Recovery of Recurrent Laryngeal Nerve Function With Neoadjuvant Treatment: Neural Characterization.

OBJECTIVES: Neoadjuvant targeted therapy has emerged as a promising treatment strategy for locally aggressive thyroid cancer. Its impact on tumor and adjacent tissues remains a nascent area of study. Here we report on a series of six subjects with locally advanced thyroid cancer and recurrent laryngeal nerve (RLN) paralysis who experienced recovery of RLN function with neoadjuvant treatment and describe the morphologic and electrophysiologic characteristics of these recovered nerves. METHODS: This is a multicenter retrospective review. Descriptive analysis was conducted to examine the following parameters for recovered nerves: (1) nerve morphology, characterized as Type A (involving epineurium only) versus Type B (extending beyond epineurium); (2) proximal stimulability (normal vs. abnormal vs. absent); and (3) surgical management (resection vs. preservation). RESULTS: Six subjects with unilateral VFP were identified. Median time to return of VF mobility was 3 months (range 2-13.5). All nerves (100%) were noted to have Type A morphology at surgery. Proximal stimulability was normal in four subjects (66.7%), abnormal in one (16.7%), and absent in one (16.7%). Nerves that had improvement of function through neoadjuvant therapy were able to be surgically preserved in five subjects (83.3%). CONCLUSIONS: This represents the first characterization of RLNs that have recovered function with neoadjuvant treatment of locally advanced thyroid cancer. Although much remains unknown, our findings indicate carcinomatous neural invasion is a reversible process and recovered nerves may demonstrate normal morphology and electrophysiologic activity. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Recurrent Laryngeal Nerve Invasion by Thyroid Cancer: Laryngeal Function and Survival Outcomes.

BACKGROUND: Recurrent laryngeal nerve (RLN) invasion by thyroid carcinoma represents an advanced disease status with potentially significant co-morbidity. METHODS: In a retrospective single-center study, we included patients with invaded RLNs operated on while using nerve monitoring techniques. We studied pre-, intra-, and postoperative parameters associated with postoperative vocal cord paralysis (VCP); 5-year recurrence-free survival (RFS); and 5-year overall survival (OS) in addition to two subgroup analyses of postoperative VCP in patients without preoperative VCP and based on source of RLN invasion. RESULTS: Of 65 patients with 66 nerves-at-risk, 39.3% reported preoperative voice complaints. Preoperative VCP was documented in 43.5%. The RLN was invaded by primary tumor in 59.3% and nodal metastasis in 30.5%. Papillary thyroid carcinoma was the most common pathologic subtype (80%). After 6 months, 81.8% had VCP. Complete tumor resection of the RLN was not associated with 5-year RFS (p = 0.24) or 5-year OS (p = 0.9). Resecting the RLN did not offer statistically significant benefit on 5-year RFS (p = 0.5) or 5-year OS (p = 0.38). Radioactive Iodine (RAI) administration was associated with improvement in 5-year RFS (p = 0.006) and 5-year OS (p = 0.004). Patients without preoperative VCP had higher IONM amplitude compared with patients with VCP. After a mean follow-up of 65.8 months, 35.9% of patients had distant metastases, whereas 36.4% had recurrence. CONCLUSION: Preoperative VCP accompanies less than half of patients with RLN invasion. Invaded RLNs may have existent electrophysiologic stimulability. Complete tumor resection and RLN resection were not associated with better 5-year RFS or OS, but postoperative RAI was. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:2285-2292, 2022.

How Many Nodes to Take? Lymph Node Ratio Below 1/3 Reduces Papillary Thyroid Cancer Nodal Recurrence.

INTRODUCTION: Papillary thyroid carcinoma (PTC) accounts for the majority of thyroid malignancies; risk of PTC recurrence over a 30-year period is approximately 30%, of which 70% occur as nodal metastases. Patients with nodal disease who are treated with therapeutic dissection are at higher risk for recurrence, but optimal nodal yield has not been defined. We aim to determine variables predictive of nodal recurrence of PTC within the first 5 years of surgery, with a focus on lymph node ratio (LNR), to inform clinical decision-making. METHODS: Retrospective chart review identified 41 patients with nodal recurrence of PTC and 284 without nodal recurrence following thyroid surgery from 2000 to 2015. Cohorts were compared with regards to clinical history, surgical findings, and tumor characteristics. RESULTS: The fraction of the patients who underwent therapeutic central or lateral lymph node dissection was significantly higher in the nodal recurrence cohort. Maximum tumor size, presence of extrathyroidal extension, largest lymph node focus, LNR, postoperative thyroglobulin level, and administration of postoperative radioactive iodine were significantly increased in the PTC nodal recurrence group. LNR greater than 0.3 held the highest level of significance as a binary cutoff and captured the larger proportion of patients in the nodal recurrence cohort (68.3%). CONCLUSION: This study demonstrates characteristics to help assess risk of nodal recurrence of PTC and suggests LNR of lower than 0.3 is optimal to reduce risk of recurrence. The next steps include cohort studies to validate findings and weight variable analysis to optimize the extent of surgical therapeutic dissection. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1883-1887, 2022.

Limitations of preoperative cytology for medullary thyroid cancer: Proposal for improved preoperative diagnosis for optimal initial medullary thyroid carcinoma specific surgery.

BACKGROUND: Preoperative diagnosis of medullary thyroid carcinoma (MTC) is often difficult, given the poor sensitivity of fine-needle aspiration (FNA) cytology for MTC. This study investigates this issue and presents recommendations for improving preoperative diagnostic paradigms in MTC cases. DESIGN/METHOD: Histopathologically confirmed MTC patients with preoperative cytologic assessment of index nodules were enrolled. FNA diagnosis, final pathology, and surgery details were collected. RESULTS: Out of 71 patients, 49 (69%) were diagnosed by FNA as either definitive MTC (35, 49%) or suspected MTC (14, 20%) and 22 (31%) patients had no indication of MTC on FNA. CONCLUSION: In a tertiary-care setting, one-third of subjects had an FNA interpretation that did not suggest the possibility of MTC. The limitations of preoperative diagnosis are especially problematic for MTC as they can cause delayed or incomplete treatment. Additional testing is proposed to improve preoperative diagnosis and surgical care of MTC patients.

The Presence of Hürthle Cells Does Not Increase the Risk of Malignancy in Most Bethesda Categories in Thyroid Fine-Needle Aspirates.

Background: Hürthle cell/oncocytic change is commonly reported on thyroid fine-needle aspiration (FNA) and may be considered an "atypical cell" by clinicians. This study aims to delineate the association between Hürthle cells in preoperative cytology and subsequent pathology of the indexed thyroid nodule and to report rates of malignancy. Methods: Retrospective review of records of 300 patients with Hürthle cell/oncocytic change on FNA and final surgical pathology at a tertiary referral center between 2000 and 2013 was performed and compared with a multi-institutional FNA cohort. The degree of Hürthle cell presence was correlated with histopathologic diagnoses. Results: In the Hürthle cell FNA group, Bethesda System for Reporting Thyroid Cytopathology (BSRTC) categories were as follows: I (nondiagnostic) 14 (4.7%); II (benign) 113 (37.7%); III (atypia of undetermined significance/follicular lesion of undetermined significance) 33 (11%); IV (follicular neoplasm/suspicious for a follicular neoplasm) 125 (41.6%); V (suspicious for malignancy) 12 (4%); and VI (malignant) 3 (1%). When categorized based on the degree of Hürthle cell change, 59 (29%) were classified as mild, 13 (6%) moderate, and 131 (65%) as predominant. When comparing the results with a multi-institutional FNA cohort (all with surgical confirmation), the presence of Hürthle cells was found to be associated with a lower risk of malignancy in all BSRTC categories, with a statistically significant difference in the BSRTC IV and V groups. The sole exception was when Hürthle cell presence was classified as predominant (defined as >75% of the cellular population); the rate of malignancy was significantly elevated in FNAs interpreted as benign/Bethesda II. Conclusions: Although Hürthle cells have been considered by clinicians as an "atypical cell," their presence does not increase the risk of malignancy within BSRTC categories overall. However, when predominant Hürthle cell change is present, the risk of malignancy is increased in the benign cytology/BSRTC category II.

Safety and reliability of a handheld stimulator for neural monitoring during thyroid surgery.

OBJECTIVE: The Checkpoint nerve stimulator (Checkpoint Surgical, Cleveland, OH) is a U.S. Food and Drug Administration-approved device for neural localization and monitoring during surgery. Its safety, efficacy, and reliability for neural monitoring during thyroid and parathyroid surgery have not been compared to more standard formats of neural monitoring. STUDY DESIGN: Retrospective review. METHODS: Vagal, recurrent, and superior laryngeal nerve monitoring were performed using both the Checkpoint stimulator and Medtronic NIM 3.0 laryngeal electromyography endotracheal tube (Medtronic, Jacksonville, FL) during thyroid and parathyroid surgery. A total of 21 operated sides in 15 patients were included for analysis. Latency and amplitude data for the Checkpoint stimulator were recorded using the NIM monitor and compared to normative endotracheal tube surface electrode data. RESULTS: Mean amplitude using the Checkpoint stimulator was 574.6 microvolts (µV), 1060.6 µV, and 182.8 µV for the vagus, recurrent laryngeal, and superior laryngeal nerves, respectively. Mean amplitude using standard laryngeal electromyography was 709 µV, 1077.0 µV, and 183.7 µV for the same nerves. Mean latency was significantly shorter with stimulation of the recurrent laryngeal nerve compared to the vagus nerve with both stimulators (P < 0.001). No neural injuries occurred during the study. CONCLUSION: The Checkpoint stimulator is a safe and reliable alternative to traditional laryngeal electromyography providing equivalent induced electromyography of the vocalis for neural monitoring during thyroid and parathyroid surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:561-565, 2020.

International neuromonitoring study group guidelines 2018: Part II: Optimal recurrent laryngeal nerve management for invasive thyroid cancer-incorporation of surgical, laryngeal, and neural electrophysiologic data.

The purpose of this publication was to inform surgeons as to the modern state-of-the-art evidence-based guidelines for management of the recurrent laryngeal nerve invaded by malignancy through blending the domains of 1) surgical intraoperative information, 2) preoperative glottic function, and 3) intraoperative real-time electrophysiologic information. These guidelines generated by the International Neural Monitoring Study Group (INMSG) are envisioned to assist the clinical decision-making process involved in recurrent laryngeal nerve management during thyroid surgery by incorporating the important information domains of not only gross surgical findings but also intraoperative recurrent laryngeal nerve functional status and preoperative laryngoscopy findings. These guidelines are presented mainly through algorithmic workflow diagrams for convenience and the ease of application. These guidelines are published in conjunction with the INMSG Guidelines Part I: Staging Bilateral Thyroid Surgery With Monitoring Loss of Signal. Level of Evidence: 5 Laryngoscope, 128:S18-S27, 2018.

International neural monitoring study group guideline 2018 part I: Staging bilateral thyroid surgery with monitoring loss of signal.

This publication offers modern, state-of-the-art International Neural Monitoring Study Group (INMSG) guidelines based on a detailed review of the recent monitoring literature. The guidelines outline evidence-based definitions of adverse electrophysiologic events, especially loss of signal, and their incorporation in surgical strategy. These recommendations are designed to reduce technique variations, enhance the quality of neural monitoring, and assist surgeons in the clinical decision-making process involved in surgical management of recurrent laryngeal nerve. The guidelines are published in conjunction with the INMSG Guidelines Part II, Optimal Recurrent Laryngeal Nerve Management for Invasive Thyroid Cancer-Incorporation of Surgical, Laryngeal, and Neural Electrophysiologic Data. Laryngoscope, 128:S1-S17, 2018.

Monitoring of the posterior cricoarytenoid muscle represents another option for neural monitoring during thyroid surgery: Normative vagal and recurrent laryngeal nerve posterior cricoarytenoid muscle electromyographic data.

OBJECTIVE: Intraoperative neural monitoring (IONM) of laryngeal nerves using electromyography (EMG) is routinely performed using endotracheal tube surface electrodes adjacent to the vocalis muscles. Other laryngeal muscles such as the posterior cricoarytenoid muscle (PCA) are indirectly monitored. The PCA may be directly and reliably monitored through an electrode placed in the postcricoid region. Herein, we describe the method and normative data for IONM using PCA EMG. STUDY DESIGN: Retrospective review. METHODS: Data were reviewed retrospectively for thyroid and parathyroid surgery patients with IONM of laryngeal nerves from January to August 2016. Recordings of vocalis and PCA EMG amplitudes and latencies with stimulation of laryngeal nerves were obtained using endotracheal (ET) tube-based and postcricoid surface electrodes. RESULTS: Data comprised EMG responses in vocalis and PCA recording channels with stimulation of the vagus, recurrent laryngeal nerve (RLN), and external branch of the superior laryngeal nerve from 20 subjects (11 left, 9 right), as well as PCA EMG threshold data with RLN stimulation from 17 subjects. Mean EMG amplitude was 725.69 ± 108.58 microvolts (µV) for the ipsilateral vocalis and 329.44 ± 34.12 µV for the PCA with vagal stimulation, and 1,059.75 ± 140.40 µV for the ipsilateral vocalis and 563.88 ± 116.08 µV for the PCA with RLN stimulation. There were no statistically significant differences in mean latency. For threshold cutoffs of the PCA with RLN stimulation, mean minimum and maximum threshold intensities were 0.37 milliamperes (mA) and 0.84 mA, respectively. CONCLUSION: This study shows robust and reliable PCA EMG waveforms with direct nerve stimulation. Further studies will evaluate feasibility and application of the PCA electrode as a complementary quantitative tool in IONM. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:283-289, 2018.

The electrophysiology of thyroid surgery: electrophysiologic and muscular responses with stimulation of the vagus nerve, recurrent laryngeal nerve, and external branch of the superior laryngeal nerve.

OBJECTIVES/HYPOTHESIS: Correlation of physiologically important electromyographic (EMG) waveforms with demonstrable muscle activation is important for the reliable interpretation of evoked waveforms during intraoperative neural monitoring (IONM) of the vagus nerve, recurrent laryngeal nerve (RLN), and external branch of the superior laryngeal nerve (EBSLN) in thyroid surgery. STUDY DESIGN: Retrospective chart review. METHODS: Data were reviewed retrospectively for thyroid surgery patients with laryngeal nerve IONM from January to December, 2015. EMG responses to monopolar stimulation of the vagus/RLN and EBSLN were recorded in bilateral vocalis, cricothyroid (CTM), and strap muscles using endotracheal tube-based surface and intramuscular hook electrodes, respectively. Target muscles for vagal/RLN and EBSLN stimulation were the ipsilateral vocalis and CTM, respectively. All other recording channels were nontarget muscles. RESULTS: Fifty surgical sides were identified in 37 subjects. All target muscle mean amplitudes were significantly higher than in nontarget muscles. With vagal/RLN stimulation, target ipsilateral vocalis mean amplitude was 1,095.7 µV (mean difference range = -814.1 to -1,078 µV, P < .0001). For EBSLN stimulation, target ipsilateral CTM mean amplitude was 6,379.3 µV (mean difference range = -6,222.6 to -6,362.3 µV, P < .0001). Target muscle large-amplitude EMG responses correlated with meaningful visual or palpable muscular responses, whereas nontarget EMG responses showed no meaningful muscle activation. CONCLUSIONS: Target and nontarget laryngeal muscles are differentiated based on divergence of EMG response directly correlating with presence or absence of visual and palpable muscle activation. Low-amplitude EMG waveforms in nontarget muscles with neural stimulation can be explained by the concept of far-field artifactual waveforms and do not correspond to a true muscular response. The surgeon should be aware of these nonphysiologic waveforms when interpreting and applying IONM during thyroid surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:764-771, 2017.

A novel thyroid cancer nodal map classification system to facilitate nodal localization and surgical management: The A to D map.

OBJECTIVES/HYPOTHESIS: To evaluate the effectiveness, reproducibility, and usability of our proposed nodal nomenclature and classification system employed for several years in our high-volume thyroid cancer unit, for the adequate localization and mapping of lymph nodes in thyroid cancer patients with extensive nodal disease. STUDY DESIGN: Retrospective review. METHODS: Thirty-three thyroid cancer patients with extensive nodal disease treated from January 2004 to May 2013 were included in our study. Preoperative ultrasound and computed tomography scans of these patients were reanalyzed by blinded radiologists to investigate the feasibility for the assignment of abnormal lymph nodes to compartments defined in our proposed nodal classification system and to identify areas of difficulty in the assignment. RESULTS: Analysis of nodal localization revealed a discrepancy in compartment agreement between the two radiologists in the assignment of abnormal nodes in nine patients (9/33, 27%). In six patients (6/33, 18%), discrepancy existed in labeling paratracheal and pretracheal nodes. In three patients (3/33, 9%), disagreement arose in the classification of retrocarotid nodes into lateral versus central compartment. A further refinement of the definition of key borderline regions of the pretracheal versus paratracheal and retrocarotid regions of our classification improved the agreement and demonstrated a complete concordance (100%) amongst the reviewing radiologists. CONCLUSIONS: The proposed nodal classification system, derived specifically for differentiated thyroid carcinoma, with readily identifiable anatomic boundaries on imaging and at surgery, facilitates communication among multidisciplinary physicians and aids in creating a uniform and reproducible radiographic nodal map to guide surgical therapy. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:2429-2436, 2017.

Changes in electromyographic amplitudes but not latencies occur with endotracheal tube malpositioning during intraoperative monitoring for thyroid surgery: Implications for guidelines.

OBJECTIVES/HYPOTHESIS: During intraoperative neural monitoring (IONM) in thyroid and parathyroid surgery, endotracheal (ET) tube migration can result in a decrease in vocalis electromyographic (EMG) amplitude without a concordant latency elevation during stimulation of the recurrent laryngeal nerve (RLN). STUDY DESIGN: Retrospective review. METHODS: Data were reviewed retrospectively for thyroid and parathyroid surgery patients with IONM of the laryngeal nerves from January 2015 to December 2015. Recordings of vocalis EMG amplitudes and latencies with RLN stimulation were obtained with the neuromonitoring ET tube surface electrodes in optimal baseline position, with vertical displacement away from the vocalis, and with rotational change away from baseline. RESULTS: ET tube surface electrode EMG recordings were obtained with stimulation of seven left and three right RLNs in a total of 10 patients. Mean vocalis EMG amplitudes were reduced with vertical displacement 1 and 2 cm both inferior and superior to baseline and with rotational change (45° and 90° clockwise and counterclockwise, 180°), although amplitude change with 45° clockwise and 180° rotation did not meet statistical significance. Mean EMG latency values did not change significantly from baseline with either rotation or vertical displacement of the ET tube. CONCLUSIONS: An isolated decrease in EMG amplitude without concordant latency elevation should warrant re-evaluation of ET tube position during thyroid and parathyroid surgery and is in contrast to a combined event, with both EMG amplitude decrease and concordant latency increase, which is more suggestive of a true neuropraxic injury. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2182-2188, 2017.