Thyroid Follicular Epithelial Cell–Derived Cancer: New Approaches and Treatment Strategies

PTC

PTC is the most commonly occurring form of differentiated thyroid cancer and accounts for 80%–85% of all thyroid cancer (17). Patients are often asymptomatic but may have cervical lymphadenopathy, hoarseness, and dysphagia. Risk factors for PTC include radiation exposure, particularly during childhood, a family history of thyroid malignancy, and inherited conditions such as familial adenomatous polyposis or Cowden syndrome (18). PTC most often affects middle-aged women. Thyroid carcinoma accounts for 1.4% of pediatric malignancies, with PTC being the most common thyroid carcinoma affecting children (3).

In 2017, the World Health Organization recognized 15 histologic subtypes of PTC: conventional/classic, papillary microcarcinoma (<1 cm in diameter), encapsulated, follicular, diffuse sclerosing, tall cell, columnar cell, cribriform-morular, hobnail, PTC with fibromatosis/fasciitislike stroma, oncocytic, solid/trabecular, spindle cell, clear cell, and Warthin-like variant (12,13). Conventional/classic, papillary microcarcinoma, encapsulated, follicular, diffuse sclerosing, and tall cell are the most common and best-documented histologic subtypes (12,13). Because histologic subtypes relate to biologic aggressiveness and prognosis, these distinctions are valuable in terms of disease management strategies and recommendations. The papillary microcarcinoma and encapsulated variants are considered the least biologically aggressive. The tall cell and hobnail variants have the potential to be more aggressive than the conventional/classic variant, and as a result, patients with these tumors may require a more aggressive disease management strategy than do those with conventional/classic papillary cancer of the same stage (12).

In addition to the histologic subtype, PTC tumors range in size and extent of the primary lesion (17). Although there may be microcarcinomas (<1 cm in diameter) and intrathyroidal lesions (>1.5 cm in diameter) that are confined to the thyroid capsule, it is not uncommon for patients to have multifocal disease, extrathyroidal extension, and cervical lymph node metastasis (17). Up to 27% of patients have cervical lymph metastasis at the initial presentation (17). Children, more commonly than adults, present with lymph node involvement or metastasis to distant sites such as the lungs (3). Overall, patients with PTC typically have a good prognosis. Increased risk for recurrence or poor prognosis is often related to age (persons > 55 y old at diagnosis), increased vascular invasion, invasion into the adjacent neck structures, and distant metastasis (17).

FTC

FTC is the second most common type of thyroid cancer after PTC and accounts for 10% of differentiated thyroid cancers (19). Unlike PTC, FTC is rarely associated with previous radiation exposure but may be associated with iodine deficiency. FTC typically occurs in a slightly older age group than PTC (40–60 y) and is also less common in children (20). Minimally invasive FTC is limited to microscopic capsular or vascular invasion, whereas widely invasive tumors may have multiple foci and extensive, widespread invasion (21). Given that vascular invasion is common with FTC, metastatic disease may be noted even when the primary thyroid lesion is small. Distant metastatic spread to the lungs or bones is found more commonly with FTC than with PTC (19–21). Poor prognosis is often related to tumor size, degree of vascular and capsular invasion, and age (20).

HCC

HCC accounts for 3% of all thyroid cancers. Previously, HCC was classified as an oxyphilic variant of FTC; however, data from genetic and molecular analysis suggest that HCC is a distinct entity (22,23). Just as with FTC, HCC occurs in a slightly older age group than PTC. Unlike FTC, HCC has more of a propensity to spread to cervical lymph nodes and has a higher risk of distant metastatic disease, particularly skeletal and pulmonary metastasis (24). Another important distinction relevant for patient management is that although metastatic lesions in FTC often concentrate RAI, HCC metastatic foci are often RAI-refractory (23,25).

PDTC

PDTC has not been studied as commonly as other follicular epithelial cell–derived thyroid cancers, partly because of its overall rarity but also because it was not classified as an independent thyroid cancer histotype until 2004 (11). According to the Turin proposal, the presence of PDTC is determined by the presence of carcinoma of follicular cell derivation, architectural patterns (solid/trabecular/insular architecture), and high-grade features such as nuclear pleomorphism, tumor necrosis, or a high mitotic rate (11–14). PDTC more commonly occurs in women 60–70 y old and is associated with aggressive characteristics such as extrathyroidal extension, regional lymph node metastasis, and distant metastasis. Just as with other forms of follicular epithelial cell–derived thyroid cancers, the most common sites of distant metastasis include the lungs and bones; however, less common metastatic sites also include the liver, skin, ovaries, and retroperitoneal space (11). Although PDTC accounts for only 4%–7% of all thyroid cancers, it represents the main cause of death from nonanaplastic follicular cell–derived thyroid cancer (11).

ATC

ATC is the most aggressive and rarest thyroid cancer. Although ATC accounts for only 1%–2% of all thyroid cancer cases, it is responsible for 14%–39% of deaths related to thyroid malignancy (26). ATC occurs primarily in the geriatric population and is more common in persons 60–70 y old. Patients with ATC often have a large, palpable thyroid mass associated with hoarseness, dyspnea, dysphagia, and vocal cord paralysis (26). The extent of disease may be restricted to the neck region or may include distant metastasis to the lungs, bone, or brain. Although ATC may develop as a singular entity, it may also evolve from or coexist with differentiated thyroid cancer (12,13,26). Given that ATC is a type of undifferentiated thyroid cancer, these cells will not maintain the characteristics and behavior of normal follicular epithelial cells and thus will not concentrate RAI.

MAPK Pathway

In recent years, there have been multiple studies evaluating the genetic alterations and molecular mechanisms underlying thyroid carcinogenesis and their prevalence in follicular epithelial cell–derived thyroid carcinomas. An understanding of these mutations may explain the diverse clinical characteristics of thyroid follicular epithelial cell–derived carcinomas and provide diagnostic information relative to treatment. Mutations in both oncogenes and tumor suppressor genes acquired along the path of tumor progression allow cancerous cells to evade the normal control of cell cycle and apoptotic processes and promote the transition from localized to metastatic disease. Oncogenic activation of the mitogen MAPK is considered the most common molecular alteration in thyroid cancer and is believed to initiate carcinogenesis (6). The MAPK pathway is a key molecular signaling pathway responsible for the regulation of several diverse cellular functions, including cellular growth, proliferation, and angiogenesis. In the normally functioning cell, the MAPK pathway is triggered by the binding and activation of receptor tyrosine kinases, which transmit growth signals from the plasma membrane to the nucleus (6). Oncogenic alterations in the MAPK pathway influence processes that are crucial for cancer development and progression. In oncogenic cells, the MAPK pathway is driven by mutations including RET/PTC, RAS, and BRAF (6). These driver mutations are initiating mutations and occur early in thyroid carcinogenesis (14).

RET/PTC Rearrangements

RET protooncogene rearrangements are most commonly found in PTC (termed RET/PTC rearrangements) and lead to the constitutive activation of the RET tyrosine kinase domain and subsequent activation of the MAPK signaling pathway (27). RET/PTC rearrangements are found in 20%–70% of PTCs and are more commonly associated with pediatric thyroid cancers (27). Although 13 RET/PTC rearrangements have been found, RET/PTC1 and RET/PTC3 are the most common. RET/PTC1 is more prevalent in sporadic PTC, and RET/PTC3 is highly prevalent in radiation-induced PTC. RET/PTC rearrangements are also found in the follicular variant of PTC and in FTC (15). The prognostic significance of RET/PTC rearrangements is not fully established. RET/PTC1 does not correlate with clinical pathologic features of PTC; however, RET/PTC3 is associated with aggressive characteristics and poor prognostic factors, including greater primary tumor size, cellular variations, and a more advanced stage at diagnosis (15,27).

RAS Mutations

The RAS oncogene mutations play an important role in thyroid oncogenesis through the regulation of 2 important signaling pathways: the MAPK cascade, which is responsible for cellular proliferation, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, which is important for cell survival (Fig. 2) (6,15). Oncogene activation in the 3 RAS protooncogenes (HRAS, KRAS, and NRAS) is found in most human cancers, including thyroid cancer. RAS mutations occur in almost every type of thyroid cancer and in benign follicular adenomas: 20%–25% of benign follicular adenomas, 10%–20% of PTCs, 30%–45% of follicular-variant papillary thyroid cancers, 30%–35% of FTCs, 20%–40% of PDTCs, and 10%–20% anaplastic thyroid cancers (ATCs) (9,28). RAS mutation alone is most likely associated with limited aggressiveness of thyroid cancer; however, RAS may coexist with other mutations such as TERT or PTEN, both of which have been implicated in aggressive clinicopathologic behavior (28,29).

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FIGURE 2.

Key molecular signaling pathways involved in thyroid cancer initiation and progression. (Left) MAPK pathway, which is activated by mutations in RET, RAS, and BRAF. (Right) Pathways involved in tumor progression, including PI3K/AKT, p53 tumor suppressor, and TERT. Blue boxes represent molecular targets for therapies approved by Food and Drug Administration. ERK = extracellular-signal–regulated kinase; MEK = mitogen/extracellular-signal–regulated kinase; mTOR = mammalian target of rapamycin; PTEN = phosphatase and tensin homolog mutation; p53 = Tp53 or tumor protein; RAF = rapidly accelerated fibrosarcoma; RAS = rat sarcoma point mutations; RET = rearrangement during transfection; TERT = telomerase reverse transcriptase. (Reprinted with permission of (6).)

BRAF Mutations

Although more than 40 point mutations have been documented in BRAF, the most frequent mutation is T1799A BRAF, resulting in V600E protein kinase (6). BRAF V600E is exclusive to PTC, PTC-derived PDTC, and ATC. The BRAF V600E mutation occurs in about 40%–45% of all PTCs and in about 60% of BRAF-associated PTCs (30). BRAF V600E mutation is noted in the potentially more aggressive PTC variants, including multinodular/diffuse forms of the follicular variant of PTC (15). BRAF V600E mutation causes constitutive activation of the BRAF kinase and MAPK signaling pathway and has been associated with aggressive clinicopathologic features such as extrathyroidal invasion, lymph node metastasis, vascular invasion, and a primary tumor of advanced stage (15). In BRAF-associated PTC, both vascular endothelial growth factor and platelet-derived growth factor are upregulated (31,32). Vascular endothelial growth factor and platelet-derived growth factor are potent stimulators of angiogenesis, a process that is vital to carcinogenesis. BRAF mutations have also been implicated in the loss of cellular differentiation resulting in decreased expression of sodium iodide symporter, TSH receptor, and thyroglobulin, thereby creating a situation for iodine-refractory disease (6,9,14). Although BRAF mutations have been implicated in aggressive behavior, there is no clear consensus. Frequently, classic PTC and papillary microcarcinomas have associated BRAF mutations. Despite these mutations, classic PTC and papillary microcarcinomas maintain an excellent prognosis. Isolated BRAF mutations may not substantially contribute to risk stratification and increased specific disease mortality. Cancer evolution is triggered by the sequential accumulation of mutations that bestow metastatic potential. BRAF mutations are frequently associated with TERT mutations. Thyroid cancers displaying both BRAF V600E and TERT mutations exhibit more aggressive clinicopathologic behavior than do thyroid cancers displaying only BRAF mutations (29).

TERT Mutations

A genetic alteration in TERT has been associated with increased aggressiveness and poor patient prognosis. Telomerase is the enzyme involved in telomere elongation, whose main function is preservation of chromosome integrity and genomic stability. Telomeres are repetitive DNA sequences at the ends of chromosomes acting as protective caps. Telomeres are continually shortened with each successive generation. When telomeres reach a critically short length, the chromosomes participate in breakage–fusion–breakage cycles resulting in cell crisis and apoptosis (29). Therefore, telomeres allow a cell to replicate only a certain number of times. Since cancer cells seek to grow at an unconstrained rate, the shortened telomeres and subsequently restricted replication present a significant problem. In cancer cells, telomere length is maintained by telomerase, which functions to elongate telomeric DNA by using its 2 components: an RNA template and a reverse transcriptase (29). Mutations in TERT are sufficient to restore the activity of the telomerase complex (15). Most adult differentiated cells do not express or have very low expression of telomerase; however, telomerase is significantly expressed in 90% of human cancers, including differentiated, poorly differentiated, and undifferentiated thyroid cancers (29). By expressing higher levels of reverse transcriptase, and therefore allowing for increased telomerase activity, carcinoma cells prevent critically short telomeres and apoptosis, meaning the oncogenic changes bestow an extended life or immortality.

Independent of its function in telomere length maintenance, TERT mutations have also been associated with metastatic capability and cellular dedifferentiation (15,29). Studies have indicated that TERT may encourage metastasis through the activation of the epithelial–mesenchymal transition. This transition is a process by which epithelial cells lose their normal characteristics such as intercellular adhesion and lack of motility and acquire mesenchymal cell properties such as reduced intercellular adhesion, increased motility, invasiveness, and apoptosis resistance (29). Activation of the epithelial–mesenchymal transition process is triggered by various stimuli resulting in the silencing of intracellular adhesion molecules such as epithelial cadherin and the upregulation genes promoting the mesenchymal shift (29). The epithelial–mesenchymal transition is also suggested to promote the dedifferentiation process, resulting in poorly differentiated or undifferentiated cancers (29).

Tp53 Mutation

Alterations in several tumor suppressor genes have been associated with thyroid oncogenesis, but the most widely studied is the Tp53 gene. p53 (also known as Tp53) is a key tumor suppressor protein known as the “guardian of the genome” because of its functions in maintaining genomic integrity through control of cell division, apoptosis, DNA repair, and angiogenesis (15). Cancer cells with a Tp53 mutation have evolved the ability to bypass the cell cycle checkpoints, to favor antiapoptotic pathways, and to proliferate uncontrollably. The amount of p53 in normal cells is maintained at a very low level; however, Tp53 mutations and p53 overexpression are frequent in several human cancers and occur in well-differentiated thyroid cancers (40% of PTCs and 22% of oncocytic FTCs), as well as in a high proportion of PDTC and ATCs (particularly those originating from PTC), which indicates that Tp53 mutations promote the transition from differentiated to undifferentiated thyroid cancer (15). Tp53 mutations are most noted in the later stages of oncogenesis and occur simultaneously with a substantial increase in cellular proliferation (15). Tp53 mutations have been noted in cancers with BRAF mutations and RET/PTC rearrangements and are believed to promote extrathyroidal extension and distant metastasis (15).

Figure 2 illustrates key molecular signaling pathways involved in thyroid cancer initiation and progression. Table 2 reviews genetic mutations associated with thyroid carcinogenesis.

TSH Suppression Therapy

In patients who have had a partial or total thyroidectomy, thyroid hormone replacement may be used not only to replace endogenous thyroid hormone but also to inhibit tumor progression or recurrence because TSH encourages cellular proliferation in differentiated thyroid cancer cells. TSH suppression therapy significantly reduces recurrence and thyroid cancer–related mortality (6,36). The goal of TSH suppression therapy is to reduce TSH to below the reference range (0.4–4.5 mIU/L). The appropriate TSH concentration as determined by the disease management team may vary among patients given the extent of surgery and the distinction between low-risk and high-risk status. Reducing TSH concentrations to 0.1 mIU/L can improve outcomes for high-risk patients; however, this reduction requires doses of thyroid hormone replacement that may induce subclinical hyperthyroidism (6). Potential adverse effects include osteoporosis in postmenopausal women, angina, and atrial fibrillation (6). In patients with low-risk thyroid cancer, a more conservative approach with the goal of thyroid hormone replacement therapy to maintain TSH at or slightly below the lower limit of normal (0.1–0.5 mIU/L) may be appropriate (36). Patients who undergo a lobectomy instead of total thyroidectomy may not require TSH suppression therapy if their TSH serum levels are maintained at the lower limit of normal (0.5–2.0 mIU/L) (36).

Figure 3 illustrates the negative-feedback loop for thyroid hormone synthesis. The hypothalamic–pituitary axis regulates TSH release through a negative-feedback loop. TSH-releasing hormone stimulates anterior pituitary thyrotrophs to secrete TSH. When TSH binds to the TSH receptor on thyroid follicular cells, it stimulates iodine uptake, thyroid hormone (triiodothyronine, tetraiodothyronine) secretion, and thyroid gland growth and differentiation. Of the thyroid hormones released, approximately 80% are in the form of tetraiodothyronine and 20% in the form of triiodothyronine (37). Triiodothyronine has a short half-life but is most active on the nuclear receptor, whereas tetraiodothyronine has a long half-life but is less active in binding to the nuclear receptor. Because tetraiodothyronine becomes deiodinated and converted into triiodothyronine by most tissues (especially the liver and kidneys), tetraiodothyronine acts as a reservoir for triiodothyronine (37). Serum levels of thyroid hormone exert negative-feedback control on TSH-releasing hormone and TSH. High thyroid hormone levels decrease TSH secretion, whereas low thyroid hormone levels stimulate TSH synthesis and secretion. As this relates to thyroid cancer, patients who have had a total thyroidectomy require TSH suppression therapy for 2 reasons: to replace endogenous thyroid hormone and to suppress TSH. TSH suppression is an important aspect of treatment because TSH may stimulate cellular proliferation in differentiated thyroid cancer cells.

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FIGURE 3.

Thyroid hormone synthesis negative-feedback loop. Arrow with plus sign indicates stimulation. Arrow with minus sign indicates inhibition. T3 = triiodothyronine; T4 = tetraiodothyronine; TRH = TSH-releasing hormone.

RAI Therapy

In previous years, many clinicians routinely recommended RAI therapy for all patients with differentiated thyroid cancer, except in patients with papillary microcarcinoma. However, the 2015 ATA guidelines proposed a more conservative approach based on specific histopathologic features that could modulate risk of recurrence or disease-specific mortality, disease follow-up implications, potential adverse effects, and physician and patient preferences (6,7,34). The goals of RAI therapy are remnant ablation, adjuvant therapy, and treatment of known residual or recurrent disease.

Remnant ablation eliminates residual clusters of presumably normal or benign thyroid tissue, which incorporates iodine and produces thyroglobulin, thereby complicating efforts to use thyroglobulin serum assays and RAI scintigraphy to identify persistent disease or recurrence (6). Potential benefits to remnant ablation include improved initial staging and the clinical use of RAI whole-body scintigraphy and thyroglobulin serum assays as a follow-up for cancer recurrence. However, use of RAI whole-body scintigraphy is not used as common as it once was because of the increased sensitivity of cervical lymph node sonography (6), which is cheaper by comparison, is more widely available, has no associated radiation exposure, has no potential side effects, and does not require discontinuation of thyroid hormone replacement therapy or use of TSHα injections (6). Cervical lymph node sonography combined with postoperative serum thyroglobulin (either with the patient taking thyroid hormone replacement or after TSH stimulation) are very sensitive methods for detecting persistent disease or a thyroid remnant, for predicting the potential for disease recurrence, and for tailoring future diagnostic and therapeutic approaches (6,33). Postoperative whole-body RAI scintigraphy may still be indicated when the extent of a thyroid remnant or residual disease cannot be accurately determined from cervical lymph node sonography and surgical reports or when the results of whole-body RAI scintigraphy may alter treatment decisions. If remnant ablation is deemed appropriate for low- to intermediate-risk patients, lower dose ranges for ¹³¹I NaI (1,110 MBq, or 30 mCi) may be preferred over high doses, depending on the size of the remnant (7,33).

Use of RAI for initial adjuvant therapy destroys microscopic foci that may or may not be present in the thyroid remnant or elsewhere in the body after surgical resection. The goals of adjuvant therapy are to reduce the risk of disease recurrence and improve long-term outcomes. Given that patients are selected for adjuvant therapy with regard to risk of recurrence instead of known disease, some patients who receive adjuvant therapy may have been adequately treated by their primary surgery (35). For patient selection and RAI dose determination, clinicians evaluate several factors, such as the likelihood of improved clinical outcomes, potential side effects, the results of postsurgical follow-up RAI scintigraphy, thyroglobulin assays, the extent of thyroid surgery, and the preferences of the patient and disease management team (35). If RAI is indicated as adjuvant therapy for patients without known distant metastasis, a dose range of up to 5,550 MBq (150 mCi) is generally recommended but should be tailored to the specific patient on the basis of individual risk, the lowest activity needed for effective treatment, and specific recommendations from the disease management team (33).

The third use of RAI therapy is for patients with known iodine-avid metastatic disease or for recurrence. Typical doses are 3,700–7,400 MBq (100–200 mCi) and may be based on the observations and experience of the disease management team or estimated by dosimetry, with a goal of limiting excess radiation exposure to the bone marrow and avoiding hematopoietic toxicities (7,33). Just as with adjuvant RAI therapy, there may be multiple factors that account for the determined dose. Dose-related impairment of testicular function and transient ovarian failure have been observed after RAI therapy. General recommendations include avoidance of pregnancy for at least 6 mo after treatment, or longer if additional RAI therapy may be indicated. For men who may receive multiple RAI treatments, consideration of sperm banking may be necessary if there is an anticipated cumulative ¹³¹I-sodium iodide dose greater than 14 GBq (378 mCi) (38).

For patients with iodine-refractory disease, RAI therapy is less likely to provide benefit. The Martinique Working Group described 5 common clinical scenarios that may indicate an iodine-refractory state: no RAI uptake on a diagnostic whole-body scan, no RAI uptake on a scan obtained several days after RAI therapy administration, lack of RAI uptake in all tumor foci, progression of differentiated thyroid cancer metastasis despite RAI uptake, and progression of differentiated thyroid cancer metastasis despite cumulative ¹³¹I NaI doses of more than 22.2 GBq (600 mCi) (35). Potential treatments for iodine-refractory disease include external radiation therapy, chemotherapy, and targeted molecular therapy.

Targeted Molecular Therapy for Advanced Differentiated Thyroid Cancer

Table 3 defines abbreviations used in discussions of targeted molecular therapy for advanced differentiated thyroid cancer.

Both papillary and follicular carcinomas are well-differentiated thyroid cancers and are considered highly treatable by conventional treatments, which include surgery, RAI ablation, and TSH suppression therapy. Although HCC is also considered differentiated and may also be treated with conventional treatments, it may prove more RAI-resistant than PTC and FTC. A small percentage of patients with differentiated thyroid cancer develop iodine-refractory metastatic disease, thereby limiting treatment options (39). Although conventional treatments may also be used in PDTC, many cases are RAI-resistant (14). Thyroid cancers that are no longer responsive to RAI therapy are still candidates for other forms of treatment, including standard chemotherapy and targeted therapy. Targeted therapy and chemotherapy differ in their mechanism of cancer treatment. Targeted drug therapy specifically prohibits the action of key proteins involved in cancer-specific activities, whereas traditional chemotherapy affects all rapidly proliferating cells, including normal cells. Targeted drug therapy is an active area of cancer research, and currently there are 2 approved drugs that target the MAPK cascade. The U.S. Food and Drug Administration approved 2 multikinase inhibitors for the treatment of advanced differentiated thyroid cancer refractory to RAI treatment: sorafenib (approved in 2013) and lenvatinib (approved in 2015). Multikinase inhibitors block the effect of tyrosine kinases that are overactive in the MAPK pathways. Sorafenib is a kinase inhibitor that inhibits multiple intracellular and cell-surface kinases (KIT, FLT-3, RET, RET/PTC, VEGFR 1-3, and PDGFR-β) (40) that are implicated in tumor cell signaling, angiogenesis, and apoptosis. Lenvatinib is also a kinase inhibitor that inhibits the vascular endothelial growth factor receptors as well as other kinases (FGF receptors, PDGFα, KIT, and RET) associated with pathogenic angiogenesis, tumor growth, and cancer progression (39,41). In addition to the multikinase inhibitors, selective kinase inhibitors are also therapeutic options for advanced differentiated thyroid carcinoma. In May 2020, the Food and Drug Administration approved a highly selective kinase inhibitor, selpercatinib, for the treatment of iodine-refractory RET-positive advanced thyroid cancer (39,42).

A promising use of kinase inhibitors in iodine-refractory differentiated thyroid cancer is the resensitization to RAI. BRAF V600E mutations coincide with reduced sodium iodine symporter expression, thereby inhibiting RAI uptake (39). In a study conducted by Rothenberg et al., 10 patients with iodine-refractory thyroid cancer received a BRAF inhibitor for 25 d. Six of the 10 patients demonstrated uptake of RAI and could be retreated with RAI (39,43). RAI resensitization has also been documented in a phase II trial with an MEK inhibitor, selumetinib, in patients expressing BRAF or RAS mutation (39). Figure 2 illustrates the key molecular signaling pathways involved in thyroid cancer initiation and progression. MEK is a downstream protein in the RAS/RAF/MEK MAPK signaling cascade. Selumetinib inhibits overstimulation of this pathway. Of the 20 patients in the trial (9 with BRAF mutation and 5 with NRAS mutation), 12 demonstrated RAI uptake in response to selumetinib use. Eight of the 12 patients could be treated with RAI. Of the 8 patients who received another RAI treatment, 5 had NRAS mutations and one had a BRAF mutation (39).

Treatment for Undifferentiated Thyroid Carcinoma

Anaplastic thyroid cancer is a diagnostic and therapeutic challenge because it is very rare, advances quickly, and is not iodine-avid, which prevents the use of RAI for evaluation and treatment. In these cases, ¹⁸F-FDG PET is useful for evaluation and follow-up after treatments. Initial treatment includes surgical resection and airway management (often a tracheostomy) followed by external-beam radiation therapy with or without use of doxorubicin, taxanes, or cisplatin (6,39,44). Patients who have unresectable cancer but without distant metastasis are generally treated with palliative chemoradiation (6). Genetic marker analysis has led to the development of therapeutic agents that target specific molecular pathways associated with ATC. For example, clinical trials with BRAF inhibitors (e.g., dabrafenib), MEK inhibitors (e.g., trametinib and lenvatinib), mTOR inhibitors, or PPARγ inhibitors may be appropriate for patients with ATC (39,44). MEK is a key protein in the MAPK signaling cascade, whereas mTOR is a key protein in the PI3K-AKT pathway. PPARγ acts as a tumor suppressor gene, upregulating important enzymes that control the cell cycle (6,44).