Thyroid Anatomy and Approach to Thyroid Nodules

The thyroid gland is normally situated in the lower neck at midline, anterior and anterolateral to the larynx and upper tracheal rings, and comprises two lobes (typically 5 ×3 × 2 cm in adults) which are linked together by an isthmus. Common carotid arteries and sternocleidomastoid muscles are located laterally to the gland [1, 2].

Thyroid nodules are common findings among the adult population with an incidence detected on thyroid ultrasound of up to 70%. However, only a small percentage of them have clinical significance. In recent years, detection of incidental thyroid nodules has increased due to extensive access to imaging modalities and improvement in imaging techniques [3–5]. When a thyroid nodule is detected, it is important to rule out malignancy (in 4–6.5%), and assess their function and possible compression effects [3, 6].

The first step in the evaluation of a patient diagnosed with a thyroid nodule is to obtain a comprehensive medical history and physical examination. Rapid growth, prior head and neck irradiation, history of certain syndromes (e.g. Cowden, multiple endocrine neoplasia type 2), family history of thyroid cancer, cervical lymphadenopathy, or vocal cord paralysis are associated with malignancy [5]. The next step is to assess thyroid function. Frequently, nodular goiter (defined as thyroid enlargement associated with thyroid nodules) has a normal function, with serum thyroid hormones levels within the normal ranges. The normal, high or low thyroid stimulating hormone (TSH) serum levels do not exclude cancer. In individuals with low TSH evaluation includes thyroid scintigraphy/radionuclide scan [5, 7]. The association of thyroid nodules with lymphocytic autoimmune thyroiditis might increase the risk of malignancy, thus serum thyroid antibodies (antithyroglobulin and thyroid peroxidase antibody) should be determined [8, 9]. The next step in the evaluation of a thyroid nodule is thyroid ultrasound.

Thyroid Scintigraphy

In patients with a thyroid nodule accompanied by a low serum TSH value, thyroid scintigraphy is recommended to evaluate whether or not the nodule is functioning [3], and also in case of multinodular goiter to orientate the FNA, especially in areas with iodine deficiency. Planar or three‐dimensional single photon emission tomography (SPECT) images are obtained 6–24 hours after radioiodine (typically sodium ¹²³I) or 20 minutes after intravenous administration of ^99mTc Pt. Nodules are characterized based on radiotracer uptake on thyroid scintigraphy as hot (higher uptake than the normal thyroid tissue), warm (equal uptake) or cold (lower uptake) [7]. Hyperfunctioning nodules have high uptake whereas background uptake in normal thyroid tissue is typically suppressed depending on TSH levels [16–18]. In contrast, background thyroid uptake is diffusely increased in Graves’ disease (Figure 16.1), which can have concomitant nodules in about a third of cases [19]. Hot nodules in adults are unlikely to be malignant but this feature does not exclude malignancy. Warm and cold nodules require FNA to exclude malignancy based on sonographic features. Discordant nodules (hot on pertechnetate and cold on iodine scintigraphy) are rare and suggest an organification defect which can appear in malignancy. Radioiodine uptake at 24 hours is useful for assessment of multinodular goiter and candidates for radioiodine therapy.

Thyroid scintigraphy and uptake are useful in the differential diagnostic and assessment of acute/subacute thyroiditis and in the detection of ectopic thyroid tissue.

^99mTc SPECT/US Fusion Imaging

Although side‐by‐side comparison of ultrasound (US) and SPECT, and integration of the results is usually beneficial for evaluation of thyroid nodules, in some conditions it can yield uncertain results. SPECT/US fusion imaging has proven to be helpful in cases with indeterminate findings and cytologic FNA results [20].

Pentavalent ^99mTc‐DMSA or ^99mTc‐MIBI Scintigraphy

Pentavalent ^99mTc‐dimercaptosuccinic acid (DMSA) scintigraphy has been historically used for diagnosis and follow‐up of patients with thyroid medullary carcinoma which arises from para‐follicular thyroid C cells [21].

^99mTc‐sesta‐methoxyisobutylisonitrile (^99mTc‐MIBI/sestamibi) is not specific for thyroid cancers; tracer uptake is proportionate to the mitochondrial respiratory chain activity. Uptake in thyroid neoplasms, including medullary thyroid carcinoma, can be incidentally seen in sestamibi parathyroid scans or myocardial perfusion imaging studies [22, 23] (Figure 16.2).

There is increasing use of tumor scintigraphy using ^99mTc‐MIBI, especially in some European countries for assessing thyroid nodules. According to various publications, the negative predictive value of a ^99mTc‐MIBI scintigraphy of an iso or hypofunctioning thyroid nodule in ^99mTc‐pertechnetate scintigraphy is more than 90%, while the positive predictive value is approximately 15–20% [24, 25].

Based on the available data, the following indications for ^99mTc‐MIBI scintigraphy are sensible and justified [24]:

• to clarify iso‐ or hypofunctional thyroid nodules with an intermediate probability of malignancy according to TIRADS criteria
  
• if the FNA is not meaningful or if there are suspicious thyroid nodules that are not easily accessible to an FNP
  
• in the case of multinodular thyroid disease with several iso or hypofunctional thyroid nodules for assessing dignity and, if necessary, selection of thyroid nodules that require FNP.

The Role of ^99mTc‐MIBI in the Differentiation of Amiodarone‐Induced Thyroid Disease (Type I, II, or III)

In amiodarone induced thyrotoxicosis (AIT), a ^99mTc‐MIBI scan is an essential tool in the differential diagnosis of different forms. The scan will show a normal or intense uptake of the radiotracer in AIT I form that will benefit from antithyroid drugs and has no indication for corticosteroids, and a decrease or complete lack of uptake in AIT II, where the inflammation is dominant and corticotherapy is mandatory. In form AIT III, both early and delayed images show low/faint ^99mTc‐MIBI uptake.

PET and Hybrid Imaging PET/CT or PET/MRI

Positron emission tomography (PET) is not routinely used for evaluation of benign thyroid diseases. However, in some cases a thyroid pathology may be incidentally found while undergoing PET/computed tomography (CT) or PET/magnetic resonance imaging (MRI) for other diagnostic purposes [22]. Incidental focal increased ¹⁸F‐FDG uptake is linked with high incidence of thyroid malignancy (27–47%) [26], especially when the maximum standardized uptake value (SUV_max) is higher than 6 (Figure 16.3).

Diffuse metabolic activity is usually suggestive of an inflammatory condition such as Hashimoto thyroiditis [26] (Figure 16.4).

With the increasing role of immunotherapy in cancer, the early response to therapy may be evaluated by molecular PET/CT imaging. Development of thyroiditis may particularly represent an early response indicator to immunotherapy and PET‐detectable immunotherapy response adverse effects (IRAE) is useful for prediction of a favorable outcome [27]. The same reaction might also be observed in adrenal glands, showing an adrenalitis posttherapy (Figure 16.5).

Incidentally detected lesions on ¹⁸F‐FDG PET/CT can be evaluated by ultrasound and FNA biopsy. In cases with diffuse uptake, measurement of TSH and thyroid antibody is suggested [26, 28].

Thyroid adenomas may demonstrate focal uptake on ⁶⁸Ga‐DOTA‐DPhe1,Tyr3‐octreotate (DOTATATE) PET/CT or other ⁶⁸Ga‐labeled somatostatin analogues (SSA) [29]. SSA and ¹⁸F‐DOPA PET/CT are also useful for assessment of medullary thyroid carcinoma, which is discussed in the neuroendocrine section [30, 31].

¹⁸F‐FDG PET is an essential tool in the evaluation of patients with differentiated thyroid cancer (DTC), detectable serum thyroglobulin level, and negative radioiodine scintigraphy (TENIS syndrome). In such patients, ¹⁸F‐FDG PET/CT is complementary to ¹²⁴I‐PET (when available), which is more sensitive than scintigraphy and SPECT for assessment of iodine avidity [32]. There is an increasing detection rate of F18‐FDG PET/CT in radioiodine negative patients with Tg levels higher than 10 ng/mL [33], being a marker of the aggressiveness of the tumor; its role is also very important in case of early assessment, staging, and response evaluation in cases with an aggressive form of DTC, in medullary thyroid cancers, and in anaplastic forms. ⁶⁸Ga‐PSMA PET/CT is being investigated in metastatic thyroid cancer and appears to detect both iodine avid and nonavid lesions with high sensitivity [34].

In patients with medullary thyroid carcinoma, the detection rate of PET for recurrent or metastatic disease correlates with post‐thyroidectomy serum calcitonin levels [35, 36]. Differentiated medullary thyroid cancer has high uptake on ¹⁸F‐DOPA or ⁶⁸Ga‐SSA PET/CT, whereas high ¹⁸F‐FDG uptake is associated with worse prognosis and dedifferentiated cancers [36, 37].

CT and MRI in Evaluation of the Thyroid Pathologies

Although CT and MRI yield detailed structural information, they have limited utility in the evaluation of thyroid nodules. However, they can be very useful in demonstrating the local extent of the malignancy invasion and distant metastasis [39]. CT and MRI can be helpful in localization of the parathyroid glands before operation. If CT is indicated for assessment of the thyroid gland, it should be performed without contrast [2]. If the intravenous contrast is necessary for the imaging and the patient is going to undergo scintigraphy or radioiodine therapy, then MRI can be used as a substitute for a CT scan. The thyroid gland appears hyperintense and homogenous on T2 MRI images. In some pathologies, such as multinodular goiter, the thyroid may appear heterogeneous. Pathologic lymph nodes can be hyper enhanced on T1 images [2].

DTC and Use of Hybrid Molecular Imaging

The incidence of DTC has been increasing and it is forecast to be one of the four most common malignancies by 2030 [40]. DTC is divided into papillary and follicular carcinomas, based on its histological features [41]. The first treatment step after diagnosis of DTCs is surgical thyroidectomy and removal of accessible metastatic sites. Thyroid remnant ablation using radioactive ¹³¹I is considered following surgery for localized disease depending on risk of recurrence. Radioiodine therapy with ¹³¹I after thyroidectomy is often indicated for metastatic disease as either adjuvant or primary therapy. In some cases, like unresectable tumors or radioiodine refractory disease, further treatments such as radiotherapy and chemotherapy may be necessary. Thyroid hormone substitution, in some cases in suppressive doses, needs to be administrated. A lifelong follow‐up is performed for these patients by periodic ultrasounds, radioiodine imaging, and measurement of thyroglobulin levels [41, 42].

Planar scintigraphy (with or without SPECT) using ¹²³I or ¹³¹I is the standard of care in the postoperative follow‐up of patients with DTC (Figure 16.6). ¹³¹I is used for detection and ablation of the remnants of the thyroid gland after surgical removal of the gland. Despite their major diagnostic and therapeutic roles, these imaging modalities do not provide the detailed anatomic information needed to localize and characterize pathologies. Recently, combination of these modalities with a CT scanner (PET/CT and SPECT/CT) has led to the development of hybrid imaging methods that overcome the limitations of molecular imaging and enhance the diagnostic accuracy [41, 43–45]. In patients in whom recurrence of the disease is suspected, thyroglobulin values are increased, and no uptake is seen in the ¹³¹I scan, ¹⁸F‐FDG PET/CT can be a useful modality in locating the recurrence spot with sensitivity and specificity of up to 85% and 90%, respectively [44]. However, this technique may have some disadvantages, including a significant number of false‐negative cases (up to 40%) [44]. ¹⁸F‐FDG‐PET/CT is generally indicated in patients with aggressive DTC (Figure 16.7), dedifferentiated or anaplastic thyroid carcinomas (Figure 16.8), and patients with a negative whole‐body scan for preoperative evaluation and staging [46].

The integration of SPECT and CT, hybrid SPECT/CT, provides more precise information in comparison with conventional planar imaging and leads to an improvement in imaging interpretation and staging of the disease [42]. SPECT/CT has an incremental role in the staging and treatment response evaluation, being able to differentiate the sites of radioiodine pathologic uptake after the administration of radioiodine in both diagnostic whole‐body scans and post‐therapeutic whole‐body scans (e.g. the uptake in the parotid gland versus metastatic latero‐cervical lymph nodes). SPECT/CT has been shown to improve the specificity of the imaging by providing both functional and anatomical data and accurate attenuation correction [47]. Figure 16.9 demonstrates the essential role of SPECT/CT in the follow‐up of DTC: the ¹³¹I whole‐body scans presented in Figure 16.9a,b show pathologic uptake of radioiodine within the lungs and a focal uptake in the dorsal spine (black arrow), although it is impossible to determine the exact location in which dorsal vertebra (a). In the posterior–anterior view (b) there is also a faint uptake in the skull that might be easily omitted or misinterpreted as focal nasal uptake (red arrow). The SPECT/CT images presented in Figure 16.9c,d show that the pathologic cranial uptake is related to an occipital metastatic osteolytic lesion. The same hybrid image was obtained for the spine, demonstrating a metastatic lesion in the 12th dorsal vertebra, confirmed by biopsy as metastases from papillary thyroid carcinoma.

PET/MRI of the thyroid has been reported to be more advantageous than PET/CT in the detection of iodine‐positive lesions. However, it has not been shown to be superior to PET/CT in differentiation of the lesions [48]. Other advantages of PET/MRI over PET/CT include its detailed soft tissue demonstration and absence of ionizing radiation. Reducing the ionizing radiation can be of great importance in patients who undergo frequent evaluations [49] or in pediatric patients.

Overview of the Embryology and Anatomy of Parathyroid Glands

Parathyroid glands can have diverse shapes, location, size, or number among different individuals. Approximately, 80–97% of the population have four parathyroid glands and about 19% have fewer or supernumerary glands [50, 51]. Up to 16% of these glands are ectopically positioned in the neck and mediastinum [51]. The superior glands originate from the fourth pharyngeal pouch and are usually located at the cricothyroid junction. The inferior glands, however, are derived from the third pharyngeal pouch and can have more variable locations, but are frequently found at the posterolateral or anterolateral side of the lower end of the thyroid gland. These glands may have ectopic locations such as the mediastinum and thymus. They are normally ovoid‐shaped and their size varies from 4 to 6 mm in length and 2 to 4 mm in width. The inferior thyroid artery usually maintains the blood supply to the parathyroid glands. However, in a small percentage of the population, the superior thyroid artery contributes to supplying blood to the superior parathyroid glands [51–53].

Overview of the Imaging Modalities used for Evaluation of Parathyroid

Primary hyperparathyroidism is diagnosed based on biochemical testing. Imaging has a role in localizing pathology in patients who are considered for surgical management. Parathyroid carcinoma is rare and may be incidentally detected in the workup of hyperparathyroidism or present with neck mass of metastatic disease to lungs, cervical lymph nodes, liver, or bone. Carcinoma should be suspected in patients presenting with parathyroid crisis.

Ultrasonography is useful for assessment of parathyroid pathologies and biopsy guidance but may be limited if the pathology is retropharyngeal, retroesophageal, or mediastinal. The combination of nuclear scintigraphy and ultrasound can be very helpful in preoperative localization [54–56]. More false‐positive results can be seen with ultrasound than scintigraphy [57]. Contrast‐enhanced CT has low sensitivity in the detection of parathyroid diseases. Some studies have reported MRI to have a sensitivity of up to 88%, which is considered to be as high as that of ^99mTc‐sestamibi scintigraphy [53, 54, 58]. However, the signal characteristics of parathyroid adenoma and cervical lymph nodes overlap and MRI is not usually considered the first modality for preoperative detection of the parathyroid lesions [59]. In some institutions, multiphase CT (4D‐CT) is used even as the first‐line modality and is reported to be superior to other conventional imaging modalities [55, 60]. When combined with ultrasound, the sensitivity of this modality in localization of the parathyroid adenoma can be up to 94% [61].

Correlative Imaging Approach in the Detection of Parathyroid Lesions