Current Concepts in the Molecular Genetics and Management of Thyroid Cancer: An Update for Radiologists
Substantial improvement in the understanding of the oncogenic pathways in thyroid cancer has led to identification of specific molecular alterations, including mutations of BRAF and RET in papillary thyroid cancer, mutation of RAS and rearrangement of PPARG in follicular thyroid cancer, mutation of RET in medullary thyroid cancer, and mutations of TP53 and in the phosphatidylinositol 3ʹ-kinase (PI3K)/AKT1 pathway in anaplastic thyroid cancer. Ultrasonography (US) and US-guided biopsy remain cornerstones in the initial workup of thyroid cancer. Surgery is the mainstay of treatment, with radioactive iodine (RAI) therapy reserved for differentiated subtypes. Posttreatment surveillance of thyroid cancer is done with US of the thyroid bed as well as monitoring of tumor markers such as serum thyroglobulin and serum calcitonin. Computed tomography (CT), magnetic resonance imaging, and fluorine 18 fluorodeoxyglucose positron emission tomography/CT are used in the follow-up of patients with negative iodine 131 imaging and elevated tumor markers. Certain mutations, such as mutations of BRAF in papillary thyroid carcinoma and mutations in RET codons 883, 918, and 928, are associated with an aggressive course in medullary thyroid carcinoma, and affected patients need close surveillance. Treatment options for metastatic RAI-refractory thyroid cancer are limited. Currently, Food and Drug Administration–approved molecularly targeted therapies for metastatic RAI-refractory thyroid cancer, including sorafenib, lenvatinib, vandetanib, and cabozantinib, target the vascular endothelial growth factor receptor and RET kinases. Imaging plays an important role in assessment of response to these therapies, which can be atypical owing to antiangiogenic effects. A wide spectrum of toxic effects is associated with the molecularly targeted therapies used in thyroid cancer and can be detected at restaging scans.
SA-CME LEARNING OBJECTIVES
After completing this journal-based SA-CME activity, participants will be able to:
■ Review the molecular genetics of thyroid cancer.
■ Discuss the role of imaging in the initial evaluation and posttreatment surveillance of thyroid cancer.
■ Describe the management of thyroid cancer, including novel molecular targeted therapies, with emphasis on the role of imaging in assessment of treatment response and detection of toxic effects.
Thyroid carcinoma is uncommon, with a lifetime risk of less than 1% in the United States (1). Although uncommon, the reported incidence of thyroid malignancies has significantly increased, almost tripling in the last few decades, mostly due to increased detection rates. For the year 2015, approximately 62 450 new cases of thyroid cancer were expected to be diagnosed, including 1950 deaths (2). Epithelial malignancies constitute the majority of thyroid malignancies and include papillary (PTC), follicular (FTC), medullary (MTC), and anaplastic (ATC) thyroid carcinomas (3). Less common types of epithelial thyroid cancer include Hürthle cell and poorly differentiated variants. The PTC, FTC, and ATC subtypes arise from the follicular thyroid cells, whereas MTC arises from the parafollicular cells (or C cells).
Surgery is the mainstay in the management of epithelial thyroid malignancies. In patients with DTC, surgery is often followed by radioactive iodine (RAI) therapy for complete ablation of normal thyroid remnants and management of potential micrometastatic disease. Management of metastatic thyroid cancer is more complex and includes a combination of surgical resection, external-beam radiation therapy (EBRT), and chemotherapy. Advanced DTC can become refractory to standard treatment strategies, with limited treatment options left for nonresectable RAI-refractory cases. In distinction to this, both MTC and ATC are inherently resistant to RAI therapy. MTC has a unique genetic makeup and treatment approach versus that with DTC. ATC is the most aggressive form of thyroid cancer, with frequent metastases at the time of diagnosis and no effective therapy.
Recent advances in the understanding of the genetic composition of thyroid malignancies have led to the development of a molecular taxonomy and the development and approval of newer molecularly targeted therapies (MTTs) (4). Imaging modalities including ultrasonography (US), computed tomography (CT), magnetic resonance (MR) imaging, and nuclear medicine studies (iodine 131 [131I] and iodine 123 [123I]) are widely used in the initial workup and posttreatment surveillance of patients with thyroid cancer. There is extensive literature on the imaging features of primary thyroid cancer, focusing primarily on differentiating benign from malignant thyroid nodules. In this article, we focus on the molecular genetics of epithelial thyroid cancer, with an overview of the imaging features of primary and metastatic epithelial thyroid cancer. We also briefly discuss the management of thyroid cancer, including novel MTTs, with emphasis on the role of imaging in assessment of treatment response and detection of toxic effects.
Clinical Features of Epithelial Thyroid Cancer
PTC is most common type of thyroid cancer, followed by FTC, MTC, and ATC, in that order (1). The major clinical features of common epithelial thyroid malignancies are summarized in Table 1. Familial forms of PTC and FTC each occur in 5% of patients, and each is associated with a characteristic mutation. Familial forms of MTC are typically bilateral and multicentric, occurring in 25% of cases (5,6).
Imaging of Primary Thyroid Cancers
Thyroid US is the initial examination of choice for evaluation of a suspected thyroid mass and provides considerably more anatomic detail than either thyroid scintigraphy or CT (7,8). US can further help in the workup by guiding fine-needle aspiration (FNA). There are no US findings that are pathognomonic for malignancy. Solid nodules with blurred or spiculated margins, hypoechoic pattern, microcalcifications, taller than wide orientation, intralesional vascular flow, and documented enlargement have been associated with increased risk for thyroid cancer (Fig 1), whereas cystic or solid hyper- and/or isoechoic nodules, large coarse calcifications, peripheral vascularity, and comet tail shadowing are features associated with low risk for thyroid cancer (9,10). A peripheral hypoechoic halo around nodules represents the capsule of the nodule or compressed surrounding thyroid parenchyma and vessels. Its absence has a specificity of 77% and a sensitivity of 67% in predicting malignancy (11). Although a mainly cystic nodule is unlikely to be malignant, a cystic component is found in 13%–26% of all thyroid cancers (12).
PTC usually appears as a solitary, hypoechoic (77%–90%), solid (90%) nodule with an irregular margin (13) (Fig 1). Punctate echogenic foci representing microcalcifications (psammoma bodies) are highly specific for PTC and are seen in 80% of cases (14). Chaotic vascularity within the nodule and septa in cystic nodules is demonstrated at color Doppler US (15). Metastatic lymph nodes are seen in 50% of patients at diagnosis and are characteristically located in the ipsilateral jugular chain and pre- and/or paratracheal region typically confined to the mid- and lower lymph node levels (level VI) (16).
US cannot be used to accurately distinguish a benign follicular adenoma from FTC unless there is frank extracapsular spread and invasion of adjacent vessels. FTC and follicular adenoma are therefore collectively described as follicular lesions, and differentiation is made after surgery. Larger size, hypoechogenicity, absence of a sonographic halo, and lack of cystic change favor the diagnosis of FTC over adenoma (17).
MTC is usually a well-defined hypoechoic solid tumor but may also have infiltrative borders. Lesions are predominantly located in the lateral upper two-thirds of the gland in the sporadic form, and diffuse involvement of both lobes is noted in the hereditary type. Punctate echogenic foci due to amyloid deposition and associated calcification may be seen within the primary thyroid lesion (80%–90%) as well as metastatic regional lymph nodes (50%–60%) (18). MTC may be mistaken for PTC because of overlapping sonographic features. Multiplicity, coarse shadowing calcifications (punctate in PTC), and hypoechoic nodes (hyperechoic in PTC) are more suggestive of MTC, which also tends to be larger and more cystic, with the solid portion demonstrating a homogeneous echotexture (19). Chaotic intralesional vascularity is demonstrated at color Doppler imaging (13).
ATC manifests as an ill-defined hypoechoic mass diffusely involving the entire lobe or gland, with areas of necrosis (78%) and dense amorphous calcifications (58%) (13,20). Multiple small chaotic intratumoral vessels are seen at color Doppler US; necrotic tumors may be avascular or hypovascular (13). Extracapsular extension is common in ATC and is seen as either subtle extension beyond the gland contour or contiguous invasion of adjacent structures (20).
US-guided biopsy is routinely used for diagnosis of thyroid nodules. Details of the techniques of thyroid biopsy have been well described elsewhere (21) and are not discussed here. The role of US-guided core biopsy in the diagnostic workup is controversial. Few studies have shown that core biopsy is safe in patients who have repeated nondiagnostic FNAs and that combined FNA and core biopsy has the highest diagnostic accuracy (22,23). However, the American Thyroid Association’s 2015 guidelines do not recommend core biopsy of thyroid nodules because of its high morbidity (24). The availability of molecular testing for genetic (BRAF, RAS, RET/PTC) and protein markers has significantly increased the diagnostic accuracy for indeterminate cytologic specimens of thyroid nodules without the need for core biopsies (25) (Fig 1).
Nuclear Medicine Studies
Radionuclide scintigraphy with technetium 99m (99mTc) pertechnetate or 123I can be helpful for thyroid nodules that are found to be indeterminate at FNA. Thyroid nodules with increased tracer uptake are almost always benign, especially in the setting of a low level of thyroid-stimulating hormone. Radionuclide imaging is also useful in evaluation of suspicious nodules in cases where FNA is contraindicated due to anticoagulant use.
All four major subtypes of thyroid cancer have been shown to take up fluorine 18 fluorodeoxyglucose (FDG); however, well-differentiated thyroid cancers may not be FDG avid. Even though FDG positron emission tomography (PET)/CT has a high negative predictive value, the specificity is low, as nonmalignant entities such as benign thyroid nodules and thyroiditis also demonstrate FDG uptake. Thyroid cancers generally have a higher standardized uptake value (SUV) than benign diseases, although there can be some overlap in SUV (26) (Fig 2). As a result, the role of FDG PET/CT in primary thyroid cancer is limited to use in cytologically indeterminate nodules to reduce the number of unnecessary thyroid resections of benign nodules (27). Focal activity in the thyroid gland at FDG PET/CT irrespective of sonographic features represents a high risk for malignancy (28). The American College of Radiology’s (ACR’s) 2015 guidelines recommend both US and FNA in patients with incidentally detected focal activity at FDG PET/CT who have a normal life expectancy and no comorbidities (29).
CT and MR Imaging
CT and MR imaging are inferior to US for characterizing thyroid nodules, and small nodules that are readily identified at US may be undetectable at CT and MR imaging. There are no reliable features to distinguish benign from malignant thyroid nodules at CT and MR imaging. Size of the thyroid nodule, local invasion, and suspicious cervical nodes can help in differentiating benign from malignant thyroid nodules in some cases (30). Diffusion-weighted MR imaging has been shown in some studies to help differentiate benign from malignant thyroid nodules (31,32). Malignant nodules tend to have lower apparent diffusion coefficient values than do benign nodules or normal thyroid glands (31). Thyroid nodules can be incidentally detected at CT and MR imaging. The ACR recommends a three-tier system based on the size of the nodule and age of the patient for management of incidental thyroid nodules to reduce the number of US-guided biopsies (30).
The main role of cross-sectional imaging is therefore to evaluate for extrathyroidal spread of tumor (26). CT or MR imaging is required to image the full extent of large thyroid tumors or tumors of any size extending beyond the thyroid capsule to invade adjacent structures. Invasion of adjacent structures, such as the trachea and esophagus, may require major reconstructive surgery, and tumors surrounding more than 270° of the carotid artery or mediastinal vessels may not be resectable (26). CT may be more useful for evaluation of low paratracheal nodes, which may be obscured by the sternum or tracheal air shadow at US (33). CT and MR imaging are also superior in demonstrating deep tissue (retrotracheal) extension and retropharyngeal and mediastinal lymphadenopathy. The use of iodinated contrast medium for workup of thyroid cancer is controversial. According to the ACR manual on contrast media, imaging with iodinated contrast material before 131I therapy is contraindicated, and consultation with the treating physician is recommended. Traditionally, iodinated contrast material has been considered as interfering with RAI imaging and treatment for up to 3 months. However, recent studies have shown that CT with iodinated contrast agent does not lead to long-term iodine retention and therefore these guidelines for delay in RAI treatment should be revisited (34,35).
Imaging of Metastatic Thyroid Cancer
When small thyroid cancers are limited to the gland, US is sufficient for staging, and no further imaging is required unless the tumor is located posterior to the trachea, where the tracheal air shadow may prohibit comprehensive evaluation of the tumor. CT and MR imaging are often used for the workup of thyroid cancer during initial staging and for surveillance to detect cervical nodal and distant metastases (36). Although CT can help detect pulmonary metastasis, MR imaging is used for evaluation of liver and brain metastases (36). FDG PET/CT is a useful tool in metastatic DTC as the metastases can have decreased RAI uptake and increased glucose metabolism due to dedifferentiation (flip-flop uptake) (37). FDG PET/CT can have a high sensitivity of 94% for detecting metastasis in the absence of RAI uptake (38). The accuracy is higher with elevated thyroglobulin levels (39). FDG PET/CT has a low detection rate for metastasis in MTC when the serum calcitonin level is less than 1000 pg/mL, but a significantly increased detection rate when serum calcitonin is greater than 1000 pg/mL (37). Metastases in MTC tend to be have low FDG uptake (37). The degree of FDG uptake has been shown to correlate with survival in ATC, with a higher standardized uptake value associated with shorter survival (37).
US is the modality of choice for imaging nodal metastases and has a sensitivity of 83% and specificity of 98% for detecting nodal metastases at presentation (40). Nodal calcification at CT and cystic nodes at MR imaging should raise suspicion for a primary thyroid cancer in a patient being investigated for lymphadenopathy. PTC (30%–90%), MTC (50%), and ATC (40%) frequently spread to cervical lymph nodes, whereas lymphatic spread is less common with FTC (10%) (41). Metastatic nodes in PTC are predominantly hyperechoic (80%) at US, contain microcalcifications (50%), and may undergo cystic necrosis (25%) (42) (Fig 3). However, in MTC nodes are typically hypoechoic with coarse shadowing calcifications and peripheral vascularity. Punctate echogenic foci due to amyloid deposition and associated microcalcification may also be present (18). Metastatic nodes in FTC are usually noncalcified and lack cystic changes, presenting as solid, homogeneous, and hypoechoic lesions with peripheral vascularity (17). Fifty percent of metastatic nodes in ATC are necrotic (43).
A minimum axial diameter of 7 mm for level II cervical nodes and 6 mm for the rest of the cervical nodes has been shown to have high sensitivity (93%) and specificity (83%) for differentiating the presence of metastases in nodes in thyroid cancer (44). Primary tumor size is useful for predicting nodal metastases. The prevalence of nodal metastasis in PTC has been reported to be 13%–55% for tumors less than 5 mm in diameter and 59%–74% for those measuring 5–10 mm (45). In the case of MTC, the prevalence is 20–30% in tumors less than 1 cm and 90% in those measuring more than 4 cm (46).
ATC is the most aggressive type of thyroid cancer and has the highest prevalence of distant metastases, occurring in 43% of patients at presentation (47). The most common sites of metastases in ATC are the lungs (78%), mediastinal lymph nodes (58%), adrenal glands (24%), liver (20%), and brain (18%). Less-common sites of metastases include the pericardium, bones, kidneys, skin, and pancreas (48). FTC has a greater tendency to spread hematogenously (21%–33%) than does PTC (2%–14%) (41). The most common sites of metastases in PTC and FTC are the lungs (50%) and bones (25%). Although distant metastases are rare in DTC, they account for the maximum disease-related mortality (49). Distant metastases are present in up to 25% of cases of MTC and in 13% of those cases are discovered at presentation (50). Common sites of metastases in MTC include the liver (49–62%), lung and mediastinum (33–35%), and bones (40–74%). Rarely, MTC may metastasize to the brain, breasts, and skin (51).
Pulmonary metastases from DTC can be either micronodular (Fig 2e) or macronodular (Fig 3), which occur with equal incidence. The micronodular pattern is typically positive at 131I whole-body PET/CT but is usually negative at chest radiography. CT of the chest has better sensitivity in detection of pulmonary metastases but can also be negative in a small number of patients with positive 131I uptake at PET/CT. On the other hand, CT can depict small pulmonary metastases that are negative at 131I PET/CT and offers the added benefit of depicting mediastinal nodes and bone metastases (26). A micronodular pattern seems to offer a better prognosis and longer survival than the macronodular type, which is hypothesized to be related to the fact that a given dose of 131I for RAI therapy is more effective in a small nodule compared with a larger nodule (52–54). Both micronodular and macronodular patterns are also seen in pulmonary metastases from MTC (Fig 2). Reticulonodular perihilar lesions and masses containing irregular hyperattenuating calcific foci have also been reported that should not be mistaken for an old granulomatous disease. Bullae formation and pulmonary fibrosis might occur as a result of desmoplastic reaction, and progression of the interstitial fibrosis may result in hyperaeration and retraction of hila (51,55).
As a result of the greater propensity for hematogenous spread, bone metastases are more frequent in FTC compared with PTC. Most metastatic lesions are located in the axial skeleton and are predominantly osteolytic, with secondary bone formation in reaction to bone destruction (56) (Fig 4). Bone metastases in MTC could be lytic, blastic, or mixed; the axial and appendicular skeletons were reported to be equally involved in a study involving 53 patients (55) (Figs 5, 6). Lytic lesions can manifest as photopenic defects on bone scans, whereas osteoblastic lesions and perimetastatic osteoblastic reaction manifest as increased radiopharmaceutical uptake (51,56).
The liver is the most common site of metastases in MTC (49%–62% of cases). Metastatic lesions are typically hypervascular at contrast-enhanced CT and MR imaging but can also outgrow their blood supply and undergo necrosis (51) (Figs 4, 5). Rarely, MTC metastatic lesions can manifest as irregular calcifications throughout the liver (Fig 6). Contrast-enhanced MR imaging has higher sensitivity than CT and FDG PET/CT in detection of MTC metastatic liver lesions. However, miliary hepatic metastases may be undetectable with any imaging modality. Additionally, metastatic MTC may involve the liver surface, where deposits are difficult to diagnose at imaging, and may require laparoscopy and biopsy (26,51).
Genomic Taxonomy of Thyroid Cancers
Genetic and epigenetic alterations are now known to be the driving forces in the tumorigenesis of thyroid cancer (Table 2). Genetic alterations that result in activation of the mitogen-activated protein kinase (MAPK) and PI3K (product of PIK3CA)/AKT1 signaling pathways play crucial roles in the initiation and progression of thyroid cancer. Preoperative diagnosis of genetic defects can be made with cytologic specimens, which can help in determining the appropriate therapy.
RET (rearranged during transfection)/PTC rearrangements are seen in 10%–20% of cases of sporadic PTC and 50%–80% of PTC arising in children or after radiation exposure (57). Activating mutations of BRAF are seen in 29–69% of cases of PTC and are associated with more aggressive behavior and poorer clinical outcome (58) (Fig 4). Identification of a BRAF mutation in an FNA specimen has been shown to be a highly accurate marker of cancer, especially when cytologic analysis is indeterminate (4).
Point mutations of the RAS oncogene are seen in approximately 40%–53% of cases of FTC (59,60). PPARG (peroxisome proliferator-activated receptor gamma) rearrangement is also seen in about 60% of cases of FTC (61). The molecular mechanism underlying MTC tumorigenesis is a mutation in the RET proto-oncogene. Germline mutations activating the RET proto-oncogene are found in 88%–95% of hereditary cases and in 40%–50% of cases of sporadic MTC (62–64).
Management of Primary Thyroid Cancer
Surgery is the first-line treatment for patients with DTC and MTC whenever possible. Patients with ATC are often not operable at the time of diagnosis due to extensive disease. According to the American Thyroid Association recommendations, total or near total thyroidectomy should be performed in all patients with primary DTC more than 1 cm in diameter, contralateral nodules, history of radiation therapy, or a first-degree relative with thyroid cancer (67). Usually surgery is followed by treatment with RAI in selected patients with DTC (tumor size >4 cm, gross extrathyroidal extension of the tumor, and distant metastases) and levothyroxine therapy in all patients with DTC to maintain low thyroid-stimulating hormone levels and to rectify postsurgical hypothyroidism (1). A posttherapy scan is usually performed 2–10 days after RAI ablation to identify metastatic disease (68). MTC and ATC are resistant to RAI therapy.
Posttreatment Surveillance: The Role of Imaging
Neck US is usually performed every 6–12 months to evaluate the thyroid bed and central and lateral cervical nodal compartments (Fig 7). Tumor markers (such as serum thyroglobulin for DTC and serum calcitonin and carcinoembryonic antigen [CEA] for MTC) are monitored at regular intervals to detect recurrent disease (1).
Management of Metastatic Thyroid Cancer
In patients whose disease is resistant to RAI (including MTC and ATC) or who have progressive metastatic disease, systemic and/or local-regional therapy is recommended according to the site of metastasis. Treatment of local-regional disease depends on the site and can include EBRT, surgical resection, and stereotactic radiation therapy (69). Indications for systemic treatment include surgically unresectable or RAI-refractory tumors, tumors unresponsive to EBRT, and patients who have shown clinically significant structural disease progression during the past 6–12 months (70).
MTTs in Thyroid Cancer
Traditional cytotoxic chemotherapy has limited efficacy in the treatment of metastatic thyroid cancer. Advances in the molecular genetics of thyroid cancer have enabled development of specific MTTs targeting various oncogenic pathways (Fig 8) (Table 3) (71,72). MTTs that have been approved for metastatic RAI-refractory DTC include sorafenib and lenvatinib. In addition, sunitinib, pazopanib, and vandetanib are being evaluated in clinical trials for DTC. Sorafenib and lenvatinib are multiple tyrosine kinase inhibitors (TKIs) targeting VEGFR, PDGFR, and RET (73–75). Sorafenib also inhibits B-Raf (the protein product of BRAF), although less potently so than the other targets.
MTTs that have been approved for metastatic MTC include vandetanib and cabozantinib. Vandetanib is an orally active TKI targeting the VEGFR, RET, and EGFR pathways and in 2011 was the first targeted drug approved for treatment of unresectable or metastatic MTC (76) (Figs 9, 10). Cabozantinib is another orally active TKI against VEGFR, c-MET, and RET (77) (Fig 11). There is no effective treatment for metastatic ATC and therefore no currently FDA-approved MTT for it. More recently, everolimus, an inhibitor of mTOR, which is part of the PI3K/AKT1 pathway, is being evaluated for metastatic ATC in clinical trials (78).
In addition to the FDA-approved drugs for treatment of metastatic thyroid cancer, many new MTTs, such as VEGF inhibitors (axitinib, motesanib, sunitinib, pazopanib, ponatinib), B-Raf inhibitors (vemurafenib, dabrafenib), and inhibitors of MEK (mitogen-activated protein kinase kinase) (selumetinib), are being developed and are currently in various phases of clinical trials (79–82). Selumetinib, as an MEK inhibitor, has been shown in early studies to enhance the uptake of RAI in RAI-refractory thyroid cancer, especially with bone and nodal metastasis (82).
MTTs in Thyroid Cancer: Role of Imaging
Imaging plays an important role in monitoring treatment response and timely detection of toxic effects associated with MTTs.
All of the MTTs currently approved for use in thyroid cancer are associated with the unique toxicity profile of antiangiogenic MTTs, including hepatobiliary, pancreatic, gastrointestinal, and cardiovascular toxic effects. Many of these toxic effects can be detected on restaging scans. Although it is uncommon, a minority of these adverse events can be fatal (1.5%–2.5%) and therefore need timely diagnosis (86,87).
Hepatobiliary Toxic Effects.—Anti-VEGF MTTs are associated with varying degrees of liver enzyme elevation in up to 1.7% of patients, with hepatic failure occurring in 0.8% patients (88). Hepatic toxic effects are often seen on restaging scans as hepatic steatosis, which can obscure underlying liver metastases (Fig 10). Gallbladder complications associated with antiangiogenic MTT can range from asymptomatic gallbladder distention to frank cholecystitis (89).
Pancreatic Complications.—Asymptomatic elevation of pancreatic enzymes is frequently seen with antiangiogenic MTTs. However, acute pancreatitis is uncommon (Fig 12). The relative risk for all grades of pancreatitis in a large meta-analysis of 22 randomized trials of anti-VEGF MTTs (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib, regorafenib) was 1.95 (P = .042; 95% confidence interval: 1.02, 3.70) compared with patients who did not receive anti-VEGF TKI (90). Diagnosis of acute pancreatitis at restaging imaging can be difficult as it is often focal and subtle, requiring a high index of suspicion (91). Irreversible pancreatic atrophy has been reported in two patients treated with sorafenib (92).
Gastrointestinal Complications.—The spectrum of manifestations of gastrointestinal toxic effects includes pneumatosis, enterocolitis, bowel perforation, and fistulization (73). Diarrhea is the most common gastrointestinal toxic effect of anti-VEGF MTT, with the highest incidence coming from vandetanib, likely related to its EGFR inhibition. Cabozantinib is particularly associated with increased risk for gastrointestinal perforation, fistula, and fatal hemorrhage, occurring in 1%–3% of patients (93).
Sarcopenia.—Wasting of the skeletal muscles, unrelated to cancer-associated cachexia, has been reported with antiangiogenic TKI, most often with sorafenib (94). CT-based analysis of body composition has been shown to be accurate in quantifying changes in skeletal muscle mass in patients treated with sorafenib (94).
Cardiovascular Toxic Effects.—Although both sorafenib and lenvatinib have been shown to be associated with higher incidences of arterial thromboembolism relative to a placebo (95), no association for either has been shown with venous thromboembolism (96). Anti-VEGF MTTs have been reported to be associated with left ventricular dysfunction (Fig 13). Due to the association of sorafenib with myocardial ischemia (97), baseline evaluation of left ventricular function with echocardiography or radionuclide ventriculography is indicated in elderly patients and patients with preexisting cardiovascular disease. Prolongation of corrected QT interval (QTc) has been reported most often with vandetanib and lenvatinib (98).
Miscellaneous Complications.—All anti-VEGF MTTs are associated with increased risk for bleeding in the form of intracranial hemorrhage, hemoptysis, and epistaxis. In a large meta-analysis of 27 randomized controlled trials using anti-VEGF MTTs, some including sorafenib and vandetanib, the prevalence of high-grade bleeding was 1.3% (99). Other potential toxic effects associated with anti-VEGF MTTs for thyroid cancer include impaired wound healing, osteonecrosis of the jaw, and posterior reversible encephalopathy. Cutaneous toxic effects in the form of squamous cell carcinomas have been seen with sorafenib (100).
Prognosis in Thyroid Cancer
Several factors determine the prognosis in epithelial thyroid cancer. Poor prognosis in PTC is associated with age older than 45 years, tumor size greater than 4 cm, high TNM stage at presentation, high VEGF expression, and V600E mutation in BRAF in combination with other driver oncogenic mutations (including PIK3CA, TP53, AKT1, and RET) (1,4,101,102). Factors associated with poor outcome in FTC include older age (>45 years), male sex, vascular and capsular invasion, tumor size greater than 4 cm, and presence of an RAS mutation (1,4,60,103). Older age (>40 years), RET mutation in codon 918, poor immunostaining for calcitonin, high CEA, and persistent hypercalcitoninemia after thyroidectomy are poor prognostic factors for MTC (1,51). In ATC, older age at diagnosis, male sex, dyspnea as a presenting symptom, greater than 6-cm tumor size, and cervical nodal metastasis at presentation portend a worse outcome (47).
Development of targeted therapies directed against some of the mutations in thyroid cancer has improved the management of RAI-refractory thyroid cancer. Posttreatment surveillance of primary thyroid cancer is done with imaging and serial tumor marker assessment. In the metastatic setting, imaging plays an important role in assessment of response to MTTs and detection of associated toxic effects. Knowledge of certain mutations in thyroid cancers that are associated with poor outcomes as well as awareness of the importance of tumor markers can help radiologists follow a risk-adapted strategy when interpreting surveillance and restaging images.
Presented as an education exhibit at the 2014 RSNA Annual Meeting.
For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships.
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Article HistoryReceived: June 29 2015
Revision requested: Nov 3 2015
Revision received: Nov 28 2015
Accepted: Jan 15 2016
Published online: Sept 12 2016
Published in print: Sept 2016