Eur Arch Otorhinolaryngol DOI 10.1007/s00405-015-3525-9
LARYNGOLOGY
Characteristics of thyroid nodules causing globus symptoms Inn-Chul Nam • Hoon Choi • Eun-Sook Kim Eun-Young Mo • Young-Hak Park • Dong-Il Sun
•
Received: 22 August 2014 / Accepted: 23 January 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract A globus sensation is one of the most common complaints in otolaryngologic clinics, and laryngopharyngeal reflux is the most common cause. However, thyroid nodules also can cause globus symptoms. The purpose of this study was to identify the characteristics of thyroid nodules that cause globus. We selected patients prospectively with a single thyroid nodule on ultrasonograms. Patients with other causes of globus symptoms were excluded using questionnaires, fiber optic laryngoscopic examinations, and a psychiatric screening tool. In total, 175 patients were enrolled. Patients were divided into two groups according to globus symptoms. Ultrasonographic characteristics and clinicopathological parameters were compared between the groups. Among various clinicopathologic and ultrasonographic parameters, size and horizontal location of the thyroid nodule showed significant differences between the groups. Nodules larger than 3 cm and those located anterior to the trachea had a tendency to cause globus symptoms. Regarding horizontal location, nodules that all parts were located anterior to the trachea showed a higher tendency to cause globus symptoms than
I.-C. Nam Y.-H. Park D.-I. Sun (&) Department of Otolaryngology, Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul St. Mary‘s Hospital, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea e-mail: [email protected] H. Choi Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea E.-S. Kim E.-Y. Mo Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
nodules that only some parts were located anterior to the trachea. In conclusion, thyroid nodules with specific size and location can cause globus symptoms, and this finding can be indicated in patient counseling. Also, conservative treatments or thyroidectomy may be helpful in relieving patients’ globus symptoms. Keywords Thyroid nodule Character Globus Signs and symptoms
Introduction The globus sensation is the feeling of a lump or foreign body in the throat. Otolaryngologists are frequently confronted with this condition; indeed, some authors report that it represents 3 % of all new clinic referrals [1]. The most common cause is laryngopharyngeal reflux (LPR), followed by lingual tonsil hypertrophy, epiglottic cyst, benign or malignant laryngeal or pharyngeal neoplasm, esophageal dysmobility, and psychiatric morbidity [2–4]. However, some patients complain of globus symptoms with none of the pathological findings mentioned above. Among these patients, some have thyroid nodules. It has been our experience that in many patients presenting with globus-type symptoms, the incidence of thyroid nodules is relatively high. Thus, we hypothesized that thyroid nodules with specific characteristics may cause globus-type symptoms; that is, some specific thyroid nodules can be a cause of globus. There are few reported studies on the relationship between thyroid pathology and globus symptoms [5–7]. These studies have addressed the possibility that thyroid pathologies, such as thyroiditis, multinodular goiter, and malignancy, could cause globus. According to these
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studies, patients who have thyroid pathologies do have a higher tendency to complain of globus symptoms, and the symptoms can be improved after thyroidectomy. The most common pathologies in these studies are inflammation (diffuse thyroiditis) and goiter. Total thyroid volume is also related to globus symptoms [5]. The larger the thyroid volume, the more patients complain of globus symptoms. These results indicate that enlargement of the thyroid, for various reasons, can cause globus symptoms, and this seems a readily understandable result. These previous studies focused only on the pathology itself, not the characteristics of the thyroid nodule. It is still unclear as to which nodules would cause globus symptoms and which would not. This is why we began the present prospective trial, the aim of which was to ascertain which thyroid nodules with which characteristics could cause globus symptoms. In this study, we analyzed the characteristics of thyroid nodules in patients with globus, in the hope that the results contribute to a better understanding of the relationship between thyroid nodules and globus symptoms.
Materials and methods Study design Patients underwent thyroid ultrasomograms from March 2013 to February 2014 were prospectively enrolled in this study. All subjects were informed of the nature of the study and gave informed consent. The institutional review board of our institution approved the design of the study. Patients scheduled to undergo thyroid ultrasonograms in the Department of Internal Medicine and Endocrine Surgery were initially asked a simple question that if he or she had globus symptoms. After the ultrasonographic examination, patients with a thyroid nodule were referred to our department. If patients showed multinodular goiter or diffuse thyroiditis, they were excluded, because these are already known to cause globus symptoms. Patients with multiple nodules were also excluded, because it might be unclear which nodule(s) caused globus symptoms. For clarity, we included only patients with a single nodule on ultrasonograms. In our department, patients were asked to complete questionnaires, and underwent a fiber optic laryngoscopic examination by an expert otolaryngologist to rule out other causes that might be the reason for the globus symptoms. Two questionnaires were applied to patients. One is a questionnaire related to LPR, and another is related to psychological symptoms. Among various causes of globus symptoms, LPR was the main concern because it is known to be the most common cause of globus symptoms. To rule
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out patients with LPR, we used the reflux symptom index (RSI) in the questionnaire and the reflux finding score (RFS) with fiber optic laryngoscopy. RSI is a powerful and easy tool to predict the presence of LPR, and is an excellent ancillary diagnostic tool for LPR a commonly used questionnaire to diagnose LPR [8, 9]. It is well known that if a patient shows a RSI score higher than 13 and a RFS score higher than seven simultaneously, the patient can be diagnosed with LPR [10]. According to these criteria, we excluded patients who we considered to have LPR. During fiber optic laryngoscopic examinations, we examined the patient’s oral cavity, pharynx, and larynx closely to check for specific findings that could also be causes of globus symptoms other than LPR. These findings included lingual tonsil hypertrophy, tonsilliths, retroverted epiglottis, and pharyngeal or laryngeal cyst or neoplasm. We also excluded patients with these findings on fiber optic laryngoscopic examinations. We also excluded patients with depressive symptoms because globus can be a form of hysterical symptom having neurotic basis showing strong association with depressive disorder and good response to anti-depressive therapy [11]. For this purpose, we applied the Korean version of Beck Depression Inventory- Fast Screen (BDIFS) to rule out psychological factors of globus symptom. The Beck depression inventory (BDI) is a 21-item selfrating scale for measuring depression that has been widely used and shows high validity in differentiating between depressed and nondepressed subjects, with high international propagation [12]. The BDI-FS consists of seven of the original BDI 21 items and was designed for use as a screening tool to detect depression, with the advantage of faster administration and reduced patient burden, while eliminating criterion contamination in patients with symptoms that could be attributable to other medical or biological factors or substance abuse [13]. The BDI-FS items are rated from 0 (never) to 3 (high likelihood) for a total score of 21: a score of 4 or higher indicates depression and has a sensitivity of 97 % and specificity of 99 % among outpatients screened for major depressive disorders. Mild depression is indicated by a score of 4–6, moderate depression by a score of 7–9, and severe depression by a score of 10 or higher [14]. Therefore we excluded patient who showed BDI-FS scores higher than 4. Finally, we included patients who were demonstrated to have single thyroid nodules on ultrasonograms, and who had no other condition that could cause globus symptoms on the questionnaire or laryngoscopic examination. We categorized the included patients into two groups according to the answer to the initial question that if the patient had globus symptom or not. Patients with globus symptoms were classified into the study group, and patients without globus symptoms were classified into the control group (Fig. 1).
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Thyroid ultrasonogram in IM, GS A question on the presence of globus sypmtom
Multinodular goiter or thyroiditis Multiple nodules
Single nodule or cyst
Refer to ENT
1. 2.
Questionnaire Laryngoscopic exam
Rule out other diseases that can cause globus symptoms 1. LPR; RSI ุ 7 with RFS ุ 13 2. 3.
BDI-FS ุ 4 Laryngoscopic exam Lingual tonsil hypertrophy Laryngeal cartilage structural anomaly Epiglottic cyst Neoplasm of pharynx or larynx
The location of nodules was evaluated in horizontal and vertical locations. The vertical location was determined as the superior, middle, or inferior portion, according to the relative location of the isthmic portion. An imaginary horizontal line from the upper and lower border of the isthmus was drawn, and the vertical location of the nodule was determined on the basis of these lines. The horizontal location was determined according to the relative location of the trachea, and categorized as ‘outside’, ‘cross’, or ‘within’. Two imaginary vertical lines from the bilateral tracheal border were also drawn. The area between the two lines was the portion of thyroid lying anterior to the trachea. If the nodule was located outside this area, it was categorized into the ‘outside group’. If whole part of the nodule was located within this area, it was classified into the ‘within group’. If some parts of the nodule was located within this area, it was classified into the ‘cross group’ (Fig. 2). Statistical analyses
Exclusion
Inclusion
Presence of globus symptoms (Initial question) yes Study group
no
Statistical analyses were performed using the SPSS software (SPSS Inc., Chicago, IL). A p value of less than 0.05 was considered to indicate statistical significance. The relationship between parameters and globus symptoms was investigated using a univariate analysis (v2 test). Variables with p \ 0.05 in the univariate analysis were included in the multivariate analysis. This was performed using binary logistic regression.
Control group
Fig. 1 Flow chart of the study design
We compared demographic profiles, ultrasonographic features, and pathological results (if the patient had undergone a cytological study) between the groups. Ultrasonographic features Patients were examined using high-resolution ultrasound by one expert consultant radiologist using a 10-MHz probe (ALOKA, prosound-a10, Tokyo, Japan). Scanning was conducted in the longitudinal and transverse planes, and covered both lobes of the thyroid and the isthmus. The parameters of the ultrasonographic features of thyroid nodules were size, side, nature, and location. For size, the largest diameters among length, height, and width were estimated. For side, nodules were categorized on the right or left lobe on the basis of the midline of the trachea. The nature of nodules was categorized as cyst, mixed nodule, spongiform nodule, and solid nodule according to the ultrasonogram findings.
Results Among 530 patients who underwent thyroid ultrasonograms during aforementioned period, 314 patients showed multiple nodules and were excluded. Among the remaining 216 patients with a single thyroid nodule, 41 patients were excluded according to the exclusion criteria (31 patients according to RSI and RFS, 4 patients with epiglottic cyst, and 6 patients with BDI-FS scores). Finally, 175 patients were enrolled (16 males, 159 females). The mean age was 54.1 ± 11.6 (range 18–82) years. Among the patients, the number with globus symptoms was 84 (48.0 %), and the number without was 91 (52.0 %). On ultrasonographic findings, the mean size of nodules was 13.2 ± 10.1 (range 3–50) mm. The sizes of nodules were categorized on the basis of 10 mm differences and, because of the lack of very large nodules, all nodules larger than 3 cm were placed in a single group. Regarding the nature of the nodules, solid nodules were the most common form (77.7 %), followed by cysts and mixed nodules (8.0 %) and spongiform nodules (6.3 %). Among the 175 patients, 78 (44.6 %) underwent ultrasonogram-guided
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Fig. 2 Horizontal location of anodule on an ultrasonogram. a ‘outside’ the trachea, b ‘cross’ the trachea, c ‘within’ the trachea. White vertical lines indicate imaginary vertical lines from the tracheal border, a white circle indicates a thyroid nodule
fine needle aspiration cytology. Among them 59 (75.6 %) showed benign pathologies, and 19 (24.4 %) showed malignancies. In the 19 malignant patients, all showed papillary carcinomas, except one who showed a follicular carcinoma on the final pathological report after a hemithyroidectomy. Details of patient’s demographics are summarized in Table 1. When we compared demographic, ultrasonographic, and pathological data between the study and control groups, size and horizontal location showed significant differences between the groups on univariate analysis (Tables 1, 2). In the multivariate analysis, size greater than 3 cm and horizontal location showed statistically significant differences. Regarding horizontal location, nodules of the crossing and within groups showed a higher probability of causing globus symptoms than outside group nodules. The odds ratio for the cross group was 13.557, and that of the within group was 16.482 (Table 3).
Discussion The globus sensation, the feeling of something in the throat, stems from the Latin word meaning ball. There are
Table 1 Patients’ demographics of the two groups
Parameters
several terms in the literature used to describe the phenomenon, including globus, globus pharyngeus, globus hystericus, and globus syndrome. As the ‘‘historical’’ term globus hystericus implies, it was once regarded as a manifestation of hysteria. Hippocrates first noted globus pharyngeus about 2,500 years ago [15]. The etiology of globus appears to be multifactorial. There is considerable debate concerning the role of gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) in patients with globus. GERD is also one of the most prevalent disorders, affecting 10–30 % of all individuals. In most patients, heartburn and regurgitation are the most common presenting symptoms of GERD. However, many patients present to otolaryngologists with atypical symptoms, such as globus. Some studies have suggested that LPR is a major cause of globus [16, 17]. The report by Sinn et al. [18] demonstrated that the globus symptom score was significantly higher in patients with LPR than in those without LPR. This is consistent with populationbased surveys that have demonstrated an increased risk of globus among patients with LPR symptoms [19]. The reported odds ratios for globus among patients with LPR range from 1.9 to 3.9.
Control group (%)
Study group (%)
Total (%)
p value
Female
80 (45.7)
79 (45.1)
159 (90.9)
0.159
Male
11 (6.3)
5 (2.9)
16 (9.1)
21–30
2 (1.1)
6 (3.4)
8 (4.6)
31–40
8 (4.6)
2 (1.1)
10 (5.7)
41–50 51–60
21 (12.0) 32 (18.3)
16 (9.1) 35 (20.0)
37 (21.1) 67 (38.3)
61–70
15 (8.6)
3 (13.1)
38 (21.7)
C71
13 (7.4)
2 (1.1)
15 (8.6)
28 (35.9)
31 (39.7)
59 (75.6)
6 (7.7)
13 (16.7)
19 (24.4)
Gender
Age (years) 0.820
Pathology Benign Malignancy
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0.225
Eur Arch Otorhinolaryngol Table 2 Ultrasonographic characteristics of nodules of the two groups
Parameters
Control group (%)
Study group (%)
Total (%)
p value
Side Right
53 (30.3)
44 (25.1)
97 (55.4)
Left
38 (21.7)
40 (22.9)
78 (44.6)
B10
46 (26.3)
26 (14.9)
72 (41.1)
B20
28 (16.0)
27 (15.4)
55 (31.4)
B30
9 (5.1)
18 (10.3)
27 (15.4)
[30
8 (4.6)
13 (7.4)
21 (12.0)
76 (43.4)
22 (12.6)
98 (56.0)
Cross
14 (8.0)
57 (32.6)
71 (40.6)
Within
1 (0.6)
5 (2.9)
6 (3.4)
0.436
Size (mm) 0.023*
Horizontal location Outside
0.000*
Vertical location Lower
28 (16.0)
27 (15.4)
55 (31.4)
Mid Upper
52 (29.7) 11 (6.3)
48 (27.4) 9 (5.1)
100 (57.1) 20 (11.4)
0.952
Nature Cystic
9 (5.1)
5 (2.9)
14 (8.0)
Mixed
2 (1.1)
12 (6.9)
14 (8.0)
74 (42.3)
62 (35.4)
136 (77.7)
6 (3.4)
5 (2.9)
11 (6.3)
Solid Spongiform
* p \ 0.05
Table 3 Multivariate logistic regression for globus symptoms Variables
b (SE)
p value
Exp (b)
95 % CI of exp (b) Lower
Upper
Size (mm) B10
0.587
B20
0.109 (0.727)
0.167
1.116
0.268
4.640
B30
0.283 (0.738)
0.393
1.328
0.12
5.643
[30
0.513 (0.864)
0.023*
1.671
0.307
9.081
2.607 (0.409)
0.000* 0.007*
13.557
6.084
30.211
Within
2.802 (1.137)
0.014*
16.482
1.774
153.167
Constant
1.377 (1.308)
Horizontal location Outside Cross
* p \ 0.05
It is clear that many patients with globus have concomitant LPR and that there is an association between LPR and globus. Thus, LPR is the most common cause of globus symptoms. However, other conditions can also cause the globus sensation. Published potential causes include cricopharyngeal spasm, psychogenic, lingual tonsillar hypertrophy, epiglottic cyst, benign or malignant laryngeal or pharyngeal neoplasm, cervical osteophytes and temporomandibular joint disorders [3, 4, 7].
0.099
Besides, thyroid pathology can also cause globus symptoms. It is well known that an enlarged thyroid can cause globus or compressive symptoms. Multinodular goiter, one of the more common indications for thyroidectomy, is associated with compressive symptoms. In a 7-year series, 33 % of patients diagnosed with benign goiter had compressive symptomatology [20]. A separate study focusing on marked thyroid gland enlargement reported an incidence of 86 % [21]. In a study that measured the volume of removed thyroid glands, the average volume of the gland in patients with compressive symptoms was 75.5 versus 37.1 mL in asymptomatic patients (p \ 0.0001) and the authors concluded that larger volume was associated with globus symptoms [5]. Recently, several studies have identified a relationship between thyroid pathology and globus symptoms. Marshall et al. [7] prospectively examined the thyroids of 43 patients with globus symptoms and 33 controls, using high-resolution ultrasound, to test the hypothesis that a higher incidence of thyroid abnormalities existed in patients with globus symptoms than in the normal population. They found that abnormalities were present in 72 % of patients with globus symptoms and in 33 % of controls (p \ 0.001) and concluded that abnormalities of the thyroid gland may be responsible for globus symptoms. The thyroid pathologies in the study were mixtures of single nodules with various sizes, multiple nodules, and diffuse thyroiditis.
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Burns et al. [6] showed a statistically significant postoperative improvement in symptom scores (p = 0.0001) in patients where significant inflammation was present in the removed histological specimen, and concluded that presence of significant thyroid inflammation was also related to globus symptoms. The most common pathologies in this study were multinodular goiter, followed by several follicular adenomas and papillary carcinomas. Another study evaluated the relationship between thyroid disease and compressive symptoms [5]. In that study, compressive symptoms included mild forms, such as globus symptoms, as well as severe forms, such as dyspnea or dysphagia. They found that among 333 patients with thyroid disease, 52 % of patients experienced compressive symptoms preoperatively, but that only 8 % continued to have compressive symptoms (p \ 0.0001) postoperatively. Compressive symptoms were present in 72 % of patients with lymphocytic thyroiditis, 71 % of patients with anaplastic thyroid cancer, and 60 % of patients with goiter. To summarize, all of these studies found that specific pathologies, such as goiter, inflammation, and malignancy, were associated with globus symptoms. However, there is no reported study evaluating which thyroid nodules with which characteristics would cause globus symptoms. Thus, we planned a prospective study to determine the specific characteristics of nodules causing globus symptoms. Because enlarged thyroid gland due to multinodular goiter or diffuse thyroiditis is already known to cause globus symptoms, we excluded those conditions and included only thyroid nodules or cysts. If there were multiple nodules or cysts, there could be bias in interpreting the results. Thus, we included only single nodules or cysts. To rule out other conditions that can cause globus symptoms, we used questionnaires, psychiatric screening tools, and performed fiber optic laryngoscopic examinations in all patients. Using these simple tools, we excluded other conditions that can cause globus symptoms. We classified enrolled patients according to the presence of globus symptoms, and compared their demographic, ultrasonographic, and pathological data. To our knowledge, this is the first reported study to determine the characteristics of nodules causing globus symptoms. We evaluated the ultrasonographic characteristics of thyroid nodules in terms of size, vertical location, horizontal location, and nature. Among these parameters, size and horizontal location showed statistically significant differences. Regarding size, it is easy to predict that a large nodule would cause globus symptoms, as multinodular goiter does. However, with smaller nodules, it is unclear what size of nodule would cause globus symptoms. There is no study, clinical trial, or consensus on this. In the multivariate analysis, nodules larger than 3 cm
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showed a statistically significant difference. Thus, a single nodule or cyst larger than 3 cm can be the cause for globus symptoms. Regarding horizontal location, we categorized nodules on the basis of the trachea. Pressure on adjacent structures may be the first evidence of a thyroid tumor, benign or malignant. The structure most commonly affected is the esophagus, with the resulting dysphagia being more a discomfort on swallowing than a true obstructive dysphagia. In a study reviewing 83 patients with thyroid adenomas, the most common symptom was dysphagia [15]. The trachea is also located close to the thyroid. Thus, it can be suggested that if a thyroid nodule is located close to the trachea, it can put pressure on the trachea and cause compressive or globus symptoms. Also, thyroid tissue on the trachea is thinner than other parts. On this basis, we categorized the horizontal location according to the relative location to the trachea: outside, cross, and within. In our results, nodules crossing and within the trachea showed a higher tendency to cause globus symptoms than outside nodules; this difference was statistically significant. Also, nodules within the trachea showed a higher tendency to cause globus symptoms than nodules crossing trachea (odds ratio 13.557 vs. 16.482). Thus, if all or part of a nodule or cyst is located on the trachea, it can cause globus symptoms. According to our results, gender was not a cause of globus symptoms. There is a report that women are more likely to suffer from globus symptoms [17]. Some authors have suggested that the reason for this is the generally higher incidence of thyroid nodules in women than men. The incidence of thyroid abnormalities in the normal population was reported to be 27 % in subjects aged 20–50 years, and the figure is higher for women (34.6 %) than for men (24.2 %) [16]. These results have been cited to explain the association between the high incidence of women suffering from globus symptoms and the high incidence of thyroid abnormalities in women. They suggested that the explanation for the association was that thyroid abnormalities were a direct cause of globus symptoms in some patients [7]. However, they did not consider other issues that could also cause globus symptoms beyond thyroid nodules. When we excluded other conditions, including LPR, gender was not a determining factor of globus symptoms in patients with thyroid nodules. Due to the imbalance of the gender ratio of the included patients, the statistical impact of our study on gender may be weak. The high percentage of female patients was inevitable because the patients were sequentially selected in a given period, and the incidence of a thyroid nodule is relatively high in female patients compared to male. If we collected patients with an even gender ratio, the results may be changed.
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Other parameters, such as age, nature, vertical location, and pathology of the nodule, showed no statistically significant difference. Some authors consider that local symptoms in adjacent structures, such as dysphagia or dyspnea in thyroid disease, may be interpreted as being more suggestive of a malignant potential, although no correlation between local symptoms and malignancy has been shown where this has been investigated. In our study, pathological evaluations were performed using ultrasonogram-guided fine needle aspiration cytology in 44.6 % of patients, and malignancy did not seem to be connected with causing globus symptoms versus benign nodules. According to recent studies, globus symptoms can also result from neurogenic origins such as chronic laryngeal irritation (irritable larynx syndrome), or postviral vagal neuropathy [22, 23]. The concept of ‘‘irritable larynx syndrome’’ was put forth in 1999 by Morrison et al. [22]. Patients with this syndrome show dysphonia, laryngospasm, and laryngeal muscle tension, as well as globus sensation. These symptoms typically worsen in the face of a sensory trigger, such as an inhaled irritant. The diagnosis of irritable larynx syndrome is clinical and based on exclusion of other identifiable neurological or psychiatric diseases. Postviral vagal neuropathy was first described by Amin and Koufman in 2001 [24]. The disorder involves a host of upper aerodigestive symptoms attributable to vagal neuropathy that occur after an acute upper respiratory tract infection (URI). The reported symptoms include dysphonia, vocal fatigue, vocal fold paresis, odynophagia, dysphagia, neuropathic pain, cough, laryngospasm, excessive throat clearing, and globus. It is impossible to objectively prove a viral causation, and therefore the diagnosis is clinical, based on the history of a URI and the absence of other discernible causes. In the current study, we excluded patients with LPR, identifiable anatomical abnormalities, and psychiatric conditions, and did not consider neurogenic cause of globus symptoms. Therefore, globus symptoms of some included patients may result from neurogenic causes. This can be a shortcoming of our study. If we had took detailed history of a URI, and examined the presence of hyperkinetic laryngeal dysfunction to rule out neurogenic causes, our results on the relation between thyroid nodules and globus symptoms could be more accurate. In conclusion, this is the first reported study to determine characteristics of thyroid nodules that can cause globus symptoms other than already known pathologies, such as multinodular goiter or thyroiditis. Nodules or cysts larger than 3 cm or located on the trachea (through some part of the nodule) can cause globus symptoms. This information can be used in counseling patients suffering from globus symptoms. Simply identifying a cause of globus symptoms can be helpful for patient reassurance, and reassurance itself can help to relieve patient symptoms.
A question raised by this study is how a thyroid nodule causing globus symptoms should be managed, if it is demonstrated to be benign. In the case of cystic nodules, simple aspiration can reduce the volume and globus symptoms can be expected to subside. However, for solid nodules, although radiofrequency ablation may be helpful, globus symptoms would probably not be improved without thyroidectomy, and globus itself is not an indication for thyroidectomy. According to the revised American Thyroid Association (ATA) management guidelines for thyroid nodules, thyroid nodules diagnosed as benign require follow-up because of a low, but not negligible, false-negative rate of up to 5 % with fine needle aspiration cytology [25]. However this false-negative rate may be even higher with nodules larger than 4 cm [26]. Thus, for benign nodules larger than 4 cm, it is generally recommended to perform a thyroidectomy. Also, according to the ATA guidelines, recurrent thyroid cysts after aspiration should be considered for surgical removal or percutaneous ethanol injection, based on compressive symptoms and cosmetic concerns. Thus, thyroidectomy (typically, hemithyroidectomy) may be helpful in relieving globus symptoms in patients who have nodules or cysts larger than 4 cm, and a thyroidectomy may be an option for the treatment of globus symptoms. The results of this study may also be useful to thyroid surgeons. Globus symptoms can be the first sign of a thyroid nodule, and this can lead to a thyroid ultrasonogram. Through this, occult thyroid nodules can be found, and early and appropriate treatment can follow. Based on the results of this study, we are planning to perform another study about the role of radiofrequency ablation and percutaneous ethanol injection for thyroid nodules and cysts in relieving globus symptoms. Conflict of interest
None.
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Eur Arch Otorhinolaryngol 8. Belafsky PC, Postma GN, Koufman JA (2001) The validity and reliability of the reflux finding score (RFS). Laryngoscope 111:1313–1317 9. Belafsky PC, Postma GN, Koufman JA (2002) Validity and reliability of the reflux symptom index (RSI). J Voice 16:274–277 10. Tezer MS, Kockar MC, Kockar O, Celik A (2006) Laryngopharyngeal reflux finding scores correlate with gastroesophageal reflux disease and Helicobacter pylori expression. Acta Otolaryngol 126:958–961 11. Cybulska EM (1997) Globus hystericus—a somatic symptom of depression? The role of electroconvulsive therapy and antidepressants. Psychosom Med 59:67–69 12. Richter P, Werner J, Heerlein A, Kraus A, Sauer H (1998) On the validity of the Beck Depression Inventory A review. Psychopathology 31:160–168 13. Poole H, Bramwell R, Murphy P (2009) The utility of the Beck Depression Inventory Fast Screen (BDI-FS) in a pain clinic population. Eur J Pain 13:865–869 14. Steer RA, Cavalieri TA, Leonard DM, Beck AT (1999) Use of the Beck Depression Inventory for Primary Care to screen for major depression disorders. Gen Hosp Psychiatry 21:106–111 15. Harar RP, Kumar S, Saeed MA, Gatland DJ (2004) Management of globus pharyngeus: review of 699 cases. J Laryngol Otol 118:522–527 16. Chevalier JM, Brossard E, Monnier P (2003) Globus sensation and gastroesophageal reflux. Eur Arch Otorhinolaryngol 260:273–276 17. Hill J, Stuart RC, Fung HK, Ng EK, Cheung FM, Chung CS, van Hasselt CA (1997) Gastroesophageal reflux, motility disorders, and psychological profiles in the etiology of globus pharyngis. Laryngoscope 107:1373–1377
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18. Sinn DH, Kim JH, Kim S, Son HJ, Kim JJ, Rhee JC, Rhee PL (2008) Response rate and predictors of response in a short-term empirical trial of high-dose rabeprazole in patients with globus. Aliment Pharmacol Ther 27:1275–1281 19. Rey E, Elola-Olaso CM, Rodrı´guez-Artalejo F, Locke GR 3rd, Dı´az-Rubio M (2006) Prevalence of atypical symptoms and their association with typical symptoms of gastroesophageal reflux in Spain. Eur J Gastroenterol Hepatol 18:969–975 20. Alfonso A, Christoudias G, Amaruddin Q, Herbsman H, Gardner B (1981) Tracheal or esophageal compression due to benign thyroid disease. Am J Surg 142:350–354 21. McHenry CR, Piotrowski JJ (1994) Thyroidectomy in patients with marked thyroid enlargement: airway management, morbidity, and outcome. Am Surg 60:586–591 22. Morrison M, Rammage L, Emami AJ (1999) The irritable larynx syndrome. J Voice 13:447–455 23. Rees CJ, Henderson AH, Belafsky PC (2009) Postviral vagal neuropathy. Ann Otol Rhinol Laryngol 118:247–252 24. Amin MR, Koufman JA (2001) Vagal neuropathy after upper respiratory infection: a viral etiology? Am J Otolaryngol 22:251–256 25. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM (2009) Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19:1167–1214 26. McCoy KL, Jabbour N, Ogilvie JB, Ohori NP, Carty SE, Yim JH (2007) The incidence of cancer and rate of false-negative cytology in thyroid nodules greater than or equal to 4 cm in size. Surgery 142:837–844 (Discussion 844 e831-833)
LARYNGOLOGY
Characteristics of thyroid nodules causing globus symptoms Inn-Chul Nam • Hoon Choi • Eun-Sook Kim Eun-Young Mo • Young-Hak Park • Dong-Il Sun
•
Received: 22 August 2014 / Accepted: 23 January 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract A globus sensation is one of the most common complaints in otolaryngologic clinics, and laryngopharyngeal reflux is the most common cause. However, thyroid nodules also can cause globus symptoms. The purpose of this study was to identify the characteristics of thyroid nodules that cause globus. We selected patients prospectively with a single thyroid nodule on ultrasonograms. Patients with other causes of globus symptoms were excluded using questionnaires, fiber optic laryngoscopic examinations, and a psychiatric screening tool. In total, 175 patients were enrolled. Patients were divided into two groups according to globus symptoms. Ultrasonographic characteristics and clinicopathological parameters were compared between the groups. Among various clinicopathologic and ultrasonographic parameters, size and horizontal location of the thyroid nodule showed significant differences between the groups. Nodules larger than 3 cm and those located anterior to the trachea had a tendency to cause globus symptoms. Regarding horizontal location, nodules that all parts were located anterior to the trachea showed a higher tendency to cause globus symptoms than
I.-C. Nam Y.-H. Park D.-I. Sun (&) Department of Otolaryngology, Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul St. Mary‘s Hospital, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea e-mail: [email protected] H. Choi Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea E.-S. Kim E.-Y. Mo Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
nodules that only some parts were located anterior to the trachea. In conclusion, thyroid nodules with specific size and location can cause globus symptoms, and this finding can be indicated in patient counseling. Also, conservative treatments or thyroidectomy may be helpful in relieving patients’ globus symptoms. Keywords Thyroid nodule Character Globus Signs and symptoms
Introduction The globus sensation is the feeling of a lump or foreign body in the throat. Otolaryngologists are frequently confronted with this condition; indeed, some authors report that it represents 3 % of all new clinic referrals [1]. The most common cause is laryngopharyngeal reflux (LPR), followed by lingual tonsil hypertrophy, epiglottic cyst, benign or malignant laryngeal or pharyngeal neoplasm, esophageal dysmobility, and psychiatric morbidity [2–4]. However, some patients complain of globus symptoms with none of the pathological findings mentioned above. Among these patients, some have thyroid nodules. It has been our experience that in many patients presenting with globus-type symptoms, the incidence of thyroid nodules is relatively high. Thus, we hypothesized that thyroid nodules with specific characteristics may cause globus-type symptoms; that is, some specific thyroid nodules can be a cause of globus. There are few reported studies on the relationship between thyroid pathology and globus symptoms [5–7]. These studies have addressed the possibility that thyroid pathologies, such as thyroiditis, multinodular goiter, and malignancy, could cause globus. According to these
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studies, patients who have thyroid pathologies do have a higher tendency to complain of globus symptoms, and the symptoms can be improved after thyroidectomy. The most common pathologies in these studies are inflammation (diffuse thyroiditis) and goiter. Total thyroid volume is also related to globus symptoms [5]. The larger the thyroid volume, the more patients complain of globus symptoms. These results indicate that enlargement of the thyroid, for various reasons, can cause globus symptoms, and this seems a readily understandable result. These previous studies focused only on the pathology itself, not the characteristics of the thyroid nodule. It is still unclear as to which nodules would cause globus symptoms and which would not. This is why we began the present prospective trial, the aim of which was to ascertain which thyroid nodules with which characteristics could cause globus symptoms. In this study, we analyzed the characteristics of thyroid nodules in patients with globus, in the hope that the results contribute to a better understanding of the relationship between thyroid nodules and globus symptoms.
Materials and methods Study design Patients underwent thyroid ultrasomograms from March 2013 to February 2014 were prospectively enrolled in this study. All subjects were informed of the nature of the study and gave informed consent. The institutional review board of our institution approved the design of the study. Patients scheduled to undergo thyroid ultrasonograms in the Department of Internal Medicine and Endocrine Surgery were initially asked a simple question that if he or she had globus symptoms. After the ultrasonographic examination, patients with a thyroid nodule were referred to our department. If patients showed multinodular goiter or diffuse thyroiditis, they were excluded, because these are already known to cause globus symptoms. Patients with multiple nodules were also excluded, because it might be unclear which nodule(s) caused globus symptoms. For clarity, we included only patients with a single nodule on ultrasonograms. In our department, patients were asked to complete questionnaires, and underwent a fiber optic laryngoscopic examination by an expert otolaryngologist to rule out other causes that might be the reason for the globus symptoms. Two questionnaires were applied to patients. One is a questionnaire related to LPR, and another is related to psychological symptoms. Among various causes of globus symptoms, LPR was the main concern because it is known to be the most common cause of globus symptoms. To rule
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out patients with LPR, we used the reflux symptom index (RSI) in the questionnaire and the reflux finding score (RFS) with fiber optic laryngoscopy. RSI is a powerful and easy tool to predict the presence of LPR, and is an excellent ancillary diagnostic tool for LPR a commonly used questionnaire to diagnose LPR [8, 9]. It is well known that if a patient shows a RSI score higher than 13 and a RFS score higher than seven simultaneously, the patient can be diagnosed with LPR [10]. According to these criteria, we excluded patients who we considered to have LPR. During fiber optic laryngoscopic examinations, we examined the patient’s oral cavity, pharynx, and larynx closely to check for specific findings that could also be causes of globus symptoms other than LPR. These findings included lingual tonsil hypertrophy, tonsilliths, retroverted epiglottis, and pharyngeal or laryngeal cyst or neoplasm. We also excluded patients with these findings on fiber optic laryngoscopic examinations. We also excluded patients with depressive symptoms because globus can be a form of hysterical symptom having neurotic basis showing strong association with depressive disorder and good response to anti-depressive therapy [11]. For this purpose, we applied the Korean version of Beck Depression Inventory- Fast Screen (BDIFS) to rule out psychological factors of globus symptom. The Beck depression inventory (BDI) is a 21-item selfrating scale for measuring depression that has been widely used and shows high validity in differentiating between depressed and nondepressed subjects, with high international propagation [12]. The BDI-FS consists of seven of the original BDI 21 items and was designed for use as a screening tool to detect depression, with the advantage of faster administration and reduced patient burden, while eliminating criterion contamination in patients with symptoms that could be attributable to other medical or biological factors or substance abuse [13]. The BDI-FS items are rated from 0 (never) to 3 (high likelihood) for a total score of 21: a score of 4 or higher indicates depression and has a sensitivity of 97 % and specificity of 99 % among outpatients screened for major depressive disorders. Mild depression is indicated by a score of 4–6, moderate depression by a score of 7–9, and severe depression by a score of 10 or higher [14]. Therefore we excluded patient who showed BDI-FS scores higher than 4. Finally, we included patients who were demonstrated to have single thyroid nodules on ultrasonograms, and who had no other condition that could cause globus symptoms on the questionnaire or laryngoscopic examination. We categorized the included patients into two groups according to the answer to the initial question that if the patient had globus symptom or not. Patients with globus symptoms were classified into the study group, and patients without globus symptoms were classified into the control group (Fig. 1).
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Thyroid ultrasonogram in IM, GS A question on the presence of globus sypmtom
Multinodular goiter or thyroiditis Multiple nodules
Single nodule or cyst
Refer to ENT
1. 2.
Questionnaire Laryngoscopic exam
Rule out other diseases that can cause globus symptoms 1. LPR; RSI ุ 7 with RFS ุ 13 2. 3.
BDI-FS ุ 4 Laryngoscopic exam Lingual tonsil hypertrophy Laryngeal cartilage structural anomaly Epiglottic cyst Neoplasm of pharynx or larynx
The location of nodules was evaluated in horizontal and vertical locations. The vertical location was determined as the superior, middle, or inferior portion, according to the relative location of the isthmic portion. An imaginary horizontal line from the upper and lower border of the isthmus was drawn, and the vertical location of the nodule was determined on the basis of these lines. The horizontal location was determined according to the relative location of the trachea, and categorized as ‘outside’, ‘cross’, or ‘within’. Two imaginary vertical lines from the bilateral tracheal border were also drawn. The area between the two lines was the portion of thyroid lying anterior to the trachea. If the nodule was located outside this area, it was categorized into the ‘outside group’. If whole part of the nodule was located within this area, it was classified into the ‘within group’. If some parts of the nodule was located within this area, it was classified into the ‘cross group’ (Fig. 2). Statistical analyses
Exclusion
Inclusion
Presence of globus symptoms (Initial question) yes Study group
no
Statistical analyses were performed using the SPSS software (SPSS Inc., Chicago, IL). A p value of less than 0.05 was considered to indicate statistical significance. The relationship between parameters and globus symptoms was investigated using a univariate analysis (v2 test). Variables with p \ 0.05 in the univariate analysis were included in the multivariate analysis. This was performed using binary logistic regression.
Control group
Fig. 1 Flow chart of the study design
We compared demographic profiles, ultrasonographic features, and pathological results (if the patient had undergone a cytological study) between the groups. Ultrasonographic features Patients were examined using high-resolution ultrasound by one expert consultant radiologist using a 10-MHz probe (ALOKA, prosound-a10, Tokyo, Japan). Scanning was conducted in the longitudinal and transverse planes, and covered both lobes of the thyroid and the isthmus. The parameters of the ultrasonographic features of thyroid nodules were size, side, nature, and location. For size, the largest diameters among length, height, and width were estimated. For side, nodules were categorized on the right or left lobe on the basis of the midline of the trachea. The nature of nodules was categorized as cyst, mixed nodule, spongiform nodule, and solid nodule according to the ultrasonogram findings.
Results Among 530 patients who underwent thyroid ultrasonograms during aforementioned period, 314 patients showed multiple nodules and were excluded. Among the remaining 216 patients with a single thyroid nodule, 41 patients were excluded according to the exclusion criteria (31 patients according to RSI and RFS, 4 patients with epiglottic cyst, and 6 patients with BDI-FS scores). Finally, 175 patients were enrolled (16 males, 159 females). The mean age was 54.1 ± 11.6 (range 18–82) years. Among the patients, the number with globus symptoms was 84 (48.0 %), and the number without was 91 (52.0 %). On ultrasonographic findings, the mean size of nodules was 13.2 ± 10.1 (range 3–50) mm. The sizes of nodules were categorized on the basis of 10 mm differences and, because of the lack of very large nodules, all nodules larger than 3 cm were placed in a single group. Regarding the nature of the nodules, solid nodules were the most common form (77.7 %), followed by cysts and mixed nodules (8.0 %) and spongiform nodules (6.3 %). Among the 175 patients, 78 (44.6 %) underwent ultrasonogram-guided
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Fig. 2 Horizontal location of anodule on an ultrasonogram. a ‘outside’ the trachea, b ‘cross’ the trachea, c ‘within’ the trachea. White vertical lines indicate imaginary vertical lines from the tracheal border, a white circle indicates a thyroid nodule
fine needle aspiration cytology. Among them 59 (75.6 %) showed benign pathologies, and 19 (24.4 %) showed malignancies. In the 19 malignant patients, all showed papillary carcinomas, except one who showed a follicular carcinoma on the final pathological report after a hemithyroidectomy. Details of patient’s demographics are summarized in Table 1. When we compared demographic, ultrasonographic, and pathological data between the study and control groups, size and horizontal location showed significant differences between the groups on univariate analysis (Tables 1, 2). In the multivariate analysis, size greater than 3 cm and horizontal location showed statistically significant differences. Regarding horizontal location, nodules of the crossing and within groups showed a higher probability of causing globus symptoms than outside group nodules. The odds ratio for the cross group was 13.557, and that of the within group was 16.482 (Table 3).
Discussion The globus sensation, the feeling of something in the throat, stems from the Latin word meaning ball. There are
Table 1 Patients’ demographics of the two groups
Parameters
several terms in the literature used to describe the phenomenon, including globus, globus pharyngeus, globus hystericus, and globus syndrome. As the ‘‘historical’’ term globus hystericus implies, it was once regarded as a manifestation of hysteria. Hippocrates first noted globus pharyngeus about 2,500 years ago [15]. The etiology of globus appears to be multifactorial. There is considerable debate concerning the role of gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) in patients with globus. GERD is also one of the most prevalent disorders, affecting 10–30 % of all individuals. In most patients, heartburn and regurgitation are the most common presenting symptoms of GERD. However, many patients present to otolaryngologists with atypical symptoms, such as globus. Some studies have suggested that LPR is a major cause of globus [16, 17]. The report by Sinn et al. [18] demonstrated that the globus symptom score was significantly higher in patients with LPR than in those without LPR. This is consistent with populationbased surveys that have demonstrated an increased risk of globus among patients with LPR symptoms [19]. The reported odds ratios for globus among patients with LPR range from 1.9 to 3.9.
Control group (%)
Study group (%)
Total (%)
p value
Female
80 (45.7)
79 (45.1)
159 (90.9)
0.159
Male
11 (6.3)
5 (2.9)
16 (9.1)
21–30
2 (1.1)
6 (3.4)
8 (4.6)
31–40
8 (4.6)
2 (1.1)
10 (5.7)
41–50 51–60
21 (12.0) 32 (18.3)
16 (9.1) 35 (20.0)
37 (21.1) 67 (38.3)
61–70
15 (8.6)
3 (13.1)
38 (21.7)
C71
13 (7.4)
2 (1.1)
15 (8.6)
28 (35.9)
31 (39.7)
59 (75.6)
6 (7.7)
13 (16.7)
19 (24.4)
Gender
Age (years) 0.820
Pathology Benign Malignancy
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0.225
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Parameters
Control group (%)
Study group (%)
Total (%)
p value
Side Right
53 (30.3)
44 (25.1)
97 (55.4)
Left
38 (21.7)
40 (22.9)
78 (44.6)
B10
46 (26.3)
26 (14.9)
72 (41.1)
B20
28 (16.0)
27 (15.4)
55 (31.4)
B30
9 (5.1)
18 (10.3)
27 (15.4)
[30
8 (4.6)
13 (7.4)
21 (12.0)
76 (43.4)
22 (12.6)
98 (56.0)
Cross
14 (8.0)
57 (32.6)
71 (40.6)
Within
1 (0.6)
5 (2.9)
6 (3.4)
0.436
Size (mm) 0.023*
Horizontal location Outside
0.000*
Vertical location Lower
28 (16.0)
27 (15.4)
55 (31.4)
Mid Upper
52 (29.7) 11 (6.3)
48 (27.4) 9 (5.1)
100 (57.1) 20 (11.4)
0.952
Nature Cystic
9 (5.1)
5 (2.9)
14 (8.0)
Mixed
2 (1.1)
12 (6.9)
14 (8.0)
74 (42.3)
62 (35.4)
136 (77.7)
6 (3.4)
5 (2.9)
11 (6.3)
Solid Spongiform
* p \ 0.05
Table 3 Multivariate logistic regression for globus symptoms Variables
b (SE)
p value
Exp (b)
95 % CI of exp (b) Lower
Upper
Size (mm) B10
0.587
B20
0.109 (0.727)
0.167
1.116
0.268
4.640
B30
0.283 (0.738)
0.393
1.328
0.12
5.643
[30
0.513 (0.864)
0.023*
1.671
0.307
9.081
2.607 (0.409)
0.000* 0.007*
13.557
6.084
30.211
Within
2.802 (1.137)
0.014*
16.482
1.774
153.167
Constant
1.377 (1.308)
Horizontal location Outside Cross
* p \ 0.05
It is clear that many patients with globus have concomitant LPR and that there is an association between LPR and globus. Thus, LPR is the most common cause of globus symptoms. However, other conditions can also cause the globus sensation. Published potential causes include cricopharyngeal spasm, psychogenic, lingual tonsillar hypertrophy, epiglottic cyst, benign or malignant laryngeal or pharyngeal neoplasm, cervical osteophytes and temporomandibular joint disorders [3, 4, 7].
0.099
Besides, thyroid pathology can also cause globus symptoms. It is well known that an enlarged thyroid can cause globus or compressive symptoms. Multinodular goiter, one of the more common indications for thyroidectomy, is associated with compressive symptoms. In a 7-year series, 33 % of patients diagnosed with benign goiter had compressive symptomatology [20]. A separate study focusing on marked thyroid gland enlargement reported an incidence of 86 % [21]. In a study that measured the volume of removed thyroid glands, the average volume of the gland in patients with compressive symptoms was 75.5 versus 37.1 mL in asymptomatic patients (p \ 0.0001) and the authors concluded that larger volume was associated with globus symptoms [5]. Recently, several studies have identified a relationship between thyroid pathology and globus symptoms. Marshall et al. [7] prospectively examined the thyroids of 43 patients with globus symptoms and 33 controls, using high-resolution ultrasound, to test the hypothesis that a higher incidence of thyroid abnormalities existed in patients with globus symptoms than in the normal population. They found that abnormalities were present in 72 % of patients with globus symptoms and in 33 % of controls (p \ 0.001) and concluded that abnormalities of the thyroid gland may be responsible for globus symptoms. The thyroid pathologies in the study were mixtures of single nodules with various sizes, multiple nodules, and diffuse thyroiditis.
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Burns et al. [6] showed a statistically significant postoperative improvement in symptom scores (p = 0.0001) in patients where significant inflammation was present in the removed histological specimen, and concluded that presence of significant thyroid inflammation was also related to globus symptoms. The most common pathologies in this study were multinodular goiter, followed by several follicular adenomas and papillary carcinomas. Another study evaluated the relationship between thyroid disease and compressive symptoms [5]. In that study, compressive symptoms included mild forms, such as globus symptoms, as well as severe forms, such as dyspnea or dysphagia. They found that among 333 patients with thyroid disease, 52 % of patients experienced compressive symptoms preoperatively, but that only 8 % continued to have compressive symptoms (p \ 0.0001) postoperatively. Compressive symptoms were present in 72 % of patients with lymphocytic thyroiditis, 71 % of patients with anaplastic thyroid cancer, and 60 % of patients with goiter. To summarize, all of these studies found that specific pathologies, such as goiter, inflammation, and malignancy, were associated with globus symptoms. However, there is no reported study evaluating which thyroid nodules with which characteristics would cause globus symptoms. Thus, we planned a prospective study to determine the specific characteristics of nodules causing globus symptoms. Because enlarged thyroid gland due to multinodular goiter or diffuse thyroiditis is already known to cause globus symptoms, we excluded those conditions and included only thyroid nodules or cysts. If there were multiple nodules or cysts, there could be bias in interpreting the results. Thus, we included only single nodules or cysts. To rule out other conditions that can cause globus symptoms, we used questionnaires, psychiatric screening tools, and performed fiber optic laryngoscopic examinations in all patients. Using these simple tools, we excluded other conditions that can cause globus symptoms. We classified enrolled patients according to the presence of globus symptoms, and compared their demographic, ultrasonographic, and pathological data. To our knowledge, this is the first reported study to determine the characteristics of nodules causing globus symptoms. We evaluated the ultrasonographic characteristics of thyroid nodules in terms of size, vertical location, horizontal location, and nature. Among these parameters, size and horizontal location showed statistically significant differences. Regarding size, it is easy to predict that a large nodule would cause globus symptoms, as multinodular goiter does. However, with smaller nodules, it is unclear what size of nodule would cause globus symptoms. There is no study, clinical trial, or consensus on this. In the multivariate analysis, nodules larger than 3 cm
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showed a statistically significant difference. Thus, a single nodule or cyst larger than 3 cm can be the cause for globus symptoms. Regarding horizontal location, we categorized nodules on the basis of the trachea. Pressure on adjacent structures may be the first evidence of a thyroid tumor, benign or malignant. The structure most commonly affected is the esophagus, with the resulting dysphagia being more a discomfort on swallowing than a true obstructive dysphagia. In a study reviewing 83 patients with thyroid adenomas, the most common symptom was dysphagia [15]. The trachea is also located close to the thyroid. Thus, it can be suggested that if a thyroid nodule is located close to the trachea, it can put pressure on the trachea and cause compressive or globus symptoms. Also, thyroid tissue on the trachea is thinner than other parts. On this basis, we categorized the horizontal location according to the relative location to the trachea: outside, cross, and within. In our results, nodules crossing and within the trachea showed a higher tendency to cause globus symptoms than outside nodules; this difference was statistically significant. Also, nodules within the trachea showed a higher tendency to cause globus symptoms than nodules crossing trachea (odds ratio 13.557 vs. 16.482). Thus, if all or part of a nodule or cyst is located on the trachea, it can cause globus symptoms. According to our results, gender was not a cause of globus symptoms. There is a report that women are more likely to suffer from globus symptoms [17]. Some authors have suggested that the reason for this is the generally higher incidence of thyroid nodules in women than men. The incidence of thyroid abnormalities in the normal population was reported to be 27 % in subjects aged 20–50 years, and the figure is higher for women (34.6 %) than for men (24.2 %) [16]. These results have been cited to explain the association between the high incidence of women suffering from globus symptoms and the high incidence of thyroid abnormalities in women. They suggested that the explanation for the association was that thyroid abnormalities were a direct cause of globus symptoms in some patients [7]. However, they did not consider other issues that could also cause globus symptoms beyond thyroid nodules. When we excluded other conditions, including LPR, gender was not a determining factor of globus symptoms in patients with thyroid nodules. Due to the imbalance of the gender ratio of the included patients, the statistical impact of our study on gender may be weak. The high percentage of female patients was inevitable because the patients were sequentially selected in a given period, and the incidence of a thyroid nodule is relatively high in female patients compared to male. If we collected patients with an even gender ratio, the results may be changed.
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Other parameters, such as age, nature, vertical location, and pathology of the nodule, showed no statistically significant difference. Some authors consider that local symptoms in adjacent structures, such as dysphagia or dyspnea in thyroid disease, may be interpreted as being more suggestive of a malignant potential, although no correlation between local symptoms and malignancy has been shown where this has been investigated. In our study, pathological evaluations were performed using ultrasonogram-guided fine needle aspiration cytology in 44.6 % of patients, and malignancy did not seem to be connected with causing globus symptoms versus benign nodules. According to recent studies, globus symptoms can also result from neurogenic origins such as chronic laryngeal irritation (irritable larynx syndrome), or postviral vagal neuropathy [22, 23]. The concept of ‘‘irritable larynx syndrome’’ was put forth in 1999 by Morrison et al. [22]. Patients with this syndrome show dysphonia, laryngospasm, and laryngeal muscle tension, as well as globus sensation. These symptoms typically worsen in the face of a sensory trigger, such as an inhaled irritant. The diagnosis of irritable larynx syndrome is clinical and based on exclusion of other identifiable neurological or psychiatric diseases. Postviral vagal neuropathy was first described by Amin and Koufman in 2001 [24]. The disorder involves a host of upper aerodigestive symptoms attributable to vagal neuropathy that occur after an acute upper respiratory tract infection (URI). The reported symptoms include dysphonia, vocal fatigue, vocal fold paresis, odynophagia, dysphagia, neuropathic pain, cough, laryngospasm, excessive throat clearing, and globus. It is impossible to objectively prove a viral causation, and therefore the diagnosis is clinical, based on the history of a URI and the absence of other discernible causes. In the current study, we excluded patients with LPR, identifiable anatomical abnormalities, and psychiatric conditions, and did not consider neurogenic cause of globus symptoms. Therefore, globus symptoms of some included patients may result from neurogenic causes. This can be a shortcoming of our study. If we had took detailed history of a URI, and examined the presence of hyperkinetic laryngeal dysfunction to rule out neurogenic causes, our results on the relation between thyroid nodules and globus symptoms could be more accurate. In conclusion, this is the first reported study to determine characteristics of thyroid nodules that can cause globus symptoms other than already known pathologies, such as multinodular goiter or thyroiditis. Nodules or cysts larger than 3 cm or located on the trachea (through some part of the nodule) can cause globus symptoms. This information can be used in counseling patients suffering from globus symptoms. Simply identifying a cause of globus symptoms can be helpful for patient reassurance, and reassurance itself can help to relieve patient symptoms.
A question raised by this study is how a thyroid nodule causing globus symptoms should be managed, if it is demonstrated to be benign. In the case of cystic nodules, simple aspiration can reduce the volume and globus symptoms can be expected to subside. However, for solid nodules, although radiofrequency ablation may be helpful, globus symptoms would probably not be improved without thyroidectomy, and globus itself is not an indication for thyroidectomy. According to the revised American Thyroid Association (ATA) management guidelines for thyroid nodules, thyroid nodules diagnosed as benign require follow-up because of a low, but not negligible, false-negative rate of up to 5 % with fine needle aspiration cytology [25]. However this false-negative rate may be even higher with nodules larger than 4 cm [26]. Thus, for benign nodules larger than 4 cm, it is generally recommended to perform a thyroidectomy. Also, according to the ATA guidelines, recurrent thyroid cysts after aspiration should be considered for surgical removal or percutaneous ethanol injection, based on compressive symptoms and cosmetic concerns. Thus, thyroidectomy (typically, hemithyroidectomy) may be helpful in relieving globus symptoms in patients who have nodules or cysts larger than 4 cm, and a thyroidectomy may be an option for the treatment of globus symptoms. The results of this study may also be useful to thyroid surgeons. Globus symptoms can be the first sign of a thyroid nodule, and this can lead to a thyroid ultrasonogram. Through this, occult thyroid nodules can be found, and early and appropriate treatment can follow. Based on the results of this study, we are planning to perform another study about the role of radiofrequency ablation and percutaneous ethanol injection for thyroid nodules and cysts in relieving globus symptoms. Conflict of interest
None.
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