If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Corresponding author at: Department of Otolaryngology-Head and Neck Surgery, Wakayama Medical University, Kimiidera 811-1, Wakayama-shi, Wakayama 641-8509, Japan.
Approximately 20% of patients with differentiated thyroid cancer (DTC) have direct tumor extension with invasion of the surrounding tissues such as the larynx, trachea, esophagus, or recurrent laryngeal nerve. Recent progress of molecular-targeted therapy, such as the use of tyrosine kinase inhibitors, improves survival outcome in patients with advanced DTC. However, induction of tyrosine kinase inhibitors for locally-advanced DTC has presented novel fatal adverse events including fistula in patients with infiltration toward to the trachea, pharynx and esophagus, and fatal bleeding in patients with great vessel invasion. Surgery therefore still has an important role in DTC management, particularly in local control. The surgical strategy for laryngeal/tracheal invasion, which commonly occurs by DTC, is decided according to the extension (depths and area) of the tumor. The “shave procedure” is performed when the tumor has superficially invaded the larynx/trachea. However, intra-luminal extension requires resection and reconstruction of the larynx/trachea wall. Large veins, such as the internal jugular vein and the subclavian vein, are also frequently directly invaded by DTC. Three types of jugular vein reconstruction have been advocated to avoid fatal complications according to bilateral jugular vein ligation. The majority of carotid artery invasion by DTC can be managed with tumor resection of the sub-adventitial layer without reconstruction surgery using an artificial vessel. In this review article, we examine surgery for advanced DTC, showing the surgical strategy toward DTC that has invaded the laryngotracheal, recurrent laryngeal nerve, esophagus/hypopharynx, or great vessels.
Surgery continues to be the gold standard therapy for thyroid cancer (TC), despite recent developments in molecular-based targeted therapy. Many patients with differentiated TC (DTC) have mild progression with good prognosis, but up to 22% of patients with DTC have direct tumor extension with invasion of the surrounding tissues such as the larynx, trachea, esophagus, or recurrent laryngeal nerve (RLN) [
. Approximately 24% of patients with DTC die of the disease by airway obstruction due to local extension, whereas 28% of patients die by respiratory failure caused by lung metastasis or malignant pleural effusion [
]. Historically, 131I radioiodine therapy has been administrated for unresectable thyroid cancer that includes distant and loco-regional foci, with thyroid-stimulating hormone suppression therapy after total thyroidectomy. Recent progression of molecular-based medicine, tyrosine kinase inhibitor (TKI) such as lenvatinib and sorafenib, improved PFS in these types of unresectable DTC with radioiodine-refractory [
]. However, administration of TKI for locally advanced DTC has caused unexpected novel fatal adverse events including fistula in patients with infiltration into the pharynx and esophagus, and fatal bleeding in patients with great vessel invasion [
]. Similarly, selpercatinib, another promising drug for TC with RET gene mutations or fusions, includes warnings and precautions about hemorrhagic events [
]. Local control of advanced TC is therefore an important matter in terms of using recent molecular targeted therapy for metastatic TC, such as lenvatinib, sorafenib, cabozantinib or selpercatinib. Dabrafenib plus trametinib, another kind of molecular targeted therapy, had no reported fatal adverse events in 16 patients with anaplastic TC with BRAF V600E mutation [
], but it is too small a number to be conclusive about its safety, and there is currently no evidence of clinical benefit for patients with locally-advanced DTC. In this article, we examine the surgical strategy and treatment for locally-advanced DTC, which is categorized as cT4 stage, in the era of selectable molecular targeted drugs.
2. Laryngotracheal invasion
The larynx/trachea is one of the surrounding structures most commonly invaded by local DTC, which occurs in approximately 6% to 21% of patients with TC. This is related to low survival ratio as an independent prognostic factor in DTC [
. According to Enomoto et al., 953 of 7064 patients (13.5%) with TC had invasion of the tracheal surface, whereas only 37 of 7064 patients (0.52%) with TC had deep invasion [
]. There was deep invasion in both the larynx and trachea in 26 of 37 patients (70.3%), but only limited tracheal invasion was seen in 10 of 37 patients (27.0%).
Complete surgical removal is still the gold standard therapy for laryngotracheal invasion of DTC. Surgical methods include the shave procedure, window resection, circumferential tracheal resection, partial laryngectomy, and total laryngectomy. To decide surgical methods, it is very important to know depth extent and areas of TC invasion, and a number of staging systems have been reported [
Pathologic staging of papillary carcinoma of the thyroid with airway invasion based on the anatomic manner of extension to the trachea: a clinicopathologic study based on 22 patients who underwent thyroidectomy and airway resection.
Pathologic staging of papillary carcinoma of the thyroid with airway invasion based on the anatomic manner of extension to the trachea: a clinicopathologic study based on 22 patients who underwent thyroidectomy and airway resection.
] Fig. 1. summarizes these staging systems and considerable representative surgical options based on the extent of invasion and anatomical occupation (area).
Fig. 1Surgical strategy for laryngotracheal invasion. A deep extension laryngotracheal lumen was classified I to IV by Shin et al
Pathologic staging of papillary carcinoma of the thyroid with airway invasion based on the anatomic manner of extension to the trachea: a clinicopathologic study based on 22 patients who underwent thyroidectomy and airway resection.
. The “shave procedure” should be performed by scalpel when there is superficial tumor invasion. In case of deep invasion to submucosa, tracheal area invasion will necessitate resection and reconstruction surgery such as window resection with tracheal-cutaneous fistula (a), and circumferential resection with end-to-end anastomosis, (b) cricoid and tracheal deep invasion required more complex surgical methods, such as window (c), bayonet line/sleeve line resection (d)
. Extensive laryngeal invasion to the vocal cords and paraglottic space required partial or total laryngectomy depending on the area and extent of invasion.
When the tumor has visibly but superficially invaded the trachea or cricothyroid muscle, the “shave procedure” is commonly performed. The outcome of this procedure in low-volume invasion is not significantly different from more aggressive forms of airway resection when complete removal has been achieved [
]. On the other hand, intra-luminal extension, deep invasion, requires resection of the tracheal wall and a portion of the larynx, including the cricotracheal cartilage.
i)
Tracheal deep invasion
When the range of deep tracheal invasion is small and there are a few rings, tracheal stoma can be closed immediately by wedge shape resection with direct suture without tracheostomy. In case of wide and deep tracheal invasion, there are two major surgical procedures for the resection and reconstruction: window resection with tracheal-cutaneous fistula (Fig. 1a), and circumferential resection with end-to-end anastomosis (Fig. 1b). Each surgical technique has advantages, disadvantages and indications [
]. Window resection is a technique wherein a tracheal wall invaded by TC is resected in all layers with a safety margin. This procedure requires tracheal-cutaneous fistula, and then it can be closed in multi-staged surgery using deltopectoral flap (DP) and local skin flap after initial stoma surgery. If the stoma is extensive, rigid reconstruction using auricular and rib cartilage may be required. Otsuki et al. showed ideal spiral tracheoplasty after extensive window resection of the trachea in two patients with DTC. They successfully recreated a framework of the trachea after extensive window resection, and closed the tracheocutaneous fistula within four months after the initial surgery [
]. Circumferential resection with end-to-end anastomosis is another major procedure for when the invading thyroid carcinoma extends into the tracheal mucosa or lumen. The airway reconstruction can be completed in one stage and the airway lumen is covered by normal tracheal mucosa [
]. The 3-0 absorbable monofilament suture (PDSII, Ethicon, Somerville, NJ) is especially suitable for end-to-end anastomosis because of low incidence of granulation at the anastomotic site and at its highest tension. After anastomosis, a leak check should be performed by inflation with water seal of the operative field. When sutures are superior to the intubation cuff, temporary deflation of the tube cuff is required for a leak test. It is then desirable to fix the anastomotic site with polyglycolic acid (PGA) mesh sheets (Neoveil, Gunze, Kyoto, Japan) with fibrin glue such as Bolheal (Teijin, Osaka, Japan). Suture leakage, a potentially fatal complication, is seen in approximately 0 to 10% of patients with circumferential resections with end-to-end anastomosis [
The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: Core questions and recommendations for treatments of thyroid cancer.
The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: Core questions and recommendations for treatments of thyroid cancer.
]. Ozaki et al. suggested tracheal deep invasion should be circumferentially resected because in their 21 cases, circumferential spread showed invasion on the mucosal side exceeding invasion on the adventitial side [
There is currently no standard of resection and reconstruction surgery for patients with TC invading into the intra-luminal cricotracheal region, although it is the most common location in deep invasion. Window resection is the most basic technique for cricotracheal deep invasion (Fig. 1c). It requires cricotracheal-cutaneous fistula, and can then usually be closed by multi-staged surgery by DP flap or local skin flap. However, the airway reconstruction with skin epithelium can cause difficulty in sputum excretion and difficulty in securing lumen during inspiration. There is no suitable cannula and thus sometimes cannula-related trouble, such as granulation of stoma, intratracheal granulation and difficulty using speech (one-way valve) cannula due to air leakage from stoma, because fistulas often form on the lateral side of the cricotrachea. Further listed problems include unsightly scarring on the neck remaining after fistula closure surgery, and loss of cricotracheal framework, which could not maintain inner lumen by retractive breathing during inspiration. Thus, in Moritani's report, only 30 of 76 patients (39%) with cricotracheal deep invasion after window resection had successful stomal closure [
]. To avoid these problems, Grillo et al. described the one-stage resection and reconstruction of the “bayonet line” in a part of the 16 patients with airway reconstruction. They modified the sleeve tracheal resection and reconstruction to the “bayonet line” to maintain the framework of cricotrachea with adjustment of caliber difference between superior and inferior [
] (Fig. 1d). Enomoto et al. further developed this to include “Tetris reconstruction”, which expanded window resection and unique one-staged reconstruction like the Tetris video game in eight patients with TC invasion of the laryngeal lumen [
]. There was improved safety over “bayonet line” resection and reconstruction, especially in cases requiring temporary tracheostomy (Fig. 1e, 2). If intra-operative bilateral laryngeal nerve damage was suspected due to the invasion of the tumor, “Tetris reconstruction” could alter to a midline laryngotracheal stoma or a multiple-stage operation for closing the stoma. In 2020, Sims et al. reported the same reconstruction method as the “stair-step procedure” in a single patient with cricotracheal invading papillary TC (PTC) [
]. Preservation of the bilateral RLN function is very important for the one-stage resection and reconstruction procedure, at least maintaining the function of one RLN. Bilateral RLN injury will likely cause severe laryngeal dysfunction and dysphonia, requiring permanent tracheostomy.
iii)
Extensive laryngeal deep invasion
Fig. 2Case of cricotracheal invasion. Differential thyroid cancer invaded into the cricotracheal lumen. Preoperative images, contrast enhanced CT image (a), and MRI T1 image (b) show a differential thyroid cancer (*) invaded cricotracheal lumen. An arrow indicates the intra-tracheal exposed tumor (c). Differential thyroid cancer was resected with invaded cricoid and trachea (d, e). Closure of the proximal and distal stump with end-to-end laryngo-tracheoplasty according to “Tetris” surgery (f).
Extensive laryngeal invasion of the vocal cords and paraglottic space usually requires laryngectomy, although partial laryngectomy might be feasible in the case of unilateral laryngeal deep invasion of the tumor. Indications of total laryngectomy are limited to recurrent disease widely involving the laryngeal lumen, and to patients lacking laryngeal function due to DTC [
As palliative treatment, endoscopic tumor ablation with neodymium: yttrium-aluminum-garnet (Nd:YAG) laser followed by electrocoagulation and microwave coagulation for residual tumor base is also a surgical option for inoperable laryngotracheal intraluminal invasion of DTC [
]. There may be a high risk, however, of intra-tracheal bleeding and fistula when molecular targeting therapy such as lenvatinib is used after this endoscopic tumor ablation [
The surgical management of locally advanced well-differentiated thyroid carcinoma: changes over the years according to the AJCC 8th edition Cancer Staging Manual.
Historically, various non-bio materials, such as metallic/polymeric wire, mesh, gauze, metal/glass tube, and silicone tracheal prostheses have been used for tracheal replacement after tumor resection following invasion of the trachea [
. They are the source of many potentially fatal problems, however, such as narrowing, collapse of the graft, infection causing pneumonia and mediastinitis, and suffocation by secretions in the airway [
]. Non-biomaterial tracheal replacement is never suitable as a standard option for surgery because of these risks. To elucidate these problems, Taniguchi et al. tried to generate a scaffold-free construct of 3D-printed multicellular spheroids consisting of chondrocytes, endothelial cells, and mesenchymal stem cells in a rat model [
]. Based on the above preclinical studies, Omori et al. reported a few clinical applications of their Marlex mesh/collagen sponge graft material for a patch replacement in small tracheal defects [
. Marlex mesh/collagen sponge graft material has not yet been used, but in the near future these materials may change surgical strategy for DTC invasion into the larynx/trachea.
3. Recurrent laryngeal nerve invasion
RLN invasion occurs in 20-47% of cases of locally advanced DTC [
. It seems to lead to a higher recurrence rate as an independent risk factor, and the death rate significantly increases by between 5 and 35% compared with DTC without RLN invasion [
. Furthermore, Chen et al. reported that independent predictors for RLN invasion included esophageal extension, tracheal extension, preoperative RLN palsy, age >45 years, largest tumor size >10 mm, and clinical lymph node metastasis [
]. Resection of involved nerves does not confer survival benefits, however, and the management of the RLN during surgery for DTC invasion of the RLN has been controversial [
]. When vocal cord function is normal preoperatively, RLN preservation should be attempted. If disease is minimally adherent to RLN, “shaving” the tumor from the nerve is recommended [
The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: Core questions and recommendations for treatments of thyroid cancer.
]. When disease encases the nerve, dissection of the nerve from the tumor without leaving gross residual tumors should be attempted. In case of gross residual disease for this dissection, nerve function remains at high risk in the short term because of disease progression and dissection involving the RLN is a possibility. There is no difference in recurrence-free ratio or survival between shaving and nerve resection [
Novel surgical methods for reconstruction of the recurrent laryngeal nerve: Microscope-guided partial layer resection and intralaryngeal reconstruction of the recurrent laryngeal nerve.
]. When the ipsilateral vocal cord is preoperatively dysfunctional, RLN resection with reconstruction is indicated. RLN reconstruction after resection is strongly recommend for recovery of vocal cord function [
The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: Core questions and recommendations for treatments of thyroid cancer.
Novel surgical methods for reconstruction of the recurrent laryngeal nerve: Microscope-guided partial layer resection and intralaryngeal reconstruction of the recurrent laryngeal nerve.
Fig. 3Case of recurrent laryngeal nerve (RLN) invasion. Differential thyroid cancer is partially adherent to RLN (a), and then shaving procedure by scalpel preserved RLN nerve fiber without leaving gross residual tumors (b).
There are currently no indications for the most appropriate reconstruction procedure, and it depends on the surgeons’ preference and the range of RLN defect. When the area of RLN resection is short, end-to-end anastomosis is thought to be the most suitable, which is by 2 to 3 point suture by 8-0 to 10-0 non-absorbable monofilament suture, such as PROLENE (Ethicon, Somerville, NJ). If end-to-end anastomosis is not possible, a switch from cervical ansa, vagus nerve, and interposition of autologous nerve grafts should be considered [
]. Most recently, to recover vocal fold movements, various kinds of tube combination therapy with molecular or gene therapy have been investigated using rat models, such as PGA-collagen tube filled with collagen fibers (Nerbridge; Toyobo Co., Ltd., Osaka, Japan) [
]. If esophageal resection cannot be done because of extensive involvement of the esophagus, patients may require nasogastric tube, percutaneous endoscopic gastrostomy or central venous port for nutrition and administration due to symptomatic esophageal obstruction.
Most esophageal invasion involves only the muscularis layer and the mucosa and there is not usually invasion of the submucosa and intraluminal extension [
]. When DTC invades the muscular layer without mucosa and submucosa of the esophagus, no additional treatment is required, but primarily closure is necessary in case of a full-thickness defect in DTC exenteration including mucosa and submucosa. Segmental resection is required when circumferential esophageal invasion is more extensive. This situation requires tissue transfer for reconstruction such as myocutaneous pedicled flap, radial forearm free flap, gastric tube, or jejunal tissue transfer (Fig. 4). The reconstruction procedures are selected according to the area and extension of the defect and the experience and preferences of the reconstructive team [
Fig. 4Case of hypopharynx invasion. Preoperative images, contrast enhanced CT image (a), MRI T1 image (b) and video laryngoscope (c) showed a differential thyroid cancer (*) and wide invasion of the mucosa and submucosa. It required segmental resection, and radial forearm free flap tissue transfer for reconstruction (arrow; d, e).
Large veins, the internal jugular vein, subclavian vein and innominate vein, are frequently directly invaded in up to 13% of patients by advanced DTC, but carotid arteries are rarely invaded [
]. By intra-luminal spread of vessels, tumor thrombus also occurs in both PTC and FTC. Molecular-targeted therapy and radiation therapy is contraindicated when there is DTC invasion into the cervical macrovascular disease because there is expected to be bleeding and rupture of the great vessels at the neck. Surgical resection is therefore only a therapeutic option. The progression of cervical pathology directly leads to thrombus formation, cerebral infarction, and tumor bleeding, so treatment as early as possible is desired [
Reconstructions after sacrificing the jugular vein due to tumor invasion remain controversial. During unilateral neck dissection, it is reported that the epidural pressure arises by an average of 15 mmHg, and elevated epidural pressure is associated with incidence of facial edema and headache [
]. When the unilateral internal jugular vein has been ligated, the occurrence of headaches is reportedly 70.5%, diplopia is 58.8%, and impaired vision is 52.9% [
]. If bilateral internal jugular vein transection is done, the complications of facial edema, increased intracranial pressure (ICP), stroke, blindness, and sometimes death may happen [
]. Sakata et al. showed bilateral jugular vein ligation decrease of 45% for local cerebral blood flow in the neocortex for a short period, but gradual recovery reaching the preoperative value by 48 hours in rat model [
]. On the other hand, unilateral jugular vein ligation does not increase ICP, but increases cerebral blood flow and cerebral oxygen consumption in the swine model [
To avoid fatal complications according to bilateral jugular vein ligation, staged ligation of the internal jugular vein or bilateral jugular vein ligation with unilateral internal jugular vein reconstruction has been proposed [
]. Mourad et al. also reported that their eight patients with reconstruction by internal jugular vein to external jugular vein (type A) had no postoperative complications including ICP increase or facial edema [
]. However, whether or not internal jugular vein reconstruction reduces the risk of the above complications at amputation of single jugular vein by DTC invasion remains controversial. Tori et al. reported no reconstruction patients with total/partial resection of the unilateral internal jugular vein due to DTC invasion, but they were all asymptomatic after surgery [
Operative strategy for differentiated thyroid carcinoma invasive to the adjacent tissue such as the trachea, nerves, esophagus, and vessels, in terms of safety and QOL.
Official J Japan Assoc Endocrine Surg Japan Soc Thyroid Surg.2012; 29: 131-134
]. Unilateral resection of the internal jugular vein seems to be no problem, but bilateral jugular vein ligation may require consideration of increasing ICP and associated disorders. Taken together, bilateral jugular vein ligation may require at least one jugular reconstruction, partial resection of the jugular vein, or staged surgery to establish collateral circulation to preserve cranial venous return [
. The carotid artery is classified into three layers, intima, media, and adventitia, and invasion from DTC mainly affects the adventitia. The majority of carotid artery invasion by DTC can be managed with tumor resection of the sub-adventitial layer, which will provide satisfactory locoregional control for patients with carotid artery invasion. Small curved scissors or scalpels can be used to strip off the sub-adventitial layer of carotid arteries (Fig. 5). Moritani reported 26 of 27 patients with PTC (96.3%) could be managed with tumor resection of the sub-adventitial layer, and only one reported patient with PTC (3.7%) required reconstruction using an artificial vessel [
]. Although small perforation has occurred during peeling, it is able to be stitched up by a non-absorbable monofilament such as PROLENE (Ethicon, Somerville, NJ). After resection of the sub-adventitial layer, the defect of sub-adventitial layer should be covered for protection by the sternocleidomastoid muscle or PGA mesh sheets (Neoveil, Gunze, Kyoto, Japan) with fibrin glue such as Bolheal (Teijin, Osaka, Japan). When it is impossible, resection and replacement of the carotid artery may be required by using artificial or autograft vessels. There is approximately 10% mortality and neuromorbidity associated with the carotid reconstruction surgery [
]. If tracheostomy is needed, replacement by using autologous blood vessels such as saphenous vein graft may be better so to prevent rupture by surgical infections [
]. A balloon occlusion test of the carotid artery should be done preoperatively to ascertain whether or not there is cerebrovascular insufficiency by clamping the carotid artery with tumor invasion [
]. Near-infrared light can penetrate the human skull and near-infrared spectroscopy (NIRS) provides noninvasive access to determine regional oxygen saturation (rSO2) of the brain [
The Diagnostic Accuracy of Intra-Operative Near Infrared Spectroscopy in Carotid Artery Endarterectomy Under Regional Anaesthesia: Systematic Review and Meta-Analysis.
], but there are no reports on prediction and prevention of postoperative strokes when NIRS was used in thyroid surgery for great vessel invasion.
Fig. 5Case of carotid artery invasion. Sub-adventitial resection of the common carotid artery with small scissors (a). After sub-adventitial peeling (b, arrowhead), it should be covered for protection by the sternocleidomastoid muscle or a polyglycolic acid (PGA) mesh sheets (Neoveil, Gunze, Kyoto, Japan) with fibrin glue such as Bolheal (Teijin, Osaka, Japan).
Recent progress of molecular targeted therapy improves survival outcome in patients with advanced TC. However, novel fatal adverse events associated with TKI for locally advanced DTC include fistula in patients with infiltration toward to the pharynx and esophagus and fatal bleeding in patients with great vessel invasion. Further demand will arise in the role of surgery for local control in advanced TC.
Funding
None.
Author Contributions
All authors have read and agreed to the published version of the manuscript.
Declaration of Competing Interest
The authors declare that there are no conflicts of interest regarding the publication of this report.
Acknowledgments
We acknowledge proofreading and editing by Benjamin Phillis at the Clinical Study Support Center, Wakayama Medical University.
Pathologic staging of papillary carcinoma of the thyroid with airway invasion based on the anatomic manner of extension to the trachea: a clinicopathologic study based on 22 patients who underwent thyroidectomy and airway resection.
The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: Core questions and recommendations for treatments of thyroid cancer.
The surgical management of locally advanced well-differentiated thyroid carcinoma: changes over the years according to the AJCC 8th edition Cancer Staging Manual.
Novel surgical methods for reconstruction of the recurrent laryngeal nerve: Microscope-guided partial layer resection and intralaryngeal reconstruction of the recurrent laryngeal nerve.
Operative strategy for differentiated thyroid carcinoma invasive to the adjacent tissue such as the trachea, nerves, esophagus, and vessels, in terms of safety and QOL.
Official J Japan Assoc Endocrine Surg Japan Soc Thyroid Surg.2012; 29: 131-134
The Diagnostic Accuracy of Intra-Operative Near Infrared Spectroscopy in Carotid Artery Endarterectomy Under Regional Anaesthesia: Systematic Review and Meta-Analysis.
00063-3&id=gr1.jpg){kind=link}
00063-3&id=gr2.jpg){kind=link}
00063-3&id=gr3.jpg){kind=link}
00063-3&id=gr4.jpg){kind=link}
00063-3&id=gr5.jpg){kind=link}