Follicular carcinoma is the second most common malignant tumor of the thyroid gland and makes up around 10–15% of TCs [2,75]. There are two subtypes of FTC: minimally invasive follicular thyroid carcinoma (mi-FTC) and widely invasive follicular thyroid carcinoma (wi-FTC) carcinoma [9,11,35,62,76] (Figure 1).

The majority (86%) of FTC is diagnosed in women above the age of 40 years [5,77]. Less than 5% of FTC is heritable and related to syndromes such as FAP, Cowden’s disease, ataxia telangiectasia, and Li-Fraumeni syndrome [78,79]. Follicular carcinoma can develop from a pre-existing follicular adenoma (FA) [9,80,81]. Unlike with PTC, ionizing radiation and Hashimoto’s thyroiditis are not risk factors for follicular carcinoma [17]. The incidence of follicular carcinoma is decreasing globally [16,18,24,30,82,83]. Much of the decline in the prevalence of FTC is due to the iodine supplementation program, increasing expertise among pathologists, advances in immunohistochemistry, and the ability to perform mutational analysis [10,30,84]. However, around 72% of other types of thyroid cancer, including the follicular variant of PTC (FVPTC), are still mistakenly diagnosed as FTC [25,34,85,86,87,88,89]. Additionally, the OC was in the past erroneously considered a sub-type of FTC [90].

Follicular carcinoma of the thyroid usually presents as a nodular goiter, and rarely, patients who have FTC may present with hyperthyroidism or distant metastases from an occult primary tumor [57,64,91]. The common sites of distant metastases from FTC include bone, lung, and brain [57,92,93]. Lymph node metastasis occurs in less than 10% of FTC. The presence of lymph node metastases in a patient who has FTC should necessitate a review of the histopathology slides to rule out a missed FVPTC or other malignancies of the thyroid gland [94]. Because of its relative rarity, the diagnostic workup, staging, risk stratification, treatment, and follow-up of FTC are according to the guidelines developed for the management of PTC [1]. Follicular carcinoma is, however, clinically and genotypically different from PTC. Follicular carcinoma is more aggressive, has a greater propensity for haematogenous metastasis, and is associated with a shorter disease-free survival compared to PTC [28,85,94]. A longstanding FTC may de-differentiate and become a poorly differentiated (PDTC) or an undifferentiated/anaplastic thyroid carcinoma (ATC) [3,7,61,95,96,97,98,99]. Follicular thyroid carcinoma can also co-exist with other malignant tumors of the thyroid gland, which include medullary thyroid carcinoma (MTC) [100,101].

Follicular carcinoma of the thyroid is rarely suspected pre-operatively except in patients who present with systemic metastasis [102,103]. The diagnostic work-up of a suspected FTC is like what is done for any patient presenting with a euthyroid nodular goiter and should include TFT, ultrasound, and FNAC [1]. None of the pre-operative investigations can confirm the diagnosis of FTC [89,102,103]. The majority of patients who have FTC are euthyroid, and the ultrasound examination is likely to show the same worrisome malignancy that is seen in PTC [104,105,106,107,108]. Among the worrisome features for malignancy on ultrasound of FTC is a solid hypoechoic lesion that is taller than wide and has increased intra-nodal vascularity, micro-calcifications, and an irregular border [104,105,106,107,109,110]. Follicular carcinoma is less likely to be multi-centric or multi-focal or be associated with regional lymph node involvement when compared with PTC [40,111]. Ultrasound also helps to pick up cervical lymph node metastasis and is complemented by a CT scan.

The Bethesda System of Reporting and Interpreting Thyroid FNAC (Bethesda System) is the most commonly used system to guide decision making regarding observation, repeat testing, additional pre-operative investigations, diagnostic lobectomy, or definitive surgical procedure for cancer [33,112,113]. The categories of the Bethesda system are non-diagnostic, benign, atypical, indeterminate, suspicious of malignancy, and malignant [33]. Result of FNAC of FTC is likely to yield a Bethesda III or IV lesion, which is an atypical or follicular neoplasm, respectively [33,114]. Follicular carcinoma is differentiated from FA by evidence of vascular and/or capsular invasion, which cannot be shown on FNAC, and FNAC is therefore not able to distinguish FTC from FA [89,102,115]. Follicular adenoma and FTC cannot be distinguished even after immunohistochemistry and mutational analysis [115]. The other thyroid conditions that may be mistaken for FTC following FNAC are adenomatous lesions of colloid goiter, FVPTC, OC, and the follicular variant of medullary carcinoma [89,116]. The diagnosis of FTC is only made after a lobectomy or total thyroidectomy. Diagnostic lobectomy is however unnecessary in up to 70% of the patients whose FNAC yielded a Bethesda System III or IV lesion, as the histology is likely to show a benign disease [33].

The AJCC/TNM staging is used to stage WDTCs, including FTC, and parameters that are considered during the staging are the age of the patient, size of the tumor, evidence of extrathyroidal extension, presence of lymph node metastasis, and/or distant metastases [117]. Patients who are older than 55 years are at high risk of tumor progression or recurrence [2,118]. The categories that are used for tumor size are <2 cm, 2–4 cm, and >4 cm, whereas the nodal involvement is divided into involvement of the central nervous system, including level VII, or lateral cervical lymph nodes [117].

The risk stratification of WDTCs considers gender and age of the patient, family history, type of tumor and histological subtype. The other parameters for risk stratification are tumor differentiation, degree of tumor necrosis, mitotic count, Ki67 index, mutational status and molecular subtypes. Lymph node status, thyroglobulin level, radio-iodine uptake, and PET/CT scan uptake are also important for risk assessment [26,35,51,94,119,120,121,122,123]. Follicular carcinoma is usually more aggressive than PTC, and the WI-FTC is likely to have distant metastases at presentation and lower disease-free survival [124,125]. The same risk scoring systems that are used in PTC are relied on for categorization of FTC, and among them are TNM staging; metastasis, age, completeness of resection, invasion, and size (MACIS); age, gender, extra-thyroidal extension, and size (AGES) and age, metastasis, extra-thyroidal extension and size (AMES) [119,121,125]. Low-risk FTC is a tumor that is less than 4 cm in maximum diameter and has no extra-thyroidal extension, lymph node, or distant metastasis, whereas an intermediate- or high-risk tumor is larger than 4 cm. A patient who has an FTC that is not completely excised, has extensive extrathyroidal extension, or has metastasized to lymph nodes or distant organs has a high-risk tumor [41,126]. Markers that have been used for risk-stratification of WDTC, including FTC, include vitamin D level and neutrophil-lymphocyte ratio (NLR) [52,53].

Patients who have FTC and are older than 55 years old are at increased risk of tumor recurrence or metastasis [2,118]. The organ involved influence the prognosis of patients who have systemic metastases. Patients who have pulmonary metastases from FTC generally do better than those who have metastases to bone, brain, liver, and other organs [93,127]. The prognosis depends on the volume of metastasis in an organ [93,127]. All the risk scoring systems, including the AJCC/TNM systems, are however not able to accurately quantify the burden of the disease, especially in patients with FTC [128]. The pathological diagnosis of FTC and its subtypes is dependent on the availability of expertise to perform the histopathological analysis [87]. Like other cancers, FTC is heterogenous, the aggressive component of the tumor may be overlooked during histopathological assessment, and a patient who has supposedly had mi-FTC and has had an appropriate lobectomy or total thyroidectomy may present years later with distant metastases [45]. The metastases are likely to have been there and were missed during the pre-operative assessment.

The management of FTC follows that of PTC, and the selection of the package of care depends on the risk of recurrence and mortality [13,111]. Lobectomy or total thyroidectomy is the primary curative management of FTC. The other treatment strategies of FTC are added depending on the level of risk [51,56,59,126,129]. Lymph node metastasis occurs in less than 10% of FTCs, and lymphadenectomy is only performed if the involvement is confirmed clinically and/or following imaging investigation [40,111]. Additional treatment that may be required during the treatment of FTC includes radioactive iodine, TSH suppression, metastectomy, tyrosine kinase inhibitors (TKIs), multi-kinase inhibitors (MKIs), and de-differentiation therapy [8,9,61,62,130]. Evidence of de-differentiation of the tumor, which is likely if the tumor is locally advanced with extensive extra-thyroidal extension or is metastatic, may also influence the decision regarding further management of FTC [3,8,61,98,131,132,133].

The diagnosis of FTC is not possible on pre-operative FNAC and is usually made following a diagnostic lobectomy, and the need for a complete thyroidectomy is only considered thereafter based on the size of the tumor and whether a patient is at high risk for recurrence or metastasis [126]. Lobectomy alone is appropriate for a tumor that is 1–4 cm in maximum diameter without high-risk features based on clinical, histological, immunohistochemical, or mutational analysis [56,59]. Total thyroidectomy should be the standard of care for FTC if the primary lesion is more than 4 cm in diameter. Mi-FCT usually has a benign course and does not require a complete thyroidectomy or radioactive iodine ablation. However, areas of major invasion may be missed during histopathological analysis, leading to the erroneous labeling of a wi-FTC as a mi-FTC [11]. The ability to perform mutational analysis is also not universally available.

Another parameter to consider is multifocality. Although the FTC is less likely to be multifocal when compared with the PTC, lobectomy alone in patients who have multifocal disease may lead to recurrence of the tumor [15,68,87]. The tumor that was left in the other lobe may de-differentiate and become a PDTC or ATC [8,54,72,124,131]. The extent of the primary tumor is another predictor of a poorer outcome in patients with FTC. Patients with macroscopic extra-thyroidal spread are at high risk of local recurrence or metastasis and should therefore be offered total thyroidectomy [68,134]. A total thyroidectomy is mandatory if the FTC is metastatic, as post-operative radioactive iodine would be required.

Radioactive iodine is indicated in the management of intermediate- and high-risk FTC for the ablation of a remnant or as adjuvant therapy or treatment of metastatic disease following total thyroidectomy [13]. The aim of ablation therapy is to prevent local recurrence and to facilitate the use of Tg as a tumor marker for monitoring during follow-up [2,3,13,135]. The standard dose of I-131 for ablation of the remnant of the thyroid is 30 mCi. The dose for ablation of the remnant is administered around 6 weeks after a near-total or total thyroidectomy, when the s-TSH level is expected to have risen to 30 mIU/mL or higher [136]. A high level of s-TSH is achieved after a period of deferral of thyroxine replacement or by using recombinant TSH [72,135]. Adjuvant I-131 is to target presumed micrometastases from an intermediate- or high-risk FTC, which were however not picked up during pre-operative evaluation [56]. A dose of up to 150 mCi is necessary for ablation of metastases from FTC and can be increased to around 200 mCi if the metastases are extensive [3,28,135,136].

The dose of I-131 is adjusted considering the age of the patient, co-morbidities, the organ involved, and the burden of the metastases [72,135]. Clinical dosimetry is, however, less accurate when compared with radioisotope-based dosimetry. Dosimetry using I-124, I-123, or I-131 is useful for guiding the most effective dose of I-131 while reducing the likelihood of side effects [13]. Radioisotope-based dosimetry may also assist in the early identification of dedifferentiated metastases from FTC that are not trapping the iodine to avoid futile treatment. Problems associated with the use of I-131 during the management of FTC include side-effects like bone marrow suppression, xerostomia, infertility, severe hypothyroidism during the suspension of thyroxine replacement, and the development of a second primary malignant tumor [127,134,137,138]. The additional concerns of the use of I-131 for treatment in patients who have extensive lungs or brain metastases are that they may develop pulmonary fibrosis that may lead to respiratory failure or brain oedema, respectively [92,127,138]. Other challenges linked to the management of FTC using I-131 include the heterogeneity of cancer. The FTC may not be I-131 avid and therefore resistant to radioactive treatment. Resistance to I-131 is likely in patients who have metastatic disease [3,47,95,99,132,135,136,139,140,141,142]. Around 10% of TC cancers are under-staged and deemed low-risk, not needing I-131 ablation or adjuvant therapy). Similarly, areas of WI-FTC may be missed during histopathological analysis [11,86].

Patients who have had a total thyroidectomy need thyroxine for replacement and suppression. All patients who have FTC require TSH suppression regardless of the risk level [13,117,126]. The intensity of TSH suppression depends on the age of the patient, the presence of co-morbidity, and the level of risk for tumor recurrence or mortality [126,143]. The TSH suppression may be severe, moderate, or minimal [144]. Severe TSH suppression is when the TSH level is below 0.01 mU/L, moderate suppression is 0.01–0.1 mU/L, and mild suppression is 0.1–0.5 mIU/L [144]. Severe and moderate TSH suppression increase the risk of cardiac and musculoskeletal side effects. Cardiac side effects of high doses of thyroxine include atrial fibrillation and an increased risk of ischemic heart disease [145,146]. Osteoporosis is among the most severe musculoskeletal complications of a suppressive dose of thyroxine [147]. Additional side effects of extreme TSH suppression include depression and weight loss [147]. Furthermore, some of the patients may be misclassified as having low-risk instead of high-risk FTC and be erroneously placed on a less intense TSH suppression program [148]. The other problem with TSH suppression in the management of FTC is in tumors that have acquired aggressive mutations, have de-differentiated, and are no longer responsive to treatment [9,83,142].

Some of the patients who have FTC may present with a tumor that has invaded the aerodigestive tract [49,149]. Mortality in half of the patients who have TC is related to local invasion of the upper aerodigestive tract and major vessels in the neck by the tumor [150]. Despite the extensive local invasion, curative resection may still be feasible unless the tumor is invading the carotid vessels or prevertebral fascia [149,151]. The nature of surgical resection may be extensive en-block resection of the larynx or oesophagus or a shaved excision [149]. Other treatment options for FTC with extensive extra-thyroidal extension include external beam radiotherapy and radiofrequency ablation [96,152]. Extensive extra-thyroidal extension is a marker of a high-risk FTC that is likely in tumors that have de-differentiated and become PDTC or ATC [96,149]. The area of de-differentiation might have been missed during the sampling and analysis of the FNAC or post-thyroidectomy specimen [96]. In some cases, the cancer might have already spread systemically, making the sometimes-debilitating en-block resection a futile operation.

The incidence of systemic metastases in FTC has been reported at 5–23% [150,153]. Follicular cancer rather than papillary thyroid cancer is more likely to metastasize to distant organs. Common sites of metastases for WDTC are the lungs, bones, brain, skin, and liver [65,93]. Male sex, older age, tumor size greater than or equal to 4 cm, vascular invasion, and lymph node involvement are some of the risk factors for systemic metastasis from FTC [153]. Systemic metastases are likely in TC with evidence of extra-thyroidal extension [153]. Poor prognostic features in patients who have metastatic FTC include age over 55 years, size of metastasis above 10mm in the maximum diameter at detection, and a high neutrophil to lymphocyte ratio). Well-differentiated FTC, especially in children, and FVPTC are relatively more I-131 avid and are therefore likely to respond to ablation or treatment [123].

The choice of treatment for FTC considers the patient’s age, comorbid conditions, sites, and number of metastases [1,5,40,51,63,72]. The prognosis of metastatic FTC is better in children and young adults, patients who have isolated lung metastases, metastases less than 5 cm in maximum diameter, and oligometastatic disease [1,2,26,40,51,56,63,66,71,72]. Patients who have intermediate- or high-risk FTC are likely to have systemic metastasis and be given adjuvant I-131 [1]. Radioactive iodine treatment is for the management of patients whose metastases are overt, and a dose of up to 200 mCi is used [117]. Treatment with I-131 is added after a patient has had a total thyroidectomy with or without resection of metastases that are amenable to resection [72]. Some of the problems associated with I-131 treatment of metastatic disease include the side effects, which are sometimes severe, like bone marrow suppression, infertility, and the development of another cancer [72,127]. A higher dose of I-131 is to be avoided in patients who have extensive pulmonary metastases and borderline lung function, multiple brain metastases, or large metastases to the vertebra, as it may lead to complications like pulmonary fibrosis, brain oedema, or instability of the spine [117,127]. However, extensive metastases are less likely to be iodine-avid as they would most probably have mutated and de-differentiated.

Patients who have metastatic FTC are in the high-risk group for WDTC and should be placed on an intense or high TSH-suppression protocol, unless there are contraindications, or it is not tolerated. The other options in the management of metastatic FTC are surgical excision, external beam radiotherapy, local ablative therapy, and kinase inhibitors. Surgical excision is preferred for the treatment of isolated metastases from FTC to most organs, including the lung, bone, brain, and liver. The TKIs are useful alone or when combined with other multi-kinase inhibitors (MKIs), especially if the FTC has dedifferentiated and is no longer retaining I-131 [72]. Examples of TKIs include lapatinib and vemurafenib [154]. The MKIs that are useful against WDTC include cabozantinib, lenvatinib, and sorafenib [71,155,156].

The lung is the commonest site of distant metastases from FTC. Patients who have pulmonary metastases from FTC have a reduced 5-year and 10-year survival of 68.5% and 54%, respectively [153]. Lung metastases in FTC are likely to be macronodular when compared with secondary tumors in PTC [153]. The success rate of I-131 in the management of pulmonary metastases from FTC is lower than the 58% that is achieved in cases of metastatic PTC [153]. Patients who have FTC are usually older than those who have PTC and are therefore more likely to have co-morbidities [68]. A tolerable dose of I-131 depends on the baseline lung function and the extent of the disease, as ablation of the extensive pulmonary metastasis and their replacement with fibrous tissue may push the patient to irreversible respiratory failure. The other options for the treatment of pulmonary metastasis from FTC include surgical excision, percutaneous ablation, stereotactic radiotherapy, and tyrosine kinase or multi-kinase inhibitors [153].

The 18F-FDG PET/CT is useful for the investigation of recurrent or metastatic FTC when it is no longer I-131 iodine-avid. De-differentiation of FTC is associated with an increase in the expression of glucose transporter receptor type 1 and therefore high uptake of 18F-FDG PET/CT [72]. The uptake of DOTA PET by some of the metastases from FTC that have lost the ability to trap iodine is even higher than that of 18F-FDGvPET/CT, which raises the possibility of utilizing 177Lu as a potential theranostic agent [153]. There are numerous society guidelines for the management of metastatic disease from differentiated thyroid cancers, and most of them address WDTCs as a group and not specifically FTC [45]. The guidelines are mainly for PTC. Ongoing research for markers predictive of poor prognosis includes the investigation of Telomerase Reverse Transcriptase (TERT) promoters and RNA H-19. Challenges associated with the management of metastatic FTC include delay in their detection, underestimation of the extent of the disease, and dealing with metastases that do not take I-131 [150]. Sometimes, metastases are missed, and FTC is erroneously labeled as low-risk and treated without total thyroidectomy, I-131 ablation, or adjuvant therapy and TSH suppression, only to present years later with systemic metastases.

Patients with FTC are more likely to develop bony metastases than those who have PTC. The bone is the second most common site of metastases from FTC. The prognosis of patients who have bone metastases is poorer when it is compared with that of patients in whom the FTC has spread to the lungs. Additionally, bone metastasis from FTC is less sensitive to I-131. The bone metastases may be symptomatic or detected on CT, MRI, 18 FDG PET CT, SPECT/CT, or WBS using I-123, I-124, or I-131. Patients who have metastatic FTC are treated with I-131 together with TSH suppression unless the metastases are no longer iodine-avid, but FTC tends to acquire aggressive mutations as it progresses and metastases. Radioisotope-based dosimetry, although not uniformly practiced, can provide guidance on the safety and efficacy of I-131 treatment and help avoid unnecessary toxicity and treatments in patients in whom the metastases are not responding to the treatment [153]. Usually, close to 30% of patients who have metastatic FTC do not respond to I-131 [153].

Brain metastases from FTC are rare and occur in less than 1% of the patients, and over 70% of the patients who have brain metastases from FTC are likely to have synchronous pulmonary metastases [28,157]. The prognosis of patients who have FTC with metastasis to the brain is poor, and the overall survival is less than 3 years even with treatment [158]. Resection for an isolated brain metastasis from FTC is preferred if it can be excised [157,159]. Severe TSH suppression should be part of the treatment of brain metastases from FTC. Treatment with I-131ne is effective if the metastases are iodine-avid and not extensive. The other options for the treatment of brain metastases from FTC include stereotactic radiosurgery, external beam radiotherapy, and multi-kinase inhibitors [28,157].

De-differentiation of FTC is a process that happens during tumor progression, and a de-differentiated cancer is likely to have new mutations and become aggressive and resistant to conventional therapy, such as I-131. De-differentiated FTC and PTC, PDTC, and ATC account for most of the deaths due to TC. The more prevalent mutations in de-differentiated TCs, including FTC, are BRAF, RAS, TP53, TERT promoter, and P13K/AKT/mTOR pathway effectors [98,160]. Both SPEC/CT and PET/CT are useful for evaluating the burden of metastases in cases where the tumor is no longer iodine-avid. The treatment of de-differentiated FTC is like that of PDTC and ATC and includes the use of TKIs or MTIs. Some of the de-differentiated FTCs may overexpress somatostatin receptor type 2 (SSTR2) and could be evaluated with 68Ga-DOTANOC PET/CT. Patients whose metastases demonstrate high uptake of 68Ga-DOTANOC may respond to treatment with 177Lu-Dotatate [161].

Guidelines relating to the follow-up of FTC are often inferred from those of PTC, even though FTC forms a unique subgroup of DTC (differentiated thyroid cancer) and, therefore, requires specific considerations. A multidisciplinary approach with well-established communication channels between clinical endocrinologists and surgeons, pathologists, oncologists, radiologists, and nuclear physicians should form the backbone of the care of a patient who has FTC. Placing the patient in the center goes a long way towards improving the quality of care and eventually securing a good outcome. An important tool in achieving this is risk stratification, which consists of both. Patients who have been treated for FTC require lifelong follow-up, regardless of the initial risk level of the tumor [121]. The follow-up is intense in the first year following definitive treatment. Dynamic risk stratification, clinical evaluation, serum basal and stimulated Tg levels, and neck ultrasound are used during follow-up monitoring. Concurrent testing for the existence of Tg antibodies must be done to reduce the likelihood of falsely low levels of Tg.

The success of the management of the FTC should be determined within the first 3–6 months. Patients can be categorized as possibly cured both biochemically and anatomically, biochemically incomplete, or anatomically residual. The primary purpose of the stringent follow-up of cases of FTC is for the timeous diagnosis of persistence or local recurrence of the tumor or the appearance of new metastases. It is also critical that the de-differentiation of FTC is detected and managed early, using agents such as TKI or de-differentiation therapy to improve the chance of long-term survival [8,72,131]. The follow-up of patients on TKIs or MKIs must be regular and stringent to watch for side-effects. The most dreadful complication is bleeding, which, although rare, may be fatal [70].

It is not usual for metastases from FTC to lie dormant and unsuspected, even for tumors that are deemed low-risk clinically, pathologically, and radiologically [54,57,148,162]. Follicular thyroid carcinoma may acquire aggressive mutations as it progresses. Some of the aggressive mutations that the FTC can acquire include TP53, TERT, and PI3K/AKT/mTOR mutations [3,6,9,47,61,98,99,132,163,164].

The outcome of patients who have FTC depends on the stage of the disease at presentation. The available staging systems for WDTC are not able to accurately predict disease-specific mortality [35]. The AJCC is the most commonly used staging system. Unfortunately, the AJCC/TNM staging on its own is not enough to direct and monitor a specific therapy. Other risk stratification systems are considered to improve the care of patients with DTC. The inclusion of intra-operative findings, histopathological changes, and genomics improves the prognostication of FTC.