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What Constitutes Adequate Surgical Therapy For Benign Nodular Goiter?
Journal of Surgical Research 154, 51–55 (2009) doi:10.1016/j.jss.2008.05.003
ASSOCIATION FOR ACADEMIC SURGERY, 2008 What Constitutes Adequate Surgical Therapy For Benign Nodular Goiter? Roy Phitayakorn, M.D., M.H.P.E., Divya Narendra, Sarah Bell, and Christopher R. McHenry, M.D.1 Department of Surgery, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio Submitted for publication February 17, 2008
INTRODUCTION Background. It is our hypothesis that the extent of thyroid resection for benign nodular thyroid disease (NTD) should be based on the extent of disease. Methods. Patients operated on for benign NTD from 1990 through 2007 were divided into 3 groups: those who underwent lobectomy for unilateral NTD (Group 1); near-total or total thyroidectomy for bilateral NTD (Group 2); and reoperation for NTD initially treated at other institutions (Group 3). The incidence of recurrence was determined for Groups 1 and 2 and the timing of diagnosis was compared to Group 3. Potential risk factors for recurrent disease were examined. Results. Five hundred forty-five patients were operated on for benign NTD. Contralateral disease was excluded in Group 1 patients using ultrasound (47.7%) and/or intraoperative palpation (100%). Five (1.9%) of 260 patients in Group 1 and 1 (0.4%) of 248 patients in Group 2 developed recurrent NTD after 7 ⴞ 4 (median ⴝ 8) and 4 y compared to a mean 19 ⴞ 11 (median ⴝ 20) y for the 37 patients in Group 3 following 1 to 3 previous thyroidectomies. Recurrent disease was diagnosed by physical exam in 24 (55.8%) and imaging in 19 (44.2%) patients. Thyroid hormone was required for postsurgical hypothyroidism in 70 (26.9%) patients in Group 1. Conclusion. Thyroid lobectomy is optimal therapy when benign NTD is limited to 1 lobe, as evidenced by a 2% recurrence rate and maintenance of euthyroidism in 73% of patients. When NTD is bilateral, total thyroidectomy is indicated to eliminate recurrence, underscoring the importance of routine preoperative ultrasound. © 2009 Elsevier Inc. All rights reserved. Key Words: nodular goiter; risk factors; recurrence; benign nodular goiter; thyroidectomy; follow-up.
Benign nodular thyroid disease (NTD) is the most common endocrine disorder throughout the world and is strongly associated with iodine deficiency [1]. Despite adequate iodine repletion in the United States since the late 1980s [2], clinically evident thyroid nodules still occur in 4 –7% of the population and up to 60 –70% of the population may have asymptomatic, nonpalpable thyroid nodules [3–5]. In our practice, patients with benign asymptomatic NTD are followed with physical examination, serum thyrotropin (TSH) levels, and neck ultrasonography. Surgical therapy is recommended for the following: progressive increase in nodule size, substernal extension, the development of compressive symptoms, radiographic evidence of tracheal, esophageal, or major vessel impingement, the development of thyrotoxicosis, cosmetic concerns, and patient preference. In patients with benign NTD who undergo operative therapy, surgical resection consists of lobectomy for patients with disease limited to 1 lobe. Contralateral disease is excluded by preoperative palpation, ultrasound examination, and intraoperative palpation. Contralateral disease that warrants total thyroidectomy includes 1 or more nodules greater than or equal to 1 cm, or any single nodule less than 1 cm with abnormal sonographic features. In patients with bilateral NTD, our preference, as well as others, is to proceed with near total or total thyroidectomy to resect all disease [6 – 8]. Potential risk factors for recurrent nodular goiter have been evaluated including the following: patient age, sex, family history of goiter, duration of symptoms, multi-NTD, and extent of thyroidectomy, with conflicting results [9 –12]. Previous research indicates that in patients with goiter, African-American race, obesity, pregnancy, and increasing age are independent risk factors for increased goiter size [13]. The purpose of this study was to determine what extent of
1
To whom correspondence and reprint requests should be addressed at Department of Surgery, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. E-mail: cmchenry@ metrohealth.org.
51
0022-4804/09 $36.00 © 2009 Elsevier Inc. All rights reserved.
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JOURNAL OF SURGICAL RESEARCH: VOL. 154, NO. 1, JUNE 1, 2009
thyroid resection constitutes adequate surgical therapy for benign NTD and what risk factors are associated with recurrence. METHODS Data were obtained from an institutional review board approved, prospectively maintained thyroid database and a retrospective chart review of a consecutive series of patients operated on for benign NTD from 1990 through 2007 by a single surgeon. Yearly follow-up is recommended for all patients who have been treated for benign NTD. Patients who have undergone total thyroidectomy are followed with a yearly neck examination and a yearly serum TSH level. Patients who have undergone thyroid lobectomy are also followed with an annual neck examination and serum TSH level. In addition, they are followed with cervical ultrasound examination every 1–2 y. Twentysix patients with an incidental thyroid microcarcinoma, defined as a papillary carcinoma ⬍1 cm identified on final pathological exam outside of the index nodule, were excluded from the study. Patients were divided into 3 groups. Group 1 consisted of patients who underwent lobectomy for unilateral benign NTD. Group 2 consisted of patients who underwent either near-total or total thyroidectomy for bilateral benign NTD. Group 3 consisted of patients with benign NTD who underwent initial surgical therapy at other institutions and were subsequently referred to our institution with recurrence. All patients in this study had preoperative and intraoperative palpation. Intraoperative palpation was performed without mobilization of the contralateral lobe. In the last 3 y of the study period, a routine ultrasound was performed by a dedicated radiologist to evaluate the location and extent of NTD. The frequency of preoperative thyroid ultrasound was determined for patients in Group 1 and the overall incidence of recurrence was determined for patients in Groups 1 and 2. We defined recurrence of NTD following surgical treatment as any new nodule either palpable on physical examination or demonstrable on ultrasound exam. The length of time for development of recurrence in Groups 1 and 2 was compared to Group 3. Patients with recurrent disease from Groups 1 and 2 were combined with patients in Group 3 and potential risk factors for recurrence of benign NTD were investigated. Potential risk factors that were evaluated included the following: patient age and body mass index at time of surgery, sex, ethnicity or race, previous exposure to ionizing radiation, family history of thyroid disease, tobacco use, or alcohol use. Patient ethnicity or race was coded as African-American or nonAfrican-American. Non-African-American was used as there were too few Hispanic, Asian, or Middle Eastern/Arabic patients to allow for separate analysis. A positive family history of thyroid disease was defined as thyroid disease that was present in a first-degree relative. In terms of previous radiation exposure, patients were specifically asked if they had any occupational exposure to radiation, accidental exposure to environmental radiation, or had received radiation as a form of medical therapy. Tobacco use was defined as the regular use of any type of tobacco product. Alcohol use was defined as the regular consumption of any type of alcoholic beverage. 2 tests were used to determine the statistical significance of nonparametric data and a Student’s t-test was used to determine the statistical significance of parametric data. A 1-way analysis of variance was performed to compare means between all 3 groups. A P value of ⬍0.05 was considered significant. The institutional review board at MetroHealth Medical Center approved the study. Data were analyzed using SPSS for Windows Version 13.0 (SPSS Inc., Chicago, IL).
RESULTS
As illustrated in Table 1, 545 patients were operated on for NTD and confirmed to have benign pathology
during the study period. Contralateral disease was excluded in Group 1 patients using ultrasound in 124 patients (47.7%) and/or intraoperative palpation in all patients. Five (1.9%) of 260 patients in Group 1 and 1 (0.4%) of 248 patients in Group 2 developed recurrent benign NTD after a mean of 7 ⫾ 4 y (median ⫽ 8 y) and 4 y, respectively, compared to a mean 19 ⫾ 11 y (median ⫽ 20 y) for the 37 patients in Group 3 following 1 to 3 previous thyroidectomies. The mean follow-up time was 2 ⫾ 3 y (median ⫽ 1 y; range ⫽ 0.1-14.33 y) for patients in Group 1 and 3 ⫾ 4 y (median ⫽ 1 y; range ⫽ 0.2-16.83 y) for patients in Group 2. Three patients in Group 1 (1.2%) and 2 patients in Group 2 (0.8%) did not have their initial postoperative follow-up with us. Recurrent disease was diagnosed by physical exam in 24 (55.8%) and imaging in 19 (44.2%) patients. Recurrent disease occurred in 2 (1.6%) of the 124 who underwent preoperative thyroid ultrasound. Seventy patients (26.9%) in Group 1 developed postsurgical hypothyroidism, which was treated with thyroid hormone replacement. Of the patients in Group 1, transient recurrent laryngeal nerve injury occurred in 1 (0.3%) and no patient developed permanent recurrent laryngeal nerve injury. Among patients in Group 2, transient recurrent laryngeal nerve injury was noted in 9 patients (3.6%) with only 1 patient (0.4%) with permanent nerve injury. None of the patients who underwent total thyroidectomy had permanent hypoparathyroidism. As illustrated in Table 2, younger age at the initial operation (34 ⫾ 13 y versus 50 ⫾ 15 y, P ⬍ 0.001) and a longer length of follow-up time (16.2 ⫾ 11.6 y versus 2.7 ⫾ 3.5 y, P ⬍ 0.001) were significantly associated with recurrence. Also, the regular consumption of alcohol was more common among patients who did not develop recurrent disease and this approached statistical significance (47.7% of patients without recurrence versus 31.0% of patients with recurrence, P ⫽ 0.052). A prior history of radiation exposure, sex, family history of thyroid disease, tobacco use, and race were not significantly different in patients who had recurrent NTD compared to patients without recurrence. DISCUSSION
The reported recurrence rate following surgical resection for benign NTD varies from 0.3 to 80% depending on the extent of initial surgery, the regional iodine status, and the length of follow-up [8, 14]. Our study demonstrated a recurrence rate of 1.9% following thyroid lobectomy when contralateral disease was excluded using ultrasonography and/or intraoperative palpation. Since this study was not prospective, it is difficult to determine whether the recurrences represented new nodule growth in a previously normal thyroid lobe remnant or progression of disease that was
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PHITAYAKORN ET AL.: BENIGN NODULAR GOITER SURGICAL THERAPY
TABLE 1 Comparative Analysis of Patients Who Underwent Thyroid Lobectomy (Group 1), Near-Total or Total Thyroidectomy (Group 2), or Reoperative Thyroidectomy for Recurrent NTD (Group 3)
Number of patients Number of patients with recurrence (%) Age at first operation (y) BMI at time of first operation (kg/m 2) Patient gender (male/female) History of radiation exposure (%) Family history of thyroid disease (%) Tobacco use (%) Alcohol use (%) Patient race African-American (%) Caucasian (%) Hispanic (%) Asian (%) Middle Eastern/Arabic (%) Mean follow-up time (y) Range of follow-up time (y) Mean time to recurrence (y)
Group 1
Group 2
Group 3
P value
260 5 (1.9%) 48 ⫾ 15 29.2 ⫾ 7.5 43/217 3 (1.2%)* 94 (36.2%) § 107 (41.2%) 㛳 131 (50.4%) #
248 1 (0.4%) 52 ⫾ 16 30.4 ⫾ 7.8 29/219 23 (9.3%) † 111 (44.8%) 㛳 99 (39.9%) 107 (43.1%)
37 37 34 ⫾ 12 N/A 5/32 4 (10.8%) ‡ 11 (29.7%) ¶ 13 (35.1%) § 12 (32.4%) §
Not applicable Not applicable P ⬍ 0.001 P ⫽ NS P ⫽ NS P ⬍ 0.001 P ⫽ NS P ⫽ NS P ⫽ 0.048
82 (31.5%) 150 (57.7%) 18 (6.9%) 10 (3.8%) 0 (0%) 2 ⫾ 3 (median ⫽ 1) 0.1–14.3 7 ⫾ 4 (median ⫽ 8)
94 (37.9%) 141 (56.9%) 8 (3.2%) 3 (1.2%) 2 (0.8%) 3 ⫾ 4 (median ⫽ 1) 0.1–16.8 4
16 (43.2%) 20 (54.1%) 0 (0%) 1 (2.7%) 0 (0%) 19 ⫾ 11 (median ⫽ 20) 1–36.0 19 ⫾ 11 (median ⫽ 20)
P ⫽ NS P ⫽ NS Not applicable Not applicable Not applicable P ⬍ 0.001 Not applicable Not applicable
NS ⫽ Not statistically significant (P ⬎ 0.05). * Nine values missing. † Seven values missing. ‡ Twelve values missing. § One value missing. 㛳 Four values missing. ¶ Two values missing. # Five values missing.
undetected at the initial operation. By reserving total thyroidectomy only for patients with proven bilateral NTD, we were able to avoid thyroid hormone supplementation in 73% of patients who underwent thyroid lobectomy. One patient who initially underwent total thyroidectomy developed recurrence of benign NTD, which may have occurred as a result of retained thyroid tissue or incomplete resection of embryonic thyroid rests [8]. There is no consensus on what constitutes appropriate methodology and timing for follow-up of patients
after surgery for benign nodular disease. Recurrent disease has been reported in the literature to occur as early as 6 mo, but it is usually not diagnosed until 4 or more y after surgery depending on the frequency and type of surveillance methods used [15–17]. Patients in this study developed recurrence at a median of 8 y with 55.8% of recurrences noted by physical examination and 43.2% of recurrences detected by follow-up imaging, either cervical ultrasound or computed tomography. Our results demonstrate that a strategy of preoperative ultrasound and/or intraoperative palpation resulted in
TABLE 2 Clinical Characteristics of Patients Who Did or Did Not Develop Recurrence
Number of patients Age at first surgery (y) Body mass index (kg/m 2) Patient gender (male/female) History of radiation exposure (%) Family history of thyroid disease (%) Tobacco use (%) Alcohol use (%) Patient race (African-American/non-African-American) Mean follow-up time (y) Range of follow-up time (y)
Recurrence
No recurrence
P value
43 34 ⫾ 13 33.6 ⫾ 6.7 5/38 4 (14.3%) 14 (34.1%) 16 (38.1%) 13 (31.0%) 19/24 16.2 ⫾ 11.6 (median ⫽ 15) 0.2–36.0
502 50 ⫾ 15 29.7 ⫾ 7.7 72/430 26 (5.3%) 202 (40.6%) 203 (40.8%) 237 (47.7%) 173/329 2.7 ⫾ 3.5 (median ⫽ 1) 0.1–16.8
Not applicable P ⬍ 0.001 NS NS NS NS NS 0.052 NS P ⬍ 0.001 Not applicable
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a low recurrence rate of only 1.9% among patients who initially underwent lobectomy at our institution. Of these patients with recurrence, none have required reoperation. As advocated by the American Thyroid Association, the American Association of Clinical Endocrinologists, and the National Comprehensive Cancer Network, we now routinely obtain an ultrasound examination in all patients with a thyroid nodule to determine if there is nodular disease elsewhere in the thyroid gland [18 –20]. A risk factor for recurrence of NTD was a younger age at the time of initial operation. This result is consistent with the natural course of benign NTD, which is typically slow-growing so the rate of recurrence likely increases as more time elapses from the initial operation. Previous researchers have noted a linear relationship between patient age, thyroid volume, and nodularity, respectively, with an average yearly increase in thyroid volume of 4.5% based on serial ultrasound measurements [21]. Interestingly, the regular consumption of alcohol may be protective against goiter recurrence. We have previously reported that regular alcohol use was protective against the development of large goiter [13] possibly due to a direct cytotoxic effect of alcohol on thyroid cells or the effect of the high iodine content in alcohol to prevent goiter in patients with subclinical iodine deficiency [22–23]. The extent of thyroidectomy for benign NTD is controversial. In the past, some authors advocated subtotal thyroidectomy for known multi-NTD, citing a lower incidence of recurrent laryngeal nerve palsy, permanent hypocalcemia, and lifelong thyroid hormone supplementation [24]. However, the use of subtotal thyroidectomy for multi-NTD has also been associated with a higher recurrence rate of 5– 43% after a mean follow-up time of 9 –10 y [25]. As surgical techniques have advanced, numerous studies have demonstrated that total thyroidectomy for benign multi-NTD can be performed with morbidity rates comparable to subtotal thyroidectomy [26 –28]. Our current practice, as well as others, is to reserve total thyroidectomy for patients with bilateral NTD or a single thyroid nodule and a history of irradiation to the head or neck [29]. In patients with a single nodule, we carefully examine the contralateral thyroid lobe using preoperative imaging and intraoperative palpation to exclude bilateral disease. Other authors have found that, even in patients who initially underwent thyroid lobectomy for a solitary nodule, and were subsequently found to have multinodular disease on final pathology, reoperation was rarely necessary (⬃3%) after a mean follow-up of 14 y [30]. One limitation of this study is the short mean follow-up time for the patients in Groups 1 and 2. We recently reviewed the literature with regard to how often patients with benign NTD should be followed
[17]. We determined that there were no prospective, annual follow-up studies in the literature and therefore it is difficult to determine a mean time to recurrence. Clinical recurrences rarely occurred before 1-y follow-up and often required more than 10 y to develop. Therefore, we would expect that the overall recurrence rate in our study would increase with longer follow-up time. This limitation emphasizes the importance of maintaining regular annual follow-up with patients after resection of benign NTD. In conclusion, thyroid lobectomy is adequate therapy in patients with benign NTD limited to 1 lobe when disease can be definitively excluded in the contralateral lobe by preoperative ultrasound and intraoperative palpation. This strategy results in an acceptable rate of recurrence of benign NTD that is most often clinically insignificant, at least in the short term. Patients with a younger age at the time of initial thyroid resection for benign NTD are at increased risk for recurrence. Regular alcohol consumption may be associated with a reduction in the development of recurrent benign NTD. REFERENCES 1. 2.
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Matovinovic J. Endemic goiter and cretinism at the dawn of the third millennium. Annu Rev Nutr 1983;3:341. Caldwell KL, Jones R, Hollowell JG. Urinary iodine concentration: United States National Health and Nutrition Examination Survey 2001–2002. Thyroid 2005;15:692. Ezzat S, Sarti DA, Cain DR, et al. Thyroid incidentalomas. Prevalence by palpation and ultrasonography. Arch Intern Med 1994;154:1838. Tan GH, Gharib H. Thyroid incidentalomas: Management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 1997;126:226. Deandrea M, Mormile A, Veglio M, et al. Fine-needle aspiration biopsy of the thyroid: Comparison between thyroid palpation and ultrasonography. Endocr Pract 2002;8:282. Mittendorf EA, McHenry CR. Follow-up evaluation and clinical course of patients with benign nodular thyroid disease. Am Surg 1999;65:653. Liu Q, Djuricin G, Prinz RA. Total thyroidectomy for benign thyroid disease. Surgery 1998;123:2. Snook KL, Stalberg PL, Sidhu SB, et al. Recurrence after total thyroidectomy for benign multinodular goiter. World J Surg 2007;31:593. Berghout A, Wiersinga WM, Drexhage HA, et al. The long-term outcome of thyroidectomy for sporadic nontoxic goiter. Clin Endocrinol (Oxf) 1989;31:193. Bistrup C, Nielsen JD, Gregersen G, et al. Preventive effect of levothyroxine in patients operated for non toxic goitre: A randomized trial of one hundred patients with nine years followup. Clin Endocrinol (Oxf) 1994;40:323. Piraneo S, Vitri P, Galimberti A, et al. Recurrence of goitre after operation for euthyroid patients. Eur J Surg 1994;160:351. Gibelin H, Sierra M, Mothes D, et al. Risk factors for recurrent nodular goiter after thyroidectomy for benign disease: Casecontrol study of 244 patients. World J Surg 2004;28:1079. Phitayakorn R, Super DM, McHenry CR. An investigation of epidemiologic factors associated with large nodular goiter. J Surg Res 2006;133:16.
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Feldkamp J, Seppel T, Becker A, et al. Iodide or L-thyroxine to prevent recurrent goiter in an iodine-deficient area: Prospective sonographic study. World J Surg 1997;21:10.
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Hegedüs L, Hansen JM, Veiergang D, et al. Does prophylactic thyroxine treatment after operation for non-toxic goitre influence thyroid size? Br Med J (Clin Res Ed) 1987;294:801.
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Phitayakorn R, McHenry CR. Follow-up after surgery for benign nodular thyroid disease: Evidence-based approach. World J Surg 2008;32:1374.
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between age, thyroid volume, thyroid nodularity, and thyroid function in patients with sporadic nontoxic goiter. Am J Med 1987;89:602. Hegedus L, Bonnema SJ, Bennedbaek FN. Management of simple nodular goiter: Current status and future perspectives. Endocr Rev 2003;24:102. Knudsen N, Bulow I, Laurberg P, et al. Alcohol consumption is associated with reduced prevalence of goitre and solitary thyroid nodules. Clin Endocrinol (Oxf) 2001;55:41. Foster RS Jr. Morbidity and mortality after thyroidectomy. Surg Gynecol Obstet 1978;146:413. Pappalardo G, Guadalaxara A, Frattaroli FM, et al. Total compared with subtotal thyroidectomy in benign nodular disease: Personal series and review of published reports. Eur J Surg 1998;164:501. Reeve TS, Delbridge L, Brady P, et al. Secondary thyroidectomy: A twenty-year experience. World J Surg 1988;12:449. Levin KE, Clark AH, Duh QY, et al. Reoperative thyroid surgery. Surgery 1992;111:604. Delbridge L, Guinea AI, Reeve TS. Total thyroidectomy for bilateral benign multinodular goiter: Effect of changing practice. Arch Surg 1999;134:1389. Olson SE, Starling J, Chen H. Symptomatic benign multinodular goiter: Unilateral or bilateral thyroidectomy? Surgery 2007;142:458. Wadström C, Zedenius J, Guinea A, et al. Multinodular goitre presenting as a clinical single nodule: How effective is hemithyroidectomy? Aust NZ J Surg 1999;69:34.
ASSOCIATION FOR ACADEMIC SURGERY, 2008 What Constitutes Adequate Surgical Therapy For Benign Nodular Goiter? Roy Phitayakorn, M.D., M.H.P.E., Divya Narendra, Sarah Bell, and Christopher R. McHenry, M.D.1 Department of Surgery, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio Submitted for publication February 17, 2008
INTRODUCTION Background. It is our hypothesis that the extent of thyroid resection for benign nodular thyroid disease (NTD) should be based on the extent of disease. Methods. Patients operated on for benign NTD from 1990 through 2007 were divided into 3 groups: those who underwent lobectomy for unilateral NTD (Group 1); near-total or total thyroidectomy for bilateral NTD (Group 2); and reoperation for NTD initially treated at other institutions (Group 3). The incidence of recurrence was determined for Groups 1 and 2 and the timing of diagnosis was compared to Group 3. Potential risk factors for recurrent disease were examined. Results. Five hundred forty-five patients were operated on for benign NTD. Contralateral disease was excluded in Group 1 patients using ultrasound (47.7%) and/or intraoperative palpation (100%). Five (1.9%) of 260 patients in Group 1 and 1 (0.4%) of 248 patients in Group 2 developed recurrent NTD after 7 ⴞ 4 (median ⴝ 8) and 4 y compared to a mean 19 ⴞ 11 (median ⴝ 20) y for the 37 patients in Group 3 following 1 to 3 previous thyroidectomies. Recurrent disease was diagnosed by physical exam in 24 (55.8%) and imaging in 19 (44.2%) patients. Thyroid hormone was required for postsurgical hypothyroidism in 70 (26.9%) patients in Group 1. Conclusion. Thyroid lobectomy is optimal therapy when benign NTD is limited to 1 lobe, as evidenced by a 2% recurrence rate and maintenance of euthyroidism in 73% of patients. When NTD is bilateral, total thyroidectomy is indicated to eliminate recurrence, underscoring the importance of routine preoperative ultrasound. © 2009 Elsevier Inc. All rights reserved. Key Words: nodular goiter; risk factors; recurrence; benign nodular goiter; thyroidectomy; follow-up.
Benign nodular thyroid disease (NTD) is the most common endocrine disorder throughout the world and is strongly associated with iodine deficiency [1]. Despite adequate iodine repletion in the United States since the late 1980s [2], clinically evident thyroid nodules still occur in 4 –7% of the population and up to 60 –70% of the population may have asymptomatic, nonpalpable thyroid nodules [3–5]. In our practice, patients with benign asymptomatic NTD are followed with physical examination, serum thyrotropin (TSH) levels, and neck ultrasonography. Surgical therapy is recommended for the following: progressive increase in nodule size, substernal extension, the development of compressive symptoms, radiographic evidence of tracheal, esophageal, or major vessel impingement, the development of thyrotoxicosis, cosmetic concerns, and patient preference. In patients with benign NTD who undergo operative therapy, surgical resection consists of lobectomy for patients with disease limited to 1 lobe. Contralateral disease is excluded by preoperative palpation, ultrasound examination, and intraoperative palpation. Contralateral disease that warrants total thyroidectomy includes 1 or more nodules greater than or equal to 1 cm, or any single nodule less than 1 cm with abnormal sonographic features. In patients with bilateral NTD, our preference, as well as others, is to proceed with near total or total thyroidectomy to resect all disease [6 – 8]. Potential risk factors for recurrent nodular goiter have been evaluated including the following: patient age, sex, family history of goiter, duration of symptoms, multi-NTD, and extent of thyroidectomy, with conflicting results [9 –12]. Previous research indicates that in patients with goiter, African-American race, obesity, pregnancy, and increasing age are independent risk factors for increased goiter size [13]. The purpose of this study was to determine what extent of
1
To whom correspondence and reprint requests should be addressed at Department of Surgery, MetroHealth Medical Center, 2500 MetroHealth Drive, Cleveland, OH 44109. E-mail: cmchenry@ metrohealth.org.
51
0022-4804/09 $36.00 © 2009 Elsevier Inc. All rights reserved.
52
JOURNAL OF SURGICAL RESEARCH: VOL. 154, NO. 1, JUNE 1, 2009
thyroid resection constitutes adequate surgical therapy for benign NTD and what risk factors are associated with recurrence. METHODS Data were obtained from an institutional review board approved, prospectively maintained thyroid database and a retrospective chart review of a consecutive series of patients operated on for benign NTD from 1990 through 2007 by a single surgeon. Yearly follow-up is recommended for all patients who have been treated for benign NTD. Patients who have undergone total thyroidectomy are followed with a yearly neck examination and a yearly serum TSH level. Patients who have undergone thyroid lobectomy are also followed with an annual neck examination and serum TSH level. In addition, they are followed with cervical ultrasound examination every 1–2 y. Twentysix patients with an incidental thyroid microcarcinoma, defined as a papillary carcinoma ⬍1 cm identified on final pathological exam outside of the index nodule, were excluded from the study. Patients were divided into 3 groups. Group 1 consisted of patients who underwent lobectomy for unilateral benign NTD. Group 2 consisted of patients who underwent either near-total or total thyroidectomy for bilateral benign NTD. Group 3 consisted of patients with benign NTD who underwent initial surgical therapy at other institutions and were subsequently referred to our institution with recurrence. All patients in this study had preoperative and intraoperative palpation. Intraoperative palpation was performed without mobilization of the contralateral lobe. In the last 3 y of the study period, a routine ultrasound was performed by a dedicated radiologist to evaluate the location and extent of NTD. The frequency of preoperative thyroid ultrasound was determined for patients in Group 1 and the overall incidence of recurrence was determined for patients in Groups 1 and 2. We defined recurrence of NTD following surgical treatment as any new nodule either palpable on physical examination or demonstrable on ultrasound exam. The length of time for development of recurrence in Groups 1 and 2 was compared to Group 3. Patients with recurrent disease from Groups 1 and 2 were combined with patients in Group 3 and potential risk factors for recurrence of benign NTD were investigated. Potential risk factors that were evaluated included the following: patient age and body mass index at time of surgery, sex, ethnicity or race, previous exposure to ionizing radiation, family history of thyroid disease, tobacco use, or alcohol use. Patient ethnicity or race was coded as African-American or nonAfrican-American. Non-African-American was used as there were too few Hispanic, Asian, or Middle Eastern/Arabic patients to allow for separate analysis. A positive family history of thyroid disease was defined as thyroid disease that was present in a first-degree relative. In terms of previous radiation exposure, patients were specifically asked if they had any occupational exposure to radiation, accidental exposure to environmental radiation, or had received radiation as a form of medical therapy. Tobacco use was defined as the regular use of any type of tobacco product. Alcohol use was defined as the regular consumption of any type of alcoholic beverage. 2 tests were used to determine the statistical significance of nonparametric data and a Student’s t-test was used to determine the statistical significance of parametric data. A 1-way analysis of variance was performed to compare means between all 3 groups. A P value of ⬍0.05 was considered significant. The institutional review board at MetroHealth Medical Center approved the study. Data were analyzed using SPSS for Windows Version 13.0 (SPSS Inc., Chicago, IL).
RESULTS
As illustrated in Table 1, 545 patients were operated on for NTD and confirmed to have benign pathology
during the study period. Contralateral disease was excluded in Group 1 patients using ultrasound in 124 patients (47.7%) and/or intraoperative palpation in all patients. Five (1.9%) of 260 patients in Group 1 and 1 (0.4%) of 248 patients in Group 2 developed recurrent benign NTD after a mean of 7 ⫾ 4 y (median ⫽ 8 y) and 4 y, respectively, compared to a mean 19 ⫾ 11 y (median ⫽ 20 y) for the 37 patients in Group 3 following 1 to 3 previous thyroidectomies. The mean follow-up time was 2 ⫾ 3 y (median ⫽ 1 y; range ⫽ 0.1-14.33 y) for patients in Group 1 and 3 ⫾ 4 y (median ⫽ 1 y; range ⫽ 0.2-16.83 y) for patients in Group 2. Three patients in Group 1 (1.2%) and 2 patients in Group 2 (0.8%) did not have their initial postoperative follow-up with us. Recurrent disease was diagnosed by physical exam in 24 (55.8%) and imaging in 19 (44.2%) patients. Recurrent disease occurred in 2 (1.6%) of the 124 who underwent preoperative thyroid ultrasound. Seventy patients (26.9%) in Group 1 developed postsurgical hypothyroidism, which was treated with thyroid hormone replacement. Of the patients in Group 1, transient recurrent laryngeal nerve injury occurred in 1 (0.3%) and no patient developed permanent recurrent laryngeal nerve injury. Among patients in Group 2, transient recurrent laryngeal nerve injury was noted in 9 patients (3.6%) with only 1 patient (0.4%) with permanent nerve injury. None of the patients who underwent total thyroidectomy had permanent hypoparathyroidism. As illustrated in Table 2, younger age at the initial operation (34 ⫾ 13 y versus 50 ⫾ 15 y, P ⬍ 0.001) and a longer length of follow-up time (16.2 ⫾ 11.6 y versus 2.7 ⫾ 3.5 y, P ⬍ 0.001) were significantly associated with recurrence. Also, the regular consumption of alcohol was more common among patients who did not develop recurrent disease and this approached statistical significance (47.7% of patients without recurrence versus 31.0% of patients with recurrence, P ⫽ 0.052). A prior history of radiation exposure, sex, family history of thyroid disease, tobacco use, and race were not significantly different in patients who had recurrent NTD compared to patients without recurrence. DISCUSSION
The reported recurrence rate following surgical resection for benign NTD varies from 0.3 to 80% depending on the extent of initial surgery, the regional iodine status, and the length of follow-up [8, 14]. Our study demonstrated a recurrence rate of 1.9% following thyroid lobectomy when contralateral disease was excluded using ultrasonography and/or intraoperative palpation. Since this study was not prospective, it is difficult to determine whether the recurrences represented new nodule growth in a previously normal thyroid lobe remnant or progression of disease that was
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PHITAYAKORN ET AL.: BENIGN NODULAR GOITER SURGICAL THERAPY
TABLE 1 Comparative Analysis of Patients Who Underwent Thyroid Lobectomy (Group 1), Near-Total or Total Thyroidectomy (Group 2), or Reoperative Thyroidectomy for Recurrent NTD (Group 3)
Number of patients Number of patients with recurrence (%) Age at first operation (y) BMI at time of first operation (kg/m 2) Patient gender (male/female) History of radiation exposure (%) Family history of thyroid disease (%) Tobacco use (%) Alcohol use (%) Patient race African-American (%) Caucasian (%) Hispanic (%) Asian (%) Middle Eastern/Arabic (%) Mean follow-up time (y) Range of follow-up time (y) Mean time to recurrence (y)
Group 1
Group 2
Group 3
P value
260 5 (1.9%) 48 ⫾ 15 29.2 ⫾ 7.5 43/217 3 (1.2%)* 94 (36.2%) § 107 (41.2%) 㛳 131 (50.4%) #
248 1 (0.4%) 52 ⫾ 16 30.4 ⫾ 7.8 29/219 23 (9.3%) † 111 (44.8%) 㛳 99 (39.9%) 107 (43.1%)
37 37 34 ⫾ 12 N/A 5/32 4 (10.8%) ‡ 11 (29.7%) ¶ 13 (35.1%) § 12 (32.4%) §
Not applicable Not applicable P ⬍ 0.001 P ⫽ NS P ⫽ NS P ⬍ 0.001 P ⫽ NS P ⫽ NS P ⫽ 0.048
82 (31.5%) 150 (57.7%) 18 (6.9%) 10 (3.8%) 0 (0%) 2 ⫾ 3 (median ⫽ 1) 0.1–14.3 7 ⫾ 4 (median ⫽ 8)
94 (37.9%) 141 (56.9%) 8 (3.2%) 3 (1.2%) 2 (0.8%) 3 ⫾ 4 (median ⫽ 1) 0.1–16.8 4
16 (43.2%) 20 (54.1%) 0 (0%) 1 (2.7%) 0 (0%) 19 ⫾ 11 (median ⫽ 20) 1–36.0 19 ⫾ 11 (median ⫽ 20)
P ⫽ NS P ⫽ NS Not applicable Not applicable Not applicable P ⬍ 0.001 Not applicable Not applicable
NS ⫽ Not statistically significant (P ⬎ 0.05). * Nine values missing. † Seven values missing. ‡ Twelve values missing. § One value missing. 㛳 Four values missing. ¶ Two values missing. # Five values missing.
undetected at the initial operation. By reserving total thyroidectomy only for patients with proven bilateral NTD, we were able to avoid thyroid hormone supplementation in 73% of patients who underwent thyroid lobectomy. One patient who initially underwent total thyroidectomy developed recurrence of benign NTD, which may have occurred as a result of retained thyroid tissue or incomplete resection of embryonic thyroid rests [8]. There is no consensus on what constitutes appropriate methodology and timing for follow-up of patients
after surgery for benign nodular disease. Recurrent disease has been reported in the literature to occur as early as 6 mo, but it is usually not diagnosed until 4 or more y after surgery depending on the frequency and type of surveillance methods used [15–17]. Patients in this study developed recurrence at a median of 8 y with 55.8% of recurrences noted by physical examination and 43.2% of recurrences detected by follow-up imaging, either cervical ultrasound or computed tomography. Our results demonstrate that a strategy of preoperative ultrasound and/or intraoperative palpation resulted in
TABLE 2 Clinical Characteristics of Patients Who Did or Did Not Develop Recurrence
Number of patients Age at first surgery (y) Body mass index (kg/m 2) Patient gender (male/female) History of radiation exposure (%) Family history of thyroid disease (%) Tobacco use (%) Alcohol use (%) Patient race (African-American/non-African-American) Mean follow-up time (y) Range of follow-up time (y)
Recurrence
No recurrence
P value
43 34 ⫾ 13 33.6 ⫾ 6.7 5/38 4 (14.3%) 14 (34.1%) 16 (38.1%) 13 (31.0%) 19/24 16.2 ⫾ 11.6 (median ⫽ 15) 0.2–36.0
502 50 ⫾ 15 29.7 ⫾ 7.7 72/430 26 (5.3%) 202 (40.6%) 203 (40.8%) 237 (47.7%) 173/329 2.7 ⫾ 3.5 (median ⫽ 1) 0.1–16.8
Not applicable P ⬍ 0.001 NS NS NS NS NS 0.052 NS P ⬍ 0.001 Not applicable
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a low recurrence rate of only 1.9% among patients who initially underwent lobectomy at our institution. Of these patients with recurrence, none have required reoperation. As advocated by the American Thyroid Association, the American Association of Clinical Endocrinologists, and the National Comprehensive Cancer Network, we now routinely obtain an ultrasound examination in all patients with a thyroid nodule to determine if there is nodular disease elsewhere in the thyroid gland [18 –20]. A risk factor for recurrence of NTD was a younger age at the time of initial operation. This result is consistent with the natural course of benign NTD, which is typically slow-growing so the rate of recurrence likely increases as more time elapses from the initial operation. Previous researchers have noted a linear relationship between patient age, thyroid volume, and nodularity, respectively, with an average yearly increase in thyroid volume of 4.5% based on serial ultrasound measurements [21]. Interestingly, the regular consumption of alcohol may be protective against goiter recurrence. We have previously reported that regular alcohol use was protective against the development of large goiter [13] possibly due to a direct cytotoxic effect of alcohol on thyroid cells or the effect of the high iodine content in alcohol to prevent goiter in patients with subclinical iodine deficiency [22–23]. The extent of thyroidectomy for benign NTD is controversial. In the past, some authors advocated subtotal thyroidectomy for known multi-NTD, citing a lower incidence of recurrent laryngeal nerve palsy, permanent hypocalcemia, and lifelong thyroid hormone supplementation [24]. However, the use of subtotal thyroidectomy for multi-NTD has also been associated with a higher recurrence rate of 5– 43% after a mean follow-up time of 9 –10 y [25]. As surgical techniques have advanced, numerous studies have demonstrated that total thyroidectomy for benign multi-NTD can be performed with morbidity rates comparable to subtotal thyroidectomy [26 –28]. Our current practice, as well as others, is to reserve total thyroidectomy for patients with bilateral NTD or a single thyroid nodule and a history of irradiation to the head or neck [29]. In patients with a single nodule, we carefully examine the contralateral thyroid lobe using preoperative imaging and intraoperative palpation to exclude bilateral disease. Other authors have found that, even in patients who initially underwent thyroid lobectomy for a solitary nodule, and were subsequently found to have multinodular disease on final pathology, reoperation was rarely necessary (⬃3%) after a mean follow-up of 14 y [30]. One limitation of this study is the short mean follow-up time for the patients in Groups 1 and 2. We recently reviewed the literature with regard to how often patients with benign NTD should be followed
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