion is present, up to 70% of these patients have strap muscle invasion [2]. Patients who have strap muscle invasion from recurrent and metastatic DTC have a higher risk of distant metastasis and a worse prognosis [2,22]. However, isolated strap muscle invasion by DTC does not necessarily portend a worse prognosis [35,37]. When the strap muscles (sternohyoid, sternothyroid, thyrohyoid and omohyoid) are invaded with DTC, the involved portion may be resection with the tumor to obtain negative margins. This approach does not result in any morbidity. 3.3. Laryngotracheal invasion Invasion of the laryngotrachea by DTC commonly results from direct tumor extension (Fig. 3). A pathologic staging system for depth of tracheal wall invasion has been proposed and those patients with complete tumor invasion into the mucosa have a worse prognosis than patients with incomplete tracheal wall invasion [38]. When determining the resectability of DTC involving the laryngotracheal tree, several considerations should be taken into account and include (1) longitudinal extent and laterality of DTC involvement, (2) depth of DTC invasion into the tracheal wall, (3) level of invasion (cervical versus mediastinum, trachea, cricoid, thyroid cartilage or larynx), and (4) associated structures involved by the tumor (Fig. 3). Depending on the extent of DTC local invasion, a limited ‘‘shave’’ resection (tumor debulking) to complete en bloc resection have been used to successfully treat patients with invasive DTC involving the laryngotrachea [1,4,5,8,13,14,18–21,35,39–45]. Shave resection of all gross tumor involving the trachea and larynx is possible when DTC is not infiltrating the tracheal perichondrium [8,12,20,39–41]. Several investigators have demonstrated that this approach has a lower morbidity and similar survival rates when compared to en bloc resection
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be considered in patients with laryngotracheal invasion from DTC depending on the extent of disease and local structures involved. Complete circumferential tracheal resection can be accomplished of up to six tracheal rings with preservation of the voice. First, the recurrent laryngeal nerves are dissected free from the tumor and trachea. The trachea is then mobilized from within the mediastinum and by dividing the thyroid muscles above the thyroid cartilage. The tumor involved trachea is then resected and a primary anastomosis performed. A penrose drain is placed near the anastamosis in case there is an air leak. 3.4. Esophageal invasion (A)
(B) Fig. 3. Locally advanced DTC involving the trachea. (A) CT scan demonstrates left tracheal wall invasion (arrow) by DTC in a patient with locally advanced DTC. (B) MRI of the neck with reconstruction demonstrates cervical tracheal invasion (arrow) in a patient with DTC recurrence.
[2,12,13,35,42]. In patients who have laryngotracheal wall invasion, shave resection may be associated with a higher recurrence rate than extended resection [6,17,18,28,41]. Some small retrospective studies comparing shave resection to extended resection (en bloc) in patients with tracheal wall invasion have documented improved survival rates in patients who had an extended resection [6,17,18,28,41]. It is unclear if shave resection with postoperative radioiodine ablation and/or external radiation therapy is clearly associated with a higher recurrence rate and worse prognosis as compared to aggressive resection with airway reconstruction, because studies comparing these surgical approaches have had small study cohorts, the extent of disease was different among patients with DTC, different surgical techniques were used and a retrospective, non-randomized or unmatched cohorts were compared. Listed in Table 1 are the different types of surgical approaches that may
Esophageal invasion by DTC is usually associated with tracheal invasion as is pharyngeal invasion with laryngeal invasion. DTC invasion of the esophagus is usually confined to the muscularis without extension into the submucosa or mucosa layers [6,12]. Dysphagia or odynophagia occurs as a result of direct DTC invasion of the esophagus or as a result of extrinsic compression in association with laryngotracheal invasion [6,10,12,19,39]. The presence of concurrent tracheoesophageal DTC invasion is associated with a grim prognosis as is isolated esophageal invasion [2,35]. In addition to CT scanning and MR imaging, barium esophagram demonstrates any esophageal stricture and the level of esophageal narrowing. Esophagoscopy also helps determine if there is intraluminal invasion, the level of narrowing and allows for tissue biopsy to confirm DTC invasion [39,43]. As with laryngotracheal invasion, shave resection to en bloc resection has been used for DTC involving the esophagus. Placement of an esophageal tube helps to facilitate the resection of DTC involving the esophagus [40]. If there is a partial esophageal invasion, a portion of the muscular layer, to obtain clear margins, can be resected without repair when the submucosa is intact. For patients with full-thickness or circumferential esophageal wall DTC invasion, a segmental or partial full-thickness resection with reconstruction using a myocutaneous, myofascial flap or primary anastamosis may be used [6,12,19,40]. In patients with DTC invading a long segment of esophagus, mobilization of the distal and proximal esophagus may be necessary or a jejunal free flap or gastroplasty may be used [43]. A colonic interposition graft is also an alternative approach if an esophagectomy can be done for DTC invading a long segment of esophagus [6]. If esophageal resection cannot be done because of extensive involvement of the esophagus with DTC, patients with symptomatic esophageal strictures may be palliated with dilation or stent placement [20]. External radiation may also provide palliation in nonoperable candidates.
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Table 1 Surgical approaches to DTC involving the laryngotrachea Surgical approach
Indication(s)
Definition
Comments
Shave excision
Tumor adherent to trachea/ perichondrium
Gross tumor removed without resecting adjacent structures
Avoids morbidity of extended resection, results similar to extended resection
Window resection
Unilateral invasion of laryngotrachea—superficial/ causing airway obstruction
Partial tracheal/laryngeal resection
o1/3 cricoid/trachea circumference may be resected without reconstruction Larger defects require flap coverage Up to 2.5 cm in length may be resection
Vertical hemilaryngectomy
Extensive unilateral invasion of trachea/larynx
Resection of larynx (cricoid/ thyroid cartilage)
Goal is to preserve speech and swallowing Closure with muscular or myocutaneous flaps
Circumferential tracheal resection
Tracheal invasion >60% of circumferene or length up to six tracheal rings
Tracheal resection required when bilateral involvement of trachea or more than two-thirds defect is created
Thyrotracheal and cricotracheal anastomosis possible
‘‘Step’’ resection is a variant of tracheal resection (laryngotracheal resection) Can be staged to reduce risk of perioperative complications Total laryngopharyngectomy/ total laryngectomy
Tumor invading the posterior trachea not allowing preservation of any laryngeal function
4. Invasive DTC in the lateral neck compartment 4.1. Vascular invasion The carotid artery is rarely invaded by advanced DTC whereas the internal jugular vein is frequently involved by poorly DTC. Limited data exist in the literature that compares surgical approaches in patients with DTC invasion of the lateral neck vascular structures [29–32, 46]. In most cases, although there is no clear direct vascular invasion of the lateral neck vascular structure, bulky extranodal extension of DTC lymph node metastasis are intimately adherent to these structures and require preoperative planning for vascular control and/or possible arterial reconstruction or venous ligation (Fig. 1B). As mentioned, internal jugular vein invasion with tumor thrombus is more common than carotid artery invasion [2,19,28,35,37]. A tumor thrombus extending to the superior vena cava and heart may lead to superior vena cava syndrome and sudden death from pulmonary embolus [33,46]. Superior vena cava syndrome in patients with advanced DTC is more common from extrinsic tumor compression than from intraluminal tumor invasion or thrombus. Superior vena
Resection of larynx without any laryngeal function preserved
Palliative surgery for decreasing the risk of airway obstruction/ hemorrhage Does not prolong survival rate
cava syndrome should be suspected in patients with advanced DTC when a positive Pemberton’s sign is present: head and neck and upper extremity edema, dilated neck veins, collateralization of venous drainage through the chest wall veins and sometimes dyspnea. Direct DTC invasion into the internal jugular vein occurs in up to 13% of patients and is most common with follicular thyroid cancer and is associated with tracheal invasion [1]. CT scanning with intravenous contrast is useful for detecting vascular invasion (Fig. 1B) [30,31,33]. Enlarged veins associated with tumor invasion or compression and filling defects on CT scan should raise concern for venous invasion. When the carotid artery is suspected to be involved, angiography will help to evaluate the arterial anatomy if reconstruction is necessary. Although intravenous contrast is iodinated and may delay the use of postoperative radioiodine ablation, these imaging studies should be used liberally when vascular involvement is suspected in order to plan the operative approach for locally advanced DTC. DTC involving the internal jugular vein may be resected en bloc with the vein without any significant morbidity or mortality [31]. Although most patients do
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not have bilateral internal jugular vein invasion from DTC, a staged operation should be performed delaying the less involved side at least 6 weeks. First, an en bloc resection is performed with reconstruction of the internal jugular vein with autologous tissue. After a delay of about 6 weeks, enough collateral vein drainage develops and the contralateral vein with the tumor can be resected. Although graft thrombosis of the venous grafts may occur, collateral venous drainage form thereby avoiding intracranial hypertension and facial edema. DTC invasion of the superior vena cava with or without venous thrombus should not preclude operative resection [33,37,46]. Some surgeons have reported successful resection of these tumors through a median sternotomy or right thoracotomy [33,37]. Such an aggressive surgical approach has been advocated because patients with superior vena cava invasion and tumor thrombus have a risk of tumor embolism and tricuspid valve obstruction [46,47]. Removal of the tumor and thrombus may be done through a cavatomy or with segmental resection of the cava and reconstruction with autogenous, cadaveric or prosthetic grafts. When the tumor thrombus extends proximal, a catheter embolectomy has also been used successfully [30]. Cardiopulmonary bypass should be available during these procedures especially when the tumor extends into the right ventricle. Carotid artery invasion by DTC has been successfully treated with shave resection, en bloc resection and reconstruction or by simple ligation [6,8,10,19,30,41]. A balloon occlusion of the involved carotid artery should be done preoperatively to determine that sacrificing the carotid artery does not result in cerebrovascular insufficiency [32]. Shave resection should be done when possible but arterial replacement with autologous arterial grafting is recommended when the artery is invaded. 4.2. Lymphatic invasion Patients with papillary thyroid cancer frequently have lymph node metastases [3]. Extranodal tumor extension and lymph node metastases larger than 2 cm are associated with a high risk of recurrence, distant metastases and a lower survival rate [3,22,48]. These patients can usually be recognized clinically because the nodal metastases are matted together. Direct invasion from DTC lymph node metastasis in the lateral neck compartment may be associated with vascular, nerve and muscle invasion. A functional modified radical neck dissection preserving the sternocleidomastoid muscle, carotid artery, internal jugular vein, vagus nerve, spinal accessory nerve and phrenic nerve is the standard approach for patients who have lymph node metastasis at the time of initial total thyroidectomy or at reoperation for recurrent DTC [3]. The transverse
Fig. 4. Cervical and mediastinal lymph node compartments. Level I— submental and submandibular nodes, Level II—upper internal jugular chain nodes, Level III—middle internal jugular chain nodes, Level IV—lower internal jugular chain nodes, Level V—spinal accessory and transverse cervical nodes, Level VI—tracheoesophageal groove nodes and perithyroidal nodes, and Level VII—infraclavicular and upper anterior mediastinal nodes (thymic).
cervical incision is extended laterally (McFee extension) to allow access to the level II, III, IV and V lymph node compartments (Fig. 4). Placement of the Kocher transverse collar incision at the level of the cricoid cartilage makes removal of high cervical nodes (level II) easier. If level I and level II lymph node compartments are involved and cannot be reached through this incision, we recommend a transverse counter-incision just below the angle of the mandible to facilitate lymph node dissection. Some surgeons extend the transverse cervical incision superiorly for the lateral neck lymph node dissection. Occasionally, in patients with extensive DTC lymph node metastases involving level VII lymph nodes, a median sternotomy may be required to allow complete excision of the involved lymph nodes (Fig. 2) [7].
5. Adjuvant therapy Although surgery remains the most effective treatment for thyroid cancer, patients with locally advanced DTC warrant additional treatment (Fig. 5). Postoperative radioiodine treatment and thyroid hormone for TSH suppression decreases the risk of recurrence and may increase survival [3,48]. Particularly in high-risk patients with DTC, a general consensus exists that
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Neck mass
FNA
Primary/recurrent DTC
Clinical features suggesting locally advanced DTC
Yes
Neck/Chest CT/MRI scan Local invasion of trachea/esophagus/carotid?
No
Metastatic disease
Curable ^ No
Surgery
Incurable ^
Yes, metastatic workup*
Locoregional disease Surgery
Surgery
Surgery vs observation**
Fig. 5. Evaluation and management of patients with locally advanced DTC. The risk of distant DTC metastasis is higher in patients with locally invasive DTC. 4Generally surgical resection of locally advanced DTC should be done to avoid morbidity and mortality from local disease. However, if the patient has widely metastatic DTC and has no local symptoms that require palliation, observation or adjuvant therapy may be considered.
radioiodine therapy and TSH suppression are beneficial. Thus total or near-total thyroidectomy should be done so that the 131-I treatment can effectively treat metastatic disease rather than just ablate the remnant thyroid tissue. The benefit of external beam radiotherapy in patients with locally advanced DTC is unclear [11,36]. This is because all the studies evaluating adjuvant external beam radiotherapy for DTC are retrospective, the extent of disease was different in the study cohorts, and different radiation fields and doses were used [11,36]. Several investigators, however, have shown that external beam radiotherapy reduces the local recurrence rate in patients who have microscopic residual disease, age older than 45 years or locally advanced DTC [11,36,49– 51]. The use of external beam radiotherapy with adriamycin may improve responses to radiation treatment [52]. For adjuvant external beam radiotherapy, 40–50 Gy in 15–20 fractions over 3–4 weeks is recommended [11]. We recommend, after as complete a surgical resection as possible, postoperative external radiotherapy in patients with locally advanced DTC when microscopic disease or gross residual disease is present.
Several chemotherapeutic regimens, mostly doxorubicin based, have been evaluated in patients with widely metastatic DTC without any significant clinical complete response or only transient partial response [53]. Preclinical studies with a variety of agents (methyltransferase inhibitors, histone deacetylase inhibitors, PPARg agonist) show promise as potential alternative treatment agents for patients with locally advanced DTC or widely metastatic DTC [53]. In addition to their antineoplastic effect, many of these agents may have a redifferentiating effect on thyroid cells (i.e. increased iodine uptake and TSH responsiveness) which could make radioiodine treatment and TSH suppression therapy more effective.
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