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Clinical Radiology 70 (2015) 536e543
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Pictorial Review
Clinical significance of patterns of incidental thyroid uptake at 18F-FDG PET/CT K. Agrawal a, *, J. Weaver b, R. Ngu c, H. Krishnamurthy Mohan a, d a
Dept of Nuclear Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London, UK School of medicine, King’s College London, London, UK c Department of Dental Maxillofacial Radiology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK d Clinical PET Centre, St Thomas’ Hospital, London, UK b
article in formation Article history: Received 4 August 2014 Received in revised form 22 December 2014 Accepted 29 December 2014
Incidental uptake of 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) in the thyroid gland is not uncommonly encountered in day-to-day practice of oncological 18F-FDG positron-emission tomography/computed tomography (PET/CT). These are often felt to be “nuisance lesions” by referring clinicians and radiologists alike. However, recognition of the importance of different patterns of FDG uptake in the thyroid gland and knowledge of the possible underlying aetiologies are crucial in ensuring that patients are managed appropriately in the clinical context of their primary diagnosis, as the underlying pathological condition may be clinically important in a significant minority of such cases. This review describes the various patterns of 18FFDG uptake within the thyroid and discusses the clinical significance and possible impact on patient management. Incidental low-grade homogeneous diffuse increased thyroid 18F-FDG uptake is usually seen in the patients with chronic thyroiditis, Grave’s disease, and hypothyroidism. Thyroid function tests and antibody profiling are advised in these patients. Incidental focal 18F-FDG thyroid uptake should raise the possibility of underlying malignancy. Ultrasound with or without fine-needle aspiration cytology is usually recommended for the evaluation of these lesions. Heterogeneous uptake with prominent focal uptake in the thyroid should be further evaluated to exclude malignancy. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction The prevalence of thyroid nodules in the general population is reported to be between 8% and 65%.1 2-[18F]-fluoro2-deoxy-D-glucose (18F-FDG) is a glucose analogue. The mechanism of 18F-FDG positron-emission tomography/ computed tomography (PET/CT) in the detection of tumours * Guarantor and correspondent: K. Agrawal, Department of Nuclear Medicine, Guy’s Hospital, Great Maze Pond, London SE19RT, UK. Tel.: þ44 020 71884106. E-mail address: [email protected] (K. Agrawal).
is based on the higher glycolytic metabolism of malignant tissue and the higher expression of membrane glucose transporter (GLUT) proteins.2 Due to the combined metabolic and anatomical information from PET/CT, it is currently widely used for cancer staging, restaging, detection of recurrent disease, and optimization of therapy in wide variety of malignancies. However, due to the nonspecific nature of 18F-FDG uptake, many benign pathological entities also show abnormal tracer uptake.3 In a study, approximately 12% of cancer patients undergoing 18F-FDG PET/CT had unexpected abnormal 18F-FDG uptake concerning for a second malignancy, of which 47% were due to
http://dx.doi.org/10.1016/j.crad.2014.12.020 0009-9260/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
K. Agrawal et al. / Clinical Radiology 70 (2015) 536e543
benign disease.4 Various patterns of incidental uptake within the thyroid on routine 18F-FDG PET/CT have been observed.5 Although in most of these patients underlying benign thyroid disease is identified, clinically significant pathological conditions have also been discovered in a small but significant number. Therefore, it is important for clinicians to understand the significance of the incidental uptake in these patients, to direct appropriate management whilst avoiding unnecessary investigations. This review describes the various patterns of 18F-FDG uptake observed within the thyroid gland and discusses their clinical significance and possible impact on patient management.
Normal variant The thyroid gland can be seen faintly on 18F-FDG PET/CT studies in patients without thyroid disease.6,7 The mechanism of tracer uptake in the normal thyroid, although not clear, most likely reflects low-grade glycolytic metabolism within thyroid epithelial cells (Fig 1).
Homogeneous diffuse thyroid uptake This probably is the most common variant of incidental uptake within the thyroid seen in clinical practice and has been reported in approximately 0.1e4.5% (mean 1.9%) of 18 F-FDG PET studies.8 A homogeneous diffuse pattern of thyroid uptake at 18F-FDG PET could be due to normal variation, chronic thyroiditis, hypothyroidism on hormonal replacement, and Graves’ disease.
537
Chronic thyroiditis and hypothyroidism The majority of studies in the literature support that chronic thyroiditis and hypothyroidism are frequent causes of diffuse thyroid uptake at 18F-FDG PET (Fig 2).9e11 Karantanis et al.9 demonstrated that 63 of 133 patients (47.4%) with diffuse thyroid uptake on 18F-FDG PET had a clinical diagnosis of hypothyroidism or autoimmune thyroiditis.9 They also noted that there is no significant correlation between maximum standardized uptake value (SUVmax) and thyroidstimulating hormone (TSH) or thyroid peroxidase (TPO) antibody levels in the serum. They recommended that even low-grade uptake in the thyroid should not be ignored as this may be associated with overt or subclinical hypothyroidism. The mechanism of uptake in the thyroid in these patients is not clear. One explanation could be the uptake of 18F-FDG within an activated lymphocyte infiltrate within the thyroid gland.
Graves’ disease It has been reported that increased 18F-FDG uptake in the thyroid in patients with Graves’ disease may be due to combination of increased blood flow and enhanced glucose utilization.12 Literature evaluation suggests approximately 30% of patients with Graves’ disease show increased 18F-FDG uptake in the thyroid.13 It has been observed that the intensity of 18FFDG uptake in the thyroid increases with increasing antithyroid antibodies. This was also seen to be associated with a shorter radioiodine half-life in Graves’ disease, which may have implications on radio-iodine therapy in these patients. Diffuse increased 18F-FDG uptake within the thyroid and
Figure 1 18F-FDG PET/CT study: axial CT (a), axial PET (b), axial fused PET/CT (c), coronal CT (d), coronal PET (e) and coronal fused PET/CT (f) images at the level of the thyroid showing normal uptake in the thyroid (arrow), which is very low grade and uniform.
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Figure 2 A 39-year-old woman with non-Hodgkin’s lymphoma was referred for 18F-FDG PET/CT for staging. Intense uptake of tracer was noted in the right axillary lymph nodes with low-grade uptake in mediastinal nodes. In addition, (a) maximum intensity projection, (b) coronal PET, (c) axial PET, (d) coronal CT, (e) axial CT, (f) coronal fused PET/CT, and (g) axial fused PET/CT images showed diffuse homogeneous uptake of tracer in the thyroid gland (arrow), which on thyroid function tests and antibody profiling confirmed Hashimoto’s thyroiditis.
symmetrically increased uptake in the skeletal muscles and thymus has been described as a clue for the diagnosis of underlying Graves’ disease.11
Follow-up In general, incidental low-grade homogeneous diffuse increased thyroid 18F-FDG uptake rarely indicates thyroid cancer and is usually seen in patients with chronic thyroiditis, Grave’s disease, and hypothyroidism. Thyroid function tests and antibody profiling should be advised in these patients. There are no current data warranting further imaging with ultrasound or fine-needle aspiration cytology (FNAC) in these patients.
Heterogeneous diffuse uptake in the thyroid Although theoretically heterogeneous uptake can be seen in the multinodular goitre, Kurata et al.14 showed that
some heterogeneous diffuse uptake or focal on diffuse uptake was related to papillary carcinoma associated with Hashimoto’s thyroiditis (Fig 3). Lymphomatous involvement of the thyroid could give similar appearances (Fig 4).15 The present authors have observed a similar pattern in a patient with primary lung cancer with secondary thyroid metastases (Fig 5).
Focal uptake The prevalence of focal uptake within the thyroid varies from 0.1% to 4.8% (mean 2%). This could represent benign disease (Fig 6), although underlying malignancy has been increasingly associated with this pattern of uptake with a reported risk of malignancy being 34.8%.8 Primary thyroid cancer (Figs 7e8) or secondary metastatic deposits from other primary sites have been identified in this group of patients.
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Figure 3 A 54 year-old woman with diffuse large B-cell lymphoma was referred for 18F-FDG PET/CT to evaluate treatment response. (a) Axial PET, (b) axial CT, (c) axial fused PET/CT; (d) coronal PET, (e) coronal CT, (f) coronal fused PET/CT, (g) sagittal PET, (h) sagittal CT, and (i) sagittal fused PET/CT images showed heterogeneous increased tracer uptake within the thyroid gland with a focal area of intense uptake in the right thyroid lobe upper pole (SUVmax 29.4). FNAC of the right thyroid upper pole nodule was suspicious for PTC, and the patient underwent thyroidectomy, which confirmed a PTC on a background of Hashimoto’s thyroiditis.
Primary thyroid cancer
Metastases
Classical papillary thyroid cancer (PTC) and follicular variant of PTC are the most prevalent primary thyroid cancer type in these patients.8
Despite the rich thyroid vasculature, it is rarely the site of metastatic disease.16 Metastasis to the thyroid is clinically established in only <1%, while a range of 3.9% to 24.2% has
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Figure 4 A 43-year-old man post-allogeneic stem cell transplant for diffuse large B-cell lymphoma, presented with a right testicular swelling. 18 F-FDG PET/CT was performed, which demonstrated uptake in the lungs, liver, testicular masses, lower leg, and lymph nodes both above and below the diaphragm. In addition, (a) coronal PET, (b) coronal CT, (c) coronal fused PET/CT; (d) axial PET, (e) axial CT, and (f) axial fused PET/CT images showed multifocal increased tracer uptake in the thyroid gland with an SUVmax 26.8 (arrow), which was presumed as lymphomatous involvement. A repeat 18F-FDG PET study [(g) maximum intensity projection image] following chemotherapy showed a mixed response to treatment with resolution of thyroid uptake (arrow) confirming the lymphomatous involvement of the thyroid.
been described in autopsy studies.17 The most frequent primary tumours with metastatic involvement of the thyroid are renal cell, breast, lung, gastric, oesophageal carcinomas, and melanoma.18 A thyroid metastasis from colorectal carcinoma is extremely rare and is usually
associated with lung and liver metastases.19 The reported time interval between the diagnosis of the primary tumour and detection of thyroid metastasis varies from 1 month to 26 years.20,21 Metastatic disease in the thyroid is usually asymptomatic or may present with scant symptoms. In rare
Figure 5 A 65-year-old woman with adenocarcinoma of the right lung underwent 18F-FDG PET/CT 3 years after right pneumonectomy for restaging. (a) Axial CT, (b) axial PET, and (c) axial fused PET/CT images at the level of the thyroid showed intense heterogeneous uptake of tracer within both lobes of the thyroid with an SUVmax of 10.7 (arrow) in addition to liver, cervical, and mediastinal lymph node disease. Ultrasound of the neck was highly suspicious for malignant involvement of the thyroid. FNAC from the thyroid showed metastatic pulmonary non-small cell carcinoma.
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Figure 6 A 35-year-old female patient with high-grade non-Hodgkin’s lymphoma was referred for 18F-FDG PET/CT to stage the disease. There was uptake of tracer in the right breast mass and right axillary lymph nodes consistent with lymphomatous involvement. In addition, (a) axial PET, (b) axial CT, (c) axial fused PET/CT, (d) coronal PET, (e) coronal CT, (f) coronal fused PET/CT, (g) sagittal PET, (h) sagittal CT, and (i) sagittal fused PET/CT images showed intense focal uptake in a hypodense lesion in the left lobe of the thyroid with SUVmax 8.4 (arrow). Ultrasoundguided FNAC of the left thyroid lesion revealed a follicular lesion favouring a hyperplastic/adenomatoid nodule but could not exclude a follicular carcinoma. A left thyroid lobectomy was undertaken, which confirmed follicular adenoma of the thyroid.
instances of rapidly growing tumour, the patient may complain of hoarseness, dysphagia, or respiratory problems.22 Thyroid function tests are usually normal and are less helpful in the diagnosis.18 Ultrasonography of the thyroid may demonstrate focal or diffusely infiltrating hypoechoic lesions and CT may show heterogeneous hypodense lesions with mild contrast enhancement.23
Utility of low-dose CT in characterizing focal uptake Choi et al.24 showed that focally increased uptake in the thyroid without a corresponding discernible focal anatomical lesion at CT indicated a benign lesion with 100% certainty.24 Conversely, some authors disagree and argue that low-dose unenhanced CT conventionally used in PET/CT
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Figure 7 A 71-year-old man was referred for restaging 18F-FDG PET/CT after diagnosis of melanoma of the right cheek. (a) Maximum intensity projection, (b) axial CT, (c) axial PET, (d) axial fused PET/CT; (e) coronal CT, (f) coronal PET, and (g) coronal fused PET/CT images showed abnormally increased 18F-FDG uptake in a hypodense nodule within the right lobe of the thyroid (arrow). Please refer to Fig 8.
Figure 8 Thyroid ultrasound of the patient mentioned in Fig 7 demonstrated a markedly hypoechoic lesion with irregular margins [arrow in (a)] in the right thyroid lobe, which was hard on elastography (b). These features were strongly suspicious for underlying malignancy. FNAC from this lesion confirmed a PTC.
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imaging has a low sensitivity in characterizing thyroid nodules.25,26
SUVmax value in characterizing focal uptake There is difference of opinion in literature on role of SUVmax in differentiating benign and malignant lesions with several studies showing statistically significant differences,16,27 whereas others show no significant difference.11,28 Although there is a significant overlap of SUVmax between benign and malignant lesions, the SUVmax of malignant thyroid lesions has been reported to be significantly higher than that of benign lesions.27,29 In the authors’ experience, a SUVmax cut-off value of 9.1 had 81.6% sensitivity and 100% specificity in differentiating benign from malignant lesions within thyroid nodules demonstrating incidental focal FDG uptake.30
Ultrasound and FNAC As the risk of malignancy of focal 18F-FDG uptake in the thyroid is high, such lesions require prompt evaluation.31 Ultrasound with or without FNAC are usually considered as the reference standard for evaluating whether lesions are benign or malignant.26 Incidental thyroid uptake should always be mentioned in the report for the attention of the referring clinician. The need for further invasive evaluation of such focal thyroid uptake should be taken in the clinical context of the patient’s primary condition and may not, of course, be appropriate in all cases.
Conclusion Incidental tracer uptake within the thyroid at routine F-FDG PET/CT presents a management issue for clinicians. Although benign thyroid disease remains the likely cause in the majority of these patients, malignancy remains a possibility in a small but significant number of patients. Recognition of the pattern of uptake can aid the clinician in guiding the appropriate management of these patients.
18
References 1. Dean DS, Gharib H. Epidemiology of thyroid nodules. Best Pract Res Clin Endocrinol Metab 2008;22:901e11. 2. Wahl RL. Targeting glucose transporters for tumor imaging: ‘‘sweet’’ idea, ‘‘sour’’ result. J Nucl Med 1996;37:1038e41. 3. Culverwell AD, Scarsbrook AF, Chowdhury FU. False-positive uptake on 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography/ computed tomography (PET/CT) in oncological imaging. Clin Radiol 2011;66:366e82. 4. Beatty JS, Williams HT, Aldridge BA, et al. Incidental PET/CT findings in the cancer patient: how should they be managed? Surgery 2009;146:274e81. 5. Liu Yiyan. Clinical significance of thyroid uptake on F18fluorodeoxyglucose positron emission tomography. Ann Nucl Med 2009;23:17e23. 6. McDougall IR, Davidson J, Segall GM. Positron emission tomography of the thyroid, with an emphasis on thyroid cancer. Nucl Med Commun 2001;22:485e92. 7. Chen YK, Chen YL, Cheng RH, et al. The significance of FDG uptake in bilateral thyroid glands. Nucl Med Commun 2007;28:117e22.
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8. Soelberg KK, Bonnema SJ, Brix TH, et al. Risk of malignancy in thyroid incidentalomas detected by 18F-fluorodeoxyglucose positron emission tomography: a systematic review. Thyroid 2012;22:918e25. 9. Karantanis D, Bogsrud TV, Miseman GA, et al. Clinical significance of diffusely increased F18-FDG uptake in the thyroid gland. J Nucl Med 2007;48:896e901. 10. Yasuda S, Shohtsu A, Ide M, et al. Chronic thyroiditis: diffuse uptake of FDG at PET. Radiology 1998;207:775e8. 11. Kim TY, Kim WB, Ryu JS, et al. F18-FDG uptake in thyroid from PET for evaluation in cancer patients: high prevalence of malignancy in thyroid PET incidentaloma. Laryngoscope 2005;115:1074e8. 12. Boerner AR, Voth E, Theissen P, et al. Glucose metabolism of the thyroid in Graves’ disease measured by F-18-fluoro-deoxyglucose positron emission tomography. Thyroid 1998;8:765e72. 13. Chen YK, Chen YL, Liao AC, et al. Elevated 18F-FDG uptake in skeletal muscles and thymus: a clue for the diagnosis of Graves’ disease. Nucl Med Commun 2004;25:115e21. 14. Kurata S, Ishibashi M, Hirromatsu Y, et al. Diffuse and diffuse-plus-focal uptake in the thyroid gland identified by using FDG-PET: prevalence of thyroid cancer and Hashimoto’s thyroiditis. Ann Nucl Med 2007;21:325e30. 15. Chander S, Zingas AP, Bloom DA, et al. Positron emission tomography in primary thyroid lymphoma. Clin Nucl Med 2004;29:572e3. 16. Elliott Jr RHE, Frantz VK. Metastatic carcinoma masquerading as primary thyroid cancer: a report of authors’ 14 cases. Ann Surg 1960;151:551e61. 17. Lin JD, Weng HF, Ho YS. Clinical and pathological characteristics of secondary thyroid cancer. Thyroid 1998;8:149e53. 18. Katsenos S, Archondakis S, Vaias M, et al. Thyroid gland metastasis from small cell lung cancer: an unusual site of metastatic spread. J Thorac Dis 2013;5:E21e4. 19. Wychulis AR, Beahrs OH, Woolner LB. Metastasis of carcinoma to the thyroid gland. Ann Surg 1964;160:169e77. 20. Menegaux F, Chigot JP. Secondary malignant tumors of the thyroid gland. Ann Chirurg 2001;10:981e4. 21. Chen H, Nicol TL, Udelsman R. Clinically significant, isolated metastatic disease to the thyroid gland. World J Surg 1999;23:177e81. S, Anielski R, Konturek A, et al. Metastases to the thyroid gland: 22. Cichon seventeen cases operated on in a single clinical center. Langenbecks Arch Surg 2006;391:581e7. 23. Ferrozz F, Campodonico F, De Chiara F, et al. Thyroid metastases: the echographic and computed tomographic aspects. Radiol Med 1997;94:214e9. 24. Choi JY, Lee KS, Kim HJ, et al. Focal thyroid lesions incidentally identified by integrated 18F-FDG PET/CT: clinical significance and improved characterization. J Nucl Med 2006;47:609e15. 25. Yi JG, Marom EM, Munden RF, et al. Focal uptake of FDG by the thyroid in patients undergoing initial disease staging with combined PET/CT for non-small cell lung cancer. Radiology 2005;236:271e5. 26. Bogsrud T, Karantanis D, Nathan MA, et al. The value of quantifying F18FDG uptake in thyroid nodules found incidentally on whole-body PETCT. Nucl Med Commun 2007;28:373e81. 27. Cohen MS, Arslan N, Dehdashti F, et al. Risk of malignancy in thyroid incidentalomas identified by fluorodeoxyglucose-positron emission tomography. Surgery 2001;130:941e6. 28. Are C, Hsu JF, Schoder H, et al. FDG-PET detected thyroid incidentalomas: need for further investigation? Ann Surg Oncol 2007;14:239e47. 29. Kang KW, Kim SK, Kang HS, et al. Prevalence and risk of cancer of focal thyroid incidentaloma identified by 18F-fluorodeoxyglucose positron emission tomography for metastasis evaluation and cancer screening in healthy subjects. J Clin Endocrinol Metab 2003;88:4100e4. 30. Agrawal K, Weaver J, Ul-hassan F, et al. Incidental focal thyroid uptake on 18F-FDG PET study d large retrospective single centre experience in the United Kingdom. In: 27th Annual Congress of the European Association of Nuclear Medicine, 18e22 October, Gothenburg, Sweden; 2014. Abstract no. OP 693. 31. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167e214.
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Pictorial Review
Clinical significance of patterns of incidental thyroid uptake at 18F-FDG PET/CT K. Agrawal a, *, J. Weaver b, R. Ngu c, H. Krishnamurthy Mohan a, d a
Dept of Nuclear Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London, UK School of medicine, King’s College London, London, UK c Department of Dental Maxillofacial Radiology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK d Clinical PET Centre, St Thomas’ Hospital, London, UK b
article in formation Article history: Received 4 August 2014 Received in revised form 22 December 2014 Accepted 29 December 2014
Incidental uptake of 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) in the thyroid gland is not uncommonly encountered in day-to-day practice of oncological 18F-FDG positron-emission tomography/computed tomography (PET/CT). These are often felt to be “nuisance lesions” by referring clinicians and radiologists alike. However, recognition of the importance of different patterns of FDG uptake in the thyroid gland and knowledge of the possible underlying aetiologies are crucial in ensuring that patients are managed appropriately in the clinical context of their primary diagnosis, as the underlying pathological condition may be clinically important in a significant minority of such cases. This review describes the various patterns of 18FFDG uptake within the thyroid and discusses the clinical significance and possible impact on patient management. Incidental low-grade homogeneous diffuse increased thyroid 18F-FDG uptake is usually seen in the patients with chronic thyroiditis, Grave’s disease, and hypothyroidism. Thyroid function tests and antibody profiling are advised in these patients. Incidental focal 18F-FDG thyroid uptake should raise the possibility of underlying malignancy. Ultrasound with or without fine-needle aspiration cytology is usually recommended for the evaluation of these lesions. Heterogeneous uptake with prominent focal uptake in the thyroid should be further evaluated to exclude malignancy. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction The prevalence of thyroid nodules in the general population is reported to be between 8% and 65%.1 2-[18F]-fluoro2-deoxy-D-glucose (18F-FDG) is a glucose analogue. The mechanism of 18F-FDG positron-emission tomography/ computed tomography (PET/CT) in the detection of tumours * Guarantor and correspondent: K. Agrawal, Department of Nuclear Medicine, Guy’s Hospital, Great Maze Pond, London SE19RT, UK. Tel.: þ44 020 71884106. E-mail address: [email protected] (K. Agrawal).
is based on the higher glycolytic metabolism of malignant tissue and the higher expression of membrane glucose transporter (GLUT) proteins.2 Due to the combined metabolic and anatomical information from PET/CT, it is currently widely used for cancer staging, restaging, detection of recurrent disease, and optimization of therapy in wide variety of malignancies. However, due to the nonspecific nature of 18F-FDG uptake, many benign pathological entities also show abnormal tracer uptake.3 In a study, approximately 12% of cancer patients undergoing 18F-FDG PET/CT had unexpected abnormal 18F-FDG uptake concerning for a second malignancy, of which 47% were due to
http://dx.doi.org/10.1016/j.crad.2014.12.020 0009-9260/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
K. Agrawal et al. / Clinical Radiology 70 (2015) 536e543
benign disease.4 Various patterns of incidental uptake within the thyroid on routine 18F-FDG PET/CT have been observed.5 Although in most of these patients underlying benign thyroid disease is identified, clinically significant pathological conditions have also been discovered in a small but significant number. Therefore, it is important for clinicians to understand the significance of the incidental uptake in these patients, to direct appropriate management whilst avoiding unnecessary investigations. This review describes the various patterns of 18F-FDG uptake observed within the thyroid gland and discusses their clinical significance and possible impact on patient management.
Normal variant The thyroid gland can be seen faintly on 18F-FDG PET/CT studies in patients without thyroid disease.6,7 The mechanism of tracer uptake in the normal thyroid, although not clear, most likely reflects low-grade glycolytic metabolism within thyroid epithelial cells (Fig 1).
Homogeneous diffuse thyroid uptake This probably is the most common variant of incidental uptake within the thyroid seen in clinical practice and has been reported in approximately 0.1e4.5% (mean 1.9%) of 18 F-FDG PET studies.8 A homogeneous diffuse pattern of thyroid uptake at 18F-FDG PET could be due to normal variation, chronic thyroiditis, hypothyroidism on hormonal replacement, and Graves’ disease.
537
Chronic thyroiditis and hypothyroidism The majority of studies in the literature support that chronic thyroiditis and hypothyroidism are frequent causes of diffuse thyroid uptake at 18F-FDG PET (Fig 2).9e11 Karantanis et al.9 demonstrated that 63 of 133 patients (47.4%) with diffuse thyroid uptake on 18F-FDG PET had a clinical diagnosis of hypothyroidism or autoimmune thyroiditis.9 They also noted that there is no significant correlation between maximum standardized uptake value (SUVmax) and thyroidstimulating hormone (TSH) or thyroid peroxidase (TPO) antibody levels in the serum. They recommended that even low-grade uptake in the thyroid should not be ignored as this may be associated with overt or subclinical hypothyroidism. The mechanism of uptake in the thyroid in these patients is not clear. One explanation could be the uptake of 18F-FDG within an activated lymphocyte infiltrate within the thyroid gland.
Graves’ disease It has been reported that increased 18F-FDG uptake in the thyroid in patients with Graves’ disease may be due to combination of increased blood flow and enhanced glucose utilization.12 Literature evaluation suggests approximately 30% of patients with Graves’ disease show increased 18F-FDG uptake in the thyroid.13 It has been observed that the intensity of 18FFDG uptake in the thyroid increases with increasing antithyroid antibodies. This was also seen to be associated with a shorter radioiodine half-life in Graves’ disease, which may have implications on radio-iodine therapy in these patients. Diffuse increased 18F-FDG uptake within the thyroid and
Figure 1 18F-FDG PET/CT study: axial CT (a), axial PET (b), axial fused PET/CT (c), coronal CT (d), coronal PET (e) and coronal fused PET/CT (f) images at the level of the thyroid showing normal uptake in the thyroid (arrow), which is very low grade and uniform.
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Figure 2 A 39-year-old woman with non-Hodgkin’s lymphoma was referred for 18F-FDG PET/CT for staging. Intense uptake of tracer was noted in the right axillary lymph nodes with low-grade uptake in mediastinal nodes. In addition, (a) maximum intensity projection, (b) coronal PET, (c) axial PET, (d) coronal CT, (e) axial CT, (f) coronal fused PET/CT, and (g) axial fused PET/CT images showed diffuse homogeneous uptake of tracer in the thyroid gland (arrow), which on thyroid function tests and antibody profiling confirmed Hashimoto’s thyroiditis.
symmetrically increased uptake in the skeletal muscles and thymus has been described as a clue for the diagnosis of underlying Graves’ disease.11
Follow-up In general, incidental low-grade homogeneous diffuse increased thyroid 18F-FDG uptake rarely indicates thyroid cancer and is usually seen in patients with chronic thyroiditis, Grave’s disease, and hypothyroidism. Thyroid function tests and antibody profiling should be advised in these patients. There are no current data warranting further imaging with ultrasound or fine-needle aspiration cytology (FNAC) in these patients.
Heterogeneous diffuse uptake in the thyroid Although theoretically heterogeneous uptake can be seen in the multinodular goitre, Kurata et al.14 showed that
some heterogeneous diffuse uptake or focal on diffuse uptake was related to papillary carcinoma associated with Hashimoto’s thyroiditis (Fig 3). Lymphomatous involvement of the thyroid could give similar appearances (Fig 4).15 The present authors have observed a similar pattern in a patient with primary lung cancer with secondary thyroid metastases (Fig 5).
Focal uptake The prevalence of focal uptake within the thyroid varies from 0.1% to 4.8% (mean 2%). This could represent benign disease (Fig 6), although underlying malignancy has been increasingly associated with this pattern of uptake with a reported risk of malignancy being 34.8%.8 Primary thyroid cancer (Figs 7e8) or secondary metastatic deposits from other primary sites have been identified in this group of patients.
K. Agrawal et al. / Clinical Radiology 70 (2015) 536e543
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Figure 3 A 54 year-old woman with diffuse large B-cell lymphoma was referred for 18F-FDG PET/CT to evaluate treatment response. (a) Axial PET, (b) axial CT, (c) axial fused PET/CT; (d) coronal PET, (e) coronal CT, (f) coronal fused PET/CT, (g) sagittal PET, (h) sagittal CT, and (i) sagittal fused PET/CT images showed heterogeneous increased tracer uptake within the thyroid gland with a focal area of intense uptake in the right thyroid lobe upper pole (SUVmax 29.4). FNAC of the right thyroid upper pole nodule was suspicious for PTC, and the patient underwent thyroidectomy, which confirmed a PTC on a background of Hashimoto’s thyroiditis.
Primary thyroid cancer
Metastases
Classical papillary thyroid cancer (PTC) and follicular variant of PTC are the most prevalent primary thyroid cancer type in these patients.8
Despite the rich thyroid vasculature, it is rarely the site of metastatic disease.16 Metastasis to the thyroid is clinically established in only <1%, while a range of 3.9% to 24.2% has
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K. Agrawal et al. / Clinical Radiology 70 (2015) 536e543
Figure 4 A 43-year-old man post-allogeneic stem cell transplant for diffuse large B-cell lymphoma, presented with a right testicular swelling. 18 F-FDG PET/CT was performed, which demonstrated uptake in the lungs, liver, testicular masses, lower leg, and lymph nodes both above and below the diaphragm. In addition, (a) coronal PET, (b) coronal CT, (c) coronal fused PET/CT; (d) axial PET, (e) axial CT, and (f) axial fused PET/CT images showed multifocal increased tracer uptake in the thyroid gland with an SUVmax 26.8 (arrow), which was presumed as lymphomatous involvement. A repeat 18F-FDG PET study [(g) maximum intensity projection image] following chemotherapy showed a mixed response to treatment with resolution of thyroid uptake (arrow) confirming the lymphomatous involvement of the thyroid.
been described in autopsy studies.17 The most frequent primary tumours with metastatic involvement of the thyroid are renal cell, breast, lung, gastric, oesophageal carcinomas, and melanoma.18 A thyroid metastasis from colorectal carcinoma is extremely rare and is usually
associated with lung and liver metastases.19 The reported time interval between the diagnosis of the primary tumour and detection of thyroid metastasis varies from 1 month to 26 years.20,21 Metastatic disease in the thyroid is usually asymptomatic or may present with scant symptoms. In rare
Figure 5 A 65-year-old woman with adenocarcinoma of the right lung underwent 18F-FDG PET/CT 3 years after right pneumonectomy for restaging. (a) Axial CT, (b) axial PET, and (c) axial fused PET/CT images at the level of the thyroid showed intense heterogeneous uptake of tracer within both lobes of the thyroid with an SUVmax of 10.7 (arrow) in addition to liver, cervical, and mediastinal lymph node disease. Ultrasound of the neck was highly suspicious for malignant involvement of the thyroid. FNAC from the thyroid showed metastatic pulmonary non-small cell carcinoma.
K. Agrawal et al. / Clinical Radiology 70 (2015) 536e543
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Figure 6 A 35-year-old female patient with high-grade non-Hodgkin’s lymphoma was referred for 18F-FDG PET/CT to stage the disease. There was uptake of tracer in the right breast mass and right axillary lymph nodes consistent with lymphomatous involvement. In addition, (a) axial PET, (b) axial CT, (c) axial fused PET/CT, (d) coronal PET, (e) coronal CT, (f) coronal fused PET/CT, (g) sagittal PET, (h) sagittal CT, and (i) sagittal fused PET/CT images showed intense focal uptake in a hypodense lesion in the left lobe of the thyroid with SUVmax 8.4 (arrow). Ultrasoundguided FNAC of the left thyroid lesion revealed a follicular lesion favouring a hyperplastic/adenomatoid nodule but could not exclude a follicular carcinoma. A left thyroid lobectomy was undertaken, which confirmed follicular adenoma of the thyroid.
instances of rapidly growing tumour, the patient may complain of hoarseness, dysphagia, or respiratory problems.22 Thyroid function tests are usually normal and are less helpful in the diagnosis.18 Ultrasonography of the thyroid may demonstrate focal or diffusely infiltrating hypoechoic lesions and CT may show heterogeneous hypodense lesions with mild contrast enhancement.23
Utility of low-dose CT in characterizing focal uptake Choi et al.24 showed that focally increased uptake in the thyroid without a corresponding discernible focal anatomical lesion at CT indicated a benign lesion with 100% certainty.24 Conversely, some authors disagree and argue that low-dose unenhanced CT conventionally used in PET/CT
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Figure 7 A 71-year-old man was referred for restaging 18F-FDG PET/CT after diagnosis of melanoma of the right cheek. (a) Maximum intensity projection, (b) axial CT, (c) axial PET, (d) axial fused PET/CT; (e) coronal CT, (f) coronal PET, and (g) coronal fused PET/CT images showed abnormally increased 18F-FDG uptake in a hypodense nodule within the right lobe of the thyroid (arrow). Please refer to Fig 8.
Figure 8 Thyroid ultrasound of the patient mentioned in Fig 7 demonstrated a markedly hypoechoic lesion with irregular margins [arrow in (a)] in the right thyroid lobe, which was hard on elastography (b). These features were strongly suspicious for underlying malignancy. FNAC from this lesion confirmed a PTC.
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imaging has a low sensitivity in characterizing thyroid nodules.25,26
SUVmax value in characterizing focal uptake There is difference of opinion in literature on role of SUVmax in differentiating benign and malignant lesions with several studies showing statistically significant differences,16,27 whereas others show no significant difference.11,28 Although there is a significant overlap of SUVmax between benign and malignant lesions, the SUVmax of malignant thyroid lesions has been reported to be significantly higher than that of benign lesions.27,29 In the authors’ experience, a SUVmax cut-off value of 9.1 had 81.6% sensitivity and 100% specificity in differentiating benign from malignant lesions within thyroid nodules demonstrating incidental focal FDG uptake.30
Ultrasound and FNAC As the risk of malignancy of focal 18F-FDG uptake in the thyroid is high, such lesions require prompt evaluation.31 Ultrasound with or without FNAC are usually considered as the reference standard for evaluating whether lesions are benign or malignant.26 Incidental thyroid uptake should always be mentioned in the report for the attention of the referring clinician. The need for further invasive evaluation of such focal thyroid uptake should be taken in the clinical context of the patient’s primary condition and may not, of course, be appropriate in all cases.
Conclusion Incidental tracer uptake within the thyroid at routine F-FDG PET/CT presents a management issue for clinicians. Although benign thyroid disease remains the likely cause in the majority of these patients, malignancy remains a possibility in a small but significant number of patients. Recognition of the pattern of uptake can aid the clinician in guiding the appropriate management of these patients.
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