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computed tomography in cytologically indeterminate thyroid nodules?
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American Journal of Otolaryngology – Head and Neck Medicine and Surgery 29 (2008) 113 – 118 www.elsevier.com/locate/amjoto
Is there a role for fluorodeoxyglucose positron emission tomography/ computed tomography in cytologically indeterminate thyroid nodules?B Nathan W. Hales, MD, Greg A. Krempl, MD, Jesus E. Medina, MD⁎ Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Received 20 January 2008
Abstract
Objective: The aim of this study was to determine the accuracy of the fluorine 18 (18F)–labeled fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scan in the evaluation of thyroid nodules in which the cytopathology of fine-needle aspiration (FNA) biopsies are classified as “indeterminate,” ie, either follicular or Hürthle cell lesion. Methods: At an academic medical center, we conducted a prospective pilot study of 15 patients with thyroid nodules in whom adequate FNA was diagnosed as indeterminate. All patients underwent a whole-body FDG-PET/CT scan followed by thyroidectomy. Preoperative FDG-PET/CT results and the histopathology of the surgical specimen were compared and statistically analyzed. Results: The FNA demonstrated follicular cells in 11 (73%) patients, Hürthle cells in 3 (20%) patients, and both types of cells in 1 (7%) patient. The histopathology of the surgical specimen revealed thyroid cancer in 7 (47%) patients. The FDG-PET/CT scan was positive in 8 patients; 4 (50%) patients were found to have cancer. The FDG-PET/CT scan was negative in 7 patients. Four of these patients had benign lesions and 3 had thyroid carcinoma. Thus, 4 (27%) patients had falsepositive FDG-PET/CT scans and 3 (20%) patients had false-negative studies. The sensitivity of FDG-PET/CT to detect a malignant focus was 57% with a specificity of 50%. The positive predictive value was 50% and the negative predictive value was 57%. Conclusions: In this pilot study of patients with cytologically indeterminate thyroid nodules, FDGPET/CT was not a predictable indicator of benign or malignant disease. Although a larger series may elucidate a role for FDG-PET/CT, the relatively low predictability shown in this study should caution clinicians about using FDG-PET/CT to consider foregoing thyroidectomy for cytologically indeterminate nodules. © 2008 Published by Elsevier Inc.
1. Introduction Oral presentation, American Head and Neck Society, 2006 Annual Meeting & Research Workshop on Biology, Prevention and Treatment of Head and Neck Cancer, Chicago, IL, August 19, 2006. ☆ This project was supported by the Resident Research Fund of The University of Oklahoma Health Sciences Center, Department of Otorhinolaryngology, and by PET Imaging of Oklahoma (Oklahoma City, OK). ⁎ Corresponding author. Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, PO Box 26901 WP 1290, Oklahoma City, OK 73190, USA. Tel.: +1 405 271 5504; fax: +1 405 271 3248. E-mail addresses: [email protected] (N.W. Hales), [email protected] (G.A. Krempl), [email protected] (J.E. Medina). 0196-0709/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.amjoto.2007.04.006
Thyroid nodules are very common; they can be found in up to 50% of the adult population [1]. The incidence of thyroid malignancy in the general population is approximately 40 to 1000 cases per million per year [2]. Early identification and diagnosis is important in appropriate treatment of thyroid cancer, as delays in the diagnosis are associated with increased mortality [3,4]. The evaluation of a thyroid nodule typically includes a fine-needle aspiration (FNA) biopsy and measurement of serum thyroid-stimulating hormone. In most centers today
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the cytopathology of FNA biopsies of thyroid lesions is reported as one of the following 4 categories: malignant neoplasm (usually papillary carcinoma), benign disease, inadequate sample, or indeterminate cytopathology (follicular cells and/or Hürthle cells). The identification of thyroid cancer can be a challenging process given that the FNA cannot always distinguish between benign and malignant nodules, especially in follicular lesions [2,5]. A number of reports have shown that between 11% and 42% of FNAs of thyroid lesions are reported as indeterminate [1,6,7]. These cytologically indeterminate nodules present a clinical dilemma to the evaluating clinician. On the one hand, surgical pathology demonstrates that 80% of these lesions are benign. On the other hand, in some series, the prevalence of malignancy within them has been reported to be as high as 51% [6-9]. Consequently, the next step in the current management of these patients is usually surgical excision, although surgery is likely to prove to be unnecessary in most cases. Unfortunately, at present, there is no alternative algorithm for a more conservative management of patients with thyroid nodules of indeterminate cytopathology.
Conventional ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), color Doppler sonography, and conventional scintigraphy with radioactive iodine or technetium Tc 99m have been used with minimal to moderate success in the characterization of such thyroid nodules [1,10-12]. These conventional diagnostic modalities rely on vascular or morphological alterations for tumor detection. In contrast, positron emission tomography (PET) with fluorine 18 (18F)–labeled fluorodeoxyglucose (FDG) relies on in vivo measurement of functional alterations of glucose metabolism for tumor detection [13-15]. Prior studies have shown a correlation between a positive FDG-PET/CT and the presence of thyroid carcinoma within thyroid “incidentalomas” and multinodular goiters [2,16-21]. Although these observations suggest a potential role for FDG-PET/CT in the evaluation of thyroid nodules, the use of FDG-PET/CT in the evaluation of cytologically indeterminate lesions has not been systematically investigated to date. The purpose of this project was to assess the accuracy of FDG-PET/CT in predicting the correct diagnosis of cytologically indeterminate thyroid nodules in a pilot series.
Table 1 Patient characteristics on presentation Patient
Sex
Age (y)
Presenting complaints
Nodule location
Nodule size (cm)
Solitary/multiple (by ultrasound)
1
F
64
Bilateral
2.3 right, 2.0 left
Multiple
2
F
37
Right lobe
2.5
Solitary
3 4
F F
42 26
Right lobe Left lobe
1.5 0.7
Solitary Solitary
5
F
41
Left lobe
4
Solitary
6
F
52
Left lobe
6
Solitary
7
F
22
Left lobe
5.6
Solitary
8
M
61
Bilateral
Largest, 1.8 right
Multiple
9
F
61
Bilateral
Largest, 3.8 right
Multiple
10
F
67
Bilateral
2.5 right, 3.4 left
Multiple, cystic
11 12 13 14
F F F F
40 70 38 38
Solitary Multiple Not available Multiple
F
53
Left lobe Bilateral Left lobe Bilateral, dominant-right sided Left lobe
2.5 2.6 isthmus, 1.9 left Not available 3.5, dominant right
15
Pain, increasing size of nodule, change in singing voice, dysphagia, dry skin, hair loss, constipation, weight gain Several-year history of slowly growing thyroid mass Fatigue, depression Incidental finding on ultrasound, asymptomatic Incidental on CT, history of uterine cancer Multinodular goiter on PET, history of breast and ovarian malignancy Asymptomatic thyroid enlargement Asymptomatic nodules on PET, asthma Asymptomatic thyroid enlargement Asymptomatic, history of breast cancer “Lump in my neck,” dysphagia Asymptomatic thyroid mass Asymptomatic thyroid nodule Progressive, dysphagia, cough, diarrhea, Asymptomatic, incidental thyroid nodule on MRI for cervical radiculopathy, history of breast cancer
1.5
Solitary
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2. Methods This study was approved by the institutional review board of The University of Oklahoma Health Science Center. The study was designed as a pilot study limited to 15 patients because of the uncertain usefulness of an FDG-PET/CT scan. Fifteen patients with thyroid nodules diagnosed as cytologically “indeterminate” (ie, either follicular or Hürthle cell lesion) by FNA were studied in a prospective manner. When more than one nodule was present, either the largest nodule or both nodules were biopsied. Patients who were pregnant, breast-feeding, unable to have surgery, or weighing greater than 400 lb (the maximal tolerable weight of the FDG-PET/CT scanner) were excluded from this study. Informed consent was obtained and all patients underwent a whole-body FDG-PET/CT scan followed by thyroidectomy. The FDG-PET/CT scan was performed with a REVEAL XVI HiREZ (Knoxville, TN) with an axial field of view of 16.2 cm and a spatial resolution of 5.8 mm. All patients fasted 4 to 6 hours before the FDG tracer administration. Patients were able to take their daily medications with the exception of diabetes or diuretic medication. The day before the test they were encouraged to drink 6 to 8 glasses of water and eat a low-carbohydrate meal as the last meal before the test. Sixty minutes (during which the patient was asked not to talk, chew
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gum, or perform other repetitive activities) after the intravenous injection of 12 to 14 mCi of [18F]FDG, a whole-body emission scan was performed. Focal uptake within the thyroid gland with a standard uptake value (SUV) of greater than 2.0 was considered a positive FDG-PET/CT scan. The presence of papillary, follicular, or Hürthle cell carcinoma was considered a positive pathology result. The preoperative FDG-PET/CT scan results and postoperative pathology were compared and statistically analyzed. 3. Results All 15 patients completed the study. Patient characteristics and presenting signs and symptoms are summarized in Table 1. The average patient age was 48 years (range, 22– 70 years). Ninety-three percent (14/15) of the patients were women. In one third (5/15) of the patients the thyroid nodules had been discovered incidentally on imaging studies other than FDG-PET/CT, which had been ordered for evaluation of other disorders. All patients underwent thyroid ultrasonography. Fifty-three percent (8/15) of the patients had a single thyroid nodule and 40% (6/15) had multiple nodules, as demonstrated on thyroid ultrasonography. One ultrasound done by an endocrinologist did not document the number or size of the nodules.
Table 2 Pathologic and surgical data No. Cytopathology
Focal/diffuse (PET)
PET (SUV)
Surgery
1 2
Follicular cells Hürthle cells
Diffuse/background Focal/entire lobe
1.5 (negative) Total thyroidectomy 3.9 (positive) Right lobectomy
3 4 5
Follicular neoplasm Follicular lesion Follicular cells with occasional atypia
Nonfocal/diffuse Diffuse/background Focal
2.9 (negative) Right lobectomy 1.5 (negative) Left lobectomy 1.7 (negative) Left lobectomy
6 7
Follicular cells Follicular lesion
8
Right: follicular, Hürthle, and multinucleated giant cells Left: follicular cells
Focal 3.8 (positive) Focal with decreased 2.8 (positive) uptake centrally Focal × 2 7.4 (positive)
9
Follicular cells
Diffuse
1.7 (negative) Total thyroidectomy
10
Hürthle cell neoplasm
6.0 (positive)
Total thyroidectomy
11
Hürthle cell neoplasm
Focal left, patchy right Focal
7.4 (positive)
Left lobectomy
12
Follicular neoplasm
Focal
4.1 (positive)
Total thyroidectomy
13
Follicular cells
Focal
1.8 (negative) Left lobectomy
14
Follicular cells
Focal
2.3 (positive)
15
Follicular cells
Focal
1.7 (negative) Left lobectomy
Left lobectomy Left lobectomy Total thyroidectomy
Right lobectomy
Pathology
Outcome
Papillary carcinoma, 1.4 cm (positive) Nodular goiter with degenerative changes (negative) Lymphocytic thyroiditis (negative) Hashimoto thyroiditis (negative) Hemorrhagic cyst, papillary thyroid carcinoma, follicular variant, 4.0 cm (positive) Multinodular hyperplasia (negative) Follicular variant of papillary thyroid carcinoma in capsule, 5.3 cm (positive) Right: papillary thyroid carcinoma, follicular variant (0.8 cm) Left: papillary thyroid carcinoma, follicular variant, 2 foci (1.0, 0.1 cm) (positive) Nodular goiter, mild lymphocytic thyroiditis (negative) Nodular hyperplasia with prominent Hürthle cell change (negative) Multinodular goiter with a dominant nodule with extensive Hürthle cell changes (negative) Papillary thyroid cancer, 3.5 cm (positive) Micropapillary carcinoma, 0.1 cm (positive) focal thyroiditis Papillary thyroid carcinoma, 1.2 cm (positive) Nodular hyperplasia, lymphocytic thyroiditis (negative)
False negative False positive True negative True negative False negative
False positive True positive True positive
True negative False positive False positive
True positive False negative True positive True negative
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Each FDG-PET/CT scan was reviewed by the same nuclear medicine radiologist and all FNA cytopathologic and surgical histopathologic evaluations were read by the same head and neck pathologist. Their findings are summarized in Table 2. The FNA biopsy demonstrated follicular cells in 11 (73%) patients, Hürthle cells in 3 (20%) patients, and both types of cells in 1 (7%) patient. The histopathology of the surgical specimen revealed thyroid cancer in 7 patients (47%): 3 papillary carcinoma (43%), 3 follicular variant of papillary thyroid carcinoma (43%), and 1 micropapillary thyroid carcinoma (14%). The FDG-PET/CT scan was positive in 8 patients, 4 (50%) of whom were found to have thyroid carcinoma. The FDG-PET/CT scan was considered negative in 7 patients; of these, 4 (57%) patients had benign lesions and 3 (43%) had thyroid carcinoma. Thus, 4 patients had a false-positive FDG-PET/CT scan (false-positive rate, 50%, 4/8) and 3 patients had a false-negative study (false-negative rate, 43%, 3/7). The sensitivity of FDG-PET/CT to detect a malignant focus was 57% and the specificity was 50%. The positive predictive value was 50% and the negative predictive value was 57%. 4. Discussion This study was undertaken because, currently, patients with thyroid nodules in whom the FNA biopsy is considered cytologically indeterminate undergo surgery. In most cases, however, the nodule is benign and surgery may not have been necessary. Therefore, there is a need to identify those patients who are likely to have thyroid carcinoma and need surgery while sparing those patients who do not. Because several studies [20-26] have suggested that FDG-PET/CT scans are often “positive” for the presence of thyroid carcinoma, it seemed reasonable to hypothesize that FDGPET/CT would be a useful tool to determine the presence of malignancy in cytologically indeterminate thyroid lesions and help in the selection of patients that would benefit from surgery. Forty-seven percent (7/15) of patients in this pilot study demonstrated thyroid carcinoma on final histopathology. Five patients included in the present study had thyroid nodules that had been discovered incidentally on imaging studies (CT, MRI, FDG-PET/CT, and ultrasound) obtained as part of the evaluation of other disorders (patients 4–6, 8, and 15; Table 1). Of these patients, 2 had imaging studies for benign conditions and 3 patients had a history of other malignancies including breast and uterine cancer. One other patient who did not have previous imaging also had a history of breast cancer (patient 10; Table 1). In total, 4 (27%) patients in this study had previous histories of other cancers, all of which were gynecologic cancers. Of these 4 patients, 2 had positive FDG-PET/CT scans (patients 6 and 10) and only 1 patient (patient 5) had thyroid cancer; however, the FDGPET/CT scan was negative (Tables 1 and 2).
All patients meeting inclusion criteria who were willing to participate in the study were included in this study, including patients with palpable and nonpalpable nodules. In this manner, a better idea of the real value of a positive FDGPET/CT scan might be assessed. We felt justified including these patients in the study based on the experience reported by several investigators. Ramos et al [17] reported 4 patients who had been found to have focal increased uptake in the thyroid on FDG-PET scan obtained for the follow-up of various cancers. In all 4 cases, thyroid carcinoma was diagnosed either by FNA biopsy (both cases of papillary carcinoma) or by surgery and histopathologic examination. These authors suggested that even when the thyroid uptake is not particularly intense, as was the case in 2 of their patients (maximum SUVs of 7.9 and 3.7, respectively) the possibility of thyroid cancer should be considered [17]. Davis et al [26] reported 5 cases of a clinically occult thyroid cancer found in patients who underwent FDG-PET scanning for metastatic evaluations. Increased uptake in the region of the thyroid was evident on the FDG-PET scan, and FNA biopsy indicated papillary carcinoma of the thyroid in all 5 cases [26]. Van den Bruel et al described 7 patients referred to them because of thyroid “hot spots,” incidentally detected by whole-body FDG-PET scan. Surgery was recommended on the basis of ultrasound guide FNA cytology. Malignancy was correctly identified in 5 (71%): 2 medullary thyroid carcinomas, 1 with lymph node invasion, and 3 papillary thyroid carcinomas. However, in 2 patients with a positive FDGPET scan, the FNA was reported as follicular neoplasm but the final histology showed follicular adenoma [16]. In a large retrospective study of 1330 cases of whole-body FDG-PET scans performed for cancer screening and evaluation for metastasis, thyroid “incidentalomas” were found in 29 (2.2%) patients [27]. Fifteen of these patients underwent surgery, 26.7% of which demonstrated malignancy. In an even larger retrospective series of 4525 cases of whole-body FDG-PET, thyroid incidentalomas were found in 2.3% (102/ 4525) of the patients [2]. Unfortunately, for various reasons, only 15 of these patients underwent surgery. Malignancy was demonstrated in 7 (47%) of them. In reviewing these retrospective studies, each suggests a potential role of FDG-PET/CT in the evaluation of thyroid nodules, whereas none of them specifically addressed the role of FDG-PET/CT in the evaluation of indeterminate thyroid nodules or prospectively assessed its accuracy in predicting the presence of thyroid cancer in such lesions. To our knowledge, this is the first study to assess prospectively the accuracy of FDG-PET/CT in the evaluation of thyroid lesions of indeterminate cytology. Our results were enlightening, yet disappointing. A positive FDG-PET/CT scan was seen in 8 patients, only 4 of which were found to have cancer; thus, 50% had falsepositive scans: 2 of these patients had nodular hyperplasia and 2 had a multinodular goiter. One potential explanation for this high rate of false positives was our use of focal, greater than 2 SUV as the criterion to consider an FDG-PET/
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CT positive. However, the SUV values for the false-positive patients were 3.8, 3.9, 6.0, and 7.4, respectively; thus, even a cutoff as high as 5.0 or higher as suggested by other authors [2,20] would have still resulted in a false-positive rate of 25% (2/8) and would have excluded 3 of the 4 true positive tests and therefore increased the false-negative rate to 60% (6/10). Furthermore, 3 patients who had thyroid carcinoma had focal thyroid uptake of 1.5, 1.7, and 2.3 SUV, respectively, on FDG-PET/CT. The FDG-PET/CT scan was negative in 7 patients. Four of these patients had benign lesions and 3 had thyroid carcinoma. Thus, the false-negative rate was 43% (3/7). A potential explanation for such a high rate of false negatives may be that the focus of thyroid carcinoma was too small, because most FDG-PET/CT scanners identify lesions greater than 1.0 cm. However, on careful review of the 3 patients with negative FDG-PET/CT scans and positive pathology, 1 patient (patient 13; Table 2) had a lesion 1.0 cm or smaller measuring 0.1 cm. The second false-negative case had a hemorrhagic cyst that measured 4.0 cm in diameter and exhibited follicular variant of papillary thyroid carcinoma in the cyst wall. The third patient had diffuse uptake on FDGPET/CT with an SUV less than 2.0 and a 1.4-cm papillary thyroid carcinoma. Therefore, in pathologically positive lesions greater than 1.0 cm in this study, the false-negative rate was 33% (2/6) if the patient with a 0.1-cm lesion is excluded. On the other hand, patient 8 had several small lesions measuring 1.0, 0.8, and 0.1 cm and had 2 focally positive areas on the FDG-PET/CT scan. It is unlikely that the size of the lesion is the major reason for the high falsenegative rate within this study. Although these explanations might allow one to think FDG-PET/CT may be unfairly judged in this pilot project, these scenarios are not infrequently encountered in patients with thyroid nodules. The consequences of the false-negative results clearly are the biggest concern brought out by our observations. If in a larger series the false-positive rate for FDG-PET/CT in indeterminate lesions was confirmed to be around 35%, but the false-negative rate was near zero, using the results of FDG-PET/CT to decide whether surgery was indicated would save a significant number of patients from undergoing unnecessary surgery and might well justify the cost given the proportion of benign nodules. However, if the false-negative rate we saw was confirmed, this would mean that 43% of those patients with cancer might be observed, with a potential delay in appropriate treatment of their cancer. Overall, the sensitivity of FDG-PET/CT to detect a malignant focus in this study was 57% and the specificity was 50%. Admittedly, studying a much larger number of patients may identify a role for FDG-PET/CT. However, our results suggest that FDG-PET/CT most likely is not a sensitive or a specific enough test to reliably detect thyroid carcinoma in indeterminate nodules of the thyroid. Therefore, clinicians should be cautious about using a FDG-PET/ CT scan in deciding whether to perform thyroidectomy in patients with such lesions.
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5. Conclusion In this pilot study of patients with cytologically indeterminate thyroid nodules, FDG-PET/CT was not a predictable indicator of the presence of thyroid carcinoma. Whereas a larger series may elucidate a role for FDG-PET/ CT, the relatively low predictability shown in this study should caution clinicians about using FDG-PET/CT to consider foregoing thyroidectomy for cytologically indeterminate nodules. The high rate of malignancy in indeterminate nodules of the thyroid, in this series, reinforces the practice of surgical removal of these lesions. References [1] Alexander EK, Heering JP, Benson CB, et al. Assessment of nondiagnostic ultrasound-guided fine needle aspirations of thyroid nodules. J Clin Endocrinol Metab 2002;87(11):4924-7. [2] 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. [3] Jana S, Abdel-Dayem HM, Young I. Nuclear medicine and thyroid cancer. Eur J Nucl Med 1999;26:1528-32. [4] Mazzaferi EL. Radioiodine and other treatments and outcomes. In: Braverman LE, Utiger RD, editors. Werner and Ingbar's the thyroid: a fundamental and clinical text. 7th ed. Philadelphia: JB LippencottRaven; 1996. p. 922-43. [5] Lind P. Multi-tracer imaging of thyroid nodules: is there a role in the preoperative assessment of nodular goiter? Eur J Nucl Med 1999;26:795-7. [6] Miller B, Burkey S, Lindberg G, et al. Prevalence of malignancy within cytologically indeterminate thyroid nodules. Am J Surg 2004;188 (5):459-62. [7] Sclabas GM, Staerkel GA, Shapiro SE. Fine-needle aspiration of the thyroid and correlation with histopathology in a contemporary series of 240 patients. Am J Surg 2003;186:702-10. [8] Goldstein RE, Netterville JL, Burkey B, et al. Implications of follicular neoplasms, atypia, and lesions suspicious for malignancy diagnosed by fine-needle aspiration of thyroid nodules. Ann Surg 2002;235:656-64. [9] Tyler DS, Winchester DJ, Caraway NP. Indeterminate fine-needle aspiration biopsy of the thyroid: identification of subgroups at high risk for invasive carcinoma. Surgery 1994;116:1054-60. [10] Bozbora A, Erbil Y, Ozarmagan S, et al. Color Doppler sonography in cold thyroid nodules for malignancy prediction. Acta Chir Belg 2002;102(4):259-62. [11] Welker MJ, Orlov D. Thyroid nodules. Am Fam Physician 2003; 67(3):559-66. [12] Galloway RJ, Smallridge RC. Imaging in thyroid cancer. Endocrinol Metab Clin North Am 1996;25:93-111. [13] Gordon BA, Flanagan FL, Dehdashti F. Whole-body positron emission tomography: normal variations, pitfalls and technical considerations. Am J Radiol 1997;169:1675-80. [14] Ghassan EH, Abass A, Ayse M, Gonca B, Hongming Z. Normal variants in [18F]-fluorodeoxyglucose PET imaging. Radiol Clin North Am 2004;42(6). [15] Haber RS, Weiser KR, Pritsker A, et al. GLUT1 glucose transporter expression in benign and malignant thyroid nodules. Thyroid 1997;7: 363-7. [16] Van den Bruel A, Maes A, De Potter T, et al. Clinical relevance of thyroid fluorodeoxyglucose-whole body positron emission tomography incidentaloma. J Clin Endocrinol Metab 2002;87(4):1517-20. [17] Ramos CD, Chisin R, Yeung HWD, et al. Incidental focal thyroid uptake on FDG positron emission tomographic scans may represent a second primary tumor. Clin Nucl Med 2001;26:193-7.
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[18] Feine U, Lietzenmayer R, Hanke JP, et al. Fluorine-18-FDG and iodine-131-iodide uptake in thyroid cancer. J Nucl Med 1996;37: 1468-72. [19] Grunwald F, Kalicke T, Feine U, et al. Fluorine-18 fluorodeoxyglucose positron emission tomography in thyroid cancer: results of a multicentre study. Eur J Nucl Med 1999;26:1547-52. [20] Uematsu H, Sadato N, Ohtsubo T, et al. Fluorine-18-fluorodeoxyglucose PET versus thallium-201 scintigraphy evaluation of thyroid tumors. J Nucl Med 1998;39(3):453-9. [21] Zhuang H, Kumar R, Mandel S, et al. Investigation of thyroid, head, and neck cancers with PET. Radiol Clin North Am 2004;42(6):1101-11. [22] Wang W, Larson SM, Fazzari M, et al. Prognostic value of [18F] fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer. J Clin Endocrinol Metab 2000;85:1107-13. [23] Musholt TJ, Musholt PB, Dehdashti F, et al. Evaluation of fluorodeoxyglucose-positron emission tomographic scanning and its association with glucose transporter expression in medullary thyroid
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American Journal of Otolaryngology – Head and Neck Medicine and Surgery 29 (2008) 113 – 118 www.elsevier.com/locate/amjoto
Is there a role for fluorodeoxyglucose positron emission tomography/ computed tomography in cytologically indeterminate thyroid nodules?B Nathan W. Hales, MD, Greg A. Krempl, MD, Jesus E. Medina, MD⁎ Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA Received 20 January 2008
Abstract
Objective: The aim of this study was to determine the accuracy of the fluorine 18 (18F)–labeled fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scan in the evaluation of thyroid nodules in which the cytopathology of fine-needle aspiration (FNA) biopsies are classified as “indeterminate,” ie, either follicular or Hürthle cell lesion. Methods: At an academic medical center, we conducted a prospective pilot study of 15 patients with thyroid nodules in whom adequate FNA was diagnosed as indeterminate. All patients underwent a whole-body FDG-PET/CT scan followed by thyroidectomy. Preoperative FDG-PET/CT results and the histopathology of the surgical specimen were compared and statistically analyzed. Results: The FNA demonstrated follicular cells in 11 (73%) patients, Hürthle cells in 3 (20%) patients, and both types of cells in 1 (7%) patient. The histopathology of the surgical specimen revealed thyroid cancer in 7 (47%) patients. The FDG-PET/CT scan was positive in 8 patients; 4 (50%) patients were found to have cancer. The FDG-PET/CT scan was negative in 7 patients. Four of these patients had benign lesions and 3 had thyroid carcinoma. Thus, 4 (27%) patients had falsepositive FDG-PET/CT scans and 3 (20%) patients had false-negative studies. The sensitivity of FDG-PET/CT to detect a malignant focus was 57% with a specificity of 50%. The positive predictive value was 50% and the negative predictive value was 57%. Conclusions: In this pilot study of patients with cytologically indeterminate thyroid nodules, FDGPET/CT was not a predictable indicator of benign or malignant disease. Although a larger series may elucidate a role for FDG-PET/CT, the relatively low predictability shown in this study should caution clinicians about using FDG-PET/CT to consider foregoing thyroidectomy for cytologically indeterminate nodules. © 2008 Published by Elsevier Inc.
1. Introduction Oral presentation, American Head and Neck Society, 2006 Annual Meeting & Research Workshop on Biology, Prevention and Treatment of Head and Neck Cancer, Chicago, IL, August 19, 2006. ☆ This project was supported by the Resident Research Fund of The University of Oklahoma Health Sciences Center, Department of Otorhinolaryngology, and by PET Imaging of Oklahoma (Oklahoma City, OK). ⁎ Corresponding author. Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, PO Box 26901 WP 1290, Oklahoma City, OK 73190, USA. Tel.: +1 405 271 5504; fax: +1 405 271 3248. E-mail addresses: [email protected] (N.W. Hales), [email protected] (G.A. Krempl), [email protected] (J.E. Medina). 0196-0709/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.amjoto.2007.04.006
Thyroid nodules are very common; they can be found in up to 50% of the adult population [1]. The incidence of thyroid malignancy in the general population is approximately 40 to 1000 cases per million per year [2]. Early identification and diagnosis is important in appropriate treatment of thyroid cancer, as delays in the diagnosis are associated with increased mortality [3,4]. The evaluation of a thyroid nodule typically includes a fine-needle aspiration (FNA) biopsy and measurement of serum thyroid-stimulating hormone. In most centers today
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the cytopathology of FNA biopsies of thyroid lesions is reported as one of the following 4 categories: malignant neoplasm (usually papillary carcinoma), benign disease, inadequate sample, or indeterminate cytopathology (follicular cells and/or Hürthle cells). The identification of thyroid cancer can be a challenging process given that the FNA cannot always distinguish between benign and malignant nodules, especially in follicular lesions [2,5]. A number of reports have shown that between 11% and 42% of FNAs of thyroid lesions are reported as indeterminate [1,6,7]. These cytologically indeterminate nodules present a clinical dilemma to the evaluating clinician. On the one hand, surgical pathology demonstrates that 80% of these lesions are benign. On the other hand, in some series, the prevalence of malignancy within them has been reported to be as high as 51% [6-9]. Consequently, the next step in the current management of these patients is usually surgical excision, although surgery is likely to prove to be unnecessary in most cases. Unfortunately, at present, there is no alternative algorithm for a more conservative management of patients with thyroid nodules of indeterminate cytopathology.
Conventional ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), color Doppler sonography, and conventional scintigraphy with radioactive iodine or technetium Tc 99m have been used with minimal to moderate success in the characterization of such thyroid nodules [1,10-12]. These conventional diagnostic modalities rely on vascular or morphological alterations for tumor detection. In contrast, positron emission tomography (PET) with fluorine 18 (18F)–labeled fluorodeoxyglucose (FDG) relies on in vivo measurement of functional alterations of glucose metabolism for tumor detection [13-15]. Prior studies have shown a correlation between a positive FDG-PET/CT and the presence of thyroid carcinoma within thyroid “incidentalomas” and multinodular goiters [2,16-21]. Although these observations suggest a potential role for FDG-PET/CT in the evaluation of thyroid nodules, the use of FDG-PET/CT in the evaluation of cytologically indeterminate lesions has not been systematically investigated to date. The purpose of this project was to assess the accuracy of FDG-PET/CT in predicting the correct diagnosis of cytologically indeterminate thyroid nodules in a pilot series.
Table 1 Patient characteristics on presentation Patient
Sex
Age (y)
Presenting complaints
Nodule location
Nodule size (cm)
Solitary/multiple (by ultrasound)
1
F
64
Bilateral
2.3 right, 2.0 left
Multiple
2
F
37
Right lobe
2.5
Solitary
3 4
F F
42 26
Right lobe Left lobe
1.5 0.7
Solitary Solitary
5
F
41
Left lobe
4
Solitary
6
F
52
Left lobe
6
Solitary
7
F
22
Left lobe
5.6
Solitary
8
M
61
Bilateral
Largest, 1.8 right
Multiple
9
F
61
Bilateral
Largest, 3.8 right
Multiple
10
F
67
Bilateral
2.5 right, 3.4 left
Multiple, cystic
11 12 13 14
F F F F
40 70 38 38
Solitary Multiple Not available Multiple
F
53
Left lobe Bilateral Left lobe Bilateral, dominant-right sided Left lobe
2.5 2.6 isthmus, 1.9 left Not available 3.5, dominant right
15
Pain, increasing size of nodule, change in singing voice, dysphagia, dry skin, hair loss, constipation, weight gain Several-year history of slowly growing thyroid mass Fatigue, depression Incidental finding on ultrasound, asymptomatic Incidental on CT, history of uterine cancer Multinodular goiter on PET, history of breast and ovarian malignancy Asymptomatic thyroid enlargement Asymptomatic nodules on PET, asthma Asymptomatic thyroid enlargement Asymptomatic, history of breast cancer “Lump in my neck,” dysphagia Asymptomatic thyroid mass Asymptomatic thyroid nodule Progressive, dysphagia, cough, diarrhea, Asymptomatic, incidental thyroid nodule on MRI for cervical radiculopathy, history of breast cancer
1.5
Solitary
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2. Methods This study was approved by the institutional review board of The University of Oklahoma Health Science Center. The study was designed as a pilot study limited to 15 patients because of the uncertain usefulness of an FDG-PET/CT scan. Fifteen patients with thyroid nodules diagnosed as cytologically “indeterminate” (ie, either follicular or Hürthle cell lesion) by FNA were studied in a prospective manner. When more than one nodule was present, either the largest nodule or both nodules were biopsied. Patients who were pregnant, breast-feeding, unable to have surgery, or weighing greater than 400 lb (the maximal tolerable weight of the FDG-PET/CT scanner) were excluded from this study. Informed consent was obtained and all patients underwent a whole-body FDG-PET/CT scan followed by thyroidectomy. The FDG-PET/CT scan was performed with a REVEAL XVI HiREZ (Knoxville, TN) with an axial field of view of 16.2 cm and a spatial resolution of 5.8 mm. All patients fasted 4 to 6 hours before the FDG tracer administration. Patients were able to take their daily medications with the exception of diabetes or diuretic medication. The day before the test they were encouraged to drink 6 to 8 glasses of water and eat a low-carbohydrate meal as the last meal before the test. Sixty minutes (during which the patient was asked not to talk, chew
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gum, or perform other repetitive activities) after the intravenous injection of 12 to 14 mCi of [18F]FDG, a whole-body emission scan was performed. Focal uptake within the thyroid gland with a standard uptake value (SUV) of greater than 2.0 was considered a positive FDG-PET/CT scan. The presence of papillary, follicular, or Hürthle cell carcinoma was considered a positive pathology result. The preoperative FDG-PET/CT scan results and postoperative pathology were compared and statistically analyzed. 3. Results All 15 patients completed the study. Patient characteristics and presenting signs and symptoms are summarized in Table 1. The average patient age was 48 years (range, 22– 70 years). Ninety-three percent (14/15) of the patients were women. In one third (5/15) of the patients the thyroid nodules had been discovered incidentally on imaging studies other than FDG-PET/CT, which had been ordered for evaluation of other disorders. All patients underwent thyroid ultrasonography. Fifty-three percent (8/15) of the patients had a single thyroid nodule and 40% (6/15) had multiple nodules, as demonstrated on thyroid ultrasonography. One ultrasound done by an endocrinologist did not document the number or size of the nodules.
Table 2 Pathologic and surgical data No. Cytopathology
Focal/diffuse (PET)
PET (SUV)
Surgery
1 2
Follicular cells Hürthle cells
Diffuse/background Focal/entire lobe
1.5 (negative) Total thyroidectomy 3.9 (positive) Right lobectomy
3 4 5
Follicular neoplasm Follicular lesion Follicular cells with occasional atypia
Nonfocal/diffuse Diffuse/background Focal
2.9 (negative) Right lobectomy 1.5 (negative) Left lobectomy 1.7 (negative) Left lobectomy
6 7
Follicular cells Follicular lesion
8
Right: follicular, Hürthle, and multinucleated giant cells Left: follicular cells
Focal 3.8 (positive) Focal with decreased 2.8 (positive) uptake centrally Focal × 2 7.4 (positive)
9
Follicular cells
Diffuse
1.7 (negative) Total thyroidectomy
10
Hürthle cell neoplasm
6.0 (positive)
Total thyroidectomy
11
Hürthle cell neoplasm
Focal left, patchy right Focal
7.4 (positive)
Left lobectomy
12
Follicular neoplasm
Focal
4.1 (positive)
Total thyroidectomy
13
Follicular cells
Focal
1.8 (negative) Left lobectomy
14
Follicular cells
Focal
2.3 (positive)
15
Follicular cells
Focal
1.7 (negative) Left lobectomy
Left lobectomy Left lobectomy Total thyroidectomy
Right lobectomy
Pathology
Outcome
Papillary carcinoma, 1.4 cm (positive) Nodular goiter with degenerative changes (negative) Lymphocytic thyroiditis (negative) Hashimoto thyroiditis (negative) Hemorrhagic cyst, papillary thyroid carcinoma, follicular variant, 4.0 cm (positive) Multinodular hyperplasia (negative) Follicular variant of papillary thyroid carcinoma in capsule, 5.3 cm (positive) Right: papillary thyroid carcinoma, follicular variant (0.8 cm) Left: papillary thyroid carcinoma, follicular variant, 2 foci (1.0, 0.1 cm) (positive) Nodular goiter, mild lymphocytic thyroiditis (negative) Nodular hyperplasia with prominent Hürthle cell change (negative) Multinodular goiter with a dominant nodule with extensive Hürthle cell changes (negative) Papillary thyroid cancer, 3.5 cm (positive) Micropapillary carcinoma, 0.1 cm (positive) focal thyroiditis Papillary thyroid carcinoma, 1.2 cm (positive) Nodular hyperplasia, lymphocytic thyroiditis (negative)
False negative False positive True negative True negative False negative
False positive True positive True positive
True negative False positive False positive
True positive False negative True positive True negative
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Each FDG-PET/CT scan was reviewed by the same nuclear medicine radiologist and all FNA cytopathologic and surgical histopathologic evaluations were read by the same head and neck pathologist. Their findings are summarized in Table 2. The FNA biopsy demonstrated follicular cells in 11 (73%) patients, Hürthle cells in 3 (20%) patients, and both types of cells in 1 (7%) patient. The histopathology of the surgical specimen revealed thyroid cancer in 7 patients (47%): 3 papillary carcinoma (43%), 3 follicular variant of papillary thyroid carcinoma (43%), and 1 micropapillary thyroid carcinoma (14%). The FDG-PET/CT scan was positive in 8 patients, 4 (50%) of whom were found to have thyroid carcinoma. The FDG-PET/CT scan was considered negative in 7 patients; of these, 4 (57%) patients had benign lesions and 3 (43%) had thyroid carcinoma. Thus, 4 patients had a false-positive FDG-PET/CT scan (false-positive rate, 50%, 4/8) and 3 patients had a false-negative study (false-negative rate, 43%, 3/7). The sensitivity of FDG-PET/CT to detect a malignant focus was 57% and the specificity was 50%. The positive predictive value was 50% and the negative predictive value was 57%. 4. Discussion This study was undertaken because, currently, patients with thyroid nodules in whom the FNA biopsy is considered cytologically indeterminate undergo surgery. In most cases, however, the nodule is benign and surgery may not have been necessary. Therefore, there is a need to identify those patients who are likely to have thyroid carcinoma and need surgery while sparing those patients who do not. Because several studies [20-26] have suggested that FDG-PET/CT scans are often “positive” for the presence of thyroid carcinoma, it seemed reasonable to hypothesize that FDGPET/CT would be a useful tool to determine the presence of malignancy in cytologically indeterminate thyroid lesions and help in the selection of patients that would benefit from surgery. Forty-seven percent (7/15) of patients in this pilot study demonstrated thyroid carcinoma on final histopathology. Five patients included in the present study had thyroid nodules that had been discovered incidentally on imaging studies (CT, MRI, FDG-PET/CT, and ultrasound) obtained as part of the evaluation of other disorders (patients 4–6, 8, and 15; Table 1). Of these patients, 2 had imaging studies for benign conditions and 3 patients had a history of other malignancies including breast and uterine cancer. One other patient who did not have previous imaging also had a history of breast cancer (patient 10; Table 1). In total, 4 (27%) patients in this study had previous histories of other cancers, all of which were gynecologic cancers. Of these 4 patients, 2 had positive FDG-PET/CT scans (patients 6 and 10) and only 1 patient (patient 5) had thyroid cancer; however, the FDGPET/CT scan was negative (Tables 1 and 2).
All patients meeting inclusion criteria who were willing to participate in the study were included in this study, including patients with palpable and nonpalpable nodules. In this manner, a better idea of the real value of a positive FDGPET/CT scan might be assessed. We felt justified including these patients in the study based on the experience reported by several investigators. Ramos et al [17] reported 4 patients who had been found to have focal increased uptake in the thyroid on FDG-PET scan obtained for the follow-up of various cancers. In all 4 cases, thyroid carcinoma was diagnosed either by FNA biopsy (both cases of papillary carcinoma) or by surgery and histopathologic examination. These authors suggested that even when the thyroid uptake is not particularly intense, as was the case in 2 of their patients (maximum SUVs of 7.9 and 3.7, respectively) the possibility of thyroid cancer should be considered [17]. Davis et al [26] reported 5 cases of a clinically occult thyroid cancer found in patients who underwent FDG-PET scanning for metastatic evaluations. Increased uptake in the region of the thyroid was evident on the FDG-PET scan, and FNA biopsy indicated papillary carcinoma of the thyroid in all 5 cases [26]. Van den Bruel et al described 7 patients referred to them because of thyroid “hot spots,” incidentally detected by whole-body FDG-PET scan. Surgery was recommended on the basis of ultrasound guide FNA cytology. Malignancy was correctly identified in 5 (71%): 2 medullary thyroid carcinomas, 1 with lymph node invasion, and 3 papillary thyroid carcinomas. However, in 2 patients with a positive FDGPET scan, the FNA was reported as follicular neoplasm but the final histology showed follicular adenoma [16]. In a large retrospective study of 1330 cases of whole-body FDG-PET scans performed for cancer screening and evaluation for metastasis, thyroid “incidentalomas” were found in 29 (2.2%) patients [27]. Fifteen of these patients underwent surgery, 26.7% of which demonstrated malignancy. In an even larger retrospective series of 4525 cases of whole-body FDG-PET, thyroid incidentalomas were found in 2.3% (102/ 4525) of the patients [2]. Unfortunately, for various reasons, only 15 of these patients underwent surgery. Malignancy was demonstrated in 7 (47%) of them. In reviewing these retrospective studies, each suggests a potential role of FDG-PET/CT in the evaluation of thyroid nodules, whereas none of them specifically addressed the role of FDG-PET/CT in the evaluation of indeterminate thyroid nodules or prospectively assessed its accuracy in predicting the presence of thyroid cancer in such lesions. To our knowledge, this is the first study to assess prospectively the accuracy of FDG-PET/CT in the evaluation of thyroid lesions of indeterminate cytology. Our results were enlightening, yet disappointing. A positive FDG-PET/CT scan was seen in 8 patients, only 4 of which were found to have cancer; thus, 50% had falsepositive scans: 2 of these patients had nodular hyperplasia and 2 had a multinodular goiter. One potential explanation for this high rate of false positives was our use of focal, greater than 2 SUV as the criterion to consider an FDG-PET/
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CT positive. However, the SUV values for the false-positive patients were 3.8, 3.9, 6.0, and 7.4, respectively; thus, even a cutoff as high as 5.0 or higher as suggested by other authors [2,20] would have still resulted in a false-positive rate of 25% (2/8) and would have excluded 3 of the 4 true positive tests and therefore increased the false-negative rate to 60% (6/10). Furthermore, 3 patients who had thyroid carcinoma had focal thyroid uptake of 1.5, 1.7, and 2.3 SUV, respectively, on FDG-PET/CT. The FDG-PET/CT scan was negative in 7 patients. Four of these patients had benign lesions and 3 had thyroid carcinoma. Thus, the false-negative rate was 43% (3/7). A potential explanation for such a high rate of false negatives may be that the focus of thyroid carcinoma was too small, because most FDG-PET/CT scanners identify lesions greater than 1.0 cm. However, on careful review of the 3 patients with negative FDG-PET/CT scans and positive pathology, 1 patient (patient 13; Table 2) had a lesion 1.0 cm or smaller measuring 0.1 cm. The second false-negative case had a hemorrhagic cyst that measured 4.0 cm in diameter and exhibited follicular variant of papillary thyroid carcinoma in the cyst wall. The third patient had diffuse uptake on FDGPET/CT with an SUV less than 2.0 and a 1.4-cm papillary thyroid carcinoma. Therefore, in pathologically positive lesions greater than 1.0 cm in this study, the false-negative rate was 33% (2/6) if the patient with a 0.1-cm lesion is excluded. On the other hand, patient 8 had several small lesions measuring 1.0, 0.8, and 0.1 cm and had 2 focally positive areas on the FDG-PET/CT scan. It is unlikely that the size of the lesion is the major reason for the high falsenegative rate within this study. Although these explanations might allow one to think FDG-PET/CT may be unfairly judged in this pilot project, these scenarios are not infrequently encountered in patients with thyroid nodules. The consequences of the false-negative results clearly are the biggest concern brought out by our observations. If in a larger series the false-positive rate for FDG-PET/CT in indeterminate lesions was confirmed to be around 35%, but the false-negative rate was near zero, using the results of FDG-PET/CT to decide whether surgery was indicated would save a significant number of patients from undergoing unnecessary surgery and might well justify the cost given the proportion of benign nodules. However, if the false-negative rate we saw was confirmed, this would mean that 43% of those patients with cancer might be observed, with a potential delay in appropriate treatment of their cancer. Overall, the sensitivity of FDG-PET/CT to detect a malignant focus in this study was 57% and the specificity was 50%. Admittedly, studying a much larger number of patients may identify a role for FDG-PET/CT. However, our results suggest that FDG-PET/CT most likely is not a sensitive or a specific enough test to reliably detect thyroid carcinoma in indeterminate nodules of the thyroid. Therefore, clinicians should be cautious about using a FDG-PET/ CT scan in deciding whether to perform thyroidectomy in patients with such lesions.
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5. Conclusion In this pilot study of patients with cytologically indeterminate thyroid nodules, FDG-PET/CT was not a predictable indicator of the presence of thyroid carcinoma. Whereas a larger series may elucidate a role for FDG-PET/ CT, the relatively low predictability shown in this study should caution clinicians about using FDG-PET/CT to consider foregoing thyroidectomy for cytologically indeterminate nodules. The high rate of malignancy in indeterminate nodules of the thyroid, in this series, reinforces the practice of surgical removal of these lesions. References [1] Alexander EK, Heering JP, Benson CB, et al. Assessment of nondiagnostic ultrasound-guided fine needle aspirations of thyroid nodules. J Clin Endocrinol Metab 2002;87(11):4924-7. [2] 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. [3] Jana S, Abdel-Dayem HM, Young I. Nuclear medicine and thyroid cancer. Eur J Nucl Med 1999;26:1528-32. [4] Mazzaferi EL. Radioiodine and other treatments and outcomes. In: Braverman LE, Utiger RD, editors. Werner and Ingbar's the thyroid: a fundamental and clinical text. 7th ed. Philadelphia: JB LippencottRaven; 1996. p. 922-43. [5] Lind P. Multi-tracer imaging of thyroid nodules: is there a role in the preoperative assessment of nodular goiter? Eur J Nucl Med 1999;26:795-7. [6] Miller B, Burkey S, Lindberg G, et al. Prevalence of malignancy within cytologically indeterminate thyroid nodules. Am J Surg 2004;188 (5):459-62. [7] Sclabas GM, Staerkel GA, Shapiro SE. Fine-needle aspiration of the thyroid and correlation with histopathology in a contemporary series of 240 patients. Am J Surg 2003;186:702-10. [8] Goldstein RE, Netterville JL, Burkey B, et al. Implications of follicular neoplasms, atypia, and lesions suspicious for malignancy diagnosed by fine-needle aspiration of thyroid nodules. Ann Surg 2002;235:656-64. [9] Tyler DS, Winchester DJ, Caraway NP. Indeterminate fine-needle aspiration biopsy of the thyroid: identification of subgroups at high risk for invasive carcinoma. Surgery 1994;116:1054-60. [10] Bozbora A, Erbil Y, Ozarmagan S, et al. Color Doppler sonography in cold thyroid nodules for malignancy prediction. Acta Chir Belg 2002;102(4):259-62. [11] Welker MJ, Orlov D. Thyroid nodules. Am Fam Physician 2003; 67(3):559-66. [12] Galloway RJ, Smallridge RC. Imaging in thyroid cancer. Endocrinol Metab Clin North Am 1996;25:93-111. [13] Gordon BA, Flanagan FL, Dehdashti F. Whole-body positron emission tomography: normal variations, pitfalls and technical considerations. Am J Radiol 1997;169:1675-80. [14] Ghassan EH, Abass A, Ayse M, Gonca B, Hongming Z. Normal variants in [18F]-fluorodeoxyglucose PET imaging. Radiol Clin North Am 2004;42(6). [15] Haber RS, Weiser KR, Pritsker A, et al. GLUT1 glucose transporter expression in benign and malignant thyroid nodules. Thyroid 1997;7: 363-7. [16] Van den Bruel A, Maes A, De Potter T, et al. Clinical relevance of thyroid fluorodeoxyglucose-whole body positron emission tomography incidentaloma. J Clin Endocrinol Metab 2002;87(4):1517-20. [17] Ramos CD, Chisin R, Yeung HWD, et al. Incidental focal thyroid uptake on FDG positron emission tomographic scans may represent a second primary tumor. Clin Nucl Med 2001;26:193-7.
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