Extent of thyroidectomy affects vocal and throat functions: A prospective observational study of lobectomy versus total thyroidectomy

Extent of thyroidectomy affects vocal and throat functions: A prospective observational study of lobectomy versus total thyroidectomy Junsun Ryu, MD, PhD,a Youn Mi Ryu, MS,a Yuh-S. Jung, MD, PhD,a Su-jin Kim, MD,b You Jin Lee, MD, PhD,c Eun-Kyung Lee, MD,c Seok-Ki Kim, MD, PhD,d Tae-Sung Kim, MD,d Tae Hyun Kim, MD, PhD,e Chang Yoon Lee, MD,f Seog Yun Park, MD, PhD,g and Ki Wook Chung, MD, PhD,h Goyang and Seoul, Korea

Background. Voice and throat dysfunction may occur in patients after thyroidectomy, even in the absence of apparent laryngeal nerve injury. We evaluated the impact of thyroid surgery on voice and throat function using perceptive, objective, and subjective measurements in a prospectively enrolled and serially followed cohort of thyroid cancer patients. We assessed the impact of surgical extent and intensity of postoperative treatment, including addition radioactive iodine treatment (RIT), on these functions. Methods. Consenting patients undergoing thyroid lobectomy (TL; n = 33), total thyroidectomy (TT; n = 41), or TT plus RIT (n = 81), none of whom had laryngeal nerve dysfunction perioperatively, were enrolled prospectively. All underwent comprehensive functional evaluations, including perceptive voice quality using the grade, roughness, breathiness, asthenia, strain (GRBAS) scale and acoustic voice analysis with multiple parameters, and filled out subjective questionnaires, including the Voice Handicap Index (VHI) and the Glasgow Edinburgh Throat Scale, before thyroidectomy and at 1, 6, and 12 months postoperatively. Results. In this study, 14–83% of the patients developed some element of voice and throat dysfunction, shown consistently in different evaluations. Typical patterns were alterations of perceptive voice, deranged acoustic parameters, and subjective worsening on the VHI and GETS. Moreover, these changes were correlated with the extent of treatment, especially within 3 months after operation, and often persisted 12 months postoperatively. RIT had no effects on voice outcomes throughout the follow-up. Conclusion. Voice and throat dysfunction are evident after thyroidectomy, more severely after TT than TL. These potential disabilities should be considered carefully to further enhance patients’ quality of life. (Surgery 2013;154:611-20.) From the Department of Otolaryngology-Head and Neck Surgery, Head & Neck Oncology Clinic,a the Departments of Surgery,b Internal Medicine, Breast & Endocrine Cancer Branch,c Department of Nuclear Medicine, Molecular Imaging & Therapy Branch,d Center for Proton Therapy,e Department of Radiology,f and Department of Pathology,g Center for Thyroid Cancer, Research Institute and Hospital, National Cancer Center, Goyang; and the Department of Surgery, and Asan Medical Center,h University of Ulsan College of Medicine, Seoul, Korea

THYROIDECTOMY, with or without postoperative radioactive iodine treatment (RIT), is the mainstay of treatment of thyroid carcinoma, which became one of the most frequent types of cancer in Korea Accepted for publication March 28, 2013. Reprint requests: Yuh-S. Jung, MD, PhD, Department of Otolaryngology-Head and Neck Surgery, Head and Neck Oncology Clinic, Center for Thyroid Cancer, Research Institute and Hospital, National Cancer Center, 809 Madu1-dong, Ilsan-gu, Goyang, Gyeonggi-do 411-764, Korea. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2013.03.011

in 2009.1 Because the 10-year survival rates of differentiated thyroid carcinoma are excellent worldwide (80–95%2,3), and approach 99% in Korea,1 optimizing quality of life (QOL) is becoming important. Although it is possible that a wider extent of resection and more aggressive treatment might cause more tissue damage, the impact of different extents of resection/lymphadenectomy and intensities of RIT on patient’s functioning and QOL have not been fully investigated and may even be neglected when selecting initial treatment plans. Thyroidectomy for thyroid cancer may cause functional impairments, including voice and SURGERY 611

612 Ryu et al

discomfort during swallowing. Injury to the recurrent laryngeal nerve (RLN) have been considered traditionally to be the main cause of alterations in postoperative voice and swallowing, with a prevalence of 0.77%4 to 13.3%.5 Hence, the prevention of RLN injury has been paramount in thyroid surgery. Even in the absence of apparent injuries to the RLN, however, vocal and throat functions can be altered sufficiently to decrease a patient’s QOL, often called post-thyroidectomy syndrome.6-9 Several etiologies, such as fibrosis,10,11 vascular changes,10 psychosocial reactions,11 and injuries to the external branch of the superior laryngeal nerve (EBSLN)12 can cause this condition. Subjective discomfort and changes in swallowing function can also occur after thyroid surgery. Although several reports have suggested shortterm, subjective voice changes of various etiologies in 28–45% of patients,6,12 with a frequency as high as 84%,13 the characteristics of these alterations, especially in relation to the intensity of treatment, have not yet been clarified. Despite emerging interest and the need to enhance treatment-related QOL, prospective, large-scale data about the long-term outcomes of voice and throat function after thyroidectomy are lacking. Most of these functional alterations have been regarded as a self-limited, short-term problem7,10,11 and thus often underestimated. Furthermore, the impact of surgical extent and postoperative intensity of treatment, including the addition of RIT, on objective functions remain unclear. Functional impacts of different extents of thyroid procedures have been often neglected while planning treatment, mainly owing to the lack of objective evidence. We, therefore, evaluated the impact of thyroid surgery on voice and throat functions, as well as the patterns of further functional recovery. We used perceptive and objective measurements, as well as using questionnaires addressing subjective symptoms related to vocal and throat function, in a prospectively enrolled and serially followed, large-scale cohort of patients with thyroid cancer without overt perioperative injury to the RLN. We also assessed the impact of extent of resection and treatment intensity, including the addition of RIT. METHODS Study design and patient selection. We enrolled prospectively 175 patients with papillary, follicular, or medullary thyroid carcinoma who underwent operation, with or without postoperative RIT, at

Surgery September 2013

the Center for Thyroid Cancer, National Cancer Center, Goyang, Korea, from November 2009 to December 2010. Patients were excluded if they were <25 or >80 years old; had T4, N1b, or M1 disease; had vocal cord immobility, nodules, polyps, or granulomas before thyroidectomy; or had poorly differentiated or anaplastic thyroid cancer on preoperative evaluation. Patients were excluded later from functional analyses if they had postoperative glottic pathologies, including nodules, polyps, and granulomas; had benign final pathology; or had insufficient follow-up measurements. Our final study cohort consisted of 155 patients, 33 men and 122 women, of mean age 47.1 ± 10.7 years (range, 29–78). Of these, 74 underwent thyroid surgery alone, including 33 who underwent thyroid lobectomy (TL) and 41 who underwent total thyroidectomy (TT), and 81 who underwent TT followed by RIT (TT/RIT; Table I). All patients underwent repeated functional evaluations, consisting of perceptive, objective, and subjective evaluations of voice and throat function, along with smoking history, stage, and pulmonary function tests. All of the patients were followed for $12 months after thyroidectomy. All participants provided informed consent according to the policies and procedures approved by the institutional review board of the National Cancer Center, Korea. The medical records of the participating patients were collected prospectively, and data were stored in a specifically designed database. Surgery and RIT. The decisions on the extent of resection and RIT were made primarily following the guidelines of American Thyroid Association for differentiated thyroid cancer14 after full interdisciplinary discussion. All thyroid operations were performed by 3 experienced thyroid surgeons involved (Y.-S.J., K.W.C., J.R.), via an open approach with a standard Kocher’s skin incision. All the procedures were performed under the general anesthesia with conventional orotracheal intubation by experienced anesthesiologists. The prethyroid strap muscles of all patients were dissected on the midline but not divided, resulting in total extracapsular thyroidectomy, either bilaterally (TT) or unilaterally (TL). During operation, the RLN was exposed, and the branches of the superior and inferior thyroid arteries were ligated as close as possible to the thyroid capsule to minimize any inadvertent damage to the EBSLN or parathyroid glands. The fascia of the cricothyroid muscle was kept undamaged with maximal effort. The EBSLN was not intentionally dissected or

Ryu et al 613

Surgery Volume 154, Number 3

Table I. Characteristics of subjects TL (n = 33) Gender, n (%) Female Male Age, mean years ± SD Histology: malignant, n (%) Papillary Follicular Medullary Abnormal pulmonary functiony Smoker, n (%) Never Former Current T stage T1a T1b T2 T3 N stage N0 N1a

TT (n = 41)

TT/RIT (n = 81)

P .219

26 (78.8) 36 (87.8) 60 (74.1) 7 (21.2) 5 (12.2) 21 (25.9) 44.8 ± 8.5 50.8 ± 11.3 47.5 ± 9.9

.038* .093

30 2 1 3

(90.9) 40 (97.6) 77 (95.0) (6.1) 0 (0.0) 4 (5.0) (3.0) 1 (2.4) 0 (0.0) (9.1) 5 (12.2) 11 (13.6)

.803

.462 22 (66.7) 32 (78.0) 50 (61.7) 5 (15.2) 3 (7.4) 14 (17.3) 6 (18.2) 6 (14.6) 17 (21.0) .001z 27 2 0 4

(81.8) 35 (85.4) 20 (24.7) (6.1) 1 (2.4) 9 (11.1) (0.0) 0 (0.0) 0 (0.0) (12.1) 5 (12.2) 52 (64.2) <.001z

31 (93.9) 39 (95.1) 41 (50.6) 2 (6.1) 2 (4.9) 40 (49.4)

*Significant at the .05 level. yForced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <65%. zSignificant at the .01 level. TL, Thyroid lobectomy; TT, total thyroidectomy; TT/RIT, total thyroidectomy followed by radioactive iodine treatment.

identified, unless it was exposed naturally during dissection of the upper pole and cricothyroid space. The remainder of the operation was performed as described.7 RIT consisted of low-dose (30 mCi, 2 times/year) or high-dose (>100 mCi) treatment 2 months after thyroidectomy. Time course. All enrolled patients were followed for $12 months. All perceptive, subjective, and acoustic measurements were performed by a speech pathologist (Y.M.R) blinded to clinical information. Evaluations were performed preoperatively, 1 month after thyroidectomy (before RIT in patients who underwent TT and RIT; mean value ± standard deviation, 1.1 ± 0.3 months) and at 6 months (2–3 months after initial RIT; 6.3 ± 0.6 months) and 12 months (3 months after second low-dose RIT; 12.6 ± 1.36 months) after thyroidectomy. Patients in the TT/RIT group started RIT about 2 months postoperatively (2.3 ± 0.6 months). We set these time points, trying to minimize the effect of T4 withdrawal. Thyroid function tests

were done simultaneously before and at 6 and 12 months after thyroidectomy. Perceptual and subjective evaluations. Perceptive voice quality was assessed using the grade, roughness, breathiness, asthenia, strain (GRBAS) scale. The Korean version of the Vocal Handicap Index (VHI), a 30-item questionnaire including functional, physical, and emotional subscales, that measured defects in verbal communication, was used for self-evaluation of voice quality.15,16 Each item on the VHI is scored using a 5-point scale (range, 0–4), with the highest score being 120 points. The Glasgow Edinburgh Throat Scale (GETS),17 a 10-item questionnaire measuring symptoms, such as altered sensation, pain, swelling, and swallowing dysfunction, was used for subjective assessment of throat-related symptoms. Each item on the GETS is scored according to a 7-point scale (range, 1–7), with the highest score being 70 points. On both the VHI and GETS, a higher score is indicative of a greater perception of functional disability. Videostrobolaryngoscopy. A 708 rigid laryngoscope-based stroboscopy system (Kay Elemetrics, Lincoln Park, NJ) was used to evaluate vocal fold motility at each follow-up session, as well as for other mucosal pathologies, including nodules, polyps, and granulomas of the glottis. Analysis of acoustic voice. Acoustic voice analysis was performed using the multidimensional voice program (MDVP) and the voice range profile program (VRP). Parameters measured during MDVP analysis included maximum phonation time, fundamental frequency (F0), speaking F0 (sF0), noise-to-harmonic ratio, jitters (%), and shimmers (%). Measurements derived from the VRP included the least (Fmin) and greatest (Fmax) fundamental frequencies (Hz); in these tests, participants produced/ɑ/at a comfortable pitch and proceeded to step or glide up to the greatest sustainable F0, including falsetto (Fmax). They then phonated at a comfortable pitch and stepped or glided down to the least possible F0, excluding vocal fry (Fmin). These procedures were repeated 3 times and averaged in each direction. Statistical analysis. Nonparametric associations were tested using the Fisher exact test or the Pearson Chi-square test. Categorical variables were analyzed by analysis of variance for repeated measures with Dunnett’s multiple comparisons post hoc test when appropriate. The Cochran’s Q and the McNemar tests were used for nonparametric variables. All statistical analyses were performed using STATA/SE version 10.1 (StataCorp LP, College Station, TX).

614 Ryu et al

RESULTS Demographics, preoperative functions, and thyroid function. The 175 patients enrolled initially were classified into 3 groups: TL (n = 37), TT (n = 47), and TT/RIT (n = 91). In the TL group, 4 patients were excluded after surgery because of vocal cord immobility (n = 1; 2.7%), insufficient postoperative follow-up measurements (n = 2), and benign final pathology (n = 1). In the TT group, 6 patients were excluded because of postoperative vocal cord immobility (n = 2; 4.3%), granuloma (n = 1), insufficient postoperative follow-up measurements (n = 2), and benign final pathology (n = 1). In the TT/RIT group, 10 patients were excluded because of postoperative vocal cord immobility (n = 5; 5.5%), granuloma (n = 2), or insufficient postoperative follow-up measurements (n = 3). Our final study cohort consisted of 155 patients, composed of the TL (n = 33; 21%), TT (n = 41; 27%), and TT/RIT (n = 81; 52%) groups (Table I). The 81 patients in the TT/RIT group in whom the RIT was started 6 weeks to 2 months after thyroidectomy (mean, 2.1 ± 0.6 months), either with a low-dose (30 mCi; n = 43 [53%]) or high-dose (100 mCi, n = 9 [11%]; 150 mCi, n = 28 [35%]; 200 mCi, n = 1 [1%]) regimen, as clinicopathologically indicated. RIT was again performed in some patients (30 mCi, n = 39 [48.1%]; 100 mCi, n = 1 [1.2%]) 8 months (mean, 8.1 ± 0.3) after thyroidectomy. None of the patients who received high-dose RITunderwent any additional RIT sessions up to 12 months, the time of the last assessment in this study. Female to male ratios were similar in the TL (26:7), TT (36:5), and TT/RIT (60:21) groups (P = .219). Patients in the TT (50.8 ± 11.3 years) and TT/ RIT (47.5 ± 9.9 years) groups were older than those in the TL group (44.8 ± 8.5 years; P = .038). Pathology was similar in the 3 groups (P = .093), with most patients having papillary carcinoma, including 30 patients (91%) in the TL, 40 (98%) in the TT, and 77 (95%) in the TT/RIT groups, although 3 patients (6%) in the TL and 4 (5%) in the TT/RIT groups had follicular carcinoma and 1 each in the TL and TT groups had medullary carcinoma. Risk factors for vocal dysfunction, including abnormal pulmonary function, defined as forced expiratory volume in 1 second/forced vital capacity of <65%,18 were similar in the TL (n = 3; 9%), TT (n = 5; 12%), and TT/RIT (n = 11; 14%) groups (P = .803), as were current smoking rates, with values of 18% (n = 6), 15% (n = 6), and 14% (n = 11), respectively (P = .462). Advanced T stage (P < .001) and N stage (P < .001) tumors were significantly more frequent in

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the TT/RIT than in the TL and TT groups, but did not differ in the latter 2 groups (Table I). Before thyroidectomy, all the evaluated functional parameters, including GRBAS, acoustic voice parameters such as jitter, shimmer, sF0, F0, Fmax, Fmin, and subjective VHI and GETS, were similar in the 3 groups (Table II). Thus, baseline functional parameters were not different between 3 comparison groups. Among the enrolled 155 patients, no patients had a T4 of <0.89 mg/mL, and no patients had TSH value of >4.05 mIU/mL in the simultaneous measurements before and at 6 and 12 months after thyroidectomy, suggesting the biases of functions owing to hypothyroidism would be minimal throughout the follow-up period. Prevalence of functional worsening after thyroidectomy. Worsening of voice and swallowing function was observed in a substantial number of patients after thyroidectomy (Table III). Some of these functional changes were not temporary and persisted up to 12 months postoperatively. F0 or sF0 decreased (>10% from baseline) and did not normalize for up to 12 months after operation (at 1 month---sF0, 42 cases [27%] and F0, 39 cases [25%]; at 6 months---sF0, 37 cases [24%] and F0, 32 cases [21%]; at 12 months---sF0, 48 cases [31%] and F0, 38 cases [25%]). Acoustic perturbations, including jitter (14.84–17.42%) and shimmer (23.23–14.84%) also worsened for up until 12 months after thyroidectomy. The most frequently observed feature was a decrease in Fmax and subsequent narrowing of pitch range, persisting at 12 months after thyroidectomy. In the majority of the patients, Fmax was decreased (at 1 month, 92 cases [59%]; at 6 months, 97 cases [63%]; at 12 months, 89 cases [57%]), and thus pitch range was narrowed (at 1 month, 91 cases [59%]; at 6 months, 101 cases [65%]; at 12 months, 95 cases [61%]). Subjective questionnaires also indicated substantial functional impairment. Serial VHI revealed that subjective vocal functions had worsened, and serial GETS indicated impaired subjective throat and swallowing functions in most patients post-thyroidectomy. Perioperative changes in voice and throat functions. Voice and throat functions changed postoperatively. All patients in the 3 groups experienced changes in several GRBAS, MDVP, and VRP parameters, as well as changes in subjective VHI and GETS scores 1 month after thyroidectomy (Table IV; Fig 1), with some of these impairments persisting for up to 12 months. Perceptive tests. On the GRBAS perceptive voice scale, all patients in the 3 groups showed increased

Ryu et al 615

Surgery Volume 154, Number 3

Table II. Prevalence of functional worsening after thyroidectomy (n = 155) 1 Month, n (%) Sf0, decrease >10%, from preoperative baseline F0, decrease >10%, from preoperative baseline Jitter, increase >10%, from preoperative baseline Shimmer, increase >10%, from preoperative baseline Fmax, decrease >10%, from preoperative baseline Pitch range, decrease >10%, from preoperative baseline VHI, increase >10%, from preoperative baseline GETS, increase >10%, from preoperative baseline

42 39 23 36 92 91 130 120

(27) (25) (15) (23) (59) (59) (84) (77)

6 Months, n (%) 37 32 23 30 97 101 100 94

(24) (21) (15) (19) (63) (65) (65) (61)

12 Months, n (%) 48 38 27 23 89 95 98 104

(31) (25) (17) (15) (57) (61) (63) (67)

F0, Fundamental frequency; Fmax, highest fundamental frequency; GETS, Glasgow Edinburgh Throat Scale; sF0, speaking fundamental frequency; TL, thyroid lobectomy; TT, total thyroidectomy; TT/RIT, total thyroidectomy and radioactive iodine treatment; VHI, Vocal Handicap Index.

roughness, persisting for 1–12 month (P < .001). Significantly impaired grade (P < .0001) and strain (P < .0001) were observed at 1 month after thyroidectomy, but normalized thereafter. Objective tests. Acoustic parameters measured by the MDVP and VRP also showed impaired profiles in line with the perceptive scale. Although few patients experienced changes in F0, sF0 decreased in the TT/RIT group, from 178.5 ± 37.5 Hz preoperatively to 166.1 ± 166.1 Hz at 1 month (P = .033) and tended to persist afterward (P = .049; Fig 1). Immediate postoperative vocal perturbations were more severe after more extensive resection (TT and TT/RIT) than less extensive resection (TL). At 1 month, jitters in the TT (1.49 ± 0.87 vs 1.98 ± 1.21; P = .041) and TT/RIT (1.29 ± 1.10 vs 1.76 ± 1.13; P = .048) groups and shimmers in the TT group (4.2 ± 1.6 vs 5.1 ± 2.6; P = .025) had worsened relative to baseline, but all normalized on subsequent follow-ups. The VRP showed difficulties in high tone phonation, especially after more extensive resection. Although Fmax did not decrease in the TL group, significant decreases in Fmax were observed in the TT group for up to 6 months, and tended to persist through the follow-ups (Table IV). In contrast, Fmin did not change in any of the 3 groups. These findings indicate that the pitch range decreased significantly in all 3 groups after surgery, and that this decrease persisted for up to 12 months. Subjective tests. The results of questionnaires evaluating vocal (VHI) and throat (GETS) functions were in line with the patterns of perceptive and acoustic parameters. We found that subjective voice functions (VHI) worsened significantly in all 3 groups, persisting for up to 12 months after thyroidectomy. Although the TL group showed only temporary worsening of throat and swallowing symptoms (GETS) at 1 month, the worsening in the TT and TT/RIT groups persisted for up to 12 months.

Functional comparisons of the TL versus TT versus TT/RIT groups. We initially questioned whether the impact of voice and throat function after thyroid surgery and the pattern of further functional recovery by comparing TL versus TT versus TT/RIT groups. First, we found preoperative functional parameters, such as GRBAS, acoustic voice parameters (jitter, shimmer, sF0, F0, Fmax, Fmin), and the subjective VHI and GETS, between TL, TT, and TT/RIT groups were not different between 3 comparison groups (Table II). Functional differences become evident, however, at 1 month after surgery (Fig 1). For example, the GRBAS parameters grade (P = .001) and roughness (P = .001) were worse in the TT and TT/RIT groups than in the TL group, as were acoustic voice parameters, such as jitter in TT and TT/RIT (P = .043). F0 during usual phonation tended to be less in the TT (174.1 ± 38.1 Hz) and TT/RIT (170.6 ± 41.2 Hz) groups than in the TL group (187.7 ± 50.5 Hz; P > .05). In contrast, the greatest F0 (Fmax) was impaired more dramatically in the TT (457.4 ± 184.4 Hz) and TT/RIT (445.6 ± 193.3 Hz) groups than in the TL group (524.9 ± 187.1 Hz) (P = .011), resulting in narrower pitch ranges in VRP in the TT (325.6 ± 173.6 Hz) and TT/RIT (316.5 ± 182.6 Hz) groups than in the TL (393.5 ± 179.5 Hz) group (P = .007). The results of subjective questionnaires were in substantial agreement, with VHI at 1 month being significantly worse in the TT (36.9 ± 28.9) and TT/RIT (34.6 ± 26.6) groups than in the TL (19.5 ± 18.6) group (P = .007). GETS, however, did not differ significantly in the TT (24.9 ± 16.2) and TT/RIT (20.4 ± 16.2) groups than in the TL (16.4 ± 16.2) group (P > .05). At later follow-up, the differences between TL, TT, and TT/RIT groups became gradually less (Fig 1). Among all measured perceptive, acoustic, and subjective parameters, only Fmax and pitch range of the TT and TT/RIT groups remained

TL (n = 33)

Grade

P Roughness

P Breathy

P Asthenic

P Strained

P Sf0, Hz

P F0, Hz

P Jitter, %

P Shimmer, %

P Fmax, Hz

P Fmin, Hz

P Pitch range, Hz

TT (n = 41)

TT/RIT (n = 81)

Preoperatively

1 Month

6 Months

12 Months

Preoperatively

1 Month

6 Months

12 Months

Preoperatively

1 Month

6 Months

12 Months

0.20 ± 0.31 Reference

0.36 ± 0.38 .087

0.24 ± 0.34 .463

0.27 ± 0.25 .328

0.24 ± 0.23 Reference

0.75 ± 0.62 <.0001y

0.34 ± 0.41 .381

0.39 ± 0.41 .189

0.30 ± 0.31 Reference

0.81 ± 0.59 <.0001y

0.37 ± 0.31 .435

0.34 ± 0.35 .435

0.29 ± 0.31 Reference

0.42 ± 0.45 .0152*

0.69 ± 0.46 <.0001y

0.69 ± 0.52 <.0001y

0.31 ± 0.41 Reference

0.82 ± 0.51 <.0001y

0.80 ± 0.40 <.0001y

0.78 ± 0.47 <.0001y

0.37 ± 0.40 Reference

0.77 ± 0.45 <.0001y

0.79 ± 0.40 <.0001y

0.88 ± 0.31 <.0001y

0 Reference

0.04 ± 0.30 .065

0.03 ± 0.17 .538

0.06 ± 0.24 .218

0.09 ± 0.21 Reference

0.09 ± 0.31 .098

0.02 ± 0.15 1

0.02 ± 0.15 1

0 Reference

0.08 ± 0.32 .173

0 1

0.04 ± 0.21 .117

0 Reference

0.03 ± 0.17 .331

0.03 ± 0.17 .335

0 1

0 Reference

0.02 ± 0.12 .381

0 1

0 1

0 Reference

0.06 ± 0.12 .102

0.02 ± 0.10 .21016

0 1

0.03 ± 0.17 Reference

0.09 ± 0.13 .456

0.09 ± 0.29 .461

0.09 ± 0.29 .461

0.02 ± 0.12 Reference

0.24 ± 0.15 .003y

0.14 ± 0.35 .095

0.07 ± 0.26 .504

0.08 ± 0.13 Reference

0.30 ± 0.14 <.0001y

0.14 ± 0.35 .234

0.06 ± 0.24 0.634

183.5 ± 42.6 Reference

174.3 ± 45.8 .310

174.8 ± 41.5 .343

171.1 ± 41.7 .170

182.3 ± 31.6 Reference

172.8 ± 34.8 .241

175.2 ± 32.6 .381

170.6 ± 31.9 .155

178.5 ± 37.5 Reference

166.1 ± 35.9 .033*

169.6 ± 34.6 .051

166.9 ± 36.0 .049*

189.6 ± 44.0 Reference

187.7 ± 50.5 .851

184.1 ± 48.2 .591

178.8 ± 53.2 .291

183.1 ± 35.8 Reference

174.1 ± 38.1 .332

180.8 ± 34.3 .809

181.4 ± 36.7 .856

184.3 ± 40.3 Reference

170.6 ± 41.2 .138

173.5 ± 41.8 .302

171.2 ± 41.9 .167

1.39 ± 0.97 Reference

1.42 ± 0.59 .271

1.16 ± 0.78 .371

1.38 ± 0.90 .967

1.49 ± 0.87 Reference

1.98 ± 1.21 .041

1.35 ± 1.08 .514

1.44 ± 0.19 .821

1.29 ± 1.10 Reference

1.76 ± 1.13 .048

1.18 ± 0.89 .508

1.60 ± 1.07 .053

4.04 ± 1.57

4.13 ± 2.00

3.66 ± 1.93

3.80 ± 1.60

4.15 ± 1.61

5.07 ± 2.62

3.83 ± 1.60

3.59 ± 1.60

4.09 ± 1.62

4.39 ± 2.50

3.79 ± 1.65

3.78 ± 1.38

Reference

.519

.702

.932

Reference

.025*

.441

.179

Reference

.301

.266

.282

599.8 ± 181.1 Reference

524.9 ± 187.1 .071

560.4 ± 202.5 .092

558.2 ± 200.9 .077

577.1 ± 207.8 Reference

457.4 ± 184.4 .006

484.7 ± 171.6 .034*

506.3 ± 224.7 .103

584.6 ± 192.2 Reference

445.6 ± 193.3 <.0001y

479.4 ± 183.4 .001y

508.8 ± 208.8 .014*

138.1 ± 22.9 Reference

131.4 ± 35.8 .684

143.1 ± 36.4 .062

144.4 ± 40.1 .065

140.6 ± 24.9 Reference

131.8 ± 30.5 .221

146.6 ± 30.0 .413

149.7 ± 28.4 .216

134.8 ± 31.7 Reference

129.1 ± 30.7 .261

144.0 ± 33.8 .071

144.3 ± 33.4 .064

461.7 ± 181.0

393.5 ± 179.5

417.3 ± 190.9

413.8 ± 85.0

436.5 ± 206.5

325.6 ± 173.6

338.1 ± 160.9

356.6 ± 109.7

449.8 ± 188.3

316.5 ± 182.6

335.4 ± 168.9

364.5 ± 89.4

P

Reference

.048*

.007y

.018*

Reference

.007y

.017*

.042*

Reference

<.0001y

.0001y

.0034y

VHI

6.5 ± 11.6 Reference

19.5 ± 18.6 .011*

19.3 ± 20.6 .012*

16.5 ± 19.2 .049*

3.5 ± 6.7 Reference

36.9 ± 28.9 <.0001y

16.2 ± 15.9 .006y

13.0 ± 12.9 .043*

5.9 ± 10.4 Reference

34.6 ± 26.6 <.0001y

19.2 ± 26.2 <.0001y

20.4 ± 22.7 <.0001y

8.4 ± 11.0 Reference

16.4 ± 16.2 .022*

12.0 ± 11.2 .303

14.5 ± 13.3 .078

7.6 ± 9.1 Reference

24.9 ± 16.2 <.0001y

16.9 ± 15.1 .003y

15.9 ± 16.3 .010y

6.0 ± 7.0 Reference

20.4 ± 16.2 <.0001y

13.8 ± 13.2 .0004y

17.3 ± 18.2 <.0001y

P GETS

P

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*Significant at the .05 level. ySignificant at the .01 level. Values are presented as means ± standard deviations. F0, Fundamental frequency; Fmax, the highest fundamental frequency; Fmin, the lowest fundamental frequency; GETS, Glasgow Edinburgh Throat Scale; SD, standard deviation; TL, thyroid lobectomy; TT, total thyroidectomy; TT/RIT, total thyroidectomy followed by radioactive iodine treatment; sF0, speaking fundamental frequency; VHI, Vocal Handicap Index.

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Table III. Perceptive, objective, and subjective parameters of voice and throat function through the perioperative course

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Table IV. Comparisons of parameters between different thyroid surgeries over the clinical course Preoperative

Grade Roughness Breathy Asthenic Strained F0, Hz Jitter, % Shimmer, % Fmax, Hz Fmin, Hz Pitch range, Hz VHI GETS

1 Month

TL (n = 33)

TT (n = 41)

TT/RIT (n = 81)

P

0.20 ± 0.31 0.29 ± 0.31 0 0 0.03 ± 0.17 189.6 ± 44.0 1.39 ± 0.97 4.04 ± 1.57 599.8 ± 181.1 138.1 ± 22.9 461.7 ± 181.0

0.24 ± 0.23 0.31 ± 0.41 0.09 ± 0.21 0 0.02 ± 0.12 183.1 ± 35.8 1.49 ± 0.87 4.15 ± 1.61 577.1 ± 207.8 140.6 ± 24.9 436.5 ± 206.5

0.30 ± 0.31 0.37 ± 0.40 0 0 0.08 ± 0.13 184.3 ± 40.3 1.29 ± 1.10 4.09 ± 1.62 584.6 ± 192.2 134.8 ± 31.7 449.8 ± 188.3

NS NS NS NS NS NS NS NS NS NS NS

6.5 ± 11.6 8.4 ± 11.0

3.5 ± 6.7 7.6 ± 9.1

5.9 ± 10.4 6.0 ± 7.0

NS NS

TL (n = 33) 0.36 0.42 0.04 0.03 0.09 187.7 1.42 4.13 524.9 131.4 393.5

± ± ± ± ± ± ± ± ± ± ±

0.38 0.45 0.30 0.17 0.13 50.5 0.59 2.00 187.1 35.8 179.5

19.5 ± 18.6 16.4 ± 16.2

TT (n = 41) 0.75 0.82 0.09 0.02 0.24 174.1 1.98 5.07 457.4 131.8 325.6

± ± ± ± ± ± ± ± ± ± ±

0.62* 0.51* 0.31 0.12 0.15 38.1 1.21* 2.62 184.4* 30.5 173.6*

36.9 ± 28.9* 24.9 ± 16.2

6 Months TT/RIT (n = 81) 0.81 0.77 0.08 0.06 0.30 170.6 1.76 4.39 445.6 129.1 316.5

± ± ± ± ± ± ± ± ± ± ±

0.59* 0.45* 0.32 0.12 0.14 41.2 1.13y 2.50 193.3* 30.7 182.6*

34.6 ± 26.6* 20.4 ± 16.2

P .001 .001 NS NS .032 NS .043 .052 .011 NS .007 .007 NS

TL (n = 33) 0.24 0.69 0.03 0.03 0.09 184.1 1.16 3.66 560.4 143.1 417.3

± ± ± ± ± ± ± ± ± ± ±

0.34 0.46 0.17 0.17 0.29 48.2 0.78 1.93 202.5 36.4 190.9

19.3 ± 20.6 12.0 ± 11.2

12 Months

TT (n = 41)

TT/RIT (n = 81)

P

TL (n = 33)

TT (n = 41)

TT/RIT (n = 81)

P

0.34 ± 0.41 0.80 ± 0.40 0.02 ± 0.15 0 0.14 ± 0.35 180.8 ± 34.3 1.35 ± 1.08 3.83 ± 1.60 484.7 ± 171.6 146.6 ± 30.0 338.1 ± 160.9

0.37 ± 0.31 0.79 ± 0.40 0 0.02 ± 0.15 0.14 ± 0.35 173.5 ± 41.8 1.18 ± 0.89 3.79 ± 1.65 479.4 ± 183.4 144.0 ± 33.8 335.4 ± 168.9

NS NS NS NS NS NS NS NS .041 NS .044

0.27 ± 0.25 0.69 ±.52 0.06 ± 0.24 0 0.09 ± 0.29 178.8 ± 53.2 1.38 ± 0.90 3.80 ± 1.60 558.2 ± 200.9 144.4 ± 40.1 413.8 ± 85.0

0.39 ± 0.41 0.78 ± 0.47 0.02 ± 0.15 0 0.07 ± 0.26 181.4 ± 36.7 1.44 ± 0.19 3.59 ± 1.60 506.3 ± 224.7 149.7 ± 28.4 356.6 ± 109.7

0.34 ± 0.35 0.88 ± 0.31 0.04 ± 0.21 0 0.06 ± 0.24 171.2 ± 41.9 1.60 ± 1.07 3.78 ± 1.38 508.8 ± 208.8 144.3 ± 33.4 364.5 ± 89.4

NS NS NS NS NS NS NS NS NS NS NS

16.2 ± 15.9 16.9 ± 15.1

19.2 ± 26.2 13.8 ± 13.2

NS NS

16.5 ± 19.2 14.5 ± 13.3

13.0 ± 12.9 15.9 ± 16.3

20.4 ± 22.7 17.3 ± 18.2

NS NS

*Significant at the .05 level, Scheffe test. yScheffe’s test TT versus TT/RIT: P < .05. Values are presented as means ± standard deviations. F0, Fundamental frequency; Fmax, the highest fundamental frequency; Fmin, the lowest fundamental frequency; GETS, Glasgow Edinburgh Throat Scale; TL, thyroid lobectomy; TT, total thyroidectomy; TT/RIT, total thyroidectomy followed by radioactive iodine treatment; SD, standard deviation; NS, not significant; sF0, speaking fundamental frequency; VHI, Vocal Handicap Index.

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Fig. 1. Serial patterns of typical functional parameters on (A) perceptive, (B) acoustic, and (C) questionnaire measurements, between different extents of thyroidectomy, before and after the operation. *P < .05compared with the TL group.

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significantly worse than those of the TL group 6 months after thyroidectomy, but these differences eventually disappeared at 12 months after thyroidectomy. The addition of RIT to TT had no effect on vocal or swallowing function throughout the course of treatment. At all time points, there were no differences between the TT and TT/RIT groups in GRBAS, acoustic parameters (sF0, F0, jitter, shimmer, and pitch range), and on subjective functional questionnaires, such as the VHI and GETS. DISCUSSION To better understand whether the extent of thyroid surgery affects functional outcomes and patterns of functional recovery in patients without apparent RLN injury, we performed a prospective, serial, comparative analysis of perceptive, objective, and related subjective QOL parameters. Although both TT and TL have been standard treatments, with an ‘‘A rating’’ in the guidelines of the American Thyroid Association,14 little has been reported about differences in functional consequences of TL and TT. Thus, the functional aspects of these procedures have been often neglected while selecting initial surgical plan. Among the 155 prospectively accrued patients who underwent TL (n = 33), TT (n = 41), or TT/ RIT (n = 81), 15–84% experienced some element of impaired vocal and/or throat function after thyroidectomy. Even patients who underwent TL, with the least extensive resection, exhibited these impairments. These impairments started immediately postoperatively. Although they usually resolved subsequently, some of these deficits persisted at 12 months after thyroidectomy. Typical patterns of post-thyroidectomy functional changes included altered perceptive GRBAS, increased voice perturbation, lowered Fmax, narrowed pitch range, and global disturbance of subjective functional parameters on the VHI and GETS scales. Even at 12 months after thyroidectomy, perceptive voice remained rougher, pitch range remained narrower, and subjective parameters on the VHI and GETS remained worse in all 3 of our patient groups. These alterations in functional parameters correlated with the extent of resection, especially

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during the immediate postoperative period and at 1 month postoperatively. Compared with TL group, the TT and TT/RIT groups exhibited rougher and more strained voices, acoustic voice parameters such as jitter were worse, and F0 tended to be less. Moreover, the frequency of forced high pitch phonation was impaired dramatically, resulting in greater narrowing in pitch range in the TT and TT/RIT groups than in the TL group. Subjective voice qualities evaluated with the VHI were in agreement with these perceptive and acoustic parameters. Although these betweengroup differences gradually decreased over time, Fmax remained persistently less with a narrower pitch range for up to 6 months after thyroidectomy. Even if these differences became insignificant, these parameters tended to be abnormal in some patients for up to 1 year. Longer follow-up evaluations for several years may be warranted to evaluate the long-term outcomes of these treatment-related functional deficits. We speculate that more extensive, bilateral thyroid surgery might cause more extensive alterations in function, aggravating functional impairments. Etiologies of post-thyroidectomy functional impairment, such as fibrosis in the operation, injury, or dysfunction of the strap muscles influencing pitch control,19,20 or slight modifications of the vascular supply, and/or venous drainage of the larynx resulting in mucosal changes,10 might be doubly more extensive in TT than TL. In addition, bilateral surgery might double the risk of injury of the EBSLN, which is a frequent cause of post-thyroidectomy dysphonia.12 These reasons might explain these functional disturbances depending on extent of the thyroidectomy shown in this study. Better controlled analyses are needed to pinpoint the reason of our results, including simultaneous laryngeal electromyographic monitoring. Non-thyroid causes such as endotracheal intubation or laryngopharyngeal reflux might cause alterations of these functional outcomes. We controlled conditions related to anesthesia and intubation and excluded any cases with laryngeal lesions suggesting intubation injuries, such as vocal cord immobility, granuloma, or other lesions like polyps, at every time point. We believe that this approach helped to decrease the bias caused by

=Parameters generally worsened significantly, usually at 1 month, occasionally 6 months, or even 12 months after operation. Wider operative thyroidectomy (TT and TT/RIT groups) caused more worsening, usually at 1 month, and this pattern persisted even until 6 months after operation in Fmax and pitch range. Fmax, Greatest fundamental frequency; GETS, Glasgow Edinburgh Throat Scale; TL, thyroid lobectomy; TT, total thyroidectomy; TT/RIT, total thyroidectomy followed by radioactive iodine treatment; VHI, Vocal Handicap Index. (Color version of figure is available online.)

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intubational disturbances when comparing the 3 groups. The portion of intubation-induced postthyroidectomy functional impairment should be studied further. Few reports have studied the effects of gastropharyngeal reflux in the post-thyroidectomy patient,21 but none have quantified the relation between the severity of reflux and the extent of thyroidectomy. The real functional impact related to laryngopharyngeal reflux should also be investigated further, by correlating dual sensor pH monitoring, along with the functional studies used in this study. We also hypothesized that the addition of RIT to TT might aggravate vocal and throat functions, at least transiently. Our analysis, however, showed no functional differences in perceptive, objective, or subjective parameters, between the TT and TT/ RIT groups. Little is known about the impact of RIT on voice and throat function. Our results are in agreement with previous findings showing that RIT alone did not impair voice and laryngeal function in patients with Graves’ disease.22 In our analysis, however, the doses of radioactive iodine and treatment conditions were not well controlled. The actual functional impact of RIT, especially whether it depends on radiation dose and number of treatments, requires additional studies, as does the functional impact of more extensive resections, including lateral neck dissection and extended resection of larynx, trachea, or esophagus, or the addition of external beam radiation therapy. In conclusion, we found that the extent of thyroid surgery had a negative impact on voice and throat symptoms, with some impairments persisting for up to 12 months after thyroidectomy. These potential morbidities, increasing with the extent of thyroid resection, suggest that the extent of thyroidectomy should be carefully decided considering its impact on voice and throat functions, to eventually optimize patients’ QOL and clinical outcome. REFERENCES 1. Ministry of Health and Welfare & National Cancer Center. Cancer facts & figures, National Cancer Registry data in Korea. Korea: Ministry of Health and Welfare & National Cancer Center; 2011. 2. Sampson E, Brierley JD, Le LW, Rotstein L, Tsang RW. Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis. Cancer 2007;110:1451-6. 3. Shaha AR, Shah JP, Loree TR. Differentiated thyroid cancer presenting initially with distant metastasis. Am J Surg 1997; 174:474-6.

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4. Bhattacharyya N, Fried MP. Assessment of the morbidity and complications of total thyroidectomy. Arch Otolaryngol Head Neck Surg 2002;128:389-92. 5. Roy AD, Gardiner RH, Niblock WM. Thyroidectomy and the recurrent laryngeal nerves. Lancet 1956;270:988-90. 6. Pereira JA, Girvent M, Sancho JJ, Parada C, Sitges-Serra A. Prevalence of long-term upper aerodigestive symptoms after uncomplicated bilateral thyroidectomy. Surgery 2003; 133:318-22. 7. Lombardi CP, Raffaelli M, D’Alatri L, Marchese MR, Rigante M, Paludetti G, et al. Voice and swallowing changes after thyroidectomy in patients without inferior laryngeal nerve injuries. Surgery 2006;140:1026-32. 8. Henry LR, Solomon NP, Howard R, Gurevich-Uvena J, Horst LB, Coppit G, et al. The functional impact on voice of sternothyroid muscle division during thyroidectomy. Ann Surg Oncol 2008;15:2027-33. 9. Lombardi CP, Raffaelli M, De Crea C, D’Alatri L, Maccora D, Marchese MR, et al. Long-term outcome of functional post-thyroidectomy voice and swallowing symptoms. Surgery 2009;146:1174-81. 10. Stojadinovic A, Shaha AR, Orlikoff RF, Nissan A, Kornak MF, Singh B, et al. Prospective functional voice assessment in patients undergoing thyroid surgery. Ann Surg 2002; 236:823-32. 11. Sinagra DL, Montesinos MR, Tacchi VA, Moreno JC, Falco JE, Mezzadri NA, et al. Voice changes after thyroidectomy without recurrent laryngeal nerve injury. J Am Coll Surg 2004;199:556-60. 12. Aluffi P, Policarpo M, Cherovac C, Olina M, Dosdegani R, Pia F. Post-thyroidectomy superior laryngeal nerve injury. Eur Arch Otorhinolaryngol 2001;258:451-4. 13. McIvor NP, Flint DJ, Gillibrand J, Morton RP. Thyroid surgery and voice-related outcomes. Aust N Z J Surg 2000;70: 179-83. 14. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-214. 15. Rosen CA, Lee AS, Osborne J, Zullo T, Murry T. Development and validation of the voice handicap index-10. Laryngoscope 2004;114:1549-56. 16. Rosen CA, Murry T, Zinn A, Zullo T, Sonbolian M. Voice handicap index change following treatment of voice disorders. J Voice 2000;14:619-23. 17. Deary IJ, Wilson JA, Harris MB, MacDougall G. Globus pharyngis: development of a symptom assessment scale. J Psychosom Res 1995;39:203-13. 18. Gass GD, Olsen GN. Preoperative pulmonary function testing to predict postoperative morbidity and mortality. Chest 1986;89:127-35. 19. Hong KH, Kim YK. Phonatory characteristics of patients undergoing thyroidectomy without laryngeal nerve injury. Otolaryngol Head Neck Surg 1997;117:399-404. 20. Debruyne F, Ostyn F, Delaere P, Wellens W. Acoustic analysis of the speaking voice after thyroidectomy. J Voice 1997;11:479-82. 21. Fiorentino E, Cipolla C, Graceffa G, Cusimano A, Cupido F, Lo Re G, et al. Local neck symptoms before and after thyroidectomy: a possible correlation with reflux laryngopharyngitis. Eur Arch Otorhinolaryngol 2011;268:715-20. 22. Isolan-Cury RW, Monte O, Cury AN, Andrada ESMA, Duprat A, Marone M, et al. Acute effects of radioiodine therapy on the voice and larynx of Basedow-Graves patients. Braz J Otorhinolaryngol 2008;74:224-9.