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Extrathyroidal Extension in Well-Differentiated Thyroid CancerMacroscopic vs Microscopic as a Predictor of Outcome
Amanda Hu, MD;
Jonathan Clark, MBBS, BSc, FRACS;
Richard J. Payne, MD, MSc, FRCSC;
Spiro Eski, MD;
Paul G. Walfish, MD, FRCPC;
Jeremy L. Freeman, MD, FRCSC
Arch Otolaryngol Head Neck Surg. 2007;133(7):644-649.
ABSTRACT
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Objective To examine the prognostic difference in well-differentiated thyroid cancer between macroscopic extrathyroidal extension (ETE), which is appreciated in the operating room, vs microscopic ETE, which is only appreciated under the microscope by the pathologist.
Design Retrospective medical record review.
Setting Tertiary care academic hospital.
Patients Among 582 patients, those who were surgically treated for stage III well-differentiated thyroid cancer with a minimum 5-year follow-up were included. Fifty-five patients (10%) (17 males and 38 females [mean age, 53.1 years]) met the selection criteria.
Main Outcome Measures Disease-specific survival and overall survival.
Results Thirty-two patients (58%) had macroscopic ETE, while 23 patients (42%) had microscopic ETE. Twenty-year disease-specific survival in the macroscopic group was 47% (8 of 17) and 45% (5 of 11) in the microscopic group (P = .45). Twenty-year overall survival in the macroscopic group was 27% (3 of 11) and 24% (4 of 17) in the microscopic group (P = .59). The only confounding factor was external beam radiation therapy (EBRT). More patients with macroscopic ETE were treated with EBRT (P = .007). When survival was stratified according to EBRT, patients with macroscopic ETE who did not receive EBRT had diminished disease-specific survival (P = .07) and overall survival (P = .12). On multivariate analysis, EBRT was the only predictor of improved disease-specific survival (P = .02) and overall survival (P = .06).
Conclusions In selected patients with macroscopic ETE, we recommend postoperative EBRT. Further investigation is required to determine whether macroscopic ETE vs microscopic ETE is an independent predictor of outcome.
INTRODUCTION
Extrathyroidal extension (ETE) is defined as extension of the primary tumor outside of the thyroid capsule and invasion into the surrounding structures (eg, strap muscles, trachea, larynx, vasculature, esophagus, and recurrent laryngeal nerve).1-2 The incidence of ETE in well-differentiated thyroid cancer (WDTC) varies in different series but ranges from 5% to 34%.1-2 Extrathyroidal extension is well established as an important adverse prognostic factor1-11 and is used in several staging systems, including the EORTC (European Organization Research Treatment Cancer),12 TNM classification,13 system by DeGroot et al,14 AGES (age, grade, ETE, and size),15 AMES (age, metastasis, ETE, and size),16 and MACIS (metastasis, age, completeness of resection, invasion, and size).17 Although ETE has been extensively studied, it is unclear whether microscopic ETE carries the same adverse outcome as macroscopic ETE. The objective of this study was to examine the prognostic difference between macroscopic ETE, which is appreciated in the operating room, vs microscopic ETE, which is only appreciated under the microscope by the pathologist.
METHODS
A retrospective medical record review of the Mount Sinai Hospital, Toronto, Ontario, Canada, thyroid cancer database was performed. The database contained 582 patients who had undergone surgery for WDTC between January 1, 1963, and December 31, 2000. All patients surgically treated for stage III WDTC, as defined by the system by DeGroot et al14 (ie, ETE), with a minimum of 5 years of follow-up were included. Duration of follow-up was defined as the time from the first surgery to the last contact. The mean follow-up was 10.9 years. This project received ethical approval from the ethics board at Mount Sinai Hospital.
Statistical analysis was performed using SPSS version 13.0 software (SPSS Inc, Cary, North Carolina). Normally distributed data were analyzed using (unpaired) t test, and nonparametric data were analyzed using Mann-Whitney test. Nominal variables with 2 categories were presented as percentages of patients and were analyzed using  2 test. Nominal variables with more than 2 categories were presented as percentages of patients and were analyzed using analysis of variance. Survival and recurrence were calculated using the Kaplan-Meier method, and differences were compared using log-rank test. Multivariate analysis was performed using Cox proportional hazards models.
RESULTS
Patient demographic, clinicopathological, and treatment data are summarized in Table 1. The presence of ETE was examined for all 582 patients. Sixty-one of 582 patients (11%) had stage III WDTC between 1963 and 2000. Six patients had less than 5 years of follow-up and were excluded. The final sample size was 55 patients (10%). Thirty-two patients (58%) had macroscopic ETE, while 23 patients (42%) had microscopic ETE. Structures involved were muscle (34 of 55 [62%]), nerve (14 of 55 [25%]), trachea (13 of 55 [24%]), blood vessels (9 of 55 [16%]), esophagus (6 of 55 [11%]), lymphatics (3 of 55 [6%]), and other (20 of 55 [36%]). Other locations included adipose tissue and thymus. There were no differences in demographic or clinicopathological data between the 2 study groups; however, there was a significant difference in the rate of external beam radiation therapy (EBRT); 83% (25 of 30) of patients with macroscopic ETE were treated with EBRT compared with 48% (11 of 23) of patients with microscopic ETE (P = .007).
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Table 1. Univariate Analysis of Demographic, Clinicopathological, and Treatment Data in the Macroscopic vs Microscopic Extrathyroidal Extension (ETE) Groups a
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In Table 2, patients who received EBRT are compared with patients who did not receive EBRT relative to established risk factors for thyroid carcinoma.15-17 There was no significant difference between the 2 groups in sex, age at surgery, distant metastases, pathologic type (eg, papillary), maximum tumor size, or incompleteness of resection.
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Table 2. Univariate Analysis of Risk Factors for Thyroid Carcinoma in the Groups With and Without External Beam Radiation Therapy (EBRT) a
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Recurrence and survival data are summarized in Table 3. Overall survival (OS) and disease-specific survival (DSS) at 20 years were 25% (7 of 28) and 46% (13 of 28), respectively. There was no significant difference in DSS and OS according to type of ETE, as shown in Figure 1 and Figure 2, respectively. However, when survival was stratified according to whether patients received adjuvant EBRT, DSS (P = .07 [Figure 3]) and OS (P = .12 [Figure 4]) were diminished for patients with macroscopic ETE who did not receive EBRT. On multivariate analysis (Table 4) using the 2 covariates of ETE and EBRT, EBRT was a significant predictor of DSS (P = .02) and was a nonsignificant predictor of OS (P = .06).
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Table 3. Univariate Analysis of Outcome Data in the Macroscopic vs Microscopic Extrathyroidal Extension (ETE) Groups a
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Figure 1. Kaplan-Meier curves for disease-specific survival (DSS) vs extrathyroidal extension (ETE). There was no significant difference in DSS between the macroscopic ETE group and the microscopic ETE group (P = .82).
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Figure 2. Kaplan-Meier curves for overall survival (OS) vs extrathyroidal extension (ETE). There was no significant difference in OS between the macroscopic ETE group and the microscopic ETE group (P = .97).
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Figure 3. Kaplan-Meier curves for disease-specific survival (DSS) vs extrathyroidal extension (ETE) among patients without external beam radiation therapy. Macroscopic ETE was associated with decreased DSS (P = .07).
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Figure 4. Kaplan-Meier curves for overall survival (OS) vs extrathyroidal extension (ETE) among patients without external beam radiation therapy. Macroscopic ETE was associated with decreased OS (P = .12).
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Table 4. Multivariate Analysis Using the 2 Covariates of Extrathyroidal Extension (ETE) and External Beam Radiation Therapy (EBRT)
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The effect of the location of ETE was also analyzed. There was no difference in recurrence or survival according to structures involved by ETE, including the trachea (P = .39 for recurrence and P = .77 for DSS). When survival was stratified according to whether patients received adjuvant EBRT, there was a significant decrease in DSS (P = .008) and an increase in recurrence (P < .001) among patients with tracheal invasion who did not receive EBRT.
COMMENT
There is convincing evidence that the presence of ETE is a predictor of negative outcomes in patients with WDTC.2-11 Despite this evidence, there are few data comparing the effect of macroscopic and microscopic ETE. Table 5 summarizes the present results and those of previous studies1-3,5, 7, 16, 18-19 of patients with WDTC and ETE; we found a 10% (61 of 582) incidence of ETE; however, the literature reports a range of 2% to 45%, which may reflect the variation in definitions used for ETE.
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Table 5. Previous Studies of Patients With Well-Differentiated Thyroid Cancer (WDTC) and Extrathyroidal Extension (ETE) a
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On preliminary analysis, there was no difference in survival between patients with macroscopic and microscopic ETE. However, EBRT was a significant confounding factor, as more patients in the macroscopic ETE group were treated with EBRT (P = .007). For other established prognostic factors for WDTC, there was no difference in the rate of EBRT (Table 2). To address this confounding factor, the patients were stratified according to EBRT. Among patients with macroscopic ETE who received EBRT, there was no difference in survival; among patients with macroscopic ETE who did not receive EBRT, there was nonsignificant decreased DSS (P = .07) and OS (P = .12). In multivariate analysis, EBRT was the only predictor of DSS (P = .02) and OS (P = .06). In contrast to other studies,20-22 we were unable to demonstrate a difference in outcome according to structures involved by ETE of WDTC. However, in patients with tracheal invasion, there were differences in disease control and in survival according to whether patients received EBRT. This suggests that EBRT negated the adverse effect of tracheal invasion.
To our knowledge, only 1 previous study23 has examined the prognostic difference between macroscopic and microscopic ETE. Gemsenjäger et al23 retrospectively reviewed 265 patients with WDTC and concluded that macroscopic ETE, but not microscopic ETE, was a significant risk factor for survival in papillary thyroid cancer (P < .001) and for disease-free survival in follicular thyroid cancer (P < .001). The results of the present study support this finding but also suggest that EBRT is effective in improving outcomes in patients with macroscopic ETE.
The following are indications for EBRT: (1) locally advanced unresectable disease or macroscopic residual disease after thyroidectomy, (2) palliative treatment of selected distant metastatic sites (ie, brain and bone), (3) radioactive iodine-resistant progressive disease, and (4) adjuvant treatment of local relapse for high-risk patients.24-28 Determining which patients are at sufficiently high risk of local relapse to justify the short-term and long-term toxic effects of radiation therapy is controversial.24-30 Brierley et al31 retrospectively reviewed 729 patients who were seen at Princess Margaret Hospital, Toronto, during 40 years. For patients older than 60 years with ETE, adjuvant EBRT resulted in statistically higher 10-year cause-specific survival (P = .04) and 10-year locoregional relapse-free (P = .01) rates. This is supported by Farahati et al,32 who retrospectively studied 238 patients with WDTC. Among 169 patients included in the study, 99 patients received EBRT, while the other 70 patients did not. They determined that patients older than 40 years with ETE and lymph node involvement from papillary carcinoma benefited the most from EBRT.
Unfortunately, the present study did not have a sufficient sample size to perform a subset analysis to determine which patients with macroscopic ETE derive the greatest benefit from EBRT. Some authors have suggested that invasion into the trachea, esophagus, nerves, and major vasculature is an appropriate indication for EBRT.26 Certainly, minimal strap muscle invasion is common, and it is unlikely that adjuvant EBRT is necessary when disease can be completely resected. Further investigation is required to determine the specific indications for local radiation therapy beyond gross residual disease after thyroidectomy.
In conclusion, for selected patients with macroscopic ETE, we recommend postoperative EBRT. Further investigation is required to determine whether macroscopic vs microscopic ETE is an independent predictor of outcome.
AUTHOR INFORMATION
Correspondence: Jeremy L. Freeman, MD, FRCSC, Department of Otolaryngology, Mount Sinai Hospital, 600 University Ave, Ste 401, Toronto, ON M5G 1X5, Canada (jfreeman{at}mtsinai.on.ca).
Submitted for Publication: August 5, 2006; final revision received January 1, 2007; accepted March 1, 2007.
Author Contributions: Drs Clark and Payne had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Hu, Clark, Payne, and Freeman. Acquisition of data: Hu, Payne, and Eski. Analysis and interpretation of data: Hu, Clark, Payne, and Walfish. Drafting of the manuscript: Hu, Clark, Payne, and Eski. Critical revision of the manuscript for important intellectual content: Hu, Clark, Payne, Walfish, and Freeman. Statistical analysis: Clark. Obtained funding: Freeman. Administrative, technical, and material support: Hu, Payne, Eski, and Freeman. Study supervision: Payne, Walfish, and Freeman.
Financial Disclosure: Dr Walfish has received unrestricted educational grants from Abbott Laboratories (Canada) and Genzyme (Canada).
Funding/Support: This study was supported in part by unrestricted educational grants from the Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases at Mount Sinai Hospital (Dr Walfish), the Temmy Latner/Dynacare Family Foundation, and the Julius Kuhl Family Foundation (Dr Walfish).
Previous Presentation: This study was presented at the American Head and Neck Society 2006 Annual Meeting and Research Workshop on the Biology, Prevention and Treatment of Head and Neck Cancer; August 19, 2006; Chicago, Illinois.
Author Affiliations: Department of Otolaryngology, University of Western Ontario, London (Dr Hu); Sydney Head and Neck Cancer Institute, Royal Prince Alfred Hospital, Sydney, Australia (Dr Clark); and Department of Otolaryngology (Drs Payne, Eski, and Freeman) and Endocrine Division and Head and Neck Oncology Program, Department of Medicine (Dr Walfish), Mount Sinai Hospital, Toronto, Ontario, Canada.
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