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Thyroid Cancer

Eugene C. Lin and Abass Alavi

Thyroid Nodules

Clinical Indication: C

Positron emission tomography (PET) has a limited role in primary evaluation of thyroid nodules. However, uptake in thyroid nodules is often seen as an incidental finding (Fig. 14.1).

Accuracy: Differentiating Benign from Malignant Nodules

1. PET. 100% sensitivity, 63% specificity1
   
   
   
   • These results were obtained using a standardized uptake value (SUV) cutoff of 2.0.
     
     
     

     
     

     Fig. 14.1 Thyroid nodule. (A) Axial positron emission tomography/computed tomography scan demonstrates focal uptake in the left thyroid. (B) Ultrasound confirms the presence of a left thyroid nodule.

   
   
2. SUV. There have been numerous SUV cutoffs suggested for distinguishing benign from malignant thyroid nodules. These should be used with caution, as published cutoffs vary greatly (from 2.0 to 8.5).² In one study,³ SUVs were unable to distinguish benign from malignant nodules. For practical purposes, focal uptake in the thyroid requires further work-up, as malignancy cannot be excluded based on SUV alone.

Pearls

1. Both benign and malignant thyroid nodules can have increased fluorodeoxyglucose (FDG) uptake, but malignant nodules are usually more metabolically active than those without cancer.
   
   
   
   1. Most malignant thyroid nodules > 1 cm will have FDG uptake.
      
   2. Approximately one third of benign thyroid nodules have FDG uptake.4
      
   3. Hürthle cell adenomas often have increased uptake.^4,5
      
   4. SUVs overlap between follicular neoplasms and benign thyroid nodules.⁶
   
   
2. Fourteen to 50% of incidentally detected thyroid nodules on PET will be malignant.^7,8
   
3. CT correlation. Correlation with computed tomography (CT) images can be helpful in determining whether thyroid FDG uptake is benign or malignant. The following features suggest benign FDG uptake:⁹
   
   
   
   1. The FDG uptake corresponds to a very low attenuation lesion (< 25 Hounsfield units [HU] on CT).
      
   2. There is no nodule on CT that corresponds to the FDG uptake.
      
   3. The FDG uptake is diffuse.
   
   
4. Known thyroid nodules. PET may be helpful in the work-up of patients with known thyroid nodules. The absence of FDG uptake in a thyroid nodule > 1 cm has a high negative predictive value for malignancy.⁴ However, PET will often miss carcinomas < 1 cm in size.⁵ The overall positive and negative predictive values are 75 and 83%, respectively.⁵
   
   
   

   
   

   Fig. 14.2 Medial neck node mimicking a thyroid nodule. (A) Focal uptake in the left neck (arrow) on axial positron emission tomography scan is suspicious for a thyroid nodule. (B) Computed tomography scan demonstrates a medial node (arrow) immediately lateral to the left thyroid lobe, corresponding to the area of fluorodeoxyglucose uptake. Conversely, a thyroid nodule can mimic a medial neck node.

Pitfalls

1. Thyroid nodule mimics. Structures adjacent to the thyroid can mimic thyroid nodules. Before thyroid nodules are diagnosed by PET, anatomical correlation is necessary.
   
   
   
   1. Nodes. Medial neck lymph nodes can be adjacent to the thyroid (Fig. 14.2).
      
   2. Vocal cord. Asymmetric vocal cord uptake secondary to vocal cord paralysis can mimic thyroid uptake (as seen in Fig. 6.14, p. 49).
      
   3. Parathyroid adenomas can have uptake.
   
   
2. Diffuse uptake. Diffuse uptake (e.g., secondary to thyroiditis) can obscure thyroid nodule uptake.

Recurrent Thyroid Cancer10–12

Clinical Indication: B

Localizing metastatic disease in patients with an elevated thyroglobulin and negative radio-iodine whole-body scan is the primary clinical indication for PET in thyroid cancer (Figs. 14.3, 14.4, and 14.5).

Fig. 14.3 Recurrent thyroid cancer. Coronal positron emission tomography/computed tomography scan demonstrates metastatic disease to the right neck nodes, superior mediastinal nodes, and lungs.

1. Work-up.10 In patients with elevated thyroglobulin and negative whole-body radioiodine scans, the following issues should be considered in determining whether PET will be helpful:
   
   
   
   1. Surgical candidate. If surgical intervention is contemplated, PET can be very useful in localizing the sites of the disease. If surgery is not a consideration, then localization of disease is less significant, and highdose radioiodine therapy without further imaging work-up should be considered.
      
      
      

      
      

      Fig. 14.4 Muscle uptake and nodal metastases. Axial positron emission tomography/computed tomography scan demonstrates increased uptake in a left neck node (arrow) secondary to metastatic thyroid cancer. Note the proximity of the node to muscle uptake (arrowheads).

      
      
      
      

      
      

      Fig. 14.5 Brown fat uptake and nodal metastases. Extensive brown fat uptake in the neck, supraclavicular regions, and superior mediastinum on a coronal positron emission tomography (PET) scan severely limits evaluation in a patient with suspected metastatic thyroid cancer. A single superior mediastinal nodal metastasis (arrow) was present. This is slightly more intense than the brown fat uptake but otherwise similar in appearance. PET/computed tomography was necessary to identify this node.

      
      
   2. Anatomical imaging. Because metastases are often confined to the neck and chest region, anatomical imaging modalities such as ultrasound and chest CT might be considered first before PET is performed.
      
   3. Prior radioiodine exposure. PET should be strongly considered in cases where high cumulative radioiodine exposure precludes or limits further radioiodine therapy.
   
   
2. Histology. In addition to papillary and follicular carcinoma, PET is useful in
   
   
   
   1. Hürthle cell subtype of follicular cancer¹³
      
   2. Insular cell subtype of follicular cancer¹⁴
      
   3. Medullary thyroid carcinoma with rising calcitonin15
   
   
3. Prognosis. A large volume of metabolically active diseased sites and high SUVs (> 10) are strong negative predictors of survival.¹⁶
   
4. Other potential indications of PET are
   
   
   
   1. As a complement to conventional work-up in patients with known neoplastic sites
      
   2. Patients with negative radioiodine scan and normal levels of serum markers in whom clinical suspicion of relapse is high
      
   3. Posttreatment response assessment

Accuracy

1. Papillary/follicular carcinoma
   
   
   
   1. PET. Sensitivity 75%, specificity 90%17
      
   2. PET/CT. Sensitivity 95%, specificity 91%¹⁸
      
   3. The diagnostic accuracy for PET/CT is 93% compared with 78% for PET alone.¹⁸
      
   4. PET is most useful when the thyroglobulin is > 10 ng/mL and the radioiodine scan is negative.
      
   5. The sensitivity is higher (85%) in patients with a negative radioiodine scan.¹⁷
   
   
2. Hürthle cell carcinoma: PET. Sensitivity 96%, specificity 95%¹³
   
3. Medullary thyroid carcinoma: PET. Sensitivity 78%, specificity 79%¹⁵
   
4. Anatomical region
   
   
   
   1. PET is most valuable for the detection of cervical lymph node metastases.¹⁹ However, for initial staging, ultrasound and contrast-enhanced CT are comparable in accuracy to PET for the detection of cervical lymph node metastases.²⁰
      
   2. In medullary thyroid cancer, PET is most valuable for detecting cervical, supraclavicular, and mediastinal metastases.
      
   3. Bone metastases. Sensitivity 85%, specificity 100% in differentiated thyroid cancer²¹

Comparison with Other Modalities

1. Papillary/follicular cancer.17 See Table 14.1.
   
   
   
   1. Relationship between FDG and radioiodine uptake. There is usually an inverse relation between FDG and radioiodine uptake in thyroid metastases (flip-flop phenomenon). Poorly differentiated metastases have FDG uptake but no or minimal radioiodine uptake, and the reverse is true in well-differentiated metastatic lesions. Somatostatin receptor scintigraphy with technetium (Tc) 99m depreotide is also able to detect disease in the setting of detectable thyroglobulin and negative radioiodine scan. There may also be a flip-flop phenomenon between FDG and Tc-99m depreotide; for example, poorly differentiated lesions may have FDG uptake but no or minimal depreotide uptake.²²
      

      
      

      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      
      

      Table 14.1 Sensitivity and specificity of Positron Emission Tomography (PET) Compared to Other Radionuclides in Papillary/Follicular Cancer

      	Sensitivity %	Specificity %
      PET	75	90
      Iodine 131	50	99
      Sestamibi/thallium	53	92

      
      
   2. FDG-positive lesions are resistant to highdose iodine 131 treatment.²³ Thyroglobulin levels are much more likely to normalize in PET-negative patients than in PET-positive patients after radioiodine therapy.²⁴
      
   3. FDG uptake correlates with thallium and sestamibi uptake.^17,25 However, FDG is preferred to thallium or sestamibi due to its superior resolution and higher sensitivity.
      
   4. Bone metastases. One study suggests that PET is comparable in sensitivity but superior in specificity and accuracy to a bone scan.²¹ However, another study²⁶ suggests that a bone scan may identify metastases that are PET negative.
   
   
2. Medullary thyroid cancer.¹⁵ One study¹⁴ suggests there is no correlation between calcitonin levels and lesion detection (the less-differentiated lesions with FDG uptake may secrete less calcitonin). In contrast, another study²⁷ suggests that PET is most useful if the calcitonin level is > 1000 ng/mL and of limited use if the calcitonin level is < 500 ng/mL (Table 14.2).

Pearls

1. Thyroglobulin level. In patients with a negative radioiodine whole-body scan and elevated thyroglobulin, PET is most useful at thyroglobulin levels > 10 ng/mL.28
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   

   Table 14.2 Sensitivity and specificity of Positron Emission Tomography Compared with Other Modalities in Medullary Thyroid Cancer

   	Sensitivity %	Specificity %
   PET	78	79
   Somatostatin receptor	25	92
   Scintigraphy
   Dimercaptosuccinic	33	78
   acid
   Sestamibi	25	100
   CT	50	20
   MRI	82	67

   
   

   Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.

   
   
2. Thyroid hormone withdrawal/recombinant thyroid-stimulating hormone (TSH). Although radioiodine imaging is most helpful when performed in patients with elevated TSH levels (thyroid hormone withdrawal or recombinant TSH administration), there are several other factors to consider with FDG PET imaging:
   
   
   
   1. Although thyroid carcinomas may increase their metabolic demand after TSH stimulation, the tumors that have FDG uptake are usually poorly differentiated and may be less dependent upon TSH.
      
   2. A TSH-stimulated hypothyroid state can decrease metabolic organ activity and may decrease metabolic activity in tumor cells.
   
   
3. Thyroid hormone withdrawal. Conflicting studies indicate both increased and decreased sensitivity with an elevated TSH after thyroid hormone withdrawal.^17,29,30
   
   
   
   • The discrepant results may represent the conflicting effects of increased tumor metabolism from TSH stimulation and decreased metabolism from hypothyroidism.
   
   
4. Recombinant TSH. Lesion detectability is greater with recombinant TSH compared with TSH suppression.³¹ Using recombinant TSH has two advantages over thyroid hormone withdrawal: patients are spared a prolonged hypothyroid state, and the possible negative effects of hypothyroidism on tumor FDG uptake are avoided. However, given the substantial cost of recombinant TSH, it is unclear whether this is cost-effective in most clinical settings.
   
5. Thyroglobulin and TSH. In patients with a thyroglobulin > 100 ng/mL, TSH stimulation is probably not necessary due to the high sensitivity of PET in this subpopulation.³²

Pitfalls

1. Pulmonary metastases. PET has poor sensitivity for pulmonary metastases from thyroid cancer < 1 cm. If pulmonary metastases are of clinical concern, a chest CT should be performed.
   
2. Muscle/brown fat. Neck muscle or brown fat uptake can be mistaken for cervical or mediastinal nodal disease (Figs. 14.4 and 14.5). Anatomical correlation is necessary to avoid such errors; this is particularly important in thyroid cancer, where the prevalence of cervical node disease is high.
   
3. Vocal cord. Unilateral vocal cord activity can cause false-positive results (as seen in Fig. 6.14, p. 49).

References

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