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Abstract

Objectives: Thyroidectomy for advanced laryngeal squamous cell carcinoma (LSCC) is controversial. This study aimed to identify predictors of thyroid gland invasion in patients with LSCC and management of the thyroid gland during total laryngectomy. Patients and Methods: Clinical data and pathological characteristics of 113 patients, who underwent laryngectomy with thyroidectomy for advanced LSCC in Guangdong Provincial People’s Hospital between 2009 and 2019, were retrospectively analyzed. The incidence and predictors of thyroid gland invasion were analyzed, and a new predictor was proposed using a parallel test. Results: Of 113 patients, 25.7% exhibited thyroid invasion. A new predictor that combined the lower third of thyroid cartilage invasion and thyroid gland invasion on computed tomography/magnetic resonance imaging (CT/MRI) was associated with pathological thyroid gland invasion (P = 0.001; sensitivity, 88.2%; negative predictive value, 95%). Conclusion: Thyroidectomy may be required during total laryngectomy in those with invasion of the lower third of thyroid cartilage and/or thyroid gland invasion revealed on CT/MRI instead of being performed routinely.

Keywords

predictors thyroid gland invasion laryngeal squamous cell carcinoma total laryngectomy thyroid cartilage

Introduction

Laryngeal squamous cell carcinoma (LSCC) is one of the most common tumors of the head and neck. Approximately 60% of patients present with advanced (stage III or IV) disease at diagnosis. Although concurrent systemic therapy, radiation therapy, and induction chemotherapy have been accepted standards of care, surgery remains the mainstay for patients with advanced LSCC, especially those with stage T4 cancers.¹ A study using the National Cancer Database found that there was a statistically significant survival benefit for patients with T4a laryngeal cancer who underwent total laryngectomy versus larynx preservation chemoradiation.²

According to the NCCN Guidelines for Head and Neck Cancers (Version 1.2021), a thyroidectomy is suggested as a routine measure during total laryngectomy in patients with advanced LSCC. LSCC can invade the thyroid gland by direct extension or, less frequently, spread indirectly by lymphatic or vascular channels.³ Hilly et al. reported that thyroid gland invasion was associated with poor overall survival.⁴

In contrast, some investigators examining postoperative complications of hypothyroidism have not supported thyroidectomy during total laryngectomy. The incidence of hypothyroidism after total laryngectomy with hemithyroidectomy can be as high as > 50%.^5,6 And the addition of postoperative radiotherapy which is mostly applied in advanced laryngeal cancers may increase this morbidity of hypothyroidism. Although simple to treat in some, postoperative hypothyroidism can be difficult to treat in others, and postoperative thyroid function needs to be followed up for > 2 years.⁷ It is associated with various morbidities including delayed wound healing, pharyngeal fistula, mood depression, hypercholesterolemia with irreversible damage to the vascular system, and cardiac morbidity.⁸ Hypoparathyroidism is a most common complication of total thyroidectomy and it is a much serious complication than hypothyroidism, which can cause hypocalcemia and lead to tetany, ventricular tachycardia, ventricular fibrillation, and mental symptoms.⁹A 12-year retrospective study reported that thyroid-preserving laryngectomy did not increase the local recurrence rate and did not have a negative effect on disease-free survival.¹⁰

Many predictors for thyroidectomy during laryngectomy have been reported in the literature. Some authors have recommended that thyroidectomy may be required only for patients considered to be at risk, such as those with thyroid cartilage invasion and tumors with subglottic extension > 10 mm. Mendelson et al. indicated that thyroidectomy may only be required during total laryngectomy for transglottic and subglottic tumors and tumors with subglottic extension >10 mm.¹¹ Gorphe et al. reported that thyroid cartilage invasion was a significant factor associated with thyroid gland invasion.¹²

To achieve local tumor control and improve patient prognosis, while reducing postoperative complications and improving quality of life, it is necessary to explore positive predictors of thyroid gland invasion in LSCC. In this study, we collected clinical and pathological data from patients with advanced LSCC undergoing total laryngectomy with thyroidectomy to identify predictors of thyroid gland invasion. We aimed to investigate the incidence of thyroid gland invasion to facilitate decision-making regarding whether to perform thyroidectomy during total laryngectomy.

Patients and Methods

In our study, data from 113 patients, who underwent total laryngectomy with thyroidectomy for advanced LSCC at Guangdong Provincial People’s Hospital (Guangzhou, China) between 2009 and 2019, were retrospectively analyzed. Inclusion criteria were as follows: patients with pathologically confirmed LSCC, staged as III or IV according to American Joint Committee on Cancer (AJCC) criteria, 8th Edition; surgery performed at Guangdong Provincial People’s Hospital as primary or salvage treatment; and total laryngectomy with partial or total thyroidectomy. Individuals with laryngeal carcinoma of other pathological types and those with LSCC who did not undergo preoperative examination or surgery at Guangdong Provincial People’s Hospital were excluded from the study.

Preoperative clinical data, pathological characteristics, and demographic information were collected, including previous treatment(s), laryngoscopy findings, computed tomography (CT), or/and magnetic resonance imaging (MRI) reviews, as well as the type of surgery and intraoperative evaluation. Radiological assessment was evaluated by two experienced radiologists who were blinded to patient information. If the assessments of the 2 radiologists were not identical, a third radiologist evaluated the films, and his assessment was used as the final result.

Eighty-four cases with complete data and 19 factors were statistically analyzed using SPSS version 25.0 (IBM Corporation, Armonk, NY, USA) for Windows (Microsoft Corporation, Redmond, WA, USA). Univariate analysis was performed using t-test/Fisher’s exact test, and multivariate analysis was performed using binary logistic regression analysis. A new predictor was proposed using a parallel test, which means if either or both of two predictors are positive, the joint predictor was judged to be positive. Moreover, the sensitivity and specificity of the positive predictors were calculated to construct a receiver operating characteristic (ROC) curve. Differences with P < 0.05 were considered to be statistically significant.

All procedures performed in this study were in accordance with the ethical standards of Research Ethics Committee Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Science (No.GDREC2019755H).

Results

The present study included 113 patients (106 men, seven women; mean [± standard deviation (SD)] age, 60.9 ± 10.9 years). The most common primary tumors were glottic (34.5% [39/113]) and transglottic (35.4% [40/113]). Clinical and pathological staging data from the 113 patients are summarized in Table 1. Tumors in more than one-half of patients (54.9% [62/113]) were moderately differentiated. Sixty-six (58.4%) patients initially underwent surgery, others experienced recurrences after surgery or/and chemoradiotherapy. Only 23.9% of patients (27/113) underwent total thyroidectomy, although hemithyroidectomy was performed in the majority (76.1% [86/113]). Twenty-nine of the 113 (25.7%) patients exhibited signs of pathological thyroid gland invasion, six (20.7%) of whom with signs of superficial invasion, while the other 23 (79.3%) exhibited parenchymal destruction. One patient had papillary thyroid carcinoma at the same time. Coincidentally, three patients exhibited latent papillary thyroid carcinoma without thyroid gland invasion in advanced LSCC.

Table 1.

Characteristics of Patients With Laryngeal Squamous Cell Carcinoma Who Underwent Laryngectomy and Thyroidectomy.

Characteristic	No. of patients (%)
Age, year (mean ± SD)	60.9±10.9
Sex
Male	106 (93.8)
Female	7 (6.2)
Tumor site
Supraglottic	17 (15.0)
Glottic	39 (34.5)
Subglottic	17 (15.0)
Transglottic	40 (35.4)
Clinical stage
III	25 (22.1)
IV	88 (77.9)
T-classification
T3	34 (30.1)
T4	79 (69.9)
N-classification
N0	70 (61.9)
N1	17 (15.0)
N2	26 (23.0)
Differentiation
Poor	20 (17.7)
Moderate	62 (54.9)
High	31 (27.4)
Previous treatment(s)
None	66 (58.4)
Surgery	36 (31.9)
Radiation	2 (1.8)
Systemic therapy	9 (8.0)
Thyroidectomy type
Hemi	86 (76.1)
Total	27 (23.9)
Thyroid involvement	29 (25.7)
Total	113(100)

Data presented as no. of patients (%) unless otherwise indicated. TNM classification according to American Joint Committee on Cancer (AJCC) Criteria, 8th Edition.

Complete radiological data were available for only 84 patients (78 men and 6 women), in whom the incidence of pathological thyroid gland invasion was 20.2% (17/84). Univariate analysis was performed for all factors. The characteristics of patients with thyroid gland invasion versus those without are summarized and compared in Table 2. The mean age was 59.4 years in the thyroid invasion group and 61.1 years in the non-invasion group, but there was no statistically significant difference between the two groups. And only one patient with thyroid gland invasion indicated by preoperative examination was pathologically confirmed. There were no statistically significant differences in these characteristics between the groups. It should be mentioned that we also analyzed preoperative radiation (P = 0.351) and the type of the primary surgery (P = 0.263) in the recurrent patients, including transoral laser surgery, open partial laryngectomy, and the results showed no statistical difference. Predictors from preoperative examinations and intraoperative evaluation associated with thyroid gland invasion (Table 3) were assessed. Results indicated that pathological thyroid gland invasion was statistically and significantly associated with invasion of the lower third of thyroid cartilage (P = 0.014), thyroid gland invasion on CT/MRI (P = 0.0001), and thyroid gland invasion in intraoperative evaluation (P = 0.0001). The lower 1/3 cartilaginous invasion was measured by preoperative imaging, and thyroid gland invasion in intraoperative evaluation was assessed by surgeons during the operation. Multivariate analysis revealed significant association between thyroid gland invasion on CT/MRI (P = 0.034) and pathological thyroid gland invasion (Table 4).

Table 2.

Characteristics of 84 Patients and Their Association With Thyroid Invasion.

Characteristic	Thyroid invasion		P-value
Characteristic	Yes	No	P-value
Age, years (mean ± SD)	59.4±12.4	61.1±9.7	0.549
Sex			0.094
Male	14	64
Female	3	3
Tumor site			0.509
Supraglottic	2	14
Glottic	5	24
Subglottic	4	7
Transglottic	6	22
Previous treatment(s)			0.101
None	8	46
Surgery	6	17
Radiation	1	0
Systemic therapy	2	4
T-classification			0.056
T3	1	26
T4	16	41
N-classification			0.063
N0	7	41
N1	2	13
N2	8	13

Data presented as n, unless otherwise indicated.

Table 3.

Predictors Associated With Thyroid Invasion.

Predictor	Thyroid invasion		P-value
Predictor	Yes	No	P-value
Vocal cord immobility	15	49	0.135
Anterior commissure invasion	14	54	1.000
Paraglottic space invasion	10	41	0.858
Pre-epiglottic space invasion	4	9	0.288
Pyriform sinus invasion	6	11	0.084
Thyroid cartilage invasion	13	37	0.167
Lower half	13	35	0.071
Lower third	13	28	0.014*
Cricoid cartilage invasion	11	40	0.706
Subglottic extension (mean ± SD)	29.7±23.2	18.7±12.0	0.149
Subglottic extension	14	48	0.539
Trachea invasion	8	19	0.140
Cervical lymph node metastasis	4	9	0.288
Thyroid invasion on CT/MRI	9	3	<0.0001*
Intraoperative evaluation	10	7	<0.0001*
Previous tracheostomy	6	24	0.968

Data presented as n, unless otherwise indicated. Values in bold type indicate statistically significant differences (i.e., p < 0.05). CT, computed tomography; MRI, magnetic resonance imaging

Table 4.

Multivariate Analysis Using the Binary Logistic Regression Test.

Predictor	P-value	OR	95% CI
Thyroid invasion on CT/MRI	0.034*	9.889	1.190–82.220
Intraoperative evaluation	0.335	2.564	0.377–17.411
Invasion of the lower 1/3 thyroid cartilage	0.103	3.208	0.789–13.044

Value in bold type indicates a statistically significant difference (i.e., p < 0.05). CI, confidence interval; CT, computed tomography; MRI, magnetic resonance imaging; OR, odds ratio

The sensitivity of thyroid gland invasion on CT/MRI was only 52.9%. We introduced a parallel test for joint prediction with the lower third of thyroid cartilage invasion and thyroid gland invasion on CT/MRI (Table 5), which means if either or both of two predictors are positive, the joint predictor was judged to be positive, it had a p-value of 0.001 and increased sensitivity to 88.2%. The specificity, positive predictive value, and negative predictive value of this joint predictor were 56.7%, 34.1%, and 95.0%, respectively. A receiver operating characteristic (ROC) curve was plotted to evaluate the performance of these predictors, and the area under the ROC curve (AUC) of the joint predictor was 0.725 (Figure 1), which means it was an acceptable discrimination.

Table 5.

Sensitivity (Se), Specificity (Sp), and Positive and Negative Predictive Values (PPV and NPV) of Positive Predictors.

Predictor	Se (%)	Sp (%)	PPV (%)	NPV (%)
A. Thyroid invasion on CT/MRI	52.9	95.5	75.0	88.9
B. Intraoperative evaluation	58.8	89.6	58.8	89.6
C. Invasion of the lower third thyroid cartilage	76.5	58.2	31.7	90.7
A//C	88.2	56.7	34.1	95.0

A//C: If either A or C is positive, it is denoted as positive. CT, computed tomography; MRI, magnetic resonance imaging

Figure 1.

Receiver operating characteristic (ROC) curve of positive predictors. Area under the ROC curve (AUC) is presented in parentheses.

Discussion

Our data demonstrated that, among 113 patients with thyroidectomy and total laryngectomy, the probability of thyroid invasion was 25.7%. In univariate analysis, statistically significant predictors included invasion of the lower third of thyroid cartilage, thyroid gland invasion on CT/MRI, and intraoperative evaluation. In multivariate analysis, only thyroid gland invasion on CT/MRI was statistically significant. To our knowledge, this was the first study to use invasion of the lower third of thyroid cartilage as a predictor, which was measured by radiologists on raw imaging data. We found that it had a statistically significant relationship with thyroid gland invasion in univariate analysis, with a sensitivity of 76.5%. Because the sensitivity of thyroid gland invasion on CT/MRI and intraoperative evaluation was not high, we used a parallel test to jointly predict and increased the sensitivity to 88.2%.

Indications for thyroidectomy during total laryngectomy remain controversial. In the present study, we proposed a new predictor that combined invasion of the lower third of thyroid cartilage and thyroid gland invasion on CT/MRI. It improves the sensitivity of thyroid gland invasion on CT/MRI and reduces the missed diagnosis. At the same time, a negative predictive value of 95% means that it can distinguish patients who do not need thyroidectomy commendably. If our results are further validated, improved strategies based on these predictors may be used to identify patients with a higher risk for thyroid gland invasion in total laryngectomy for advanced LSCC.

Several studies have shown that subglottic extension was the only statistically significant factor in thyroid gland invasion.¹³ Since the thyroid gland is located in front of the 2/3/4 tracheal rings and below the glottis, laryngeal tumor with subglottic extension may invade the thyroid gland directly. In our study, the subglottic extension was emphatically analyzed as a categorical variable and a continuous variable. However, the P-values obtained showed no statistical correlation with thyroid gland invasion, regardless of the tumor site. Thus, our current study might not suggest that subglottic extension was the predictor in thyroid gland invasion. We hypothesized that subglottic invasion might be less important than previous studies had thought, and thyroid cartilage invasion was more valuable. It may be the same as Strome et al’s claim that tumor progression occurs mainly in the paraglottic space and extralaryngeal compartments and the potential for mucosal diffusion is limited.¹⁴ LSCC may spread to extralaryngeal tissue via a variety of paths.¹⁵ Lesions spread downward through thyroid cartilage, cricoid cartilage, and cricothyroid membrane; laterally through paraglottic space along the conus elasticus of the trachea; and laterally outside the skeletal framework of the larynx through the cricopharyngeal muscle, cricothyroid muscle, and surrounding fascia.¹⁶ Also, it might be related to the inadequate number of cases and the ethnicity of the study group. More cases and studies of different human species are needed to explain this.

Cartilage invasion has been reported to be a predictor of thyroid gland invasion.¹⁷ However, the difference in our study was that there was no statistical relationship between thyroid cartilage invasion and thyroid gland invasion (P = 0.167). Considering that most cases of thyroid gland invasion occur by direct extension,¹⁸ and the thyroid gland is adjacent to the lower part of the thyroid cartilage, we believe that the lower part of the thyroid cartilage may be more related to thyroid gland invasion. We then analyzed the relationship between invasion of the lower half and lower third of thyroid cartilage invasion and thyroid gland invasion, respectively. Univariate analysis revealed that invasion of the lower third of thyroid cartilage could be used as a predictor of thyroid gland invasion. It indicated that whether a thyroidectomy was performed in a patient with LSCC could not be predicted by invasion of the upper and middle part of thyroid cartilage.

Preoperative CT is an effective method for ruling out thyroid gland invasion.¹⁹ The negative predictive value in our study (88.9%) supports this concept. However, local control of the tumor is critical. The sensitivity (52.9%) predicted by thyroid gland invasion on CT/MRI means that nearly one-half of patients were underdiagnosed according to thyroid gland invasion, which would lead to a poor prognosis for these patients. As a solution, we introduced invasion of the lower third of thyroid cartilage, which was a more sensitive predictor related to thyroid gland invasion for joint prediction. When patients with advanced LSCC exhibited invasion of the lower third of thyroid cartilage or/and thyroid gland invasion on CT/MRI, the predictor was markedly positive and thyroidectomy was recommended. Its sensitivity increased to 88.2% and negative predictive value increased to 95%. This indicated that 88.2% of patients with thyroid gland invasion could be identified using this new predictor, which demonstrated a correct probability of 95% that the new predictor reflected an uninvaded thyroid gland.

In previous studies, the incidence of thyroid gland invasion in advanced laryngeal cancer ranges from 1% to 30%.^20,21 The incidence of thyroid gland invasion fell within this range in the present study. In 2013, a meta-analysis reported an overall pooled incidence of thyroid gland invasion in 1287 patients of 10.7%.²² In other words, it is unnecessary for nearly 90% of patients to undergo thyroidectomy during total laryngectomy. Thyroidectomy must not be performed routinely.²³ Therefore, thyroidectomy may only be required during total laryngectomy for selected cases involving tumors invading the lower third of thyroid cartilage or/and thyroid gland invasion on CT/MRI. The new predictor may inform surgeons as to whether to perform thyroidectomy during total laryngectomy for patients with advanced LSCC. It emphasizes the importance of preoperative evaluation and made a tradeoff between ensuring local control of tumor(s) and reducing postoperative complications, which would promote individualized treatment.

There were limitations to the present study, the first of which were its retrospective, single-center design. Second, the study population was the one that selected for thyroidectomy with laryngectomy by the surgeon’s existing criteria and the data has selection bias relating to the prevalence of thyroid gland invasion. Third, because some patient medical records were incomplete, the number of cases that were analyzed was reduced. Moreover, there may have been latent thyroid gland invasions that remained undetected. The caution should be exercised among potential predictors such as T-classification (P = 0.056), N-classification (P = 0.063), and lower-half thyroid cartilage invasion (P = 0.071) as their P-value was close to 0.05 in our results. Large-scale, prospective, and multicenter studies are needed in the future.

Conclusion

In the present study, 25.7% of patients with advanced LSCC exhibited thyroid gland invasion. A new predictor that combined invasion of the lower third of thyroid cartilage and thyroid gland invasion on CT/MRI was associated with thyroid gland invasion. Thyroidectomy may be required during total laryngectomy for selected cases involving tumors that invade the lower third of thyroid cartilage and/or thyroid gland invasion on CT/MRI. In the future, more validation studies are needed to confirm this.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Science and Technology Program of Guangzhou City, China (201707010489 to Z.L.) and the Matching Scientific Research Fund for Guangdong Provincial Outstanding Young Medical Talent by Guangdong Provincial People’s Hospital (KJ012019453 to Z. L).

ORCID iD

Zhongming Lu

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