The greatest challenge in imaging thyroid cancer is distinguishing thyroid cancer from benign disease in the thyroid gland. Although thyroid cancer represents the most common endocrine malignancy in adults , it is still rare compared with benign thyroid nodules, which are seen on high-resolution ultrasound in more than 30% of men and 50% of women over 50 years . The prevalence of thyroid cancer in typical patient cohorts may range from 1% in a general practice/radiology setting to 10% or higher in a specialist clinic , depending to a large extent on the referral pattern and the type of institution. When a patient presents with symptoms such as a palpable lateral neck mass or hoarseness, or has a genetic syndrome, the likelihood for malignancy is markedly increased. The clinical management of patients suspected for thyroid cancer is described in detail in the current guidelines of the American Thyroid Association (ATA) .
The present review will focus on imaging of the four common cancer types in the thyroid gland: papillary (PTC), follicular (FTC), poorly differentiated (PDTC) and anaplastic (ATC), as well as medullary (MTC) (Table 1) [5–7,8▪,9–11]. PTC and FTC are both derived from the follicular epithelium. They share the ability to take up iodine due the expression of sodium-iodide-symporter (NIS) and are often grouped together as differentiated thyroid cancer (DTC) [4,12]. Generally, thyroid cancer imaging is performed in three different scenarios: primary detection and initial staging of thyroid cancer, to monitor therapy after surgery and to diagnose suspected recurrence.
IMAGING OF DIFFERENTIATED THYROID CANCER: PRIMARY DETECTION AND STAGING
Primary imaging for DTC serves to establish the diagnosis of DTC, exclude malignancy in the contralateral thyroid lobe if hemithyroidectomy is considered, detect local invasion, and identify and map lymph node metastases to the lateral neck.
The mainstay for primary diagnosis thyroid cancer is high-resolution ultrasound of the thyroid gland including ultrasound-guided fine needle biopsy (FNB) of any suspect thyroid nodules . Five criteria on brightness-mode (B-mode) ultrasound help identify malignancy in thyroid nodules: solidity, hypoechogenecity, taller than wide shape (anterior-posterior diameter larger than width in an axial scan; N. B. 92% of isthmic PTC are wider than tall ), irregular margin, and macro- and microcalcification [14,15]. Note that follicular neoplasms including FTC often have a different appearance as a solitary, well defined, solid, homogeneous, isoechoic or hypoechoic nodule, with a peripheral halo, parallel orientation to the skin surface and no lymph node enlargement [8▪,16].
The major new advance in recent years has been the development of easy to use classification systems for thyroid nodules on thyroid ultrasound. The following dominate: The classifications proposed by the ATA  and American Association of Clinical Endocrinologists (AACE) , and the Thyroid Imaging Reporting and Data Systems (TIRADS) released by the Korean Society of Thyroid Radiology (K-TIRADS) , the European Thyroid Association (EU-TIRADS)  and the American College of Radiology (ACR-TIRADS) [15,19▪]. In a recent meta-analysis comparing the performance of the three TIRADS, categories 4 and 5 had a sensitivity of about 90% for the detection of DTC with specificities between 50 and 60% . In a recent prospective study comparing five common systems side-by-side with thyroid cytology as independent reference standard, ACR-TIRADS was the most specific . In our opinion, it is also the easiest to apply and to teach.
Several other criteria of malignancy are not included in the above systems. Capsular abutment and loss of the hyperechogenic thyroid capsule may indicate local invasion . Hard texture on ultrasound elastography and central vessels on Doppler ultrasound are rather machine-dependent [14,15]. Contrast-enhanced ultrasound, which is useful for visualization of parathyroid glands , entails additional costs for the contrast agent while it does not obviate FNB.
None of the common TIRADS take into account the functional state of a thyroid nodule. ATA and AACE guidelines recommend performing thyroid scintigraphy in addition to ultrasound in all patients evaluated for thyroid nodules who have subnormal serum thyrotropin (TSH) [4,17]. Hyperfunctioning ‘hot’ nodules are difficult to distinguish from hypofunctioning ‘cold’ nodules based on ultrasound alone (Fig. 1), and ultrasound classification systems will recommend FNB in at least 25% [23▪,24,25] even though hot nodules are nearly always benign [26,27]. Reversely, focal uptake of [18F]fluorodeoxy-glucose (FDG) on general oncology imaging  and of [99mTc]MIBI on parathyroid imaging  indicates thyroid malignancy (mostly PTC) in up to 30% of cases. The prognostic relevance of coincidently discovered secondary thyroid cancer is unclear [30,31]. A recent study suggests that EU-TIRADS may help avoid unnecessary FNB among FDG-positive nodules [32,33].
From a size of 10 mm and above, every suspicious thyroid nodule should undergo ultrasound-guided FNB . Multinodular goiter does not appear to increase of risk DTC per se. A pragmatic approach is to take FNB of the three most suspicious nodules . The optimal technique for FNB is hotly debated. We prefer non-aspiration FNB, using three to four needle passes under local anaesthesia [35,36].
ATA guidelines recommend the Bethesda classification for thyroid cytology (Table 2) [37–39]. FNB works best for PTC, which has a characteristic appearance on cytology (Fig. 2). Cytological diagnosis of FTC is impossible, as the differential diagnosis of FTC versus follicular adenoma relies on the detection of vascular and or/or capsular invasion in a histological specimen. In both entities, cytology will only show varying degrees of atypia . Similarly, the diagnosis of follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), a benign tumour, requires histopathology . Finally, the cytological appearance of MTC is protean, and the follicular variant of PTC may be difficult to differentiate from follicular neoplasms .
Bethesda V and VI nodules will usually be treated by surgery with the possible exception of solitary PTC less than 10 mm in the absence of suspicious lymph nodes . Categories Bethesda III and IV are ‘cytologically indeterminate’. Bethesda III nodules should primarily undergo repeat cytology. The goal of category IV is to identify all potential follicular carcinomas, usually leading to hemithyroidectomy. ATA guidelines recommend molecular testing – when available – to rule in and out malignancy . When there is a possibility for PTC, we routinely analyse samples for a somatic BRAF mutation. When positive, this will establish the diagnosis of PTC with more than 99% specificity (rule-in test). Rule-out-testing to exclude malignancy in Bethesda III and IV nodules is expensive . Functional imaging with [18F]FDG-PET [42,43] and [99mTc]MIBI  will however have similar diagnostic performance. Cytology is unreliable for the detection of MTC. In our institution, we have chosen to screen all patients scheduled for surgery for elevated serum calcitonin. Likewise, cytology cannot be relied on to identify parathyroid adenomas . In patients under evaluation for hyperparathyroidism, we therefore routinely analyse the washout from the FNB needle for parathyroid hormone [36,46].
Cervical ultrasound for thyroid disease should always include screening for suspicious regional LN. The following three signs in B-mode ultrasound increase the likelihood of malignancy: round shape, hypoechogenicity, loss of hilar echo [47,48]. Cystic lymph nodes are almost pathognomonic of PTC (Fig. 2) but may also occur in squamous cell cancer. The hallmark of a malignant lymph node is focal hyperperfusion on Doppler ultrasound (Fig. 3a) [48,49].
When thyroid cancer is established based on FNB, we routinely perform a second ultrasound examination to specifically exclude lymph node metastases in the lateral neck, both ipsilateral and contralateral, with particular attention to lymph nodes at the edges of lymph node dissection regions. In addition to B-mode, every lymph node is examined with high-resolution Doppler (Fig. 3). In case of suspicious lymph nodes, we perform ultrasound-guided FNB of one lymph node per lateral cervical compartment. The technique is similar to FNB of thyroid lesions. However, cytology may only reveal lymphatic cells or fluid with macrophages in case of cystic lymph nodes. We therefore routinely supplement cytology with biochemistry: thyroglobulin in case of DTC, calcitonin in case of MTC [36,49]. Rarely, lymph node metastases can occur with a very small or no detectable primary in the thyroid gland . In these cases, detection of malignancy rests on lymph node biopsy. Imaging of lymph nodes in the central compartment (level IV) is challenging to perform with ultrasound  but has limited relevance in institutions in which central lymph node dissection is part of the surgical routine.
Variations in vascular anatomy need to be recorded. We routinely document the common origin of right subclavian and carotid arteries from the innominate artery, as a subclavian artery originating directly from the aortic isthmus and passing behind the trachea (lusorian artery) is associated with a nonrecurrent inferior laryngeal nerve with major implications for surgical management .
In case of locally and regionally advanced disease, guidelines recommend computed tomography (CT) . We prefer contrast-enhanced CT (CE-CT) for improved delineation of vascular anatomy and for the detection of regional lymph node metastases, especially in cases with MTC. The role of preoperative [18F]FDG PET/CT in addition to CE-CT is at present not firmly established [53–55]. However, we routinely perform [18F]FDG PET with coregistered CE-CT of neck and mediastinum down to the tracheal bifurcation. Since 2019, we also include PET/MR  for a better delineation the central viscera and of cystic lymph nodes (Fig. 2).
Error-free communication between endocrine surgeon and imaging specialist is paramount. We routinely summarize the findings in a hand drawing of all pertinent imaging findings in relation to the patient's vascular anatomy . The drawings are scanned in and stored alongside the ultrasound images in the Picture Archival and Communications System and follow the patient into the operating theatre (Fig. 2).
IMAGING OF DIFFERENTIATED THYROID CANCER: THERAPY MONITORING
DTC expresses NIS. It has therefore the ability to take up radioactive iodine, at least under conditions of TSH stimulation, either endogenous (4 weeks’ withdrawal of levothyroxine leading to a TSH >30 mU/l) or by intramuscular injection of recombinant human TSH (rhTSH) . Three radioactive isotopes can be used: 131I (physical half-life 8 days), which emits both gamma radiation, which is needed for conventional nuclear medicine imaging, and beta radiation, which irradiates the surrounding tissue with a maximum range of approx. 2 mm; 123I (13 h), a gamma emitter; and 124I (4 days), a positron emitter [58,59].
Until the turn of the millennium, many institutions routinely applied 131I to ablate thyroid remnant tissue after total thyroidectomy apart from using it to treat regional or distant iodine-avid metastases . Thyroid ablation has come under increasing scrutiny, at least for patients with low-risk thyroid cancer [4,61▪▪,62–64]. Following ablation, the distribution of radioactivity is documented by planar whole-body scintigraphy, and – ideally – three-dimensional conventional imaging using single photon emission computed tomography (SPECT) in combination with CT .
Three aspects are important. First, we routinely perform cervical ultrasound in conjunction with SPECT/CT to detect regional lymph node metastases that were overlooked on preoperative staging. Small iodine-avid lymph node metastases can be followed up with ultrasound, as 131I may be curative, while iodine-negative lymph node metastases require repeat surgery . Second, SPECT/CT helps to identify iodine avid accessory thyroid tissue such a pyramidal lobe that may otherwise be mistaken for thyroid remnants . Third, Post therapeutic 131I scintigraphy can be the only imaging modality to detect – and treat – miliary pulmonary metastases in PTC, as the lung lesions are too small to be picked up by routine chest CT .
After ablation, routine imaging consists of periodic cervical ultrasound. Two retrospective series suggest that a follow-up regime including ultrasound performed 4 weeks, 1 year and 5 years after initial surgical therapy will detect about 90% of recurrences in low-risk DTC [68–70].
IMAGING OF DIFFERENTIATED THYROID CANCER: RECURRENCE
Distinguishing true recurrence from persisting disease that was overlooked on primary therapy can be difficult [57,71▪▪]. Recurrence of DTC is suspected when a patient detects a new painless lump in the neck, when there is a rise of serum thyroglobulin (Tg), and in case of persisting high levels of anti-thyro-globulin antibodies .
Initial imaging should include ultrasound of the neck including ultrasound-guided FNB of suspicious lesions [4,49]. Reactive lymph node at the edge of a previous systematic lymph node dissection may be difficult to distinguish from metastases, as they often are hypoechoic and enlarged with an abnormal shape. Doppler-ultrasound may help, but the definitive diagnosis often rests on FNB with determination of Tg in the washout from the biopsy needle .
Functional imaging of DTC has two components: demonstrating iodine avid disease that can be treated with high-dose 131I, and demonstrating cancer tissue that has lost the ability to concentrate iodine and that needs to be treated by surgery or external beam therapy .
Imaging for iodine avid disease is performed under TSH stimulation using 123I or 131I whole-body scintigraphy, ideally supplemented by SPECT/CT of neck and mediastinum to both increase sensitivity and improve localization . 124I PET is the most sensitive method for the detection or characterization of small lesions . For pretherapeutic dosimetry, a small activity of 124I, typically 37–74 MBq, is injected or ingested. Images are taken 48 h, and if positive, 96 h later . Post therapeutic planar scintigraphy 72–96 h after the application at least 3000 MBq 131I is still the most sensitive method for the detection of miliary pulmonary metastases in PTC , for which high-dose 131I therapy is curative .
The mainstay for imaging recurrent DTC including iodine-refractory disease is [18F]FDG PET . When DTC de-differentiates, DTC may fail to express NIS, and glucose uptake is upregulated. An important caveat is that glucose uptake is also upregulated in inflammatory foci, which often leads to false positive findings in cervical lymph nodes . Patient-based pooled sensitivity and specificity of [18F]FDG for the detection of recurrent DTC are both 80% . However, these estimates are probably overoptimistic, as diagnostic studies often lack a reference standard that is truly independent of imaging and/or sufficient follow-up . In our own series of 51 patients imaged for suspected recurrent DTC from 2009 to 2014, lesion-based sensitivity of [18F]FDG PET was 85% and specificity was 70%. Post-PET ultrasound including ultrasound-guided FNB of all suspicious lesions increased specificity to 90% while maintaining sensitivity . TSH stimulation increases lesional uptake of [18F]FDG , but it may no longer be needed due to the improved sensitivity of the most recent generation of PET scanners.
[68Ga]DOTATOC has been used for DTC imaging [76,77] but without convincing evidence that it is superior to [18F]FDG. Two recent case series show that ligands to prostate-specific membrane antigen (PSMA) may show focal uptake in patients with rising serum Tg, negative 131I scintigraphy and [18F]FDG-PET [78,79]. However, unspecific foci especially in the thorax are frequently encountered on imaging with [18F]PSMA-1007, which has a higher resolution than the 68Ga-labeled PSMA ligands . PSMA PET for thyroid cancer therefore needs confirmation in larger series with a firm diagnostic standard that is independent of imaging, ideally cytology or histology. 68Ga-labelled fibroblast activation protein inhibitor (FAPI) is an oligopeptide that has moderate uptake in thyroid cancer . The tracer excels in imaging pancreatic cancer, as it is cancer-specific without uptake in inflammatory lesions . Another new PET tracer, [18F]tetrafluoroborate (TFB) is taken up by NIS [82▪▪]. In a recent study in 25 patients with suspected DTC, [18F]TFB-PET showed focal uptake in recurrent tumor in 13 patients while 131I SPECT-CT was positive only in 3 [82▪▪].
IMAGING OF MEDULLARY THYROID CANCER
The primary diagnosis of MTC follows the same principles as for DTC with two caveats: cytology is unreliable; micrometastases to cervical lymph node are common, and macrometastases to lymph node may be discontinuous and often contralateral . Unlike DTC, MTC does not express NIS, and therefore has no iodine uptake. Three tracers are first choice for imaging MTC: [18F]FDOPA, [68Ga]DOTATOC (and analogues) and [18F]FDG [83,84,85▪]. The latter is least sensitive, but useful with increasing de-differentiation, particularly when S-CEA rises more rapidly than S-calcitonin [85▪]. Only one study compared the three tracers in the same patients . The most sensitive tracer for well differentiated MTC is [18F]FDOPA [87▪,88]. However, it is available only at very few select institutions. [68Ga]DOTATOC, an increasingly ubiquitous tracer for neuroendocrine tumours, is not quite as sensitive, but more so than [18F]FDG [85▪]. Note that [68Ga]DOTATOC may show physiological uptake in the stellate ganglia (Fig. 3 h.j) . Other tracers that have been used for imaging MTC include radioactively labelled gastrin analogues , but there are at present no series that document the superiority of these new tracers over [18F]FDOPA.
We use [68Ga]DOTATOC rather than [18F]FDG for staging before primary surgery, while we are eagerly awaiting the forthcoming production of [18F]FDOPA in our own cyclotron unit. For staging-suspected recurrent disease, we routinely complement ultrasound and FNB at our own institution with [18F]FDOPA with coregistered CE-CT of neck and mediastinum at a cooperating center abroad (Fig. 3).
IMAGING OF ANAPLASTIC THYROID CANCER
ATC is one of the most aggressive human cancers. Still, up to 20% of patients experience lasting cure after radical surgery in combination with radiochemotherapy if cancer is limited to the thyroid gland and regional lymph nodes [91,92]. The main differential diagnosis is thyroid lymphoma, which is primarily treated with chemotherapy, often in combination with radiation. [18F]FDG is the PET imaging agent of choice for both [93,94]. In case of ATC, we routinely perform [18F]FDG PET/CT with CE-CT and PET/MR of neck and mediastinum, supplemented by core-needle biopsy (CNB) of the primary tumour for histological confirmation before surgery. In addition to CNB, we aspirate cells from the tumour and perform flow cytometry to exclude lymphoma . MRI and endoscopy are important to establish intactness of the central viscera.
The mainstay of thyroid cancer imaging is cervical ultrasound in combination with ultrasound-guided FNB. Thyroid scintigraphy with [99mTc]pertechnetate is used in patients with suppressed TSH for the detection of toxic nodules, which are nearly always benign. Imaging methods for DTC are scintigraphy with radioactive iodine isotopes and [18F]FDG-PET. Recommended imaging methods for MTC are [18F]FDOPA (when available), [68Ga]DOTATOC and [18F]FDG-PET.
We thank Hans Kristian Haugland, PhD, from the Department of Pathology at Haukeland University Hospital for the cytology images and valuable advice regarding cytology, and Lars Rokne Reisæter, MD, from the Department of Radiology for helpful review of our manuscript.
Financial support and sponsorship
Conflicts of interest
M. B. is an advisor (unpaid) for Segami Corp., Inc., Columbus/MD.
This manuscript has not been submitted elsewhere.
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