|Year : 2017 | Volume
| Issue : 2 | Page : 51-56
Role of fluorodeoxyglucose positron emission tomography-Computed tomography in thyroid malignancy
Ajay Manickam, Tsewang Yougyal Bhutia, Kapila Manikantan, Pattatheyil Arun
Department of Head and Neck Surgical Oncology, Tata Medical Center, Kolkata, West Bengal, India
|Date of Web Publication||22-Jan-2018|
Dr. Pattatheyil Arun
Department of Head and Neck Surgical Oncology, Tata Medical Center, 14 Main Arterial Road (EW), Kolkata - 700 156, West Bengal
Source of Support: None, Conflict of Interest: None
The role of FDG PET CT in thyroid malignancy is not clearly established. Malignancy of the thyroid remains poses issues very different from the squamous carcinomas of the upper aerodigestive tract where PET-CT is usually used. Though this is the most common endocrine malignancy, many a times it is difficult to diagnose malignancy in thyroid nodules. The biology of well differentiated thyroid cancer, medullary carcinoma, poorly differentiated carcinoma and anaplastic carcinoma varies significantly and management strategies differ dramatically. FDG PET can be used as a wonderful tool in thyroid malignancy for selected indications.
Keywords: PET CT, Differentiated thyroid cancer, Thyroid malignancy
|How to cite this article:|
Manickam A, Bhutia TY, Manikantan K, Arun P. Role of fluorodeoxyglucose positron emission tomography-Computed tomography in thyroid malignancy. J Head Neck Physicians Surg 2017;5:51-6
|How to cite this URL:|
Manickam A, Bhutia TY, Manikantan K, Arun P. Role of fluorodeoxyglucose positron emission tomography-Computed tomography in thyroid malignancy. J Head Neck Physicians Surg [serial online] 2017 [cited 2021 May 12];5:51-6. Available from: https://www.jhnps.org/text.asp?2017/5/2/51/223760
| Introduction|| |
The application of fluorodeoxyglucose positron emission tomography–computed tomography (FDG PET/CT) in the management of head and neck cancer is on the rise with well-designed trials expanding the utility of this modality of imaging in situ ations such as initial workup, detection of unknown primary, assessment of disease in salvage situations, and comprehensive evaluation for distant metastasis. However, the role of FDG PET/CT in thyroid malignancy is not clearly established. Malignancy of the thyroid remains poses issues very different from the squamous carcinomas of the upper aerodigestive tract where PET/CT is usually used. Although this is the most common endocrine malignancy, many a times it is difficult to diagnose malignancy in thyroid nodules. The biology of well-differentiated thyroid cancer, medullary carcinoma, poorly differentiated carcinoma, and anaplastic carcinoma varies significantly, and management strategies differ dramatically. Rarely, the thyroid gland can also be a station for the direct spread of cancers from the adjacent region such as the larynx, hypopharynx, and cervical esophagus and may harbour metastasis from cancers of another site such as kidney, lung, and breast have been reported. The various malignant neoplasms of the thyroid are listed in [Table 1].
There is increasing evidence in the literature on the utility of PET and integrated PET/CT using different radiopharmaceuticals in patients with thyroid cancer. The aim of this review article is to perform an overview of the role of FDG PET/CT in the management of thyroid cancers.
| Search Strategy and Data Abstraction Methods|| |
A comprehensive literature search was carried out with the help of the articles published in PubMed/Medline, database to find relevant published articles in the English language on the role of FDG-PET in thyroid cancer. We used a search algorithm based on a combination of the terms: (a) “FDG PET” or “positron emission tomography” and (b) “thyroid.” To expand our search, references of the retrieved articles were also screened for additional studies. All those studies or subsets in studies that satisfied all of the following criteria were included: (a) FDG-PET or PET/CT performed in patients with thyroid swelling and cancer. The exclusion criteria were (a) articles not within the field of interest of this paper; (b) case reports or small case series. Thirty-five articles were selected after preliminary review addressing the role of PET/CT in various thyroid malignancies.
| Positron Emission Tomography–computed Tomography in Differentiated Thyroid Cancer|| |
The increased use of FDG-PET for cancers of nonthyroid origin, such as lymphomas or squamous carcinomas has thrown up cases called “PET-incidentalomas” akin to thyroid nodules revealed on ultrasonography of the neck in otherwise asymptomatic individuals. Chen et al. reported thyroid incidentalomas with focal increased FDG uptake were found in 1.2%–4.3% of patients or healthy participants on PET examination in several studies. Kang et al. in a retrospective analysis of 22,674 FDG PET/CT scans showed focal uptake in 483 participants (2.1%). Among the 286 patients who underwent fine-needle aspiration biopsy (FNAB), 68 patients (24.3%) demonstrated papillary thyroid carcinoma on the final pathologic findings. Similarly, Cohen et al. has also shown that in patients with diffuse uptake, the probability of malignancy is low. Most such cases are caused by thyroiditis. Incidental focal FDG uptake in the thyroid harbors a 30%–50% risk of malignancy. Treglia et al. performed a meta-analysis of 34 studies evaluating incidental focal thyroid uptake detected by FDG PET/CT (n = 215,057) and found a pooled malignancy risk of 36.2% (95% confidence interval (CI): 33.8%–38.6%). Diffuse thyroid FDG uptake is most commonly benign and is usually caused by chronic lymphocytic thyroiditis, suggesting that diffuse uptake is more in favor of an inflammatory pathology and focal uptake needs exclusion of malignancy. The detection of focal uptake, thus, mandates an FNAB with cytology to ascertain its nature.
Positron emission tomography–computed tomography in nodules with indeterminate fine-needle aspiration biopsy
The BETHESDA  classification was evolved to provide a clinical correlation to cytology in assessing the risk of a thyroid nodule to harbor malignancy. While BETHESDA 2 and 5 provide conclusive evidence with respect to the nodule being benign or malignant, when classified into BETHESDA 3 or 4, the final confirmation can be arrived at only after pathologic examination of the nodule following thyroidectomy. Deandreis et al. conducted a prospective study with 56 patients who were planned for thyroid surgery with FNAB findings of thyroid nodules of indeterminate significance. The addition of FDG-PET findings to neck ultrasound did not provide any additional diagnostic benefit. The sensitivity and specificity of FDG-PET in the presurgical evaluation of indeterminate thyroid nodules are too low to recommend FDG-PET routinely. Giovanella et al. showed that a negative FDG PET/CT scan accurately excluded malignancy in thyroid nodules with nondiagnostic ultrasound (US)-FNC procedures, but histology was still necessary to distinguish benign from malignant disease in FDG PET/CT-positive nodules.
| Positron Emission Tomography–computed Tomography in Evaluation of Cervical Nodes|| |
Existing modalities of imaging the neck are quite sensitive and specific for routine evaluation of the neck for metastasis. For evaluation of the regional lymph nodes, high-resolution real-time US can detect nodal metastases as small as 0.5 cm, but ultrasound has limited use in assessing the central compartment due to the sternal shadow. CT produces high-resolution cross-sectional images of the neck and characteristics such as rim enhancement, shape, and presence of necrosis are particularly helpful for evaluating regional metastases. While the role of PET/CT in the assessment of regional and distant metastasis is very well established in squamous cell carcinoma of the head and neck region, its role in differentiated thyroid cancer is not well established. Jeong et al. in his study shows that at all lymph node levels (levels I-VI), PET/CT showed a sensitivity of 30.4%, a specificity of 96.2%, and a diagnostic accuracy of 86.9%. The corresponding values for US and contrast-enhanced CT (CECT) were 41.3%, 97.4%, 89.1% (US), and 34.8%, 96.2%, 87.2% (CECT). Considering only the lateral cervical node group (levels I–V), PET/CT showed a sensitivity of 50%, a specificity of 97% and a diagnostic accuracy of 92.3%. The corresponding values for US and CECT were 53.9%, 97.9%, 93.5% (US), and 42.3%, 96.6%, 91.2% (CECT). The diagnostic results for US, CECT, and PET/CT on the initial evaluation of the cervical lymph nodes did not differ significantly on a level-by-level basis. Suggesting that integrated FDG PET/CT does not provide any additional benefit when compared to US and CECT for the initial evaluation of cervical node levels in patients with papillary thyroid carcinoma.
Positron emission tomography–computed tomography as a prognostic tool
Differentiated carcinoma of the thyroid generally carries a good prognosis except in a select set of patients. Although survival rates are excellent, recurrences in the neck are a source of significant morbidity. It is recommended that patients be put on long-term follow-up to detect these recurrences early. Whole body iodine scan is one of the key investigations performed for the detection of recurrence and subsequent metastatic events. Most differentiated thyroid cancer presents as localized disease in the event of a recurrence and rates of distant metastasis in low, in the range of 4%–7%. Hence, PET/CT to rule out distant metastasis during follow-up is not recommended. An Iodine131 whole body scan is a potent tool used in the surveillance of differentiated thyroid carcinoma. However, many recurrent tumors de-differentiate and lose the ability to concentrate iodine resulting in a condition called TENIS(Thyroglobulin Elevated Negative Iodine Scan )where the radioioine scan is erroneously negative but the thyroglobulin levels are high or continue to rise, It has been observed that these de-differentiated tumors are comparitively more metabolicclay active and thus more glucose avid than their radio-iodine counterparts [Figure 1], Most authorities consider a thyroid-stimulating hormone-stimulated Tg level of 10 ng/ml or greater to merit action. Such action can include empirically determined therapy with 131I or imaging with PET or PET/CT to identify the source of Tg production.
|Figure 1: A 42-year-old female with papillary thyroid carcinoma who underwent fluorodeoxyglucose positron emission tomography–computed tomography study after thyroidectomy and radioiodine ablation. Radioiodine whole-body scans were negative. The patient was found to have persistently elevated thyroglobulin level. Her thyroglobulin level at the time of the study was 30.2 ng/mL. Anterior maximum intensity projections of head and neck axial fused positron emission tomography–computed/tomography images head and neck show recurrent thyroid papillary cancer with increased fluorodeoxyglucose activity consistent with recurrent disease in thyroid bed. Fine-needle aspiration cytology of lesions confirmed diagnosis|
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Wang et al. performed FDG-PET on 37 patients with differentiated thyroid cancer after surgery and radioiodine ablation who had negative diagnostic 131I whole-body scans during routine follow-up. Serum Tg, Tg autoantibodies, neck ultrasounds, and other clinically indicated imaging procedures were performed to detect residual disease. In those with elevated Tg levels, FDG-PET localized occult disease in 71%, was false positive in one, and was false negative in five patients. The majority of false-negative FDG-PET occurred in patients with minimal cervical adenopathy. Surgical resections, biopsies, 131 therapy, and differentiation therapy were performed based on the PET results. The FDG-PET result changed the clinical management in 19 of the 37 patients. In patients with elevated Tg levels, FDG-PET had a positive predictive value of 92%. In patients with low-Tg levels, FDG-PET had a negative predictive value of 93%. Several studies have found correlation between positivity on FDG PET/CT and the level of thyroglobulin in blood in cases of TENIS.
Shammas et al. in his study of 61 patients showed that the sensitivity of FDG PET/CT in detecting recurrent disease increased with a corresponding increase in thyroglobulin levels. Wheras it was 63% when thyroglobulin levels were <5 ng/ml, the sensitivity rose to 72%when thyroglobulin levels rose to >10ng/ml.
Dong et al. performed a meta-analysis of 25 studies comprising of 789 patients and concluded that FDG PET/CT has a high pooled sensitivity of 93% for detecting recurrence and metastasis in differentiated thyroid cancer in the absence of radioiodine uptake.
It is amply clear from these studies that PET-CT is emerging as the primary imaging modalilty for localisation of recurrent disease with TENIS, its diagnostic accuracy increasing with rise in thyroglobulin levels.
| Positron Emission Tomography–computed Tomography in Hurthle Cell Cancer|| |
Hurthle cell cancers are an aggressive histologic subtype of thyroid cancer that has a high propensity for distant metastasis and is associated with prognosis worse in comparison to the differentiated thyroid cancers. These tumors are FDG avid and unlike their differentiated counterparts, do not take up radioactive iodine. Riemann et al., in his multicenter study, has shown that PET/CT is the best tool for diagnosing Hurthle cell cancer in comparison to whole-body iodine scan and ultrasound imaging. He showed that the sensitivity and specificity of FDG-PET in diagnosing Hurthle cell cancer is 92% and 95%, respectively. Lowe et al. showed that sensitivity of FDG-PET in diagnosing Hurthle cell carcinoma was high at 92%. Studies by Plotkin et al. also reported FDG-PET to have a sensitivity of 92% in accurately diagnosing the lesions in case of Hurthle cell thyroid carcinoma. There is current evidence that the FDG-PET acts as a valuable tool in assessing the extent of the Hurthle cell cancer.
| Positron Emission Tomography–computed Tomography in Medullary Thyroid Cancer|| |
Medullary thyroid carcinoma (MTC) is a relatively uncommon tumor arises from the parafollicular C-cells of the thyroid. It accounts for 5%–10% of all thyroid malignancies. MTC may occur in sporadic (75%) or, rarely, familiar forms (25%), when it may be part of a multiple endocrine neoplasia syndrome. Surgery in the form of the total thyroidectomy and node dissection is the only effective treatment in the majority of MTC patients. Measurements of serum calcitonin and carcinoembryonic antigen (CEA) levels are highly sensitive methods in the early detection of MTC, but the localization of metastatic foci can be difficult. In MTC; FDG PET/CT is not routinely recommended in the primary staging of the disease, but it has been reported to be useful in the follow-up to evaluate high levels of calcitonin and CEA. Overall, the studies using FDG-PET or PET/CT have reported conflicting results about the diagnostic performance of these functional imaging methods in patients with suspected recurrent MTC.
In particular, sensitivity of these methods ranged from 17% to 93%., whereas specificity, when reported, ranged from 68% to 100%. A possible explanation for these heterogeneous findings could be related to diversity between the studies in technical aspects and inclusion criteria (patients with known lesions vs. patients with occult disease at conventional imaging methods; patients with slowly progressive disease vs. patients with more aggressive disease).
False-positive results also occurred using FDG-PET and PET/CT and were typically due to inflammatory lesions. Diehl et al. have reported a sensitivity of 78% and specificity of 79%. A recent meta-analysis of the published data by Treglia et al. reviewed 24 major studies. Despite the heterogeneity in the definition of true negative and false negatives, examination techniques and inclusion criteria in these studies, on a per patient pooled analysis, the authors calculated a detection rate of 59% (95% CI: 54%–63%) for 18F-FDG PET or PET/CT in patients with suspected recurrent medullary thyroid cancer. The detection rate of 18F-FDG PET/CT was higher in advanced disease (for serum calcitonin levels).
False-negative results of FDG-PET and PET/CT could be related to small lesions or to the slow growth of neuroendocrine tumors. Both factors impact the diagnostic accuracy of these imaging modalities. False-positive results also occurred using FDG-PET and PET/CT, and were typically due to inflammatory lesions. It should be noted that a significant number of recurrent MTC, based on rising levels of tumor markers, remained unidentified using FDG-PET or PET/CT. On the other hand, it should be considered that FDG-PET and PET/CT were often performed in patients with suspected recurrent MTC after negative conventional imaging studies, affecting the surgical management of patients with recurrent MTC when hypermetabolic lesions were detected.
Based on the literature findings, the diagnostic performance of FDG-PET or PET/CT in patients with recurrent MTC improved in patients with higher serum calcitonin and CEA levels. Furthermore, sensitivity of FDG-PET and PET/CT improved in patients with shorter tumor markers (calcitonin and CEA) doubling times, confirming the usefulness of these imaging methods in patients with more aggressive disease (with high glucose consumption and high-FDG uptake) compared to those with slowly progressive disease (with low glucose consumption and low-FDG uptake),
Detection rates were also found to be higher in patients with lower calcitonin and CEA doubling time (for calcitonin doubling time <12 months, detection rate: 76%, and for CEA doubling time <24 months, detection rate: 91%). This is reasonable, as the tumors with higher rate of proliferation are expected to have a higher metabolic rate and increased glucose consumption and thus higher detectability with FDG-PET/CT.
Fluorine-18-dihydroxyphenylalanine PET (FDOPA-PET) is also used as an important tool in the diagnosis of recurrent medullary carcinoma thyroid. Comparative analyses between FDOPA and FDG have shown better results with FDOPA in terms of sensitivity and specificity and a complementary role of the two radiopharmaceuticals in the assessment of recurrent MTC. Beheshti et al. found a superiority of FDOPA-PET/CT compared to FDG-PET/CT in 19 MTC patients evaluated after primary surgery (sensitivity on a per-patient-based analysis was 81% versus 58%, respectively. Marzola et al. evaluated 18 patients who underwent both PET/CT methods for suspected MTC recurrence. These authors found a higher sensitivity of FDOPA-PET/CT compared to FDG-PET/CT on a per-patient-based analysis (83% vs. 61%, respectively). FDOPA PET is also an important tool in the diagnosis of recurrent medullary carcinoma thyroid.
| Positron Emission Tomography–computed Tomography in Anaplastic Thyroid Cancer|| |
Anaplastic thyroid cancer (ATC) is a rapidly growing and aggressive type of thyroid carcinoma. More than 75% of patients will have local invasion, and 50% of patients will have distant metastases at the time of presentation, and despite aggressive treatments, the cure and long-term survival rates remain poor for these patients. The most common site for distant metastases is the lungs, and less common sites are to the bone marrow and brain. ATC lesions, due to their poorly differentiated state, typically have low iodine uptake and decreased thyroglobulin production and consistently show high-FDG uptake [Figure 2]. The American Thyroid Association recommends FDG-PET and PET/CT for the evaluation of distant skeletal metastasis, apart from that the other advantages of using PET scan in ATC are evaluation of surgical candidacy, as well as follow-up imaging, with a higher sensitivity than CT alone (99.6% vs. 62%; P < 0.002) to detect lesions. Bogsrud et al. reported that both standardized uptake value (SUVmax) and FDG uptake volume were found to be of prognostic value for survival of patients with ATC. Poisson et al. report that patients with SUV >18 on FDG-PET/CT had significantly worse 6-month survival rates than did those with SUV <18 (20% vs. 80%), as did patients with FDG uptake volume >300 mL compared with patients with FDG uptake volume <300 mL (10% vs. 90%).
|Figure 2: A 65-year-old male with anaplastic thyroid cancer. Anterior maximum intensity projections of head and neck and body (axial positron emission tomography right) and fused positron emission tomography–computed tomography (left) images show large necrotic mass (arrows) in lower anterior neck with intense peripheral fluorodeoxyglucose uptake (maximum standardized uptake value, 11.4)|
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| Conclusion|| |
The role of PET/CT in the management of differentiated thyroid carcinoma and medullary carcinoma of the thyroid is still evolving. Incidental focal uptake in whole-body PET/CT with raise suspicions of a potentially malignant nodule, but eventual FNAB and ultrasound correlation are needed for further confirmation of malignancy. The role of PET/CT in the determination of malignant potential of nodules reported as BETHESDA 3 or 4, is not of much effectiveness. Further, PET/CT does not show any significant benefit over existing modalities in the evaluation of cervical lymph nodal status either before surgery or during surveillance. In cases of TENIS, FDG-PET is being used to localize recurrent dedifferentiated lesions which are not picked up by routine ultrasonography or cross-sectional imaging. Radio-avidity of Hurthle cell cancer puts PET/CT in the forefront of other diagnostic tools in the exact localization of the disease. In medullary carcinoma, thyroid FDG-PET is an important tool in diagnosis, but other radiopharmaceutical PET/CT like F-DOPA is mainly used either alone or in synergy eith PET-CT. In case of anaplastic carcinoma, FDG-PET can be used as the diagnostic tool to evaluate distant skeletal metastasis. American Thyroid Association has recently incorporated indications of FDG-PET in the diagnosis and prognosis of Hurthle cell cancer, and as a limited indication, to evaluate skeletal metastasis in ATC.
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[Figure 1], [Figure 2]