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Incidental thyroid nodule: patterns of diagnosis and rate of malignancy
The American Journal of Surgery (2009) 197, 320 –324
The Midwest Surgical Association
Incidental thyroid nodule: patterns of diagnosis and rate of malignancy Judy Jin, M.D.a, Scott M. Wilhelm, M.D.a, Christopher R. McHenry, M.D.b,* a
Department of Surgery, University Hospitals Case Medical Center; bDepartment of Surgery, MetroHealth Medical Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio, United States KEYWORDS: Imaging modality; Incidental thyroid nodule; Malignancy; Pre-existing malignancy; Thyroid incidentaloma
Abstract BACKGROUND: The clinical significance of thyroid incidentalomas is controversial. METHODS: The rate of malignancy was determined for patients with an incidentally discovered thyroid nodule, and results were stratified according to imaging modality as well as presence and type of pre-existing malignancy. RESULTS: One hundred fifty patients were identified, of which 88 with a known malignancy were screened for metastases. Twenty-three (15%) patients were diagnosed with thyroid malignancy. Incidental nodules identified on positron emission tomography scan were malignant in 33% of the patients compared with 11% for those identified on computed axial tomography (P ⫽ .016). The rate of thyroid malignancy in patients with pre-existing nonthyroid malignancy (18%) was not significantly different from patients without a history of malignancy (13%, P ⫽ .36). COMMENTS: Thyroid incidentalomas are associated with a high rate of malignancy. The rate of malignancy is highest for nodules discovered on positron emission tomography scan and is no different in patients with or without pre-existing malignancy. © 2009 Published by Elsevier Inc.
A thyroid incidentaloma is defined as an unsuspected, focal thyroid lesion initially discovered by a radiographic imaging modality or at the time of a nonthyroid neck surgery in a patient without history of thyroid disease. Thyroid incidentalomas are detected because of the widespread use of ultrasound (US), computed axial tomography (CAT) and, more recently, positron emission tomography (PET). PET scan is being used with increasing frequency for tumor staging and screening for metastases in patients with known malignancies. Thyroid incidentalomas have been documented in 16% of cross-sectional neck scans (CT, magnetic resonance imaging [MRI]),1,2 9.4% of carotid duplex scans,3 and 2% to 3% of PET scans.4 – 6 The significance of an incidentally discovered thyroid nodule is * Corresponding author. Tel.: ⫹01-216-778-4753; fax: ⫹01-216-778-3774. E-mail address: [email protected] Manuscript received August 2, 2008; revised manuscript October 20, 2008
0002-9610/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.amjsurg.2008.10.006
controversial. Recent studies7–9 have shown that thyroid incidentalomas have a higher rate of thyroid malignancy than the previously reported rate of 5% for palpable thyroid nodules found on physical examination.10 The objectives of this study were (1) to determine the pattern of diagnosis and rate of malignancy in incidentally discovered thyroid nodules; (2) to assess whether the presence of a pre-existing nonthyroid malignancy in a patient with a thyroid incidentaloma is associated with a higher rate of thyroid malignancy, and (3) to differentiate the rate of thyroid malignancy based on the radiographic modality that detected the incidental thyroid nodule.
Methods Patients with an incidentally discovered thyroid nodule were identified from a prospective database maintained by 2
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Incidental thyroid nodule
endocrine surgeons (S. M. W. and C. R. M) from January 2001 to May 2008. Incidental thyroid nodules were discovered either during an evaluation for metastatic disease for a known nonthyroid malignancy or because of evaluation or treatment of some other medical problems. Patients were excluded from the study if they had a previous history of thyroid cancer, previous thyroid surgery, or a known history of nodular thyroid disease. All patients underwent subsequent US examination of the thyroid gland. Fine-needle aspiration (FNA) biopsy was performed for all incidentally discovered thyroid nodules ⱖ1 cm or nodules ⬍1 cm with abnormal sonographic features. The cytologic results were classified into the following categories: benign, malignant, indeterminate (follicular neoplasm, Hurthle cell neoplasm, suspicious for papillary cancer), and nondiagnostic (insufficient cells for diagnosis). Thyroidectomy was recommended for all patients with a malignant, indeterminate, or persistently nondiagnostic cytologic result. Additional management was based on final pathology. This study was reviewed and approved by the Institutional Review Boards at University Hospitals Case Medical Center and MetroHealth Medical Center. Information extracted from the database included patient age at the time of referral, patient sex, the diagnostic modality that identified the incidental thyroid nodule, and the reason the initial diagnostic modality was obtained. Nodule size as determined by US examination was recorded. Additional information obtained included FNA biopsy result, type of surgical resection performed, and the final pathology result. Statistical analysis was performed using the R program.11 For comparison of parametric data, Student’s t test was used. Fisher’s exact test was used for nonparametric data. P ⬍ .05 was considered significant.
Results One hundred fifty patients with an incidentally discovered thyroid nodule were identified. There were 111 (74%) women. The mean age for all patients was 61 years (range 21 to 90). Eighty-eight patients with a known nonthyroid malignancy were referred by their oncologist for a thyroid nodule that was incidentally discovered during screening for metastatic disease. The primary malignancies were of gastrointestinal (n ⫽ 45) and nongastrointestinal (breast [n ⫽ 14], genitourinary [n ⫽ 12], skin and soft tissue [n ⫽ 12], lung [n ⫽ 8], and hematologic [n ⫽ 7]) origin. Some patients had as many as 3 pre-existing primary malignancies at the time of evaluation for an incidentally discovered thyroid nodule. The remainder of the patients had no previous malignancy and were initially referred for radiographic evaluation of their respiratory, neurovascular, or musculoskeletal complaints or illness. The most common imaging modalities that discovered the incidental thyroid nodules were CT in 84 (56%), PET in 21 (14%), US in 21
321 (14%), MRI in 8 (5%), chest x-ray in 7 (5%), and octreotide scan in 2 (1%) patients. Seven patients (5%) had an incidental nodule discovered at the time of nonthyroid neck surgery. The mean size of the incidentally discovered nodules was 2.1 cm (range .4 to 8.0) based on US thyroid examination. One hundred twenty-five (82%) patients met criteria for FNA biopsy of the identified thyroid nodule. In 62 patients, the FNA biopsy was benign and included colloid nodule, nodular Hashimoto’s thyroiditis, multinodular goiter, and adenomatous hyperplasia. Forty-nine patients had an indeterminate FNA biopsy specimen (follicular neoplasm [n ⫽ 38], Hurthle cell neoplasm [n ⫽ 6], and suspicious for papillary cancer [n ⫽ 5]). Nine patients had a biopsy specimen consistent with papillary thyroid carcinoma. In 5 patients, the FNA biopsy was nondiagnostic. Fifty percent of the patients who had an incidental thyroid nodule detected during metastatic workup and who underwent FNA biopsy had either a malignant or indeterminate result. Similarly, 51% of patients without a previous history of malignancy who underwent a FNA biopsy for nodule found on an imaging study, which was obtained for evaluation of some other medical problem, had a malignant or indeterminate result (P ⫽ .99). FNA biopsy was not performed in the 7 patients with an incidental thyroid nodule discovered during nonthyroid neck surgery. Sixty-five patients underwent thyroidectomy, 37 underwent total thyroidectomy, and 28 underwent lobectomy and isthmusectomy. Final pathology showed malignancy in 23 (35%) patients. The overall rate of malignancy for the entire population of patients with an incidentally discovered thyroid nodule was 15%. Twenty-one patients, including 6 with microcarcinoma, had papillary thyroid carcinoma. Two patients had metastatic disease, 1 had renal cell carcinoma, and 1 had melanoma. Two patients with thyroid malignancy had a history of upper thoracic radiation for the treatment of breast cancer, and both were found to have papillary microcarcinoma. Sixteen of the 23 patients diagnosed with thyroid cancer had a pre-existing nonthyroid malignancy. The rate of thyroid malignancy in the group of patients with a pre-existing nonthyroid malignancy was 18% compared with 13% in the group without a pre-existing malignancy; however, the difference was not significant (P ⫽ .36). Further analysis of the 16 patients with a known history of malignancy who were subsequently diagnosed with a thyroid malignancy showed that 5 patients had a gastrointestinal and 11 had a nongastrointestinal malignancy (Table 1). Thyroid malignancy occurred in 21% of patients with a pre-existing nongastrointestinal malignancy and 11% of patients with a pre-existing gastrointestinal malignancy (P ⫽ .27). Of the 84 patients with an incidental thyroid nodule discovered on CT, 9 (11%) had a thyroid malignancy compared with 7 (33%) of the 21 patients with an incidental thyroid nodule found on PET scan (P ⫽ .016).
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Table 1 Histology and size of thyroid malignancy diagnosed in patients with pre-existing nonthyroid malignancy and an incidentally discovered thyroid nodule Patient no.
Pre-existing malignancy
Thyroid malignancy (cm)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Breast (Edinburgh, Scotland) Breast (Edinburgh, Scotland) Pheochromocytoma, breast, angiosarcoma Breast (Edinburgh, Scotland), lung, kidney Lymphoma Melanoma Melanoma Melanoma Prostate Prostate Kidney Colon Colon Colon Gastrointestinal stromal tumor of the small intestine Appendiceal adenocarcinoma
Papillary microcarcinoma (.05) Papillary thyroid carcinoma (3.80) Papillary microcarcinoma (.25) Papillary microcarcinoma (.50) Papillary thyroid carcinoma (2) Papillary thyroid carcinoma (1.90) Metastatic melanoma (7) Papillary thyroid carcinoma (1.50) Papillary thyroid carcinoma (4) Papillary thyroid carcinoma (2.90) Metastatic renal cell carcinoma (1.50) Papillary microcarcinoma (.40) Papillary microcarcinoma (.70) Papillary thyroid carcinoma (1.70) Papillary microcarcinoma (.70) Papillary thyroid carcinoma (1.20)
Comments Incidental thyroid nodules are being found with increasing frequency during screening and workup for both benign and malignant diseases, likely a result of the widespread availability and advancement in radiographic imaging technology. However, there are no evidence-based guidelines for the management of thyroid incidentalomas.12 It was first believed that these nodules were of no clinical significance because they would have most likely remained unnoticed, only to be found incidentally at autopsy.13 As a result, practitioners have been uncertain as to how to manage an incidentally discovered thyroid nodule. Fifteen percent of the incidentally discovered thyroid nodules in our series were malignant. This rate of malignancy for an incidentally discovered thyroid nodule was higher than expected, although other investigators have reported similar results. Nam-Goong et al reported a malignancy rate of 12% in patients who underwent surgical resection of an incidental thyroid nodule ranging in size between .5 and 1.2 cm7. Papini et al found a malignancy rate of 8% in a similar patient population.14 Kim et al reported a malignancy rate of 21.6% in Korean patients who underwent neck ultrasonography during routine health screening.8 Wilhelm et al reported a 24% rate of malignancy in patients with a history of a known nonthyroid malignancy and an incidental thyroid nodule.9 As was true in other series, most malignant thyroid incidentalomas in our patients were primary thyroid malignancies.4,5,15 When we compared the malignancy rate in patients with a known pre-existing malignancy with those patients who did not have previous malignancy, the rates were not significantly different. Contrary to what we initially hypothesized, the rate of second primary malignancy (ie, thyroid) was not significantly higher in patients with a known preexisting malignancy. Vassilopoulou-Sellin et al observed that a previous history of breast cancer did not contribute to
an increased risk of thyroid malignancy, whereas thyroid cancer was associated with a higher risk of subsequent breast cancer.16 There were 45 cases of gastrointestinal malignancy and 53 cases of nongastrointestinal malignancy in this series. Sixteen patients in this cohort had thyroid malignancy. The rate of thyroid malignancy in the nongastrointestinal malignancy group was twice as high as that in the gastrointestinal malignancy group. Most of the thyroid malignancies were papillary thyroid carcinomas, and only 2 of these cases were metastatic in origin. Metastases to thyroid gland are uncommon and accounting for ⬍1% of all thyroid malignancy. In our series, metastatic disease in the thyroid gland originated from a melanoma and a renal cell carcinoma in 1 patient each. Thyroid metastases have also been reported to originate from other sites, including the lung, breast, esophagus, stomach, colon, and uterus.5,6,15,17 The tendency to develop thyroid malignancy may be increased in patients with primary malignancies of nongastrointestinal origin. An incidental thyroid nodule in patients with head and neck cancer has been reported to have a malignancy rate as high as 41%.18 In our study, we had no patients with pre-existing head and neck cancer. With regard to the modality of detection, most incidental thyroid nodules in our series were discovered because of CT or PET imaging. Incidental thyroid nodules discovered on PET scan had a higher rate of malignancy than those detected on CT scan. The overall prevalence of incidental thyroid nodules detected by PET scan is 2% to 3%.4 – 6 PET does not detect all incidental thyroid nodules, only the ones that are metabolically active. The prevalence of malignancy in an incidentally discovered thyroid nodule on PET imaging in patients with a tissue diagnosis has been reported to vary between 14% and 50%.4 – 6,19 This is much higher than the 11%
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rate of thyroid malignancy for a nodule detected by CT in our series and a 4% rate of malignancy reported by others.1 In our series, we found a 33% rate of malignancy in incidental thyroid nodules discovered on PET imaging. Clinicians have tried to correlate certain features found on PET imaging with malignancy. Diffuse fluorodeoxy glucose uptake in the thyroid gland usually represents benign disease, most commonly thyroiditis, and less commonly nodular goiter or Grave’s disease, whereas focal thyroid uptake is more of a concern for malignancy.15,20 Metastatic involvement of the thyroid gland is a rare cause for diffuse fluorodeoxy glucose uptake on PET imaging.5 Are et al reported that only 2 (1.2%) of 162 patients with diffuse uptake had a malignancy on tissue diagnosis.5 Another feature that has been evaluated is the maximum standardized uptake value (SUVmax) of a thyroid nodule found on PET. Although a few studies have reported higher SUVmax for malignant thyroid lesions;4,15 in most studies SUVmax has not been able to differentiate benign and malignant lesions.5,6,18 There are several limitations to our study. One is referral bias. Most patients in our study were referred by their oncologists or primary care physicians after identification of the incidental thyroid nodules on diagnostic imaging tests. The total number of patients screened before endocrine surgery referral and the exact pattern of referral was unknown. We speculate that the rate we see in our practice is higher because of referral bias. In a study using PET scan by Kang et al, a population of patients who were screened for metastases were compared with a group of healthy volunteers. The rate of malignancy for thyroid incidentalomas was 2.9%, and there was no difference between the group of patients screened for metastases and the group of healthy volunteers.15 A second limitation may be the inclusion of patients with papillary microcarcinomas in the total number of patients with malignant thyroid tumor. Papillary microcarcinomas are common incidental findings and are usually indolent in their behavior; as a result their inclusion may have falsely increased the true rate of malignancy. If we excluded the 6 cases of microcarcinomas, the malignancy rate would be 11%, which is still higher than the 5% rate that has been historically reported. In conclusion, the results of our prospective study confirms previous findings that an incidental thyroid nodule is associated with a high rate of malignancy. When a thyroid nodule is discovered during screening or staging for another primary malignancy, it is imperative that US examination of the thyroid gland be obtained for further evaluation of the nodule and the rest of the thyroid gland. The exception is the patient with a primary malignancy and extensive metastatic disease in whom it does not make sense to pursue additional investigation because of limited life expectancy. A thyroid incidentaloma ⱖ1 or ⬍1 cm with abnormal sonographic features should be further evaluated with FNA biopsy. Furthermore, because of the high rate of malignancy that we
323 observed in patients with an incidental thyroid nodule detected on PET scan, we have a low threshold to biopsy any nodules under these circumstances regardless of size when technically feasible.
References 1. Shetty SK, Maher MM, Hahn PF, et al. Significance of incidental thyroid lesions detected on CT: correlation among CT, sonography, and pathology. AJR Am J Roentgenol 2006;187:1349 –56. 2. Youserm DM, Huang T, Loevner LA, et al. Clinical and economic impact of incidental thyroid lesions found with CT and MR. AJNR Am J Neuroradiol 1997;18:1423– 8. 3. Steele SR, Martin MJ, Mullenix PS, et al. The significance of incidental thyroid abnormalities identified during carotid duplex ultrasonography. Arch Surg 2005;140:981–5. 4. Cohen MS, Arslan N, Dehdashti F, et al. Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucose-positron emission tomography. Surgery 2001;130:941– 6. 5. Are C, Hsu JF, Schoder H, et al. FDG-PET detected thyroid incidentalomas: need for further investigation? Ann Surg Oncol 2007;14: 239 – 47. 6. Kim TY, Kim WB, Ryu JS, et al. 18F-fluorodeoxyglucose uptake in thyroid from positron emission tomogram (PET) for evaluation in cancer patients: high prevalence of malignancy in thyroid PET incidentaloma. Laryngoscope 2005;115:1074 – 8. 7. Nam-Goong IS, Kim HY, Gong G, et al. Ultrasonography-guided fine-needle aspiration of thyroid incidentaloma: correlation with pathological findings. Clin Endocrinol 2004;60:21– 8. 8. Kim DL, Song KH, Kim SK. High prevalence of carcinoma in ultrasonography-guided fine needle aspiration cytology of thyroid nodules. Endocr J 2008;55:135– 42. 9. Wilhelm SM, Robinson AV, Krishnamurthi SS, et al. Evaluation and management of incidental thyroid nodules in patients with another primary malignancy. Surgery 2007;142:581–7. 10. Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med 1968;69:537– 40. 11. Team RDCR. A Language and Environment for Statistical Computing. R Foundation for Statistical Computing Vienna, Austria; 2007. 12. Gough J, Scott-Coombes D, Fausto Palazzo F. Thyroid incidentaloma: an evidence-based assessment of management strategy. World J Surg 2008;32:1264 – 8. 13. Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 1955;15:1270 – 80. 14. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and colorDoppler features. J Clin Endocrinol Metab 2002;87:1941– 6. 15. Kang KW, Kim SK, Kang HS, et al. Prevalence and risk of cancer of focal thyroid incidentaloma identified by 18 F-fluorodeoxyglucose positron emission tomography for metastasis evaluation and cancer screening in healthy subjects. J Clin Endocrinol Metab 2003;88:4100 – 4. 16. Vassilopoulou-Sellin R, Palmer L, Taylor S, et al. Incidence of breast carcinoma in women with thyroid carcinoma. Cancer 1999;85:696 – 705. 17. Nakhjavani MK, Gharib H, Goellner JR, et al. Metastasis to the thyroid gland. A report of 43 cases. Cancer 1997;79:574 – 8. 18. Nam SY, Roh JL, Kim JS, et al. Focal uptake of (18)F-fluorodeoxyglucose by thyroid in patients with nonthyroidal head and neck cancers. Clin Endocrinol 2007;67:135–9. 19. Chen YK, Liu FY, Yen RF, et al. Compare FDG-PET and Tc-99m tetrofosmin SPECT to detect metastatic thyroid carcinoma. Acad Radiol 2003;10:835–9.
324 20. Salvatori M, Melis L, Castaldi P, et al. Clinical significance of focal and diffuse thyroid diseases identified by (18)F-fluorodeoxyglucose positron emission tomography. Biomed Pharmacother 2007;61:488 –93.
Discussion Herbert Chen, M.D. (Madison, Wisconsin): One of the key findings in this article is that in patients with incidentally discovered thyroid nodules, the malignancy rate is 15%, which is 3 times higher than the overall population of people with thyroid nodules. I have 3 questions for you. First, I was surprised that the most common imaging modality that detected a thyroid nodule was CAT. I would have guessed US because at our institution, we are referred a high number of patients undergoing neck US for carotid disease or for primary hyperparathyroidism. I wonder how many of these thyroid nodules are found during preoperative localization for parathyroid adenomas and if US is part of your practice for those patients? Second, in the 21 patients with incidental thyroid nodules that were found on PET, 7 were cancerous. Could you tell us the pathology of the other 14 lesions? Specifically, were they all neoplastic? Last, many of your patients had thyroid nodules found during workup for a metastatic nonthyroid cancer. I assume that some of these patients were eventually diagnosed with metastatic disease from their primary cancer. Could you comment on the need for thyroidectomy in patients with a second metastatic cancer? Do you think we should aggressively treat the thyroid disease in the setting of a metastatic nonthyroid cancer, such as colon cancer? Judy Jin, M.D. (Cleveland, Ohio): The first question regards detection using CAT scan versus US. A key point in our presentation was that we do have a referral bias, so ⬍50% of these patients were found to have incidental thyroid nodules during screening for metastases. CAT scan still
The American Journal of Surgery, Vol 197, No 3, March 2009 remains the most popular imaging modality to screen for metastases. Previous studies actually indicated the incidence using CAT or MRI is approximately 16 %, a bit higher than the 9% quoted for carotid duplex. Regarding your question of using US to look for primary hyperparathyroidism, 5 patients had thyroid nodules identified during US localization of their parathyroid problem. A few patients were found to have a thyroid nodule during parathyroidectomy. Regarding the pathology for patients who had their thyroid nodule discovered on PET scan, 7 had malignancy. For the rest of the 14 patients, 6 had neoplastic pathology (3 being follicular cell adenoma and 3 being Hurthle cell adenoma), and the other patients had benign pathology, most commonly multinodular goiter. The last question regards the management strategy for thyroid malignancy if the patient already has metastatic disease from a primary pre-existing malignancy. The most important point is the overall prognosis of the metastatic disease. If the overall prognosis is poor, there is no indication for operating on the thyroid even with thyroid malignancy. However, in the case of a relatively good prognosis from treatable metastatic disease, we recommend treating the metastatic disease first. Then, if the patient can tolerate further surgery, we would perform thyroidectomy for the thyroid malignancy. Steven A. DeJong, M.D. (Maywood, Illinois): Just a brief question to pin down 1 of your conclusions. Given the relatively high rate of malignancy in PET-positive thyroid nodules, would you be satisfied with a benign needle biopsy result, or would you recommend lobectomy? Judy Jin, M.D. (Cleveland, Ohio): Regarding PET-positive thyroid nodules, which have a higher rate of thyroid malignancy, we do have a lower threshold for first performing biopsy and then surgical resection. However, a few patients in our database with PET-positive nodules were benign on needle biopsy specimen, and we have followed them without surgery.
The Midwest Surgical Association
Incidental thyroid nodule: patterns of diagnosis and rate of malignancy Judy Jin, M.D.a, Scott M. Wilhelm, M.D.a, Christopher R. McHenry, M.D.b,* a
Department of Surgery, University Hospitals Case Medical Center; bDepartment of Surgery, MetroHealth Medical Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio, United States KEYWORDS: Imaging modality; Incidental thyroid nodule; Malignancy; Pre-existing malignancy; Thyroid incidentaloma
Abstract BACKGROUND: The clinical significance of thyroid incidentalomas is controversial. METHODS: The rate of malignancy was determined for patients with an incidentally discovered thyroid nodule, and results were stratified according to imaging modality as well as presence and type of pre-existing malignancy. RESULTS: One hundred fifty patients were identified, of which 88 with a known malignancy were screened for metastases. Twenty-three (15%) patients were diagnosed with thyroid malignancy. Incidental nodules identified on positron emission tomography scan were malignant in 33% of the patients compared with 11% for those identified on computed axial tomography (P ⫽ .016). The rate of thyroid malignancy in patients with pre-existing nonthyroid malignancy (18%) was not significantly different from patients without a history of malignancy (13%, P ⫽ .36). COMMENTS: Thyroid incidentalomas are associated with a high rate of malignancy. The rate of malignancy is highest for nodules discovered on positron emission tomography scan and is no different in patients with or without pre-existing malignancy. © 2009 Published by Elsevier Inc.
A thyroid incidentaloma is defined as an unsuspected, focal thyroid lesion initially discovered by a radiographic imaging modality or at the time of a nonthyroid neck surgery in a patient without history of thyroid disease. Thyroid incidentalomas are detected because of the widespread use of ultrasound (US), computed axial tomography (CAT) and, more recently, positron emission tomography (PET). PET scan is being used with increasing frequency for tumor staging and screening for metastases in patients with known malignancies. Thyroid incidentalomas have been documented in 16% of cross-sectional neck scans (CT, magnetic resonance imaging [MRI]),1,2 9.4% of carotid duplex scans,3 and 2% to 3% of PET scans.4 – 6 The significance of an incidentally discovered thyroid nodule is * Corresponding author. Tel.: ⫹01-216-778-4753; fax: ⫹01-216-778-3774. E-mail address: [email protected] Manuscript received August 2, 2008; revised manuscript October 20, 2008
0002-9610/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.amjsurg.2008.10.006
controversial. Recent studies7–9 have shown that thyroid incidentalomas have a higher rate of thyroid malignancy than the previously reported rate of 5% for palpable thyroid nodules found on physical examination.10 The objectives of this study were (1) to determine the pattern of diagnosis and rate of malignancy in incidentally discovered thyroid nodules; (2) to assess whether the presence of a pre-existing nonthyroid malignancy in a patient with a thyroid incidentaloma is associated with a higher rate of thyroid malignancy, and (3) to differentiate the rate of thyroid malignancy based on the radiographic modality that detected the incidental thyroid nodule.
Methods Patients with an incidentally discovered thyroid nodule were identified from a prospective database maintained by 2
J. Jin et al.
Incidental thyroid nodule
endocrine surgeons (S. M. W. and C. R. M) from January 2001 to May 2008. Incidental thyroid nodules were discovered either during an evaluation for metastatic disease for a known nonthyroid malignancy or because of evaluation or treatment of some other medical problems. Patients were excluded from the study if they had a previous history of thyroid cancer, previous thyroid surgery, or a known history of nodular thyroid disease. All patients underwent subsequent US examination of the thyroid gland. Fine-needle aspiration (FNA) biopsy was performed for all incidentally discovered thyroid nodules ⱖ1 cm or nodules ⬍1 cm with abnormal sonographic features. The cytologic results were classified into the following categories: benign, malignant, indeterminate (follicular neoplasm, Hurthle cell neoplasm, suspicious for papillary cancer), and nondiagnostic (insufficient cells for diagnosis). Thyroidectomy was recommended for all patients with a malignant, indeterminate, or persistently nondiagnostic cytologic result. Additional management was based on final pathology. This study was reviewed and approved by the Institutional Review Boards at University Hospitals Case Medical Center and MetroHealth Medical Center. Information extracted from the database included patient age at the time of referral, patient sex, the diagnostic modality that identified the incidental thyroid nodule, and the reason the initial diagnostic modality was obtained. Nodule size as determined by US examination was recorded. Additional information obtained included FNA biopsy result, type of surgical resection performed, and the final pathology result. Statistical analysis was performed using the R program.11 For comparison of parametric data, Student’s t test was used. Fisher’s exact test was used for nonparametric data. P ⬍ .05 was considered significant.
Results One hundred fifty patients with an incidentally discovered thyroid nodule were identified. There were 111 (74%) women. The mean age for all patients was 61 years (range 21 to 90). Eighty-eight patients with a known nonthyroid malignancy were referred by their oncologist for a thyroid nodule that was incidentally discovered during screening for metastatic disease. The primary malignancies were of gastrointestinal (n ⫽ 45) and nongastrointestinal (breast [n ⫽ 14], genitourinary [n ⫽ 12], skin and soft tissue [n ⫽ 12], lung [n ⫽ 8], and hematologic [n ⫽ 7]) origin. Some patients had as many as 3 pre-existing primary malignancies at the time of evaluation for an incidentally discovered thyroid nodule. The remainder of the patients had no previous malignancy and were initially referred for radiographic evaluation of their respiratory, neurovascular, or musculoskeletal complaints or illness. The most common imaging modalities that discovered the incidental thyroid nodules were CT in 84 (56%), PET in 21 (14%), US in 21
321 (14%), MRI in 8 (5%), chest x-ray in 7 (5%), and octreotide scan in 2 (1%) patients. Seven patients (5%) had an incidental nodule discovered at the time of nonthyroid neck surgery. The mean size of the incidentally discovered nodules was 2.1 cm (range .4 to 8.0) based on US thyroid examination. One hundred twenty-five (82%) patients met criteria for FNA biopsy of the identified thyroid nodule. In 62 patients, the FNA biopsy was benign and included colloid nodule, nodular Hashimoto’s thyroiditis, multinodular goiter, and adenomatous hyperplasia. Forty-nine patients had an indeterminate FNA biopsy specimen (follicular neoplasm [n ⫽ 38], Hurthle cell neoplasm [n ⫽ 6], and suspicious for papillary cancer [n ⫽ 5]). Nine patients had a biopsy specimen consistent with papillary thyroid carcinoma. In 5 patients, the FNA biopsy was nondiagnostic. Fifty percent of the patients who had an incidental thyroid nodule detected during metastatic workup and who underwent FNA biopsy had either a malignant or indeterminate result. Similarly, 51% of patients without a previous history of malignancy who underwent a FNA biopsy for nodule found on an imaging study, which was obtained for evaluation of some other medical problem, had a malignant or indeterminate result (P ⫽ .99). FNA biopsy was not performed in the 7 patients with an incidental thyroid nodule discovered during nonthyroid neck surgery. Sixty-five patients underwent thyroidectomy, 37 underwent total thyroidectomy, and 28 underwent lobectomy and isthmusectomy. Final pathology showed malignancy in 23 (35%) patients. The overall rate of malignancy for the entire population of patients with an incidentally discovered thyroid nodule was 15%. Twenty-one patients, including 6 with microcarcinoma, had papillary thyroid carcinoma. Two patients had metastatic disease, 1 had renal cell carcinoma, and 1 had melanoma. Two patients with thyroid malignancy had a history of upper thoracic radiation for the treatment of breast cancer, and both were found to have papillary microcarcinoma. Sixteen of the 23 patients diagnosed with thyroid cancer had a pre-existing nonthyroid malignancy. The rate of thyroid malignancy in the group of patients with a pre-existing nonthyroid malignancy was 18% compared with 13% in the group without a pre-existing malignancy; however, the difference was not significant (P ⫽ .36). Further analysis of the 16 patients with a known history of malignancy who were subsequently diagnosed with a thyroid malignancy showed that 5 patients had a gastrointestinal and 11 had a nongastrointestinal malignancy (Table 1). Thyroid malignancy occurred in 21% of patients with a pre-existing nongastrointestinal malignancy and 11% of patients with a pre-existing gastrointestinal malignancy (P ⫽ .27). Of the 84 patients with an incidental thyroid nodule discovered on CT, 9 (11%) had a thyroid malignancy compared with 7 (33%) of the 21 patients with an incidental thyroid nodule found on PET scan (P ⫽ .016).
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Table 1 Histology and size of thyroid malignancy diagnosed in patients with pre-existing nonthyroid malignancy and an incidentally discovered thyroid nodule Patient no.
Pre-existing malignancy
Thyroid malignancy (cm)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Breast (Edinburgh, Scotland) Breast (Edinburgh, Scotland) Pheochromocytoma, breast, angiosarcoma Breast (Edinburgh, Scotland), lung, kidney Lymphoma Melanoma Melanoma Melanoma Prostate Prostate Kidney Colon Colon Colon Gastrointestinal stromal tumor of the small intestine Appendiceal adenocarcinoma
Papillary microcarcinoma (.05) Papillary thyroid carcinoma (3.80) Papillary microcarcinoma (.25) Papillary microcarcinoma (.50) Papillary thyroid carcinoma (2) Papillary thyroid carcinoma (1.90) Metastatic melanoma (7) Papillary thyroid carcinoma (1.50) Papillary thyroid carcinoma (4) Papillary thyroid carcinoma (2.90) Metastatic renal cell carcinoma (1.50) Papillary microcarcinoma (.40) Papillary microcarcinoma (.70) Papillary thyroid carcinoma (1.70) Papillary microcarcinoma (.70) Papillary thyroid carcinoma (1.20)
Comments Incidental thyroid nodules are being found with increasing frequency during screening and workup for both benign and malignant diseases, likely a result of the widespread availability and advancement in radiographic imaging technology. However, there are no evidence-based guidelines for the management of thyroid incidentalomas.12 It was first believed that these nodules were of no clinical significance because they would have most likely remained unnoticed, only to be found incidentally at autopsy.13 As a result, practitioners have been uncertain as to how to manage an incidentally discovered thyroid nodule. Fifteen percent of the incidentally discovered thyroid nodules in our series were malignant. This rate of malignancy for an incidentally discovered thyroid nodule was higher than expected, although other investigators have reported similar results. Nam-Goong et al reported a malignancy rate of 12% in patients who underwent surgical resection of an incidental thyroid nodule ranging in size between .5 and 1.2 cm7. Papini et al found a malignancy rate of 8% in a similar patient population.14 Kim et al reported a malignancy rate of 21.6% in Korean patients who underwent neck ultrasonography during routine health screening.8 Wilhelm et al reported a 24% rate of malignancy in patients with a history of a known nonthyroid malignancy and an incidental thyroid nodule.9 As was true in other series, most malignant thyroid incidentalomas in our patients were primary thyroid malignancies.4,5,15 When we compared the malignancy rate in patients with a known pre-existing malignancy with those patients who did not have previous malignancy, the rates were not significantly different. Contrary to what we initially hypothesized, the rate of second primary malignancy (ie, thyroid) was not significantly higher in patients with a known preexisting malignancy. Vassilopoulou-Sellin et al observed that a previous history of breast cancer did not contribute to
an increased risk of thyroid malignancy, whereas thyroid cancer was associated with a higher risk of subsequent breast cancer.16 There were 45 cases of gastrointestinal malignancy and 53 cases of nongastrointestinal malignancy in this series. Sixteen patients in this cohort had thyroid malignancy. The rate of thyroid malignancy in the nongastrointestinal malignancy group was twice as high as that in the gastrointestinal malignancy group. Most of the thyroid malignancies were papillary thyroid carcinomas, and only 2 of these cases were metastatic in origin. Metastases to thyroid gland are uncommon and accounting for ⬍1% of all thyroid malignancy. In our series, metastatic disease in the thyroid gland originated from a melanoma and a renal cell carcinoma in 1 patient each. Thyroid metastases have also been reported to originate from other sites, including the lung, breast, esophagus, stomach, colon, and uterus.5,6,15,17 The tendency to develop thyroid malignancy may be increased in patients with primary malignancies of nongastrointestinal origin. An incidental thyroid nodule in patients with head and neck cancer has been reported to have a malignancy rate as high as 41%.18 In our study, we had no patients with pre-existing head and neck cancer. With regard to the modality of detection, most incidental thyroid nodules in our series were discovered because of CT or PET imaging. Incidental thyroid nodules discovered on PET scan had a higher rate of malignancy than those detected on CT scan. The overall prevalence of incidental thyroid nodules detected by PET scan is 2% to 3%.4 – 6 PET does not detect all incidental thyroid nodules, only the ones that are metabolically active. The prevalence of malignancy in an incidentally discovered thyroid nodule on PET imaging in patients with a tissue diagnosis has been reported to vary between 14% and 50%.4 – 6,19 This is much higher than the 11%
J. Jin et al.
Incidental thyroid nodule
rate of thyroid malignancy for a nodule detected by CT in our series and a 4% rate of malignancy reported by others.1 In our series, we found a 33% rate of malignancy in incidental thyroid nodules discovered on PET imaging. Clinicians have tried to correlate certain features found on PET imaging with malignancy. Diffuse fluorodeoxy glucose uptake in the thyroid gland usually represents benign disease, most commonly thyroiditis, and less commonly nodular goiter or Grave’s disease, whereas focal thyroid uptake is more of a concern for malignancy.15,20 Metastatic involvement of the thyroid gland is a rare cause for diffuse fluorodeoxy glucose uptake on PET imaging.5 Are et al reported that only 2 (1.2%) of 162 patients with diffuse uptake had a malignancy on tissue diagnosis.5 Another feature that has been evaluated is the maximum standardized uptake value (SUVmax) of a thyroid nodule found on PET. Although a few studies have reported higher SUVmax for malignant thyroid lesions;4,15 in most studies SUVmax has not been able to differentiate benign and malignant lesions.5,6,18 There are several limitations to our study. One is referral bias. Most patients in our study were referred by their oncologists or primary care physicians after identification of the incidental thyroid nodules on diagnostic imaging tests. The total number of patients screened before endocrine surgery referral and the exact pattern of referral was unknown. We speculate that the rate we see in our practice is higher because of referral bias. In a study using PET scan by Kang et al, a population of patients who were screened for metastases were compared with a group of healthy volunteers. The rate of malignancy for thyroid incidentalomas was 2.9%, and there was no difference between the group of patients screened for metastases and the group of healthy volunteers.15 A second limitation may be the inclusion of patients with papillary microcarcinomas in the total number of patients with malignant thyroid tumor. Papillary microcarcinomas are common incidental findings and are usually indolent in their behavior; as a result their inclusion may have falsely increased the true rate of malignancy. If we excluded the 6 cases of microcarcinomas, the malignancy rate would be 11%, which is still higher than the 5% rate that has been historically reported. In conclusion, the results of our prospective study confirms previous findings that an incidental thyroid nodule is associated with a high rate of malignancy. When a thyroid nodule is discovered during screening or staging for another primary malignancy, it is imperative that US examination of the thyroid gland be obtained for further evaluation of the nodule and the rest of the thyroid gland. The exception is the patient with a primary malignancy and extensive metastatic disease in whom it does not make sense to pursue additional investigation because of limited life expectancy. A thyroid incidentaloma ⱖ1 or ⬍1 cm with abnormal sonographic features should be further evaluated with FNA biopsy. Furthermore, because of the high rate of malignancy that we
323 observed in patients with an incidental thyroid nodule detected on PET scan, we have a low threshold to biopsy any nodules under these circumstances regardless of size when technically feasible.
References 1. Shetty SK, Maher MM, Hahn PF, et al. Significance of incidental thyroid lesions detected on CT: correlation among CT, sonography, and pathology. AJR Am J Roentgenol 2006;187:1349 –56. 2. Youserm DM, Huang T, Loevner LA, et al. Clinical and economic impact of incidental thyroid lesions found with CT and MR. AJNR Am J Neuroradiol 1997;18:1423– 8. 3. Steele SR, Martin MJ, Mullenix PS, et al. The significance of incidental thyroid abnormalities identified during carotid duplex ultrasonography. Arch Surg 2005;140:981–5. 4. Cohen MS, Arslan N, Dehdashti F, et al. Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucose-positron emission tomography. Surgery 2001;130:941– 6. 5. Are C, Hsu JF, Schoder H, et al. FDG-PET detected thyroid incidentalomas: need for further investigation? Ann Surg Oncol 2007;14: 239 – 47. 6. Kim TY, Kim WB, Ryu JS, et al. 18F-fluorodeoxyglucose uptake in thyroid from positron emission tomogram (PET) for evaluation in cancer patients: high prevalence of malignancy in thyroid PET incidentaloma. Laryngoscope 2005;115:1074 – 8. 7. Nam-Goong IS, Kim HY, Gong G, et al. Ultrasonography-guided fine-needle aspiration of thyroid incidentaloma: correlation with pathological findings. Clin Endocrinol 2004;60:21– 8. 8. Kim DL, Song KH, Kim SK. High prevalence of carcinoma in ultrasonography-guided fine needle aspiration cytology of thyroid nodules. Endocr J 2008;55:135– 42. 9. Wilhelm SM, Robinson AV, Krishnamurthi SS, et al. Evaluation and management of incidental thyroid nodules in patients with another primary malignancy. Surgery 2007;142:581–7. 10. Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med 1968;69:537– 40. 11. Team RDCR. A Language and Environment for Statistical Computing. R Foundation for Statistical Computing Vienna, Austria; 2007. 12. Gough J, Scott-Coombes D, Fausto Palazzo F. Thyroid incidentaloma: an evidence-based assessment of management strategy. World J Surg 2008;32:1264 – 8. 13. Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 1955;15:1270 – 80. 14. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and colorDoppler features. J Clin Endocrinol Metab 2002;87:1941– 6. 15. Kang KW, Kim SK, Kang HS, et al. Prevalence and risk of cancer of focal thyroid incidentaloma identified by 18 F-fluorodeoxyglucose positron emission tomography for metastasis evaluation and cancer screening in healthy subjects. J Clin Endocrinol Metab 2003;88:4100 – 4. 16. Vassilopoulou-Sellin R, Palmer L, Taylor S, et al. Incidence of breast carcinoma in women with thyroid carcinoma. Cancer 1999;85:696 – 705. 17. Nakhjavani MK, Gharib H, Goellner JR, et al. Metastasis to the thyroid gland. A report of 43 cases. Cancer 1997;79:574 – 8. 18. Nam SY, Roh JL, Kim JS, et al. Focal uptake of (18)F-fluorodeoxyglucose by thyroid in patients with nonthyroidal head and neck cancers. Clin Endocrinol 2007;67:135–9. 19. Chen YK, Liu FY, Yen RF, et al. Compare FDG-PET and Tc-99m tetrofosmin SPECT to detect metastatic thyroid carcinoma. Acad Radiol 2003;10:835–9.
324 20. Salvatori M, Melis L, Castaldi P, et al. Clinical significance of focal and diffuse thyroid diseases identified by (18)F-fluorodeoxyglucose positron emission tomography. Biomed Pharmacother 2007;61:488 –93.
Discussion Herbert Chen, M.D. (Madison, Wisconsin): One of the key findings in this article is that in patients with incidentally discovered thyroid nodules, the malignancy rate is 15%, which is 3 times higher than the overall population of people with thyroid nodules. I have 3 questions for you. First, I was surprised that the most common imaging modality that detected a thyroid nodule was CAT. I would have guessed US because at our institution, we are referred a high number of patients undergoing neck US for carotid disease or for primary hyperparathyroidism. I wonder how many of these thyroid nodules are found during preoperative localization for parathyroid adenomas and if US is part of your practice for those patients? Second, in the 21 patients with incidental thyroid nodules that were found on PET, 7 were cancerous. Could you tell us the pathology of the other 14 lesions? Specifically, were they all neoplastic? Last, many of your patients had thyroid nodules found during workup for a metastatic nonthyroid cancer. I assume that some of these patients were eventually diagnosed with metastatic disease from their primary cancer. Could you comment on the need for thyroidectomy in patients with a second metastatic cancer? Do you think we should aggressively treat the thyroid disease in the setting of a metastatic nonthyroid cancer, such as colon cancer? Judy Jin, M.D. (Cleveland, Ohio): The first question regards detection using CAT scan versus US. A key point in our presentation was that we do have a referral bias, so ⬍50% of these patients were found to have incidental thyroid nodules during screening for metastases. CAT scan still
The American Journal of Surgery, Vol 197, No 3, March 2009 remains the most popular imaging modality to screen for metastases. Previous studies actually indicated the incidence using CAT or MRI is approximately 16 %, a bit higher than the 9% quoted for carotid duplex. Regarding your question of using US to look for primary hyperparathyroidism, 5 patients had thyroid nodules identified during US localization of their parathyroid problem. A few patients were found to have a thyroid nodule during parathyroidectomy. Regarding the pathology for patients who had their thyroid nodule discovered on PET scan, 7 had malignancy. For the rest of the 14 patients, 6 had neoplastic pathology (3 being follicular cell adenoma and 3 being Hurthle cell adenoma), and the other patients had benign pathology, most commonly multinodular goiter. The last question regards the management strategy for thyroid malignancy if the patient already has metastatic disease from a primary pre-existing malignancy. The most important point is the overall prognosis of the metastatic disease. If the overall prognosis is poor, there is no indication for operating on the thyroid even with thyroid malignancy. However, in the case of a relatively good prognosis from treatable metastatic disease, we recommend treating the metastatic disease first. Then, if the patient can tolerate further surgery, we would perform thyroidectomy for the thyroid malignancy. Steven A. DeJong, M.D. (Maywood, Illinois): Just a brief question to pin down 1 of your conclusions. Given the relatively high rate of malignancy in PET-positive thyroid nodules, would you be satisfied with a benign needle biopsy result, or would you recommend lobectomy? Judy Jin, M.D. (Cleveland, Ohio): Regarding PET-positive thyroid nodules, which have a higher rate of thyroid malignancy, we do have a lower threshold for first performing biopsy and then surgical resection. However, a few patients in our database with PET-positive nodules were benign on needle biopsy specimen, and we have followed them without surgery.