Continuing Education Activity

The thyroid gland functions to produce the thyroid hormone, which is needed by the body to carry out different metabolism. Follicles comprise the thyroid and are the functional and structural units of the gland. Thyroid cancer is one of the most common endocrine tumors and is classified as differentiated or undifferentiated. Differentiated cancers include papillary and follicular thyroid carcinoma, and undifferentiated types include medullary thyroid and anaplastic cancer. This activity reviews follicular thyroid cancer, describing the etiology, epidemiology, histology, evaluation, staging, and complications of follicular thyroid cancer and the role of interprofessional teams in caring for patients with this condition.

Objectives:

• Outline the typical presentation of a patient with follicular cancer.
• Describe the typical evaluation findings associated with follicular cancer.
• Explain the treatment options for patients with follicular cancer.
• Review the importance of improving care coordination amongst interprofessional team members to improve outcomes for patients with follicular cancer.

Introduction

The thyroid is an endocrine gland located just below the cricoid cartilage in the neck, and it is composed of both the right and the left lobes separated by an isthmus. The thyroid gland produces thyroid hormone, which the body needs to support various metabolic functions. Follicles comprise the thyroid gland and are its functional and structural units.[1] Epithelial cells line the follicles, which may be cuboidal or columnar, depending on activity. These cells may undergo abnormal growth, leading to follicular malignancy. Thyroid cancer is among the most common endocrine tumors and is classified as differentiated or undifferentiated.[2] Differentiated cancers include papillary and follicular thyroid carcinoma, and undifferentiated types include medullary thyroid cancer and anaplastic cancer. Papillary thyroid cancer accounts for most varieties. Follicular thyroid cancer is the second most prevalent type, accounting for 10 to 15% of all thyroid cancer.[3] Undifferentiated types are rare compared to differentiated types.[4]

Up to half of follicular carcinoma cases harbor RAS point mutations, while one-third harbor PAX-PPAR-gamma rearrangements, and only 3% harbor both.[5][6] Follicular thyroid cancer is a tumor of the follicular cells, which are cuboidal epithelial cells and have capsular and vascular invasive properties. Compared with follicular carcinoma, follicular adenoma is benign and occurs more commonly, with a ratio estimated at 5 to 1.[7] This topic focuses more on the follicular type of thyroid cancer, discussing the etiology, epidemiology, histology, evaluation, staging, and complications of follicular thyroid cancer.

Etiology

The cause of thyroid cancer has links to radiation exposure, iodine intake, diabetes, obesity, Hashimoto thyroiditis, exogenous estrogen use, and dietary choices.[2] After the 1986 Chornobyl explosion, many radiation-induced cancers were observed, including thyroid cancer.[8] The position of the thyroid makes it an easy target for radiation exposure. The thyroid is very sensitive to radiation at a younger age, and after exposure, the relative risk of having cancer is estimated to persist for over 50 years.[9] Apart from nuclear radiation, individuals can also get exposure through x-rays and computed tomography scans. The increased use of these imaging studies could lead to an increased incidence of thyroid cancer. There is a controversy on whether iodine excess or deficiency causes thyroid cancer.[10]

In some studies, like Knobel et al in 2007, it was found that iodine intake was a predisposing factor for thyroid cancer.[11] In another study by Fortner J.G et al, it was observed that iodine deficiency could lead to thyroid epithelial cell carcinomas.[12] Diabetes and obesity also share links with the rise in thyroid cancer.[13] Hashimoto thyroiditis has been reported to cause thyroid cancer as well, mostly believed because it leads to an increase in the production of pro-inflammatory cytokines and oxidative stress.[2] Diet choices play a significant role in the incidence of thyroid cancer. Foods such as cabbage, broccoli, cauliflower, chicken, pork, and poultry have been found to cause an increased incidence of thyroid cancer. In contrast, vegetables such as persimmons and tangerines are inversely associated with thyroid cancer incidence.[14] Too much multivitamin use has been shown to cause an increased incidence of thyroid cancer due to iodine content.[14] High nitrate or nitrite-containing foods have also been shown to increase the incidence of thyroid cancer.

Some occupations have been correlated with an increased incidence of thyroid cancer. Occupational exposure to radiation, pesticides, and working in the textile industry has also shown an increased association with thyroid cancer.[15]

Epidemiology

Thyroid cancer ranks as the ninth most common cancer and accounts for 3.8% of all new cancer cases in the United States.[16] In 2017, the number of new cases of thyroid cancer was projected to be 56,780, with females having a higher incidence compared to males.[17] Follicular thyroid cancer is the second most common cause of thyroid cancer, and it accounts for 4% to 39% of all thyroid cancers.[18] Follicular thyroid cancer is more common in older females, with a female-to-male ratio of 3 to 1 and an average age of presentation at 60 years old.[7] Some results show that follicular thyroid cancer incidence is approximately 10% in iodine-sufficient areas and 25 to 40% in areas of iodine deficiency.[7] In the United States, the incidence of follicular thyroid cancer has decreased due to the elimination of iodine deficiency.[7][19]

History and Physical

Patients with thyroid carcinoma might have an enlargement of the thyroid gland due to the presence of a nodule in either or both thyroid lobes. They can occasionally be symptomatic with either hypothyroid or hyperthyroid characteristics, but they are usually asymptomatic. 

Evaluation

Ultrasound imaging and ultrasound-guided fine needle aspiration or core biopsy are used to diagnose primary thyroid carcinoma. Ultrasound of primary thyroid cancer usually shows solid hypoechoic nodules with microcalcifications, poorly defined margins, and a dominant intranodular vascular pattern, rather than perinodular.[20] Computed tomography and magnetic resonance imaging are used to evaluate extrathyroidal tumor extension, but not the thyroid nodule itself.[20] The samples obtained by fine-needle aspiration or core biopsy are then examined under the microscope for confirmation. Follicular thyroid carcinoma is diagnosed based on pathologic confirmation of follicular cells that do not have the nuclear atypia seen in papillary thyroid cancer, including capsular and vascular invasion. Therefore, the basis of evaluation is primarily the pathologist's histological findings. Thyroid carcinoma is classified as follicular if it is invasive and predominantly composed of follicles. Histologic findings have been reported to vary among pathologists, leading to controversy in the classification of follicular thyroid carcinoma.[21] See Image. Metastatic Follicular Thyroid Carcinoma, CT Scan.

Treatment / Management

The treatment and management of follicular thyroid carcinoma depend on the stage at presentation. Follicular thyroid carcinoma with minimally invasive characteristics is treated with thyroid lobectomy and isthmectomy, but for invasive follicular carcinoma, total thyroidectomy, radioiodine ablation, and thyrotropin-suppressing medications are all recommended.[22][23][24] A study reported a 2.1-fold increase in follicular thyroid cancer recurrence in those who did not undergo radioiodine ablation compared to those who did, which is why the standard treatment recommendation is total thyroidectomy followed by radioiodine ablation.[25][26] 

For patients with metastasis to bones and soft tissues, either radiotherapy or chemotherapy, or both, are indicated after the total thyroidectomy. Chemotherapies reported to control tumor progression and prolong progression-free survival include tyrosine kinase inhibitors such as sorafenib, lenvatinib, vandetanib, and cabozantinib.[27] Newer agents working through new pathways also show some good responses.[28] Thyroglobulin levels are measured to monitor for recurrence. 

Differential Diagnosis

Differential diagnosis of follicular thyroid carcinoma includes a follicular variant of papillary thyroid carcinoma, papillary thyroid carcinoma, noninvasive follicular thyroid neoplasm with papillary-like nuclear features or NIFTP, and follicular adenoma.[29] There is a controversy with the pathologic diagnosis of follicular thyroid carcinoma, and identification could differ from 1 pathologist to another. This controversy stems from 2 factors: the degree of nuclear atypia and the degree of capsular or vascular invasion.[21][30] 

NIFTP is 1 of the newest categories added to the pathology description of thyroid cancer cases. It is now considered benign, so it is recommended to be treated as such.[31][32][33] Special criteria for ultrasound-based radiologic diagnosis are being developed to distinguish malignant from benign lesions.[31][34][35]

Staging

The TNM staging system is used to classify differentiated thyroid carcinoma. The T describes the tumor's size. Tx indicates that the primary tumor cannot be assessed; T0 means the tumor is not palpable; T1 means less than 1cm; T2 means 1 to 4 cm; T3 means greater than 4 cm; and T4 means any tumor size with extrapyramidal invasion. The N signifies lymph node involvement. Nx signifies regional adenopathy is not assessable, N0 means no palpable cervical adenopathy, N1 means ipsilateral cervical adenopathy, N2 means contralateral or bilateral cervical adenopathy, and finally, N3 means fixed cervical nodes. M means metastasis, with M0 indicative of no distant metastasis, and M1 indicates distant metastasis. Follicular thyroid carcinoma is classified into stages from I through IV. Stage I under 45 years old is any T, N, and M0, and over 45 years old is T1, N0, M0; for stage II under 45 years old is any T, N, and M1, and over 45 years old is T2, N0, M0; stage III is described for over 45 years of age with T4, N0, M0, and stage IV is defined with any T, N, M1.[18]

Prognosis

The thyroid cancer death rate has remained steady despite the increase in incidence. Thyroid cancer is among the lowest mortality cancers in the United States.[36] In 2017, an estimated 2010 deaths occurred due to thyroid cancer compared to more than 150,000 deaths from lung cancer.[17] Follicular thyroid cancer has a worse prognosis compared to papillary thyroid cancer due to its higher incidence of distant metastasis, and patients frequently present with more advanced-stage disease.[17] 

Even though follicular thyroid cancers have distant metastasis, metastasis to lymph nodes is uncommon, and its occurrence is estimated to be fewer than 10%.[37] On the other hand, some studies reported that there is no prognostic difference between follicular thyroid cancer and papillary thyroid cancer when controlling for factors such as age and sex.[21][38][39] 

The overall 10-year survival of follicular cancer depends on the level of invasiveness. For minimally invasive cancers, 10-year survival is reported to be 98%, and for invasive follicular cancer, it is 80%.[7] Some studies report that the survival rate ranges from 46% to 97%, depending on the degree of capsular or vascular invasion.[21] The mortality rate of follicular thyroid carcinoma ranges from 5 to 15%, and those with capsular invasive characteristics have an overall worse prognosis than those without invasion.[40][41]

Complications

The most worrisome complication associated with follicular thyroid cancer is metastasis. Studies have reported metastases mostly to bones, lungs, and lymph nodes. In a study by Parasmeswaran et al (2017), 42% of subjects had metastasis to the bones, 33% to the lungs, and 8% to the lymph nodes.[3] The incidence of distance metastasis in follicular thyroid carcinoma is estimated to be 6 to 20%.[42] Other complications correlate with surgery. The external and recurrent laryngeal nerves are near the thyroid gland and can mistakenly get damaged during surgery or resected due to invasion.[43] This causes hoarseness in the patient's voice. There are also reports of hematoma and keloid formation in some patients after the surgery.[43] Because the patient is undergoing total thyroidectomy, hypothyroidism always develops, and patients require thyroxine replacement therapy. 

Deterrence and Patient Education

Although the prognosis of thyroid cancer has been reported to be good compared to other forms of cancer, the mention of the word "cancer" is still a concern for most patients. For instance, most patients still opt for surgical thyroid removal even if they have non-invasive follicular thyroid cancer that can be followed due to its slow growth. Patients and their physicians must work together to decide the best treatment option.[4] Knowledge gained by patients enables them to make better decisions about their health.

Enhancing Healthcare Team Outcomes

The incidence of thyroid cancer has increased over the past few decades, attributed to its overdiagnosis.[44][45] As a result, in 2017, USPTF recommended against screening for thyroid cancer with either neck palpation or ultrasound in asymptomatic patients.[17] In 2015, the American Thyroid Association recommended active surveillance of low-risk thyroid carcinomas with serial ultrasound and stated that not all patients require surgery. Also, the organization released guidelines in 2015 stating that thyroid nodules less than 1 cm should not be biopsied.[17] 

Health providers, including clinicians (MDs, DOs, NPs, and PAs) and other healthcare professionals (eg, nurses and pharmacists), should operate as an interprofessional team. All interprofessional team members must coordinate their activities through open communication channels and maintain accurate, up-to-date patient records. They should all be aware of these guidelines; this prevents potential harm to patients from overtreatment of low-risk thyroid cancers and helps appropriately treat patients with high-risk diseases. Reportedly, the overall cost of thyroid cancer in 2019 was nearly 21 billion dollars due to surgery costs.[17] Not all thyroid neoplasms require surgery, and physicians should keep this in mind when managing patients who develop thyroid cancer.

Review Questions

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Disclosure: Damilola Ashorobi declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.

Disclosure: Peter Lopez declares no relevant financial relationships with ineligible companies.