Follicular thyroid cancer (including oncocytic carcinoma of the thyroid)

INTRODUCTION — Thyroid follicular epithelial-derived cancers include papillary, follicular, and anaplastic cancer. Papillary and follicular cancers are considered differentiated cancers. Follicular thyroid cancer is less common than papillary thyroid cancer. In iodine-sufficient areas, up to 12 percent of all thyroid cancers are follicular cancers, whereas 85 percent are papillary. The molecular pathogenesis, clinical features, diagnosis, and prognostic features of follicular thyroid cancer will be provided here. Papillary thyroid cancer and the management of differentiated thyroid cancer are discussed separately. (See "Papillary thyroid cancer: Clinical features and prognosis" and "Differentiated thyroid cancer: Overview of management".)

EPIDEMIOLOGY — Follicular thyroid cancer tends to occur in an older population when compared with other differentiated thyroid cancers. Its peak incidence is between ages 40 and 60 years, as compared with papillary thyroid cancer incidence peaking earlier, between the ages of 30 to 50 years. In addition, follicular thyroid cancer is approximately three times more common in women than in men [1].

Iodine may also play a role in the epidemiology of follicular thyroid cancer. In iodine-deficient regions of the world, there is a higher prevalence of follicular cancer compared with iodine-sufficient regions. With the introduction of iodine, some studies showed that the incidence of follicular thyroid cancer decreased, while papillary thyroid cancer increased [2,3]. In a report from Poland, rates of follicular thyroid cancer actually decreased between 1982 and 2012, a time during which rates of papillary thyroid cancer were increasing [4]. In an analysis of 90,803 incident cases of thyroid cancer from the SEER 9 registry data (1975 to 2016), the incidence of follicular thyroid cancer was fairly stable during the study period [5]. (See "Papillary thyroid cancer: Clinical features and prognosis", section on 'Incidence'.)

RISK FACTORS — Risk factors for follicular thyroid cancer are similar to those for papillary thyroid cancer and include a history of radiation exposure during childhood, a history of thyroid cancer in a first-degree relative, or a family history of a thyroid cancer syndrome. Radiation exposure of the thyroid during childhood is the most clearly defined environmental factor associated with benign and malignant thyroid tumors. (See "Papillary thyroid cancer: Clinical features and prognosis", section on 'Risk factors'.)

MOLECULAR PATHOGENESIS — Most follicular thyroid cancers are probably of monoclonal origin. In addition, oncogene activation is common. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer", section on 'Follicular thyroid cancer'.)

Factors associated with follicular thyroid cancer include:

RAS mutations — Point mutations of the RAS oncogene are seen in approximately 40 percent of follicular cancers [6]. These mutations (N-RAS, H-RAS, and K-RAS, in order of decreasing frequency) occur more commonly in follicular thyroid cancers than in follicular adenomas [7,8]. RAS mutations are not specific to follicular thyroid cancer; they also account for a small portion of papillary thyroid cancers, particularly the follicular-variant papillary thyroid cancer [8].

RAS mutations in follicular thyroid cancer appear to be associated with more aggressive cancers and higher mortality [9]. In addition, RAS mutations may be found in poorly differentiated and anaplastic thyroid cancers [9].

PAX8-PPAR gamma 1 — PAX8-PPAR gamma 1 is a gene rearrangement seen in follicular adenomas and cancers. This fusion protein of a thyroid-specific transcription factor (PAX8) and a nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma, is associated with approximately 10 percent of follicular adenomas and 41 percent of follicular cancers [10]. This fusion protein may help distinguish follicular adenoma from follicular carcinoma [11]. It is thought that PAX8-PPAR gamma 1 induces a negative effect on thiazolidinedione activation by PPAR gamma, leading to loss of growth inhibitory controls [12].

The fact that follicular thyroid cancer contains either RAS mutations or a PAX8-PPAR gamma 1 rearrangement, but not both, indicates that similar, yet distinct molecular events may originate with these two oncogenes.

Other — Other factors, such as p53, c-myc, c-fos, telomerase reverse transcriptase (TERT) promoter mutations, and thyroid-stimulating hormone (TSH) receptor mutations, have also been implicated [13,14]. Unlike papillary thyroid cancer, follicular thyroid cancer is rarely associated with RET/PTC mutations or BRAF mutations [15,16].

Follicular thyroid cancer can be seen as part of familial neoplastic syndromes, such as Cowden syndrome (PTEN), Carney complex type 1 (PRKAR1alpha), or Werner syndrome (WRN). (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Thyroid' and "Carney complex", section on 'Endocrine tumors'.)

CLINICAL FEATURES

Clinical presentation — Patients with follicular thyroid cancer typically present with a thyroid nodule. Thyroid nodules come to clinical attention when noted by the patient, as an incidental finding during routine physical examination or during a radiologic procedure, such as carotid ultrasonography, neck computed tomography (CT), or positron emission tomography (PET) scanning. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Evaluation'.)

Histology — The histology ranges from normal, well-differentiated epithelium with follicular development and colloid (findings associated with a good prognosis) to poorly differentiated with solid growth, absence of follicles, marked nuclear atypia, and extensive vascular and/or capsular invasion (characteristics that are associated with a worse prognosis) (picture 1) [17] (see 'Prognostic features' below). Typically, the microfollicular architecture is uniform with an invariant collection of cuboidal cells lining the follicles. In addition, features consistent with papillary cancer, such as psammoma bodies and nuclear changes (ground-glass appearance, longitudinal grooves, nuclear overlapping, and inclusions), should be absent. Microscopically, the diagnosis of follicular cancer requires distinguishing adenoma from cancer through identification of tumor extension through the tumor capsule and/or vascular invasion (picture 2 and picture 3).

●Follicular thyroid cancer – Well differentiated follicular thyroid cancers are classified into one of the three following groups based on the type and extent of invasion [17-21]:

•"Minimally invasive follicular thyroid cancer," which includes tumors with invasion only of the capsule of the tumor without vascular invasion (American Thyroid Association [ATA] low-risk tumor) (table 1).

•"Encapsulated angioinvasive follicular thyroid cancer," which includes encapsulated tumors with any evidence of vascular invasion. We further risk-stratify angioinvasive encapsulated follicular thyroid cancers based on the number of vessels involved as either ATA low risk (<4 foci of vascular invasion, often referred to as limited or minimal vascular invasion) or ATA high risk (≥4 foci of vascular invasion, often referred to as extensive vascular invasion) (table 1).

•"Widely invasive follicular thyroid cancer," which includes tumors with clinically obvious gross invasion of the thyroid gland and extrathyroidal soft tissues, usually with extensive vascular invasion often involving extrathyroidal vessels. It is important to note that vascular invasion alone, even if ≥4 foci, does not provide sufficient evidence to classify the tumor as widely invasive follicular thyroid cancer in the absence of gross invasion.

Uncommon histologic variants of follicular thyroid cancer are rarely seen (eg, clear cell variant, signet-ring cell type, follicular thyroid cancer with glomeruloid pattern, and spindle cell follicular thyroid cancer) [22]. It is unclear whether the biological outcomes of these subtypes differ substantially from classic follicular thyroid cancer.

●Oncocytic carcinoma of the thyroid – Historically, oncocytic carcinoma of the thyroid (previously called Hürthle cell cancer) was considered to be a variant of follicular thyroid cancer. However, recent clinical and molecular studies clearly indicate that oncocytic carcinoma of the thyroid is a distinct tumor type [22]. Clinically, oncocytic carcinoma of the thyroid often has a similar clinical presentation to follicular thyroid cancer (usually asymptomatic thyroid nodule in older patients) and a similar pattern of distant metastases (lung, bone, brain). Histologically, it is characterized by the presence of a cell population of "oncocytes," mostly eosinophilic oxyphilic cells with abundant cytoplasm, closely packed mitochondria, and round oval nuclei with prominent nucleoli (picture 4) [23]. Unlike follicular thyroid cancer, oncocytic carcinoma of the thyroid has more of a propensity to spread to cervical lymph nodes [24]. While metastatic lesions in follicular thyroid cancer often concentrate radioiodine, oncocytic carcinoma of the thyroid metastatic foci are often radioiodine refractory. Furthermore, the molecular profile of oncocytic carcinoma of the thyroid is very distinct from follicular thyroid cancer (see "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer", section on 'Follicular thyroid cancer'). Thus, oncocytic carcinoma of the thyroid is now considered a distinct form of follicular cell-derived thyroid cancer.

Lymph node involvement — Follicular tumors are more typically uninodular when compared with papillary thyroid cancer. While vascular invasion is frequent with follicular cancer, spread to lymph nodes is uncommon, occurring in only 8 to 13 percent of cases [25]. However, lymph node involvement is more common in oncocytic carcinoma of the thyroid [26]. In contrast, lymph node involvement is very common in papillary thyroid cancer. (See "Papillary thyroid cancer: Clinical features and prognosis", section on 'Histology'.)

Metastases — Follicular thyroid cancer typically spreads via hematogenous dissemination. Distant metastases occur in 10 to 15 percent of patients with follicular cancer, even in those with small primary tumors, although tumors <2 cm in size have not been associated with metastatic disease [27]. Common sites of distant metastases are bone (with lytic lesions) and lung and, less commonly, the brain, liver, bladder, and skin (image 1) [26].

Although rare, functional thyroid cancer metastases can cause symptomatic hyperthyroidism. Nearly all patients reported have had widely metastatic follicular thyroid cancer, often involving bone among other organs [28,29]. The majority of patients with functional thyroid cancer metastases have had high serum triiodothyronine (T3) but normal thyroxine (T4) concentrations (T3-thyrotoxicosis). The mechanism is high activity of the type 1 and type 2 iodothyronine deiodinases in tumor tissues, ie, exogenously administered levothyroxine is converted to T3 [30]. A few of these patients have also had serum TSH receptor-stimulating antibodies, the presence of which would be expected to increase the hormonal synthetic capacity of the cancer [29].

The functional metastases can be identified by whole-body radioiodine imaging. Treatment may require a variety of approaches including thionamides, radioiodine, surgery, or external radiotherapy. (See "Differentiated thyroid cancer: Overview of management" and "Differentiated thyroid cancer: Radioiodine treatment" and "Differentiated thyroid cancer: External beam radiotherapy".)

DIAGNOSIS — The actual diagnosis of follicular thyroid cancer requires histologic evaluation of the thyroid after surgery and the identification of tumor capsule and/or vascular invasion.

Although fine-needle aspiration (FNA) is the initial diagnostic tool of choice in evaluating thyroid nodules, exceeding the utility of physical exam, laboratory evaluation, and imaging tests, FNA biopsy cannot diagnose follicular thyroid cancer (unlike papillary thyroid cancer), because it cannot distinguish between follicular adenomas and cancers. These FNA specimens are often indeterminant lesions, categorized as follicular neoplasms or atypia of undetermined significance (AUS), with epithelial cells arranged in a pattern of microfollicles, scant or absent colloid, and few macrophages. (See "Atlas of thyroid cytopathology", section on 'Follicular neoplasm'.)

For patients with initial cytologic results showing follicular neoplasm or repeat aspirates confirming a reading of AUS, further evaluation is necessary. Evaluation may include molecular testing of FNA aspirates or, if no such testing is not available, diagnostic lobectomy. Molecular testing of FNA aspirates can reduce but not eliminate the number of patients who require diagnostic surgery. The use of molecular markers in the evaluation of thyroid nodules is reviewed in detail separately. (See "Evaluation and management of thyroid nodules with indeterminate cytology in adults", section on 'Molecular markers' and "Atlas of thyroid cytopathology", section on 'Follicular neoplasm' and "Evaluation and management of thyroid nodules with indeterminate cytology in adults", section on 'Evaluation and management'.)

PROGNOSTIC FEATURES — The prognosis for differentiated thyroid cancers is best for young patients who have minimal capsular and vascular invasion. Given that follicular cancer typically occurs in older patients, it is more commonly associated with an aggressive clinical course, distant metastases, and higher mortality than papillary thyroid cancer. Women may have a better prognosis than men [26].

Stage — Postoperative staging, based upon the clinicopathologic features of each case, is important for providing prognostic information. We use both the tumor, node, metastasis (TNM) classification scheme for prediction of disease-specific mortality (table 2) and the American Thyroid Association (ATA) risk of recurrence staging system for initial assessment of risk of recurrence (table 1). While initial risk stratification can be used to guide initial therapeutic and diagnostic follow-up strategy decisions, it is important to recognize that initial risk estimates may need to change as new data are accumulated during follow-up for each individual patient. Staging is reviewed in more detail elsewhere. (See "Differentiated thyroid cancer: Clinicopathologic staging".)

Age — Age is a significant prognostic factor [26,31]. The 10-year survival rate for patients with differentiated thyroid cancer is over 95 percent if the patient is less than 40 years of age [32]. Patients in whom the diagnosis occurs between ages 40 to 59 years have an 80 percent 10-year survival rate.

Tumor characteristics — Other prognostic factors associated with higher mortality include:

●Distant metastasis – Up to 25 percent of cases of follicular thyroid cancer may include distant metastasis [33].

●Vascular invasion.

●Capsular extension – Minimally invasive follicular cancer (MIFC) has been associated with good survival and is considered low risk when compared with widely invasive follicular cancer (WIFC). WIFC typically occurs in an older population, with larger tumor size, invasion into the thyroid, and distant metastases. When both extensive capsule and vascular invasion are present, distant metastases are present in more than 50 percent of cases [17].

●Tumor size – Unlike papillary thyroid cancer, no "occult" follicular thyroid cancer or microcarcinoma with minimal mortality risk exists. Smaller tumors should be examined using the same risk categories as used with larger tumors. There is a linear relationship when comparing the size of the tumor with cancer mortality and recurrence [31].

●Early recurrence, which more commonly occurs in older male patients [34].

●Oncocytic carcinoma of the thyroid may be associated with poorer prognosis than follicular cancer, perhaps related to the tumor's poor affinity for taking up radioiodine. In one study, the 10-year, disease-free interval was 75 percent for follicular cancer and 41 percent for oncocytic carcinoma of the thyroid [35]. Oncocytic carcinoma of the thyroid has been shown to have an increased recurrence rate in local lymph nodes [26].

●Insular cancer, a poorly differentiated follicular thyroid cancer variant, also carries a poor prognosis as it is commonly found to be an invasive tumor with extensive regional and distant metastasis [36].

TREATMENT — Papillary and follicular cancers are treated similarly despite numerous biologic differences [37]. The optimum treatment, however, remains controversial as there is a lack of randomized controlled trials comparing various modalities in follicular thyroid cancer. Therefore, treatment strategies for follicular thyroid cancer are based primarily upon indirect evidence from papillary thyroid cancer data. Treatment should be based upon risk assessment of each individual patient. An important part of treatment is continued reassessment of the risks of recurrence and mortality as new information is gathered during follow-up evaluations. The management of differentiated thyroid cancer is reviewed in detail separately. (See "Differentiated thyroid cancer: Overview of management".)

●Surgery is the primary mode of therapy for patients with differentiated thyroid cancer. Preoperative ultrasound is important for planning the surgical procedure. (See "Differentiated thyroid cancer: Overview of management", section on 'Surgical management' and "Differentiated thyroid cancer: Surgical treatment", section on 'Approach to thyroidectomy'.)

●Postoperative management includes treatment with thyroid hormone suppressive therapy (most patients) and radioiodine (high-risk and selected intermediate-risk patients). Postoperative management depends upon the risk of recurrence/persistent disease (table 1). (See "Differentiated thyroid cancer: Overview of management", section on 'Subsequent management based on risk classification'.)

●Other, less common treatment modalities for follicular thyroid cancer include external beam radiotherapy (EBRT) and chemotherapy. EBRT is typically reserved for older patients with nonresectable metastatic disease that does not take up iodine or has been resistant to therapy with radioiodine. Pain relief for bony lesions and spinal cord compression may also indicate a need for EBRT. (See "Differentiated thyroid cancer: External beam radiotherapy", section on 'Indications for EBRT'.)

●For patients with metastatic differentiated thyroid cancer (papillary or follicular) that persists despite radioiodine, TSH-suppressive thyroid hormone therapy, and external radiotherapy, treatment options include observation, kinase inhibitors that primarily target angiogenesis, and traditional cytotoxic chemotherapy. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy".)

MONITORING — Monitoring patients thought to be disease free for recurrence is an important goal for long-term therapy. Methods of evaluation for recurrence depend upon initial therapy and risk of recurrence, and they should be individualized for each patient. (See "Differentiated thyroid cancer: Overview of management", section on 'Monitoring response to therapy'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Thyroid cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Follicular thyroid cancer, a well-differentiated tumor of thyroid epithelium, is the second most common type of thyroid cancer after papillary thyroid cancer. It is more common in iodine-deficient areas and tends to occur in an older population when compared with papillary thyroid cancer. (See 'Epidemiology' above.)

●Molecular pathogenesis – Most follicular thyroid cancers contain either RAS mutations or a PAX8-PPAR gamma 1 rearrangement but not both, indicating that similar yet distinct molecular events may originate with these two oncogenes. (See 'Molecular pathogenesis' above.)

●Clinical presentation and diagnosis – Patients with follicular thyroid cancer typically present with a thyroid nodule. Fine-needle aspiration (FNA) biopsy alone cannot distinguish between follicular adenomas and cancers. These FNA specimens are often indeterminant lesions, categorized as follicular neoplasms or atypia of undetermined significance (AUS). The actual diagnosis of follicular thyroid cancer requires histologic evaluation of the thyroid after surgery and the identification of tumor capsule and/or vascular invasion. (See 'Clinical features' above and 'Diagnosis' above.)

●Prognostic features – Important prognostic features include stage, age, and tumor characteristics (tumor size, vascular invasion, capsular extension, histologic grade, Hürthle cell or insular variant, and distant metastases). (See 'Prognostic features' above.)

●Treatment – The treatment options available for follicular thyroid cancer are the same as for all differentiated thyroid cancers. The management of differentiated thyroid cancer is discussed separately. (See "Differentiated thyroid cancer: Overview of management" and 'Treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Stephanie L Lee, MD, PhD, and Sonia Ananthakrishnan, MD, who contributed to an earlier version of this topic review.