- Email: [email protected]
Impact of the 2009 American Thyroid Association guidelines on the choice of operation for well-differentiated thyroid microcarcinomas
Impact of the 2009 American Thyroid Association guidelines on the choice of operation for well-differentiated thyroid microcarcinomas Jennifer B. Ogilvie, MD, Kepal N. Patel, MD, and Keith S. Heller, MD, New York, NY
Background. The 2009 ATA Guidelines state ‘‘lobectomy alone may be sufficient treatment for small (<1 cm), low risk, unifocal, intrathyroidal papillary carcinomas in the absence of . . . nodal metastases.’’ We determined how often these criteria are satisfied, and whether tumor size alone can dictate operative management. Methods. Medical records of 346 patients with well-differentiated thyroid cancer (WDTC) who underwent thyroidectomy from January 1, 2007 to November 10, 2009, were reviewed. There were 130 patients with tumors #1 cm and negative lateral nodes. Pathology reports were reviewed to identify adverse features including multifocality, extrathyroidal extension, vascular invasion, and central node metastases. Results. Eighty-four percent underwent total thyroidectomy and 16% central node dissection. All but 2 patients had papillary cancer. Sixty-one percent with cancers 6--10 mm (group 1) had adverse pathologic features compared with 32% with cancers <6 mm (group 2). Multifocality was most common: 55% in group 1 versus 32% in group 2 (P = .004). Positive central nodes were identified in 23% of group 1 versus 4% of group 2 (P = .004). Of patients in group 1, 88% had positive or suspicious fine-needle aspiration biopsy (FNAB) preoperatively. Conclusion. We recommend that total thyroidectomy be considered as the initial operation for thyroid tumors 6--10 mm in size in which the preoperative FNAB is diagnostic or suspicious for WDTC. (Surgery 2010;148:1222-7.) From the Department of Surgery, Division of Endocrine Surgery, New York University Langone Medical Center, New York, NY
RECOMMENDATION 26 of the 2009 Revised American Thyroid Association (ATA) Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer states: ‘‘For patients with thyroid cancer >1 cm, the initial surgical procedure should be a near-total or total thyroidectomy unless there are contraindications to this surgery. Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically
Presented at the 31st Annual Meeting of the American Association of Endocrine Surgeons, Pittsburgh, Pennsylvania, April 18–20, 2010. Accepted for publication September 16, 2010. Reprint requests: Keith S. Heller, MD, NYU Langone Medical Center, 530 First Avenue, HCC, Suite 6H, New York, NY 10016. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2010.09.007
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or clinically involved cervical nodal metastases. Recommendation rating: A.’’1 Well-differentiated thyroid microcarcinomas (WDTMC) are defined as carcinomas #1 cm in size.2-4 They are often diagnosed incidentally after thyroidectomy performed for other indications.5 Outcomes after treatment of WDTMC are excellent, with recurrence rates of 3.5--5.7%4,6-9 and long-term cancer-specific mortality of 0.3--2.0%.8-10 In the largest retrospective series to date, total thyroidectomy was demonstrated to decrease recurrence and improve survival in patients with papillary thyroid cancer (PTC) >1 cm, but not in patients with PTC #1 cm.10 Section B13 of the 2009 ATA Guidelines defines patients with a low risk of thyroid cancer recurrence as those with the following characteristics: 1) no local or distant metastases; 2) all macroscopic tumor has been resected; 3) there is no tumor invasion of locoregional tissues or structures; 4) the tumor does not have aggressive histology (eg, tall cell, insular, columnar cell carcinoma) or vascular
Surgery Volume 148, Number 6 invasion; and 5) if 131I is given, there is no 131I uptake outside the thyroid bed on the first posttreatment, whole-body radioactive iodine scan.1
The 2009 ATA guidelines suggest that patients with well-differentiated thyroid cancer (WDTC) #1 cm and none of the risk factors listed may be treated with thyroid lobectomy alone. The purpose of this study was to determine how often WDTMC meet these criteria for thyroid lobectomy, and whether size alone can dictate operative management when the ATA guidelines are followed. METHODS The medical records of all 378 patients who underwent thyroid operations with a postoperative diagnosis of thyroid cancer at NYU Langone Medical Center by the 3 members of NYU Endocrine Surgery Associates from January 1, 2007 through November 11, 2009, were reviewed. Twenty-one patients who had undergone previous operations elsewhere for thyroid cancer, as well as 7 patients with medullary thyroid cancer, 3 with poorly differentiated thyroid cancer, and 1 with insular cancer were excluded from further analysis. Of these 346 previously untreated patients with WDTC, all 130 patients with tumors #10 mm and lateral cervical lymph nodes not suspicious for metastases on either ultrasonography or physical examination were selected for further study. These patients were retrospectively divided into 2 groups: group 1, with tumors 6--10 mm and group 2, with tumors #5 mm. Indications for surgery included cytologic findings on fine-needle aspiration biopsy (FNAB), symptomatic or enlarging multinodular goiter, and Graves’ disease. The extent of thyroidectomy (lobectomy versus total thyroidectomy) was determined by the operating surgeon based on preoperative evaluation, patient preference, and intraoperative findings. Central compartment lymph node sampling or central compartment dissection was performed if suspicious nodes were identified at the time of surgery, or electively at the discretion of the surgeon. Tumor size was measured by the pathologist from the unfixed, fresh surgical specimen. The largest tumor diameter is reported. In patients with multifocal cancer, the size of the largest tumor was documented. Incidental cancers were defined as tumors found on pathologic study of the surgical specimen that were not related to the indication for thyroidectomy. When incidental WDTMC were discovered on microscopic sections, their size was measured directly on the stained slides. Pathology reports were reviewed for adverse features
Ogilvie, Patel, and Heller 1223
including multifocality, bilaterality, extrathyroidal extension, lymphovascular invasion, and central compartment lymph node metastases. Statistical analysis was performed using GraphPad InStat version 3.0a for Macintosh (GraphPad Software, San Diego, CA). Contingency tables were analyzed by the Fisher exact test and comparison of means by an unpaired t test. P # .05 was considered significant. This study was approved by the NYU Cancer Institute Protocol Review and Monitoring Committee and by the NYU Institutional Review Board. RESULTS There were 98 women and 32 men, ranging in age from 16 to 84 years (mean, 50; standard deviation, 14). WDTMC was found incidentally after thyroidectomy performed for other indications in 52 patients (40%). Among the remaining 78 patients, preoperative FNAB was interpreted as PTC in 44 patients (56%), suspicious for PTC in 22 (28%), follicular neoplasm in 5 (6%), H€ urthle cell (oncocytic) neoplasm in 3 (4%), and atypical in 4 (5%). Three patients (3%) had a history of radiation exposure. Total thyroidectomy was performed in 106 of 130 patients (82%). In 5 of these 106 patients (5%), a completion thyroidectomy was performed after WDTMC was diagnosed after lobectomy. Thyroid lobectomy alone was performed in 24 patients (18%). A central compartment lymph node dissection was performed in 21 patients (16%). At least 1 central compartment lymph node was removed in 66 patients (51%). There was no invasion of the trachea or esophagus by tumor in any of these patients nor anything more than minimal, superficial invasion of the overlying strap muscles. All clinically apparent tumor was removed in all patients. Pathologic findings revealed that all but 2 of the 130 patients (98%) had PTC, including 103 patients with conventional PTC (79%), 19 with follicular variant PTC (15%), and 6 with other PTC subtypes (5%). There were no patients with tall cell or columnar variants of PTC. One patient had follicular cancer and 1 had H€ urthle cell (oncocytic) cancer. After excluding the 3 patients who had a history of prior radiation exposure and the 2 patients who did not have PTC, the pathology reports of the remaining 125 patients were analyzed to determine the presence of adverse pathologic features. At least 1 adverse pathologic feature was identified in 59 patients (47%). This included 55 patients with multifocal tumors (44%), 10 with microscopic
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Table. A comparison of patient characteristics and adverse pathologic features between groups 1 and 2 Number of patients Gender (male/female) Mean age at diagnosis, yrs (range) Incidental tumors Total thyroidectomy Central nodes removed Multifocal tumors Bilateral tumors (% all patients) Bilateral tumors (% patients with total thyroidectomy) Extrathyroidal extension Lymphovascular invasion Positive central nodes (% all patients) Positive central nodes (% patients with nodes removed) At least 1 adverse pathologic feature identified
extrathyroidal tumor extension (8%), and 21 with lymphovascular invasion (17%). Of the 55 patients with multifocal tumors, 38 (69%) had bilateral disease. Of the 64 patients who had $1 central compartment lymph node removed, 18 (28%) had metastases to $1 central nodes. A comparison of groups 1 and 2 is shown in the Table. Patients in group 1 were slightly younger than those in group 2. Only 13% of cancers in group 1 had incidental cancers, compared with 75% in group 2. Patients in group 1 were more likely to have undergone total thyroidectomy and to have had central lymph nodes removed than those in group 2. Adverse pathologic features studied were significantly more likely to be present in patients in group 1. Most important, only 39% of patients in group 1 had no adverse pathologic features, compared with 68% in group 2. DISCUSSION Of all patients undergoing surgery for WDTC, we found that 38% had tumors #1 cm. This is consistent with the rates of WDTMC found in other large contemporary series, which range from 24 to 49%.9,11,12 Of the WDTMC, 98% in our series were PTC. There were no cases of tall cell or columnar variant PTC. The World Health Organization defines papillary thyroid microcancers (PTMC) as cancers #1 cm that are found incidentally.3 Interestingly, only 40% of WDTMC in our patients were incidental; the remainder were referred for operative intervention based on FNAB. The current ATA guidelines do not recommend routine FNAB for subcentimeter nodules, unless associated with high clinical risk factors such as family history, radiation exposure,
Group 1 (6--10 mm)
Group 2 (#5 mm)
P value
69 19/50 47 (16-84) 9 (13%) 62 (90%) 42 (61%) 38 (55%) 30 (43%) 30 (48%) 9 (13%) 20 (29%) 16 (23%) 16 (38%)
56 12/44 52 (26-83) 42 (75%) 39 (70%) 22 (39%) 18 (32%) 8 (14%) 8 (21%) 1 (2%) 1 (2%) 2 (4%) 2 (9%)
.53 .04 <.0001 .006 .02 .01 .0004 .006 .02 <.0001 .002 .02
42 (61%)
18 (32%)
.002
suspicious appearance on ultrasonography, or positron emission tomography positivity.1 Despite these recommendations, 60% of our patients overall and 87% of patients with tumors of 6--10 mm were referred for operative intervention based on suspicious FNAB. Of these FNAB, 84% were interpreted as either suspicious for malignancy or malignant. The likelihood of malignancy in FNAB interpreted as suspicious for malignancy is estimated to be 50--75% by the National Cancer Institute ‘‘Thyroid Fine-Needle Aspiration State of the Science Conference’’ of 2008,13 and ranges from 60% to 100% in large, retrospective series.14-16 For this reason, we generally recommend that patients with FNAB suspicious for malignancy undergo the same operation that would be performed for malignant FNAB. Tumor size has been found to be a prognostic indicator in most risk stratification systems for WDTC including AJCC/UICC, AGES, AMES, OSU, MACIS, and NTCTCS.17 Even among PTMC, size seems to be an important prognostic indicator, with significantly higher rates of recurrence in tumors >5 mm (14%), compared with tumors <5 mm (3%).9 Adverse pathologic features in addition to size are also associated with higher recurrence rates. Extrathyroidal extension9 and angiolymphatic invasion18 have both been associated with significantly higher risk of recurrence in PTMC, as have multifocality19 and central compartment lymph node metastases.8,20 Most WDTMC are PTC, as seen in our series. PTMC is often multifocal, ranging from 23% to 44%, and between 25% and 64% have cervical lymph node metastases.4,19,21-23 In our series, 44% were multifocal, and $28% had central lymph node metastases. Multifocality and central lymph node metastases, as well as additional adverse features of angiolymphatic invasion
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and extrathyroidal extension, were significantly more common in patients with tumors of 6--10 mm. Although the optimal operative management of WDTMC remains controversial, both the European Thyroid Cancer Taskforce and the ATA state that thyroid lobectomy may be sufficient for solitary WDTMC with no additional adverse risk factors.1,24 The main basis of the current ATA recommendations is a large, retrospective study of the National Cancer Data Base by Bilimoria et al,10 which showed that the extent of the operation did not affect recurrence or survival in PTMC. Baudin et al,19 studying a large series of PTMC, found that both multifocality and less than near-total thyroidectomy were associated with an increased risk of recurrence, and recommended total thyroidectomy for multifocal PTMC. A recent retrospective study from the National Thyroid Cancer Treatment Cooperative Study also found that patients with multifocal PTMC had higher rates of tumor recurrence (18%) after less than near-total thyroidectomy, compared with patients with unifocal PTMC (4%), although recurrence rates after neartotal thyroidectomy versus less than total thyroidectomy among all patients with multifocal PTMC did not reach statistical significance.25 Chow et al22 found that multifocal tumors were associated with increased likelihood of cervical lymph node recurrence than unifocal tumors, but observed no difference in recurrence between PTMC treated with lobectomy versus total thyroidectomy. Recurrence rates in this series were 5%, with 1% mortality.22 Finally, the Mayo Clinic initially found a lower recurrence rate in patients with PTMC treated with more aggressive initial operation.8 However, the extent of the initial operation was not found to be a significant predictor of recurrence in their larger follow-up study if the tumor was completely resected.4 In this study, we have shown that, among patients with WDTC #1 cm, additional adverse risk factors including multifocality, extrathyroidal extension, angiolymphatic invasion, and central lymph node metastases were present in 47%, and $1 adverse factor was present in 61% of patients with tumors of 6--10 mm. In this latter group of patients, the diagnosis of WDTC was established or suspected preoperatively in most patients. The majority of these patients, therefore, had $1 indication for total thyroidectomy based on the ATA guidelines. This study demonstrates that almost two thirds of WDTMC between 6 and 10 mm and one third of WDTMC #5 mm would not meet ATA criteria for thyroid lobectomy. In conclusion, this study makes no claims that total thyroidectomy decreases local recurrence or
increases survival in patients with WDTMC. It does not address the indications for central lymph node dissection in these patients. Nor does it discuss whether the complications resulting from total thyroidectomy outweigh its possible benefits. It is not our intent to address the question of the appropriate evaluation of thyroid nodules #1 cm or the need for FNAB of small nodules. However, this study does demonstrate that the diagnosis of WDTMC is either established or strongly suspected preoperatively in most patients found to have cancers between 6 and 10 mm, and that 61% of them would not be suitable for thyroid lobectomy if the current ATA guidelines were followed. In preoperative discussions with patients with positive or suspicious FNAB, this information may be useful in discussing the advantages and disadvantages of the operative options of initial total thyroidectomy or lobectomy with possible completion thyroidectomy at a later date. We suggest that total thyroidectomy be strongly considered as the initial operation for thyroid tumors 6--10 mm in size in which the preoperative FNAB is diagnostic or suspicious for WDTC. REFERENCES 1. 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. 2. Baloch ZW, LiVolsi VA. Microcarcinoma of the thyroid. Adv Anat Pathol 2006;13:69-75. 3. DeLellis RA. Pathology and genetics of tumours of endocrine organs. Lyon: IARC Press; 2004. 4. Hay ID, Hutchinson ME, Gonzalez-Losada T, McIver B, Reinalda ME, Grant CS, et al. Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery 2008;144:980-7. 5. Lo CY, Chan WF, Lang BH, Lam KY, Wan KY. Papillary microcarcinoma: is there any difference between clinically overt and occult tumors? World J Surg 2006;30:759-66. 6. Mazzaferri EL. Management of low-risk differentiated thyroid cancer. Endocr Pract 2007;13:498-512. 7. Sanders LE, Cady B. Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg 1998;133:419-25. 8. Hay ID, Grant CS, van Heerden JA, Goellner JR, Ebersold JR, Bergstralh EJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery 1992;112: 1139-46. 9. Noguchi S, Yamashita H, Uchino S, Watanabe S. Papillary microcarcinoma. World J Surg 2008;32:747-53. 10. Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246:375-81. 11. Miccoli P, Minuto MN, Ugolini C, Panicucci E, Berti P, Massi M, et al. Intrathyroidal differentiated thyroid carcinoma: tumor size-based surgical concepts. World J Surg 2007;31:888-94. 12. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973--2002. JAMA 2006;295:2164-7.
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13. Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Randolph G, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36:425-37. 14. Yang J, Schnadig V, Logrono R, Wasserman PG. Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer 2007;111:306-15. 15. Yassa L, Cibas ES, Benson CB, Frates MC, Doubilet PM, Gawande AA, et al. Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer 2007;111:508-16. 16. Ito Y, Amino N, Yokozawa T, Ota H, Ohshita M, Murata N, et al. Ultrasonographic evaluation of thyroid nodules in 900 patients: comparison among ultrasonographic, cytological, and histological findings. Thyroid 2007;17:1269-76. 17. Lang BH, Lo CY, Chan WF, Lam KY, Wan KY. Staging systems for papillary thyroid carcinoma: a review and comparison. Ann Surg 2007;245:366-78. 18. Arora N, Turbendian HK, Kato MA, Moo TA, Zarnegar R, Fahey TJ III. Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two? Thyroid 2009;19:473-7. 19. Baudin E, Travagli JP, Ropers J, Mancusi F, Bruno-Bossio G, Caillou B, et al. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience. Cancer 1998;83:553-9. 20. Sugitani I, Fujimoto Y. Symptomatic versus asymptomatic papillary thyroid microcarcinoma: a retrospective analysis of surgical outcome and prognostic factors. Endocr J 1999;46:209-16. 21. Wada N, Duh QY, Sugino K, Iwasaki H, Kameyama K, Mimura T, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg 2003;237:399-407. 22. Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH. Papillary microcarcinoma of the thyroid---prognostic significance of lymph node metastasis and multifocality. Cancer 2003;98: 31-40. 23. Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, et al. Papillary microcarcinoma of the thyroid: how should it be treated? World J Surg 2004;28:1115-21. 24. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154:787-803. 25. Ross DS, Litofsky D, Ain KB, Bigos T, Brierley JD, Cooper DS, et al. Recurrence after treatment of micropapillary thyroid cancer. Thyroid 2009;19:1043-8.
DISCUSSION Dr Orlo H. Clark (San Francisco, CA): How is this going to change your practice, especially when you find these are incidental? If you did know it was there, and you did not do a total thyroidectomy---I know you did mostly total thyroidectomy, even in the noncancer group, I wonder how it’s going to change. When we follow our patients who have these incidental cancers, most of us try to ignore them, but you can’t do that completely. Were the thyroglobulin or ultrasound different in the 2 groups, #5 mm and 6--10 mm, in your follow-up? What was the follow-up?
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Dr Keith S. Heller (New York, NY): I didn’t look at follow-up, because I really wanted to avoid trying to decide what was the operation of choice. The simple answer is that our follow-up is too short to draw any conclusions about outcome. How is it going to change my practice? I actually think that the majority of these microcancers are adequately treated with a lobectomy. However, I don’t work in a vacuum, and the endocrinologists that I work with will insist that the patients who don’t meet ATA criteria go back for a completion thyroidectomy because they are convinced that they need radioactive iodine. This recommendation is not made because I’m convinced I’m going to cure more people, but because I really do want to avoid unnecessary completion thyroidectomies. I do think that probably everybody in this room can do total thyroidectomies safely. Dr Bradford Mitchell (Morgantown, WV): I share your bias toward total thyroidectomy and avoiding completion thyroidectomy, and I compliment you for making the point that this is a safe operation for the members of this audience. Now, the question I have for you is: How did you calculate the cost--benefit ratio of recommending it only for the 62%, as opposed to the 33% that were <5 mm? Dr Keith S. Heller (New York, NY): I didn’t do a cost-benefit analysis. I use this information in my discussion with the patient. I would tell a patient with an 8-mm, FNAB-positive nodule in the thyroid that we can do a lobectomy, but that there is a 60% chance that he or she will need a second operation. If that’s okay with the patient, then I’m okay with doing a lobectomy. Most of my patients, when given that option, opt for a total thyroidectomy at the first operation. Dr Subhash Patel (Chicago, IL): You stated that most of your microcarcinomas were not incidental. However, they are quite small, 8 mm, 5 mm, or less. Were your FNAs image-guided biopsies, or do you have sensitive fingers with 60% positive FNA? Dr Keith S. Heller (New York, NY): No, they were almost all image guided. Most of these nodules were discovered on carotid duplex scans, other unrelated imaging studies, or thyroid ultrasounds, many of which were inappropriate or unnecessary. But they come to me having had a biopsy, and it’s difficult to say, ‘‘I wouldn’t have done the biopsy; therefore, ignore the diagnosis.’’ Dr Scott Wilhelm (Cleveland, OH): In terms of your indication for biopsying <1-cm nodules, certainly I’ll drop my criteria down to 8 mm or something if it’s a positron emission tomography scan--positive nodule. I’m just curious if you could comment why you were dropping your criteria down. Dr Keith S. Heller (New York, NY): Let me make it very clear, I did not do these biopsies. I am getting a very stiff neck in my office, shaking my head, looking at the charts and saying, ‘‘Why did they do this?’’ If you look at the radiologists’ guidelines, you are only supposed to put needles in subcentimeter nodules that are sonographically suspicious. The problem is
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that the criteria for sonographically suspicious include solid and hypoechoic, which includes a lot of nodules. Dr Irving B. Rosen (Toronto, Ontario, Canada): I want to congratulate you on your study and the honesty which that study implies. I just rise to say that about a decade ago, one of my residents, at his own initiative, ran through a study comparing micronodular with macronodular palpable disease, and he found exactly what you’re describing. The adverse features were identical. He, therefore,
Ogilvie, Patel, and Heller 1227
proposed that, indeed, if we are going to use adverse features as a basis for doing a total or near-total thyroidectomy, then you should do it in micronodular disease. He presented that paper. He was then attacked, literally, in the discussion period. I then went to his rescue. I was similarly attacked by Dr Clark, among others. So, like yourself, you can’t be too overbearing in your conclusions; but nevertheless, those are the facts of thyroid life, I think---cancer, anyways.
Background. The 2009 ATA Guidelines state ‘‘lobectomy alone may be sufficient treatment for small (<1 cm), low risk, unifocal, intrathyroidal papillary carcinomas in the absence of . . . nodal metastases.’’ We determined how often these criteria are satisfied, and whether tumor size alone can dictate operative management. Methods. Medical records of 346 patients with well-differentiated thyroid cancer (WDTC) who underwent thyroidectomy from January 1, 2007 to November 10, 2009, were reviewed. There were 130 patients with tumors #1 cm and negative lateral nodes. Pathology reports were reviewed to identify adverse features including multifocality, extrathyroidal extension, vascular invasion, and central node metastases. Results. Eighty-four percent underwent total thyroidectomy and 16% central node dissection. All but 2 patients had papillary cancer. Sixty-one percent with cancers 6--10 mm (group 1) had adverse pathologic features compared with 32% with cancers <6 mm (group 2). Multifocality was most common: 55% in group 1 versus 32% in group 2 (P = .004). Positive central nodes were identified in 23% of group 1 versus 4% of group 2 (P = .004). Of patients in group 1, 88% had positive or suspicious fine-needle aspiration biopsy (FNAB) preoperatively. Conclusion. We recommend that total thyroidectomy be considered as the initial operation for thyroid tumors 6--10 mm in size in which the preoperative FNAB is diagnostic or suspicious for WDTC. (Surgery 2010;148:1222-7.) From the Department of Surgery, Division of Endocrine Surgery, New York University Langone Medical Center, New York, NY
RECOMMENDATION 26 of the 2009 Revised American Thyroid Association (ATA) Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer states: ‘‘For patients with thyroid cancer >1 cm, the initial surgical procedure should be a near-total or total thyroidectomy unless there are contraindications to this surgery. Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically
Presented at the 31st Annual Meeting of the American Association of Endocrine Surgeons, Pittsburgh, Pennsylvania, April 18–20, 2010. Accepted for publication September 16, 2010. Reprint requests: Keith S. Heller, MD, NYU Langone Medical Center, 530 First Avenue, HCC, Suite 6H, New York, NY 10016. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2010.09.007
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or clinically involved cervical nodal metastases. Recommendation rating: A.’’1 Well-differentiated thyroid microcarcinomas (WDTMC) are defined as carcinomas #1 cm in size.2-4 They are often diagnosed incidentally after thyroidectomy performed for other indications.5 Outcomes after treatment of WDTMC are excellent, with recurrence rates of 3.5--5.7%4,6-9 and long-term cancer-specific mortality of 0.3--2.0%.8-10 In the largest retrospective series to date, total thyroidectomy was demonstrated to decrease recurrence and improve survival in patients with papillary thyroid cancer (PTC) >1 cm, but not in patients with PTC #1 cm.10 Section B13 of the 2009 ATA Guidelines defines patients with a low risk of thyroid cancer recurrence as those with the following characteristics: 1) no local or distant metastases; 2) all macroscopic tumor has been resected; 3) there is no tumor invasion of locoregional tissues or structures; 4) the tumor does not have aggressive histology (eg, tall cell, insular, columnar cell carcinoma) or vascular
Surgery Volume 148, Number 6 invasion; and 5) if 131I is given, there is no 131I uptake outside the thyroid bed on the first posttreatment, whole-body radioactive iodine scan.1
The 2009 ATA guidelines suggest that patients with well-differentiated thyroid cancer (WDTC) #1 cm and none of the risk factors listed may be treated with thyroid lobectomy alone. The purpose of this study was to determine how often WDTMC meet these criteria for thyroid lobectomy, and whether size alone can dictate operative management when the ATA guidelines are followed. METHODS The medical records of all 378 patients who underwent thyroid operations with a postoperative diagnosis of thyroid cancer at NYU Langone Medical Center by the 3 members of NYU Endocrine Surgery Associates from January 1, 2007 through November 11, 2009, were reviewed. Twenty-one patients who had undergone previous operations elsewhere for thyroid cancer, as well as 7 patients with medullary thyroid cancer, 3 with poorly differentiated thyroid cancer, and 1 with insular cancer were excluded from further analysis. Of these 346 previously untreated patients with WDTC, all 130 patients with tumors #10 mm and lateral cervical lymph nodes not suspicious for metastases on either ultrasonography or physical examination were selected for further study. These patients were retrospectively divided into 2 groups: group 1, with tumors 6--10 mm and group 2, with tumors #5 mm. Indications for surgery included cytologic findings on fine-needle aspiration biopsy (FNAB), symptomatic or enlarging multinodular goiter, and Graves’ disease. The extent of thyroidectomy (lobectomy versus total thyroidectomy) was determined by the operating surgeon based on preoperative evaluation, patient preference, and intraoperative findings. Central compartment lymph node sampling or central compartment dissection was performed if suspicious nodes were identified at the time of surgery, or electively at the discretion of the surgeon. Tumor size was measured by the pathologist from the unfixed, fresh surgical specimen. The largest tumor diameter is reported. In patients with multifocal cancer, the size of the largest tumor was documented. Incidental cancers were defined as tumors found on pathologic study of the surgical specimen that were not related to the indication for thyroidectomy. When incidental WDTMC were discovered on microscopic sections, their size was measured directly on the stained slides. Pathology reports were reviewed for adverse features
Ogilvie, Patel, and Heller 1223
including multifocality, bilaterality, extrathyroidal extension, lymphovascular invasion, and central compartment lymph node metastases. Statistical analysis was performed using GraphPad InStat version 3.0a for Macintosh (GraphPad Software, San Diego, CA). Contingency tables were analyzed by the Fisher exact test and comparison of means by an unpaired t test. P # .05 was considered significant. This study was approved by the NYU Cancer Institute Protocol Review and Monitoring Committee and by the NYU Institutional Review Board. RESULTS There were 98 women and 32 men, ranging in age from 16 to 84 years (mean, 50; standard deviation, 14). WDTMC was found incidentally after thyroidectomy performed for other indications in 52 patients (40%). Among the remaining 78 patients, preoperative FNAB was interpreted as PTC in 44 patients (56%), suspicious for PTC in 22 (28%), follicular neoplasm in 5 (6%), H€ urthle cell (oncocytic) neoplasm in 3 (4%), and atypical in 4 (5%). Three patients (3%) had a history of radiation exposure. Total thyroidectomy was performed in 106 of 130 patients (82%). In 5 of these 106 patients (5%), a completion thyroidectomy was performed after WDTMC was diagnosed after lobectomy. Thyroid lobectomy alone was performed in 24 patients (18%). A central compartment lymph node dissection was performed in 21 patients (16%). At least 1 central compartment lymph node was removed in 66 patients (51%). There was no invasion of the trachea or esophagus by tumor in any of these patients nor anything more than minimal, superficial invasion of the overlying strap muscles. All clinically apparent tumor was removed in all patients. Pathologic findings revealed that all but 2 of the 130 patients (98%) had PTC, including 103 patients with conventional PTC (79%), 19 with follicular variant PTC (15%), and 6 with other PTC subtypes (5%). There were no patients with tall cell or columnar variants of PTC. One patient had follicular cancer and 1 had H€ urthle cell (oncocytic) cancer. After excluding the 3 patients who had a history of prior radiation exposure and the 2 patients who did not have PTC, the pathology reports of the remaining 125 patients were analyzed to determine the presence of adverse pathologic features. At least 1 adverse pathologic feature was identified in 59 patients (47%). This included 55 patients with multifocal tumors (44%), 10 with microscopic
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Table. A comparison of patient characteristics and adverse pathologic features between groups 1 and 2 Number of patients Gender (male/female) Mean age at diagnosis, yrs (range) Incidental tumors Total thyroidectomy Central nodes removed Multifocal tumors Bilateral tumors (% all patients) Bilateral tumors (% patients with total thyroidectomy) Extrathyroidal extension Lymphovascular invasion Positive central nodes (% all patients) Positive central nodes (% patients with nodes removed) At least 1 adverse pathologic feature identified
extrathyroidal tumor extension (8%), and 21 with lymphovascular invasion (17%). Of the 55 patients with multifocal tumors, 38 (69%) had bilateral disease. Of the 64 patients who had $1 central compartment lymph node removed, 18 (28%) had metastases to $1 central nodes. A comparison of groups 1 and 2 is shown in the Table. Patients in group 1 were slightly younger than those in group 2. Only 13% of cancers in group 1 had incidental cancers, compared with 75% in group 2. Patients in group 1 were more likely to have undergone total thyroidectomy and to have had central lymph nodes removed than those in group 2. Adverse pathologic features studied were significantly more likely to be present in patients in group 1. Most important, only 39% of patients in group 1 had no adverse pathologic features, compared with 68% in group 2. DISCUSSION Of all patients undergoing surgery for WDTC, we found that 38% had tumors #1 cm. This is consistent with the rates of WDTMC found in other large contemporary series, which range from 24 to 49%.9,11,12 Of the WDTMC, 98% in our series were PTC. There were no cases of tall cell or columnar variant PTC. The World Health Organization defines papillary thyroid microcancers (PTMC) as cancers #1 cm that are found incidentally.3 Interestingly, only 40% of WDTMC in our patients were incidental; the remainder were referred for operative intervention based on FNAB. The current ATA guidelines do not recommend routine FNAB for subcentimeter nodules, unless associated with high clinical risk factors such as family history, radiation exposure,
Group 1 (6--10 mm)
Group 2 (#5 mm)
P value
69 19/50 47 (16-84) 9 (13%) 62 (90%) 42 (61%) 38 (55%) 30 (43%) 30 (48%) 9 (13%) 20 (29%) 16 (23%) 16 (38%)
56 12/44 52 (26-83) 42 (75%) 39 (70%) 22 (39%) 18 (32%) 8 (14%) 8 (21%) 1 (2%) 1 (2%) 2 (4%) 2 (9%)
.53 .04 <.0001 .006 .02 .01 .0004 .006 .02 <.0001 .002 .02
42 (61%)
18 (32%)
.002
suspicious appearance on ultrasonography, or positron emission tomography positivity.1 Despite these recommendations, 60% of our patients overall and 87% of patients with tumors of 6--10 mm were referred for operative intervention based on suspicious FNAB. Of these FNAB, 84% were interpreted as either suspicious for malignancy or malignant. The likelihood of malignancy in FNAB interpreted as suspicious for malignancy is estimated to be 50--75% by the National Cancer Institute ‘‘Thyroid Fine-Needle Aspiration State of the Science Conference’’ of 2008,13 and ranges from 60% to 100% in large, retrospective series.14-16 For this reason, we generally recommend that patients with FNAB suspicious for malignancy undergo the same operation that would be performed for malignant FNAB. Tumor size has been found to be a prognostic indicator in most risk stratification systems for WDTC including AJCC/UICC, AGES, AMES, OSU, MACIS, and NTCTCS.17 Even among PTMC, size seems to be an important prognostic indicator, with significantly higher rates of recurrence in tumors >5 mm (14%), compared with tumors <5 mm (3%).9 Adverse pathologic features in addition to size are also associated with higher recurrence rates. Extrathyroidal extension9 and angiolymphatic invasion18 have both been associated with significantly higher risk of recurrence in PTMC, as have multifocality19 and central compartment lymph node metastases.8,20 Most WDTMC are PTC, as seen in our series. PTMC is often multifocal, ranging from 23% to 44%, and between 25% and 64% have cervical lymph node metastases.4,19,21-23 In our series, 44% were multifocal, and $28% had central lymph node metastases. Multifocality and central lymph node metastases, as well as additional adverse features of angiolymphatic invasion
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and extrathyroidal extension, were significantly more common in patients with tumors of 6--10 mm. Although the optimal operative management of WDTMC remains controversial, both the European Thyroid Cancer Taskforce and the ATA state that thyroid lobectomy may be sufficient for solitary WDTMC with no additional adverse risk factors.1,24 The main basis of the current ATA recommendations is a large, retrospective study of the National Cancer Data Base by Bilimoria et al,10 which showed that the extent of the operation did not affect recurrence or survival in PTMC. Baudin et al,19 studying a large series of PTMC, found that both multifocality and less than near-total thyroidectomy were associated with an increased risk of recurrence, and recommended total thyroidectomy for multifocal PTMC. A recent retrospective study from the National Thyroid Cancer Treatment Cooperative Study also found that patients with multifocal PTMC had higher rates of tumor recurrence (18%) after less than near-total thyroidectomy, compared with patients with unifocal PTMC (4%), although recurrence rates after neartotal thyroidectomy versus less than total thyroidectomy among all patients with multifocal PTMC did not reach statistical significance.25 Chow et al22 found that multifocal tumors were associated with increased likelihood of cervical lymph node recurrence than unifocal tumors, but observed no difference in recurrence between PTMC treated with lobectomy versus total thyroidectomy. Recurrence rates in this series were 5%, with 1% mortality.22 Finally, the Mayo Clinic initially found a lower recurrence rate in patients with PTMC treated with more aggressive initial operation.8 However, the extent of the initial operation was not found to be a significant predictor of recurrence in their larger follow-up study if the tumor was completely resected.4 In this study, we have shown that, among patients with WDTC #1 cm, additional adverse risk factors including multifocality, extrathyroidal extension, angiolymphatic invasion, and central lymph node metastases were present in 47%, and $1 adverse factor was present in 61% of patients with tumors of 6--10 mm. In this latter group of patients, the diagnosis of WDTC was established or suspected preoperatively in most patients. The majority of these patients, therefore, had $1 indication for total thyroidectomy based on the ATA guidelines. This study demonstrates that almost two thirds of WDTMC between 6 and 10 mm and one third of WDTMC #5 mm would not meet ATA criteria for thyroid lobectomy. In conclusion, this study makes no claims that total thyroidectomy decreases local recurrence or
increases survival in patients with WDTMC. It does not address the indications for central lymph node dissection in these patients. Nor does it discuss whether the complications resulting from total thyroidectomy outweigh its possible benefits. It is not our intent to address the question of the appropriate evaluation of thyroid nodules #1 cm or the need for FNAB of small nodules. However, this study does demonstrate that the diagnosis of WDTMC is either established or strongly suspected preoperatively in most patients found to have cancers between 6 and 10 mm, and that 61% of them would not be suitable for thyroid lobectomy if the current ATA guidelines were followed. In preoperative discussions with patients with positive or suspicious FNAB, this information may be useful in discussing the advantages and disadvantages of the operative options of initial total thyroidectomy or lobectomy with possible completion thyroidectomy at a later date. We suggest that total thyroidectomy be strongly considered as the initial operation for thyroid tumors 6--10 mm in size in which the preoperative FNAB is diagnostic or suspicious for WDTC. REFERENCES 1. 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. 2. Baloch ZW, LiVolsi VA. Microcarcinoma of the thyroid. Adv Anat Pathol 2006;13:69-75. 3. DeLellis RA. Pathology and genetics of tumours of endocrine organs. Lyon: IARC Press; 2004. 4. Hay ID, Hutchinson ME, Gonzalez-Losada T, McIver B, Reinalda ME, Grant CS, et al. Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60-year period. Surgery 2008;144:980-7. 5. Lo CY, Chan WF, Lang BH, Lam KY, Wan KY. Papillary microcarcinoma: is there any difference between clinically overt and occult tumors? World J Surg 2006;30:759-66. 6. Mazzaferri EL. Management of low-risk differentiated thyroid cancer. Endocr Pract 2007;13:498-512. 7. Sanders LE, Cady B. Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg 1998;133:419-25. 8. Hay ID, Grant CS, van Heerden JA, Goellner JR, Ebersold JR, Bergstralh EJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery 1992;112: 1139-46. 9. Noguchi S, Yamashita H, Uchino S, Watanabe S. Papillary microcarcinoma. World J Surg 2008;32:747-53. 10. Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246:375-81. 11. Miccoli P, Minuto MN, Ugolini C, Panicucci E, Berti P, Massi M, et al. Intrathyroidal differentiated thyroid carcinoma: tumor size-based surgical concepts. World J Surg 2007;31:888-94. 12. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973--2002. JAMA 2006;295:2164-7.
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13. Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Randolph G, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36:425-37. 14. Yang J, Schnadig V, Logrono R, Wasserman PG. Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer 2007;111:306-15. 15. Yassa L, Cibas ES, Benson CB, Frates MC, Doubilet PM, Gawande AA, et al. Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer 2007;111:508-16. 16. Ito Y, Amino N, Yokozawa T, Ota H, Ohshita M, Murata N, et al. Ultrasonographic evaluation of thyroid nodules in 900 patients: comparison among ultrasonographic, cytological, and histological findings. Thyroid 2007;17:1269-76. 17. Lang BH, Lo CY, Chan WF, Lam KY, Wan KY. Staging systems for papillary thyroid carcinoma: a review and comparison. Ann Surg 2007;245:366-78. 18. Arora N, Turbendian HK, Kato MA, Moo TA, Zarnegar R, Fahey TJ III. Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two? Thyroid 2009;19:473-7. 19. Baudin E, Travagli JP, Ropers J, Mancusi F, Bruno-Bossio G, Caillou B, et al. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience. Cancer 1998;83:553-9. 20. Sugitani I, Fujimoto Y. Symptomatic versus asymptomatic papillary thyroid microcarcinoma: a retrospective analysis of surgical outcome and prognostic factors. Endocr J 1999;46:209-16. 21. Wada N, Duh QY, Sugino K, Iwasaki H, Kameyama K, Mimura T, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg 2003;237:399-407. 22. Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH. Papillary microcarcinoma of the thyroid---prognostic significance of lymph node metastasis and multifocality. Cancer 2003;98: 31-40. 23. Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K, et al. Papillary microcarcinoma of the thyroid: how should it be treated? World J Surg 2004;28:1115-21. 24. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW, Wiersinga W. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 2006;154:787-803. 25. Ross DS, Litofsky D, Ain KB, Bigos T, Brierley JD, Cooper DS, et al. Recurrence after treatment of micropapillary thyroid cancer. Thyroid 2009;19:1043-8.
DISCUSSION Dr Orlo H. Clark (San Francisco, CA): How is this going to change your practice, especially when you find these are incidental? If you did know it was there, and you did not do a total thyroidectomy---I know you did mostly total thyroidectomy, even in the noncancer group, I wonder how it’s going to change. When we follow our patients who have these incidental cancers, most of us try to ignore them, but you can’t do that completely. Were the thyroglobulin or ultrasound different in the 2 groups, #5 mm and 6--10 mm, in your follow-up? What was the follow-up?
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Dr Keith S. Heller (New York, NY): I didn’t look at follow-up, because I really wanted to avoid trying to decide what was the operation of choice. The simple answer is that our follow-up is too short to draw any conclusions about outcome. How is it going to change my practice? I actually think that the majority of these microcancers are adequately treated with a lobectomy. However, I don’t work in a vacuum, and the endocrinologists that I work with will insist that the patients who don’t meet ATA criteria go back for a completion thyroidectomy because they are convinced that they need radioactive iodine. This recommendation is not made because I’m convinced I’m going to cure more people, but because I really do want to avoid unnecessary completion thyroidectomies. I do think that probably everybody in this room can do total thyroidectomies safely. Dr Bradford Mitchell (Morgantown, WV): I share your bias toward total thyroidectomy and avoiding completion thyroidectomy, and I compliment you for making the point that this is a safe operation for the members of this audience. Now, the question I have for you is: How did you calculate the cost--benefit ratio of recommending it only for the 62%, as opposed to the 33% that were <5 mm? Dr Keith S. Heller (New York, NY): I didn’t do a cost-benefit analysis. I use this information in my discussion with the patient. I would tell a patient with an 8-mm, FNAB-positive nodule in the thyroid that we can do a lobectomy, but that there is a 60% chance that he or she will need a second operation. If that’s okay with the patient, then I’m okay with doing a lobectomy. Most of my patients, when given that option, opt for a total thyroidectomy at the first operation. Dr Subhash Patel (Chicago, IL): You stated that most of your microcarcinomas were not incidental. However, they are quite small, 8 mm, 5 mm, or less. Were your FNAs image-guided biopsies, or do you have sensitive fingers with 60% positive FNA? Dr Keith S. Heller (New York, NY): No, they were almost all image guided. Most of these nodules were discovered on carotid duplex scans, other unrelated imaging studies, or thyroid ultrasounds, many of which were inappropriate or unnecessary. But they come to me having had a biopsy, and it’s difficult to say, ‘‘I wouldn’t have done the biopsy; therefore, ignore the diagnosis.’’ Dr Scott Wilhelm (Cleveland, OH): In terms of your indication for biopsying <1-cm nodules, certainly I’ll drop my criteria down to 8 mm or something if it’s a positron emission tomography scan--positive nodule. I’m just curious if you could comment why you were dropping your criteria down. Dr Keith S. Heller (New York, NY): Let me make it very clear, I did not do these biopsies. I am getting a very stiff neck in my office, shaking my head, looking at the charts and saying, ‘‘Why did they do this?’’ If you look at the radiologists’ guidelines, you are only supposed to put needles in subcentimeter nodules that are sonographically suspicious. The problem is
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that the criteria for sonographically suspicious include solid and hypoechoic, which includes a lot of nodules. Dr Irving B. Rosen (Toronto, Ontario, Canada): I want to congratulate you on your study and the honesty which that study implies. I just rise to say that about a decade ago, one of my residents, at his own initiative, ran through a study comparing micronodular with macronodular palpable disease, and he found exactly what you’re describing. The adverse features were identical. He, therefore,
Ogilvie, Patel, and Heller 1227
proposed that, indeed, if we are going to use adverse features as a basis for doing a total or near-total thyroidectomy, then you should do it in micronodular disease. He presented that paper. He was then attacked, literally, in the discussion period. I then went to his rescue. I was similarly attacked by Dr Clark, among others. So, like yourself, you can’t be too overbearing in your conclusions; but nevertheless, those are the facts of thyroid life, I think---cancer, anyways.